PubMed

medRxiv. 2023 Jul 1:2023.06.28.23291995. doi: 10.1101/2023.06.28.23291995. Preprint.ABSTRACTBACKGROUND: The influence of genetics and environment on the association of the plasma proteome with body mass index (BMI) and changes in BMI remain underexplored, and the links to other omics in these associations remain to be investigated. We characterized protein-BMI trajectory associations in adolescents and adults and how these connect to other omics layers.METHODS: Our study included two cohorts of longitudinally followed twins: FinnTwin12 ( N =651) and the Netherlands Twin Register (NTR) ( N =665). Follow-up comprised four BMI measurements over approximately 6 (NTR: 23-27 years old) to 10 years (FinnTwin12: 12-22 years old), with omics data collected at the last BMI measurement. BMI changes were calculated using latent growth curve models. Mixed-effects models were used to quantify the associations between the abundance of 439 plasma proteins with BMI at blood sampling and changes in BMI. The sources of genetic and environmental variation underlying the protein abundances were quantified using twin models, as were the associations of proteins with BMI and BMI changes. In NTR, we investigated the association of gene expression of genes encoding proteins identified in FinnTwin12 with BMI and changes in BMI. We linked identified proteins and their coding genes to plasma metabolites and polygenic risk scores (PRS) using mixed-effect models and correlation networks.RESULTS: We identified 66 and 14 proteins associated with BMI at blood sampling and changes in BMI, respectively. The average heritability of these proteins was 35%. Of the 66 BMI-protein associations, 43 and 12 showed genetic and environmental correlations, respectively, including 8 proteins showing both. Similarly, we observed 6 and 4 genetic and environmental correlations between changes in BMI and protein abundance, respectively. S100A8 gene expression was associated with BMI at blood sampling, and the PRG4 and CFI genes were associated with BMI changes. Proteins showed strong connections with many metabolites and PRSs, but we observed no multi-omics connections among gene expression and other omics layers.CONCLUSIONS: Associations between the proteome and BMI trajectories are characterized by shared genetic, environmental, and metabolic etiologies. We observed few gene-protein pairs associated with BMI or changes in BMI at the proteome and transcriptome levels.PMID:37425750 | PMC:PMC10327285 | DOI:10.1101/2023.06.28.23291995

bioRxiv. 2023 Jun 3:2023.06.03.543565. doi: 10.1101/2023.06.03.543565. Preprint.ABSTRACTChagas Disease (CD), caused by Trypanosoma cruzi (T. cruzi) protozoa, is a complicated parasitic illness with inadequate medical measures for diagnosing infection and monitoring treatment success. To address this gap, we analyzed changes in the metabolome of T. cruzi-infected mice via liquid chromatography tandem mass spectrometry analysis of clinically-accessible biofluids: saliva, urine, and plasma. Urine was the most indicative of infection status, across mouse and parasite genotypes. Metabolites perturbed by infection in the urine include kynurenate, acylcarnitines, and threonylcarbamoyladenosine. Based on these results, we sought to implement urine as a tool for assessment of CD treatment success. Strikingly, it was found that mice with parasite clearance following benznidazole antiparasitic treatment had comparable overall urine metabolome to mice that failed to clear parasites. These results match with clinical trial data in which benznidazole treatment did not improve patient outcomes in late-stage disease. Overall, this study provides insights into new small molecule-based CD diagnostic methods and a new approach to assess functional treatment response.PMID:37425694 | PMC:PMC10326868 | DOI:10.1101/2023.06.03.543565

Bioinform Adv. 2023 Apr 21;3(1):vbad053. doi: 10.1093/bioadv/vbad053. eCollection 2023.ABSTRACTSUMMARY: Computational analysis and interpretation of metabolomic profiling data remains a major challenge in translational research. Exploring metabolic biomarkers and dysregulated metabolic pathways associated with a patient phenotype could offer new opportunities for targeted therapeutic intervention. Metabolite clustering based on structural similarity has the potential to uncover common underpinnings of biological processes. To address this need, we have developed the MetChem package. MetChem is a quick and simple tool that allows to classify metabolites in structurally related modules, thus revealing their functional information.AVAILABILITYAND IMPLEMENTATION: MetChem is freely available from the R archive CRAN (http://cran.r-project.org). The software is distributed under the GNU General Public License (version 3 or later).PMID:37424942 | PMC:PMC10322652 | DOI:10.1093/bioadv/vbad053

