PubMed

Front Cell Infect Microbiol. 2023 Feb 24;13:1127041. doi: 10.3389/fcimb.2023.1127041. eCollection 2023.ABSTRACTBACKGROUND: Increasing evidence supports that gut microbiota plays an important role in the development of cardiovascular diseases. The prevalence of sarcopenia is increasing in patients with heart failure. Muscle wasting is an independent predictor of death in heart failure patients.AIMS: In this study, we aimed to explore the characteristics of gut microbiota and metabolites in heart failure patients with or without sarcopenia.METHODS: Fecal samples of 33 heart failure patients without sarcopenia, 29 heart failure patients with sarcopenia, and 15 controls were collected. The intestinal microbiota was analyzed using 16S rRNA sequencing and the metabolites were detected using the gas chromatography-mass spectrometry method.RESULTS: There were significant differences in the overall microbial community structure and diversity between control and heart failure patients with or without sarcopenia. However, no clear clustering of samples was observed in heart failure with and without sarcopenia patients. Several bacterial, particularly Nocardiaceae, Pseudonocardiaceae, Alphaproteobacteria, and Slackia were significantly enriched in the heart failure patients without sarcopenia, while Synergistetes was more abundant in the heart failure patients with sarcopenia. Isobutyric acid, isovaleric acid, and valeric acid were lower in heart failure patients with sarcopenia than that without sarcopenia but lacked significance.CONCLUSIONS: This study demonstrates that there are differences in the gut microbiota between control individuals and heart failure patients with or without sarcopenia. Modulating the gut microbiota may be a new target for the prevention and treatment of sarcopenia in heart failure patients.PMID:36909727 | PMC:PMC9998919 | DOI:10.3389/fcimb.2023.1127041

bioRxiv. 2023 Feb 27:2023.02.27.530280. doi: 10.1101/2023.02.27.530280. Preprint.ABSTRACTThis exploratory study tested and validated the use of data fusion and machine learning techniques to probe high-throughput omics and clinical data with a goal of exploring the etiology of developmental dyslexia. Developmental dyslexia is the leading learning disability in school aged children affecting roughly 5-10% of the US population. The complex biological and neurological phenotype of this life altering disability complicates its diagnosis. Phenome, exome, and metabolome data was collected allowing us to fully explore this system from a behavioral, cellular, and molecular point of view. This study provides a proof of concept showing that data fusion and ensemble learning techniques can outperform traditional machine learning techniques when provided small and complex multi-omics and clinical datasets. Heterogenous stacking classifiers consisting of single-omic experts/models achieved an accuracy of 86%, F1 score of 0.89, and AUC value of 0.83. Ensemble methods also provided a ranked list of important features that suggests exome single nucleotide polymorphisms found in the thalamus and cerebellum could be potential biomarkers for developmental dyslexia and heavily influenced the classification of DD within our machine learning models.PMID:36909570 | PMC:PMC10002702 | DOI:10.1101/2023.02.27.530280

Res Sq. 2023 Feb 28:rs.3.rs-2511186. doi: 10.21203/rs.3.rs-2511186/v1. Preprint.ABSTRACTWithin the field of amyloid and prion disease there is a need for a more comprehensive understanding of the fundamentals of disease biology. In order to facilitate the progression treatment and underpin comprehension of toxicity, fundamental understanding of the disruption to normal cellular biochemistry and trafficking is needed. Here, by removing the complex biochemistry of the brain, we have utilised known prion forming strains of Saccharomyces cerevisiae carrying different conformational variants of the Rnq1p to obtain Liquid Chromatography-Mass Spectrometry (LC-MS) metabolic profiles and identify key perturbations of prion presence. These studies reveal that prion containing [ RNQ + ] cells display a significant reduction in amino acid biosynthesis and distinct perturbations in sphingolipid metabolism, with significant downregulation in metabolites within these pathways. Moreover, that native Rnq1p appears to downregulate ubiquinone biosynthesis pathways within cells, suggesting that Rnq1p may play a lipid/mevalonate-based cytoprotective role as a regulator of ubiquinone production. These findings contribute to the understanding of how prion proteins interact in vivo in both their prion and non-prion confirmations and indicate potential targets for the mitigation of these effects. We demonstrate specific sphingolipid centred metabolic disruptions due to prion presence and give insight into a potential cytoprotective role of the native Rnq1 protein. This provides evidence of metabolic similarities between yeast and mammalian cells as a consequence of prion presence and establishes the application of metabolomics as a tool to investigate prion/amyloid-based phenomena.PMID:36909567 | PMC:PMC10002837 | DOI:10.21203/rs.3.rs-2511186/v1