Front Endocrinol (Lausanne). 2023 Jun 22;14:1119599. doi: 10.3389/fendo.2023.1119599. eCollection 2023.ABSTRACTPURPOSE: Menopause is a risk factor for pelvic organ prolapse (POP) and is frequently associated with diminished vaginal wall support. To uncover relevant molecular mechanisms and provide potential therapeutic targets, we evaluated changes in the transcriptome and metabolome of the vaginal wall in ovariectomized rats to identify important molecular changes.METHODS: Sixteen adult female Sprague-Dawley rats were randomly assigned to either the control or menopause group. Seven months after the operation, hematoxylin and eosin (H&E) staining and Masson trichrome staining were used to observe changes in the rat vaginal wall structure. Differentially expressed genes (DEGs) and metabolites (DEMs) in the vaginal wall were detected by RNA-sequencing and LC-MS, respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of DEGs and DEMs were performed.RESULTS: We verified that long-term menopause causes vaginal wall injury by H&E and Masson trichrome staining. From the multiomics analyses, 20,669 genes and 2193 metabolites were identified. Compared with the control group, 3255 DEGs were found in the vaginal wall of long-term menopausal rats. Bioinformatics analysis showed that the DEGs were mainly enriched in mechanistic pathways, including cell-cell junction, extracellular matrix, muscle tissue developments, the PI3K-Akt signaling pathway, the MAPK signaling pathway, tight junctions and the Wnt signaling pathway. Additionally, 313 DEMs were found, and they consisted mostly of amino acids and their metabolites. DEMs were also enriched in mechanistic pathways, such as glycine, serine and threonine metabolism, glycerophospholipid metabolism, gap junctions and ferroptosis. Coexpression analysis of DEGs and DEMs revealed that biosynthesis of amino acids (isocitric acid and PKM) and glycerophospholipid metabolism (1-(9Z-hexadecenoyl)-sn-glycero-3-phosphocholine and PGS1) are critical metabolic pathways, suggesting that POP induced by menopause may be associated with the regulation of these processes.CONCLUSION: The findings showed that long-term menopause greatly exacerbated vaginal wall support injury by decreasing the biosynthesis of amino acids and interfering with glycerophospholipid metabolism, which may result in POP. This study not only clarified that long-term menopause exacerbates damage to the vaginal wall but also provided insight into the potential molecular mechanisms by which long-term menopause induces POP.PMID:37424873 | PMC:PMC10324610 | DOI:10.3389/fendo.2023.1119599

MethodsX. 2023 Apr 25;10:102199. doi: 10.1016/j.mex.2023.102199. eCollection 2023.ABSTRACTThe Regions of Interest Multivariate curve Resolution (ROIMCR) methodology has gained significance for analyzing mass spectrometry data. The new SigSel package improves the ROIMCR methodology by providing a filtering step to reduce computational costs and to identify chemical compounds giving low-intensity signals. SigSel allows the visualization and assessment of ROIMCR results and filters out components resolved as interferences and background noise. This improves the analysis of complex mixtures and facilitates the identification of chemical compounds for statistical or chemometrics analysis. SigSel has been tested using metabolomics samples of mussels exposed to the sulfamethoxazole antibiotic. It begins by analyzing the data according to their charge state, eliminating signals considered background noise, and reducing the size of the datasets. In the ROIMCR analysis, the resolution of 30 ROIMCR components was achieved. After evaluating these components, 24 were ultimately selected explaining 99.05% of the total data variance. From ROIMCR results, chemical annotation is performed using different methods: •Generating a list of signals and reanalyzing them in a data-dependent analysis.•Comparing the ROIMCR resolved mass spectra to those stored in online repositories.•Searching MS signals of chemical compounds in the ROIMCR resolved spectra profiles.PMID:37424752 | PMC:PMC10326443 | DOI:10.1016/j.mex.2023.102199