bioRxiv. 2023 Mar 1:2023.02.28.530478. doi: 10.1101/2023.02.28.530478. Preprint.ABSTRACTAberrant tumor metabolism is a hallmark of cancer in which metabolic rewiring can support tumor growth under nutrient deficient conditions. KRAS mutations occur in 35-45% of all colorectal cancer (CRC) cases and are difficult to treat. The relationship between mutant KRAS and aberrant metabolism in CRCs has not been fully explored and could be a target for intervention. We previously acquired non-targeted metabolomics data from 161 tumor tissues and 39 normal colon tissues from stage I-III chemotherapy naïve CRC patients. In this study, we revealed that tumors from male patients with KRAS mutations only, had several altered pathways that suppress ferroptosis, including glutathione biosynthesis, transsulfuration activity, and methionine metabolism. To validate this phenotype, MC38 CRC cells (KRAS G13R ) were treated with a ferroptosis inducer; RAS-selected lethal (RSL3). RSL3 altered metabolic pathways in the opposite direction to that seen in KRAS mutant tumors from male patients confirming a suppressed ferroptosis metabolic phenotype in these patients. We further validated gene expression data from an additional CRC patient cohort (Gene Expression Omnibus (GEO), and similarly observed differences in ferroptosis-related genes by sex and KRAS status. Further examination of the relationship between these genes and overall survival (OS) in the GEO cohort showed that KRAS mutant tumors are associated with poorer 5-year OS compared to KRAS wild type tumors, and only in male patients. Additionally, high compared to low expression of GPX4, FTH1, FTL , which suppressed ferroptosis, were associated with poorer 5-year OS only in KRAS mutant tumors from male CRC patients. Low compared to high expression of ACSL4 was associated with poorer OS for this group. Our results show that KRAS mutant tumors from male CRC patients have suppressed ferroptosis, and gene expression changes that suppress ferroptosis associate with adverse outcomes for these patients, revealing a novel potential avenue for therapeutic approaches.PMID:36909561 | PMC:PMC10002683 | DOI:10.1101/2023.02.28.530478

bioRxiv. 2023 Mar 2:2023.03.01.530642. doi: 10.1101/2023.03.01.530642. Preprint.ABSTRACTNuclear Magnetic Resonance is a powerful platform that reveals the metabolomics profiles within biofluids or tissues and contributes to personalized treatments in medical practice. However, data volume and complexity hinder the exploration of NMR spectra. Besides, the lack of fast and accurate computational tools that can handle the automatic identification and quantification of essential metabolites from NMR spectra also slows the wide application of these techniques in clinical. We present NMRQNet, a deep-learning-based pipeline for automatic identification and quantification of dominant metabolite candidates within human plasma samples. The estimated relative concentrations could be further applied in statistical analysis to extract the potential biomarkers. We evaluate our method on multiple plasma samples, including species from mice to humans, curated using three anticoagulants, covering healthy and patient conditions in neurological disorder disease, greatly expanding the metabolomics analytical space in plasma. NMRQNet accurately reconstructed the original spectra and obtained significantly better quantification results than the earlier computational methods. Besides, NMRQNet also proposed relevant metabolites biomarkers that could potentially explain the risk factors associated with the condition. NMRQNet, with improved prediction performance, highlights the limitations in the existing approaches and has shown strong application potential for future metabolomics disease studies using plasma samples.PMID:36909516 | PMC:PMC10002723 | DOI:10.1101/2023.03.01.530642