Access Microbiol. 2023 Jun 29;5(6):acmi000432. doi: 10.1099/acmi.0.000432. eCollection 2023.ABSTRACTObjective. The present study was carried out to establish the chemical profile of the methanolic extract of Polyalthia longifolia stem bark and investigate its antibacterial property against some human pathogenic bacteria. Methods. The extract was analysed using liquid and gas chromatography coupled to mass spectrometry. Antibacterial activity of P. longifolia extract against some human pathogenic bacteria was screened using the AlamarBlue method, and MIC and MBC were determined. Results and Conclusion. Liquid chromatography-mass spectrometry (LC-MS) revealed the presence of 21 compounds among which 12 were identified. Gas chromatography-mass spectrometry (GC-MS) allowed identification of 26 compounds, the three major ones being the following: cis vaccenic acid (17.79 %), 3-ethyl-3-hydroxyandrostan-17-one (13.80 %) and copaiferic acid B (12.82 %). P. longifolia extract was active against Gram-positive bacteria with MIC ranging from 1 to 2 mg ml-1 and MBC from 2 to 6 mg ml-1. This study demonstrated the bactericidal effect of the methanolic extract of Polyalthia longifolia stem bark against some human pathogenic bacteria, including methicillin-resistant S. aureus . This effect could be related to the presence in the extract of a broad diversity of well-known compounds with established pharmacological properties. These results support the ethnomedicinal use of P. longifolia stem bark in Cameroon for the management of methicillin-resistant S. aureus (MRSA)-related infections.PMID:37424570 | PMC:PMC10323783 | DOI:10.1099/acmi.0.000432

Access Microbiol. 2023 Jun 28;5(6):acmi000535.v5. doi: 10.1099/acmi.0.000535.v5. eCollection 2023.ABSTRACTClitoria ternatea flowers are rich in anthocyanins and possess various biological activities. Specifically, the antibacterial mechanism of action of C. ternatea anthocyanins remains unknown and was investigated in Escherichia coli . A time-kill assay was used to assess the antibacterial activity and the metabolic perturbations in E. coli were investigated utilizing liquid chromatography-mass spectrometry (LC-MS)-based metabolomics. Pathway analyses were carried out for metabolites showing ≥2-fold changes. The anthocyanin fraction remarkably reduced the growth of E. coli at 4 h by 95.8 and 99.9 % at minimum inhibitory concentration (MIC) and 2× MIC, respectively. The anthocyanin fraction (MIC) had a bacteriostatic effect and was shown to have perturbed glycerophospholipids (1-acyl-sn-glycero-3-phosphoethanolamine, phosphatidylglycerol, diacylglycerol and cardiolipin), amino acids (valine, tyrosine and isoleucine) and energy (ubiquinone and NAD) metabolites at 1 and 4 h. This study demonstrated significant metabolic perturbations of the glycerophospholipid, amino acid and energy metabolism, with these being the key pathways involved in the bacteriostatic activity of anthocyanins from C. ternatea, which may have promise as bacteriostatic agents for E. coli -related infections.PMID:37424541 | PMC:PMC10323780 | DOI:10.1099/acmi.0.000535.v5

Biotechnol Bioeng. 2023 Jul 10. doi: 10.1002/bit.28494. Online ahead of print.ABSTRACTHuman macrophages are innate immune cells with diverse, functionally distinct phenotypes, namely, pro-inflammatory M1 and anti-inflammatory M2 macrophages. Both are involved in multiple physiological and pathological processes, including would healing, infection, and cancer. However, the metabolic differences between these phenotypes are largely unexplored at single-cell resolution. To address this knowledge gap, an untargeted live single-cell mass spectrometry-based metabolomic profiling coupled with a machine-learning data analysis approach was developed to investigate the metabolic profile of each phenotype at the single-cell level. Results show that M1 and M2 macrophages have distinct metabolic profiles, with differential levels of fatty acyls, glycerophospholipids, and sterol lipids, which are important components of plasma membrane and involved in multiple biological processes. Furthermore, we could discern several putatively annotated molecules that contribute to inflammatory response of macrophages. The combination of random forest and live single-cell metabolomics provided an in-depth profile of the metabolome of primary human M1 and M2 macrophages at the single-cell level for the first time, which will pave the way for future studies targeting the differentiation of other immune cells.PMID:37424521 | DOI:10.1002/bit.28494