Front Plant Sci. 2023 Feb 24;14:1144449. doi: 10.3389/fpls.2023.1144449. eCollection 2023.ABSTRACTFlavonoids are one of the most important bioactive components in litchi (Litchi chinensis Sonn.) seeds and have broad-spectrum antiviral and antitumor activities. Litchi seeds have been shown to inhibit the proliferation of cancer cells and induce apoptosis, particularly effective against breast and liver cancers. Elucidating the distribution of flavonoids is important for understanding their physiological and biochemical functions and facilitating their efficient extraction and utilization. However, the spatial distribution patterns and expression states of flavonoids in litchi seeds remain unclear. Herein, matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was used for in situ detection and imaging of the distribution of flavonoids in litchi seed tissue sections for the first time. Fifteen flavonoid ion signals, including liquiritigenin, apigenin, naringenin, luteolin, dihydrokaempferol, daidzein, quercetin, taxifolin, kaempferol, isorhamnetin, myricetin, catechin, quercetin 3-β-d-glucoside, baicalin, and rutin, were successfully detected and imaged in situ through MALDI-MSI in the positive ion mode using 2-mercaptobenzothiazole as a matrix. The results clearly showed the heterogeneous distribution of flavonoids, indicating the potential of litchi seeds for flavonoid compound extraction. MALDI-MS-based multi-imaging enhanced the visualization of spatial distribution and expression states of flavonoids. Thus, apart from improving our understanding of the spatial distribution of flavonoids in litchi seeds, our findings also facilitate the development of MALDI-MSI-based metabolomics as a novel effective molecular imaging tool for evaluating the spatial distribution of endogenous compounds.PMID:36909412 | PMC:PMC9998689 | DOI:10.3389/fpls.2023.1144449

Front Plant Sci. 2023 Feb 24;14:1137630. doi: 10.3389/fpls.2023.1137630. eCollection 2023.ABSTRACTApple scar skin viroid (ASSVd) can infect apple trees and cause scar skin symptoms. However, the associated physiological mechanisms are unclear in young saplings. In this study, ASSVd-infected and control 'Odysso' and 'Tonami' apple saplings were examined to clarify the effects of ASSVd on apple tree growth and physiological characteristics as well as the leaf metabolome. The results indicated that leaf ASSVd contents increased significantly after grafting and remained high in the second year. Leaf size, tree height, stem diameter, branch length, and leaf photosynthetic efficiency decreased significantly in viroid-infected saplings. In response to the ASSVd infection, the chlorophyll a and b contents decreased significantly in 'Odysso', but were unchanged in 'Tonami'. Moreover, the N, P, K, Fe, Mn, and Ca contents decreased significantly in the leaves of viroid-infected 'Odysso' or 'Tonami'. Similarly, the CAT and POD contents decreased significantly in the viroid-infected saplings, but the SOD content increased in the viroid-infected 'Tonami' saplings. A total of 15 and 40 differentially abundant metabolites were respectively identified in the metabolome analyses of 'Odysso' and 'Tonami' leaves. Specifically, in the viroid-infected 'Odysso' and 'Tonami' samples, the L-2-aminobutyric acid, 6″-O-malonyldaidzin, and D-xylose contents increased, while the coumarin content decreased. These metabolites are related to the biosynthesis of isoflavonoids and phenylpropanoids as well as the metabolism of carbohydrates and amino acids. These results imply that ASSVd affects apple sapling growth by affecting physiological characteristics and metabolism of apple leaves. The study data may be useful for future investigations on the physiological mechanisms underlying apple tree responses to ASSVd.PMID:36909405 | PMC:PMC9998556 | DOI:10.3389/fpls.2023.1137630

Front Plant Sci. 2023 Feb 24;14:1103468. doi: 10.3389/fpls.2023.1103468. eCollection 2023.ABSTRACTINTRODUCTION: Colored-leaf plants are increasingly popular for their aesthetic, ecological, and social value, which are important materials for research on the regulation of plant pigments. However, anthocyanin components and the molecular mechanisms of anthocyanin biosynthesis in colored-leaf poplar remain unclear. Consequently, an integrative analysis of transcriptome and metabolome is performed to identify the key metabolic pathways and key genes, which could contribute to the molecular mechanism of anthocyanin biosynthesis in the colored-leaf cultivars poplar.METHODS: In this study, integrated metabolite and transcriptome analysis was performed to explore the anthocyanin composition and the specific regulatory network of anthocyanin biosynthesis in the purple leaves of the cultivars 'Quanhong' (QHP) and 'Zhongshanyuan' (ZSY). Correlation analysis between RNA-seq data and metabolite profiles were also performed to explore the candidate genes associated with anthocyanin biosynthesis. R2R3-MYB and bHLH TFs with differential expression levels were used to perform a correlation analysis with differentially accumulated anthocyanins.RESULTS AND DISCUSSION: A total of 39 anthocyanin compounds were detected by LC-MS/MS analysis. Twelve cyanidins, seven pelargonidins, five delphinidins, and five procyanidins were identified as the major anthocyanin compounds, which were differentially accumulated in purple leaves of QHP and ZSY. The major genes associated with anthocyanin biosynthesis, including structural genes and transcription factors, were differentially expressed in purple leaves of QHP and ZSY through RNA-sequencing (RNA-seq) data analysis, which was consistent with quantitative real-time PCR analysis results. Correlation analysis between RNA-seq data and metabolite profiles showed that the expression patterns of certain differentially expressed genes in the anthocyanin biosynthesis pathway were strongly correlated with the differential accumulation of anthocyanins. One R2R3-MYB subfamily member in the SG5 subgroup, Podel.04G021100, showed a similar expression pattern to some structural genes. This gene was strongly correlated with 16 anthocyanin compounds, indicating that Podel.04G021100 might be involved in the regulation of anthocyanin biosynthesis. These results contribute to a systematic and comprehensive understanding of anthocyanin accumulation and to the molecular mechanisms of anthocyanin biosynthesis in QHP and ZSY.PMID:36909390 | PMC:PMC9998943 | DOI:10.3389/fpls.2023.1103468

Front Plant Sci. 2023 Feb 24;14:1137465. doi: 10.3389/fpls.2023.1137465. eCollection 2023.ABSTRACTAcidification can seriously affect the growth of tea trees and the yield and quality of tea leaves. In this study, we analyzed the effects of acidification on the physicochemical properties, microorganisms and metabolites of tea rhizosphere soils with different pH values, and the results showed that with the increase of soil pH, the organic matter content, cation exchange capacity, microbial biomass carbon, microbial biomass nitrogen, microbial respiration intensity, bacterial number and actinomyces number in tea rhizosphere soil all showed an increasing trend, while the fungi number decreased. The results of soil metabolite analysis showed that 2376, 2377 and 2359 metabolites were detected in tea rhizosphere soil with pH values of 3.29, 4.74 and 5.32, respectively, and the number of similar compounds reached 2331, accounting for more than 98%. The results of soil metabolite content analysis showed that with the increase of soil pH, the total contents of metabolite of tea rhizosphere soil increased significantly. The results of correlation analysis between physicochemical indexes of soil and microorganisms and soil metabolites showed that physicochemical indexes of soil and microorganisms were significantly correlated with 221 soil metabolites, among which 55 were significantly positively correlated and 166 were significantly negatively correlated. Based on correlation interaction network analysis, 59 characteristic compounds were obtained and divided into 22 categories, among which 7 categories compounds showed a significant increasing trend with the increase of soil pH, while the other 15 categories compounds showed the opposite trend. Based on the functional analysis of characteristic metabolites, this study found that with the increase of soil pH in tea rhizosphere, the diversity and number of soil microorganisms increased, and the cyclic ability of C and N of tea rhizosphere soil was enhanced, which in turn might lead to the enhancement of resistance of tea tree and promote the growth of tea tree.PMID:36909384 | PMC:PMC9998672 | DOI:10.3389/fpls.2023.1137465

Front Plant Sci. 2023 Feb 23;14:1144265. doi: 10.3389/fpls.2023.1144265. eCollection 2023.ABSTRACTCadmium (Cd) pollution is a serious threat to plant growth and human health. Although the mechanisms controlling the Cd response have been elucidated in other species, they remain unknown in Sorghum (Sorghum bicolor (L.) Moench), an important C4 cereal crop. Here, one-week-old sorghum seedlings were exposed to different concentrations (0, 10, 20, 50, 100, and 150 μM) of CdCl2 and the effects of these different concentrations on morphological responses were evaluated. Cd stress significantly decreased the activities of the enzymes peroxidase (POD), superoxide dismutase (SOD), glutathione S-transferase (GST) and catalase (CAT), and increased malondialdehyde (MDA) levels, leading to inhibition of plant height, decreases in lateral root density and plant biomass production. Based on these results, 10 μM Cd concentration was chosen for further transcription and metabolic analyses. A total of 2683 genes and 160 metabolites were found to have significant differential abundances between the control and Cd-treated groups. Multi-omics integrative analysis revealed that the flavonoid biosynthesis pathway plays a critical role in regulating Cd stress responses in sorghum. These results provide new insights into the mechanism underlying the response of sorghum to Cd.PMID:36909379 | PMC:PMC9996021 | DOI:10.3389/fpls.2023.1144265