J Alzheimers Dis. 2023 Jul 7. doi: 10.3233/JAD-230291. Online ahead of print.ABSTRACTBACKGROUND: Characterizing the periodontal status of patients with Alzheimer's disease (AD), investigating differences in salivary metabolism between patients with and without AD under the same periodontal conditions, and understanding how it is related to oral flora are critical.OBJECTIVE: We aimed to examine the periodontal condition of patients with AD and to screen salivary metabolic biomarkers from the saliva of individuals with and without AD with matched periodontal conditions. Furthermore, we aimed to explore the possible relationship between salivary metabolic changes and oral flora.METHODS: In total, 79 individuals were recruited into the experiment for periodontal analysis. Especially, 30 saliva samples from the AD group and 30 from healthy controls (HCs) with matched periodontal conditions were selected for metabolomic analysis. The random-forest algorithm was used to detect candidate biomarkers. Among these, 19 AD saliva and 19 HC samples were selected to investigate the microbiological factors influencing the alterations in saliva metabolism in patients with AD.RESULTS: The plaque index and bleeding on probing were considerably higher in the AD group. Further, Cis-3-(1-carboxy-ethyl)-3,5-cyclohexadiene-1,2-diol, dodecanoic acid, genipic acid, and N, N-dimethylthanolamine N-oxide were determined as candidate biomarkers, based on the area under the curve (AUC) value (AUC = 0.95). The results of oral-flora sequencing showed that dysbacteriosis may be a reason for the differences in AD saliva metabolism.CONCLUSION: Dysregulation of the proportion of specific bacterial flora in saliva plays a vital role in metabolic changes in AD. These results will contribute to further improving the AD saliva biomarker system.PMID:37424468 | DOI:10.3233/JAD-230291

Gut Microbes. 2023 Jan-Dec;15(1):2233149. doi: 10.1080/19490976.2023.2233149.ABSTRACTIntestinal stem cells (ISCs) are critical for the development and rapid turnover of intestinal epithelium. The regulatory effects of gut microbiota and their metabolites on ISCs stemness remain elusive. Fucose has been demonstrated to mediate host-microbe interactions in the intestine. However, the association between fucose, gut bacteria, and ISCs stemness remains unclear. To investigate the effects of fucose on ISCs-mediated intestinal epithelial cells (IECs) development, we administered fucose to 4-week-old mice for 4 weeks. ISCs stemness, IECs proliferation, and differentiation were examined. Variations in gut microbes and metabolism were detected using 16S rDNA sequencing and metabolomic analysis. Fucose was added to the bacterial culture medium to further study its effects on metabolism. Crypts were isolated from the mouse ileum for organoids culture in vitro to evaluate the effects of metabolites and the underlying mechanism. The results showed that fucose accelerated ISCs proliferation and secretory lineage differentiation in mice, whereas antibiotics eliminated these effects. The composition and functions of gut bacteria were altered by fucose treatment, while significant increases in Akkermansia and propanoate metabolism were noted. Propionic acid and propionate have been shown to promote organoid development. Fucose fermentation increases the production of propionic acid in Akkermansia muciniphila and enhances its ability to increase the stemness of ISCs. Moreover, ileal contents from fucose-treated mice promoted organoid development in a Gpr41/Gpr43-dependent manner. Fucose administration activates the Wnt signaling pathway in ISCs, and Wnt inhibitors suppress the effects of fucose. We conclude that fucose accelerates ISC-mediated intestinal epithelial development by promoting Akkermansia-related propanoate metabolism. These findings provide new insights into the promotion of gut homeostasis and the application potential of fucose as a prebiotic.PMID:37424378 | DOI:10.1080/19490976.2023.2233149