Front Endocrinol (Lausanne). 2023 Feb 23;14:1081667. doi: 10.3389/fendo.2023.1081667. eCollection 2023.ABSTRACTFemales typically carry most of the burden of reproduction in mammals. In humans, this burden is exacerbated further, as the evolutionary advantage of a large and complex human brain came at a great cost of women's reproductive health. Pregnancy thus became a highly demanding phase in a woman's life cycle both physically and emotionally and therefore needs monitoring to assure an optimal outcome. Moreover, an increasing societal trend towards reproductive complications partly due to the increasing maternal age and global obesity pandemic demands closer monitoring of female reproductive health. This review first provides an overview of female reproductive biology and further explores utilization of large-scale data analysis and -omics techniques (genomics, transcriptomics, proteomics, and metabolomics) towards diagnosis, prognosis, and management of female reproductive disorders. In addition, we explore machine learning approaches for predictive models towards prevention and management. Furthermore, mobile apps and wearable devices provide a promise of continuous monitoring of health. These complementary technologies can be combined towards monitoring female (fertility-related) health and detection of any early complications to provide intervention solutions. In summary, technological advances (e.g., omics and wearables) have shown a promise towards diagnosis, prognosis, and management of female reproductive disorders. Systematic integration of these technologies is needed urgently in female reproductive healthcare to be further implemented in the national healthcare systems for societal benefit.PMID:36909346 | PMC:PMC9996332 | DOI:10.3389/fendo.2023.1081667

Front Endocrinol (Lausanne). 2023 Feb 24;14:1077604. doi: 10.3389/fendo.2023.1077604. eCollection 2023.ABSTRACTINTRODUCTION: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder that often coexists with a metabolic disorder. Studies have demonstrated that the malfunction of adipose tissue, particularly abdominal adipose tissue, could exacerbate reproductive and metabolic problems in PCOS patients. Adipose tissue-secreted signaling mediators (e.g., lipids and metabolites) would then interact with other body organs, including the ovary, to maintain the systemic equilibrium.METHODS: In this study, we examined adipose samples from PCOS patients and unaffected individuals using a liquid chromatography-mass spectrometry-based metabonomics approach (LC-MS/MS). PCOS biomarkers were selected using multivariate statistical analysis.RESULTS: Our pathway analysis revealed that these differential metabolites could be engaged in inflammatory diseases and mitochondrial beta-oxidation. We further developed an in vitro PCOS cell model to examine the effects of hyperandrogenism on granulosa cells and related metabolic disorders. We noted that isoleucine recovered the promotive effect on cell apoptosis, inhibitory effect on cell proliferation, sex hormone secretion, and mitochondrial function induced by dehydroepiandrosterone. Our gas chromatography-mass spectrometry targeted analysis (GC-MS/MS) revealed that isoleucine was significantly decreased in PCOS patients.DISCUSSION: Based on these results, we speculate that metabolome alterations are vital in ameliorating PCOS symptoms. This may be a novel therapeutic target for PCOS treatment. Our study provides preliminary evidence that these findings will enhance our ability to accurately diagnose and intervene in PCOS.PMID:36909330 | PMC:PMC10003901 | DOI:10.3389/fendo.2023.1077604

Front Endocrinol (Lausanne). 2023 Feb 24;14:1072461. doi: 10.3389/fendo.2023.1072461. eCollection 2023.ABSTRACTBACKGROUND: More than half of the cases of fetal structural anomalies have no known cause with standard investigations like karyotype testing and chromosomal microarray. The differential metabolic profiles of amniotic fluid (AF) and maternal blood may reveal valuable information about the physiological processes of fetal development, which may provide valuable biomarkers for fetal health diagnostics.METHODS: This cohort study of singleton-pregnant women had indications for amniocentesis, including structural anomalies and a positive result from maternal serum screening or non-invasive prenatal testing, but did not have any positive abnormal karyotype or chromosomal microarray analysis results. A total of 1580 participants were enrolled between June 2021 and March 2022. Of the 1580 pregnant women who underwent amniocentesis, 294 were included in the analysis. There were 137 pregnant women in the discovery cohort and 157 in the validation cohort.RESULTS: High-coverage untargeted metabolomic analysis of AF revealed distinct metabolic signatures with 321 of the 602 metabolites measured (53%) (false discovery rate, q < 0.005), among which amino acids predominantly changed in structural anomalies. Targeted metabolomics identified glutamate and glutamine as novel predictive markers for structural anomalies, their vital role was also confirmed in the validation cohort with great predictive ability, and the area under the receiver operating characteristic curves (AUCs) were 0.862 and 0.894 respectively. And AUCs for glutamine/glutamate were 0.913 and 0.903 among the two cohorts.CONCLUSIONS: Our results suggested that the aberrant glutamine/glutamate metabolism in AF is associated with nonchromosomal modificantions fetal structural anomalies. Based on our findings, a novel screening method could be established for the nonchromosomal modificantions fetal structural anomalies. And the results also indicate that monitoring fetal metabolic conditions (especially glutamine and glutamine metabolism) may be helpful for antenatal diagnosis and therapy.PMID:36909308 | PMC:PMC9998993 | DOI:10.3389/fendo.2023.1072461

Front Physiol. 2023 Feb 22;14:1107660. doi: 10.3389/fphys.2023.1107660. eCollection 2023.ABSTRACTDeveloping effective long-term sperm storage strategies to maintain activity requires an understanding of the underlying spermatophore developmental phase in drones. Here we compared the developmental processes and metabolites about seminal vesicles of drones from different parentages (0-24 d)in honeybee colonies, including mated queens, virgin queens, and worker bees. The results showed a similar developmental trend of seminal vesicles in thethree groups of drones on the whole, although there were significant differences in developmental levels, as well as in other indicators. Correlation analysis showed significant positive correlations between seminal vesicle width and sperm viability. The metabolomics of the seminal vesicles in drones from mated queens showed differences of the metabolites in each stage. Particularly, squalene identified among them was validated a protective effect on sperm vitality in vitro experiments. Together the results of these assays support that there were significant differences in the developmental levels of seminal vesicles among the three groups of drones in honeybees, wherein a significant correlation between sperm viability and the developmental levels of seminal vesicles were dissected. The metabolomics analysis and semen storage experiments in vitro display signatures of squalene that may act as an effective protective agent in maintaining sperm viability. Collectively, our findings indicate that spermatophore development in drones provides metabolite support, which contributes to research on the differences of sperm viability among drones in the future.PMID:36909221 | PMC:PMC9992413 | DOI:10.3389/fphys.2023.1107660

Front Pharmacol. 2023 Feb 24;14:1106733. doi: 10.3389/fphar.2023.1106733. eCollection 2023.ABSTRACTAcute Respiratory Distress Syndrome (ARDS) is triggered by a variety of insults, such as bacterial and viral infections, including SARS-CoV-2, leading to high mortality. In the murine model of ARDS induced by Staphylococcal enterotoxin-B (SEB), our previous studies showed that while SEB triggered 100% mortality, treatment with Resveratrol (RES) completely prevented such mortality by attenuating inflammation in the lungs. In the current study, we investigated the metabolic profile of SEB-activated immune cells in the lungs following treatment with RES. RES-treated mice had higher expression of miR-100 in the lung mononuclear cells (MNCs), which targeted mTOR, leading to its decreased expression. Also, Single-cell RNA-seq (scRNA seq) unveiled the decreased expression of mTOR in a variety of immune cells in the lungs. There was also an increase in glycolytic and mitochondrial respiration in the cells from SEB + VEH group in comparison with SEB + RES group. Together these data suggested that RES alters the metabolic reprogramming of SEB-activated immune cells, through suppression of mTOR activation and its down- and upstream effects on energy metabolism. Also, miR-100 could serve as novel potential therapeutic molecule in the amelioration of ARDS.PMID:36909201 | PMC:PMC9999031 | DOI:10.3389/fphar.2023.1106733

J Pharm Anal. 2023 Feb;13(2):187-200. doi: 10.1016/j.jpha.2022.11.006. Epub 2022 Nov 21.ABSTRACTEpidemiological and animal studies indicate that pre-existing diabetes increases the risk of Parkinson's disease (PD). However, the mechanisms underlying this association remain unclear. In the present study, we found that high glucose (HG) levels in the cerebrospinal fluid (CSF) of diabetic rats might enhance the effect of a subthreshold dose of the neurotoxin 6-hydroxydopamine (6-OHDA) on the development of motor disorders, and the damage to the nigrostriatal dopaminergic neuronal pathway. In vitro, HG promoted the 6-OHDA-induced apoptosis in PC12 cells differentiated to neurons with nerve growth factor (NGF) (NGF-PC12). Metabolomics showed that HG promoted hyperglycolysis in neurons and impaired tricarboxylic acid cycle (TCA cycle) activity, which was closely related to abnormal mitochondrial fusion, thus resulting in mitochondrial loss. Interestingly, HG-induced upregulation of pyruvate kinase M2 (PKM2) combined with 6-OHDA exposure not only mediated glycolysis but also promoted abnormal mitochondrial fusion by upregulating the expression of MFN2 in NGF-PC12 cells. In addition, we found that PKM2 knockdown rescued the abnormal mitochondrial fusion and cell apoptosis induced by HG+6-OHDA. Furthermore, we found that shikonin (SK), an inhibitor of PKM2, restored the mitochondrial number, promoted TCA cycle activity, reversed hyperglycolysis, enhanced the tolerance of cultured neurons to 6-OHDA, and reduced the risk of PD in diabetic rats. Overall, our results indicate that diabetes promotes hyperglycolysis and abnormal mitochondrial fusion in neurons through the upregulation of PKM2, leading to an increase in the vulnerability of dopaminergic neurons to 6-OHDA. Thus, the inhibition of PKM2 and restoration of mitochondrial metabolic homeostasis/pathways may prevent the occurrence and development of diabetic PD.PMID:36908857 | PMC:PMC9999299 | DOI:10.1016/j.jpha.2022.11.006

Front Public Health. 2023 Feb 23;11:1082074. doi: 10.3389/fpubh.2023.1082074. eCollection 2023.ABSTRACTBACKGROUND AND AIM: Shift work, especially including night shifts, has been found associated with several diseases, including obesity, diabetes, cancers, and cardiovascular, mental, gastrointestinal and sleep disorders. Metabolomics (an omics-based methodology) may shed light on early biological alterations underlying these associations. We thus aimed to evaluate the effect of night shift work (NSW) on serum metabolites in a sample of hospital female nurses.METHODS: We recruited 46 nurses currently working in NSW in Milan (Italy), matched to 51 colleagues not employed in night shifts. Participants filled in a questionnaire on demographics, lifestyle habits, personal and family health history and work, and donated a blood sample. The metabolome was evaluated through a validated targeted approach measuring 188 metabolites. Only metabolites with at least 50% observations above the detection limit were considered, after standardization and log-transformation. Associations between each metabolite and NSW were assessed applying Tobit regression models and Random Forest, a machine-learning algorithm.RESULTS: When comparing current vs. never night shifters, we observed lower levels of 21 glycerophospholipids and 6 sphingolipids, and higher levels of serotonin (+171.0%, 95%CI: 49.1-392.7), aspartic acid (+155.8%, 95%CI: 40.8-364.7), and taurine (+182.1%, 95%CI: 67.6-374.9). The latter was higher in former vs. never night shifters too (+208.8%, 95%CI: 69.2-463.3). Tobit regression comparing ever (i.e., current + former) and never night shifters returned similar results. Years worked in night shifts did not seem to affect metabolite levels. The Random-Forest algorithm confirmed taurine and aspartic acid among the most important variables in discriminating current vs. never night shifters.CONCLUSIONS: This study, although based on a small sample size, shows altered levels of some metabolites in night shift workers. If confirmed, our results may shed light on early biological alterations that might be related to adverse health effects of NSW.PMID:36908447 | PMC:PMC9999616 | DOI:10.3389/fpubh.2023.1082074

Aquat Toxicol. 2023 Mar 4:106471. doi: 10.1016/j.aquatox.2023.106471. Online ahead of print.ABSTRACTAlthough the toxicity of silver nanoparticles (AgNPs) has been widely reported, the persistence and reversibility of AgNPs toxicity are poorly understood. In the present work, AgNPs with particle sizes of 5 nm, 20 nm, and 70 nm (AgNPs5, AgNPs20, and AgNPs70) were selected to investigate the nanotoxicity and recovery effects of Chlorella vulgaris in the exposure (72 h) and recovery (72 h) stages using non-targeted metabolomics techniques. The exposure of AgNPs exerted size-dependent effects on several aspects of C. vulgaris physiology, including growth inhibition, chlorophyll content, intracellular silver accumulation, and differential expression of metabolites, and most of these adverse effects were reversible. Metabolomics revealed that AgNPs with small sizes (AgNPs5 and AgNPs20) mainly inhibited glycerophospholipid and purine metabolism, and the effects were reversible. In contrast, AgNPs with large sizes (AgNPs70) reduced amino acid metabolism and protein synthesis by inhibiting aminoacyl-tRNA biosynthesis, and the effects were irreversible, demonstrating the persistence of nanotoxicity of AgNPs. The size-dependent persistence and reversibility of AgNPs toxicity provides new insights to further understand the mechanisms of toxicity of nanomaterials.PMID:36907725 | DOI:10.1016/j.aquatox.2023.106471

J Ethnopharmacol. 2023 Mar 10:116365. doi: 10.1016/j.jep.2023.116365. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Tripterygium wilfordii tablets (TWT) is widely used to treat autoimmune diseases such as rheumatoid arthritis. Celastrol, one main active ingredient in TWT, has been shown to produce a variety of beneficial effects, including anti-inflammatory, anti-obesity, anti-cancer, and immunomodulatory. However, whether TWT could protect against Concanavalin A (Con A)-induced hepatitis remains unclear.THE AIM OF THE STUDY: This study aims to investigate the protective effect of TWT against Con A-induced hepatitis and elucidate the underlying mechanism.MATERIALS AND METHODS: Metabolomic analysis, pathological analysis, biochemical analysis, qPCR and Western blot analysis and the Pxr-null mice were used in this study.RESULTS: The results indicated that TWT and its active ingredient celastrol could protect against Con A-induced acute hepatitis. Plasma metabolomics analysis revealed that metabolic perturbations related to bile acid and fatty acid metabolism induced by Con A were reversed by celastrol. The level of itaconate in the liver was increased by celastrol and speculated as an active endogenous compound mediating the protective effect of celastrol. Administration of 4-octanyl itaconate (4-OI) as a cell-permeable itaconate mimicker was found to attenuate Con A-induced liver injury through activation of the pregnane X receptor (PXR) and enhancement of the transcription factor EB (TFEB)-mediated autophagy.CONCLUSIONS: Celastrol increased itaconate and 4-OI promoted activation of TFEB-mediated lysosomal autophagy to protect against Con A-induced liver injury in a PXR-dependent manner. Our study reported a protective effect of celastrol against Con A-induced AIH via an increased production of itaconate and upregulation of TFEB. The results highlighted that PXR and TFEB-mediated lysosomal autophagic pathway may offer promising therapeutic target for the treatment of autoimmune hepatitis.PMID:36907478 | DOI:10.1016/j.jep.2023.116365

Ecotoxicol Environ Saf. 2023 Mar 10;254:114749. doi: 10.1016/j.ecoenv.2023.114749. Online ahead of print.ABSTRACTHypoxia in water environment has become increasingly frequent and serious due to global warming and environmental pollution. Revealing the molecular mechanism of fish hypoxia adaptation will help to develop markers of environmental pollution caused by hypoxia. Here, we used a multi-omics method to identify the hypoxia-associated mRNA, miRNA, protein, and metabolite involved in various biological processes in Pelteobagrus vachelli brain. The results showed that hypoxia stress caused brain dysfunction by inhibiting energy metabolism. Specifically, the biological processes involved in energy synthesis and energy consumption are inhibited in P. vachelli brain under hypoxia, such as oxidative phosphorylation, carbohydrate metabolism and protein metabolism. Brain dysfunction is mainly manifested as blood-brain barrier injury accompanied by neurodegenerative diseases and autoimmune diseases. In addition, compared with previous studies, we found that P. vachelli has tissue specificity in response to hypoxia stress and the muscle suffers more damage than the brain. This is the first report to the integrated analysis of the transcriptome, miRNAome, proteome, and metabolome in fish brain. Our findings could provide insights into the molecular mechanisms of hypoxia, and the approach could also be applied to other fish species. DATA AVAILABILITY: The raw data of transcriptome has been uploaded to NCBI database (ID: SUB7714154 and SUB7765255). The raw data of proteome has been uploaded to ProteomeXchange database (PXD020425). The raw data of metabolome has been uploaded to Metabolight (ID: MTBLS1888).PMID:36907096 | DOI:10.1016/j.ecoenv.2023.114749