Comb Chem High Throughput Screen. 2023 Jul 7. doi: 10.2174/1386207326666230707110651. Online ahead of print.ABSTRACTBACKGROUND: An endophytic fungal strain Penicillium crustosum was isolated from the seagrass Posidonia oceanica and investigated to identify its antimicrobial constituents and characterize its metabolome composition. The ethyl acetate extract of this fungus exhibited antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) as well as an anti-quorum sensing effect against Pseudomonas aeruginosa.METHODS: The crude extract was profiled by UHPLC-HRMS/MS and the dereplication was assisted by feature-based molecular networking. As a result, more than twenty compounds were annotated in this fungus. To rapidly identify the active compounds, the enriched extract was fractionated by semi-preparative HPLC-UV applying a chromatographic gradient transfer and dry load sample introduction to maximise resolution. The collected fractions were profiled by 1H-NMR and UHPLC-HRMS.RESULTS: The use of molecular networking-assisted UHPLC-HRMS/MS dereplication allowed preliminary identification of over 20 compounds present in the ethyl acetate extract of P. crustosum. The chromatographic approach significantly accelerated the isolation of the majority of compounds present in the active extract. The one-step fractionation allowed the isolation and identification of eight compounds (1-8).CONCLUSION: This study led to the unambiguous identification of eight known secondary metabolites as well as the determination of their antibacterial properties.PMID:37424340 | DOI:10.2174/1386207326666230707110651

Gut Microbes. 2023 Jan-Dec;15(1):2231596. doi: 10.1080/19490976.2023.2231596.ABSTRACTThe gut microbiota is involved in the production of numerous metabolites that maintain host wellbeing. The assembly of the gut microbiome is highly dynamic, and influenced by many postnatal factors, moreover, little is known about the development of the gut metabolome. We showed that geography has an important influence on the microbiome dynamics in the first year of life based on two independent cohorts from China and Sweden. Major compositional differences since birth were the high relative abundance of Bacteroides in the Swedish cohort and Streptococcus in the Chinese cohort. We analyzed the development of the fecal metabolome in the first year of life in the Chinese cohort. Lipid metabolism, especially acylcarnitines and bile acids, was the most abundant metabolic pathway in the newborn gut. Delivery mode and feeding induced particular differences in the gut metabolome since birth. In contrast to C-section newborns, medium- and long-chain acylcarnitines were abundant at newborn age only in vaginally delivered infants, associated by the presence of bacteria such as Bacteroides vulgatus and Parabacteroides merdae. Our data provide a basis for understanding the maturation of the fecal metabolome and the metabolic role of gut microbiota in infancy.PMID:37424334 | DOI:10.1080/19490976.2023.2231596

Biomed Environ Sci. 2023 Jun 20;36(6):537-541. doi: 10.3967/bes2023.065.NO ABSTRACTPMID:37424247 | DOI:10.3967/bes2023.065

Immunol Rev. 2023 Jul 9. doi: 10.1111/imr.13235. Online ahead of print.ABSTRACTFerroptosis is a form of iron-dependent regulated cell death characterized by the accumulation of toxic lipid peroxides, particularly in the plasma membrane, leading to lytic cell death. While it plays a crucial role in maintaining the overall health and proper functioning of multicellular organisms, it can also contribute to tissue damage and pathological conditions. Although ferroptotic damage is generally recognized as an immunostimulatory process associated with the release of damage-associated molecular patterns (DAMPs), the occurrence of ferroptosis in immune cells or the release of immunosuppressive molecules can result in immune tolerance. Consequently, there is ongoing exploration of targeting the upstream signals or the machinery of ferroptosis to therapeutically enhance or inhibit the immune response. In addition to introducing the core molecular mechanisms of ferroptosis, we will focus on the immune characteristics of ferroptosis in pathological conditions, particularly in the context of infection, sterile inflammation, and tumor immunity.PMID:37424139 | DOI:10.1111/imr.13235

Mol Nutr Food Res. 2023 Jul 9:e2200883. doi: 10.1002/mnfr.202200883. Online ahead of print.ABSTRACTSCOPE: Soybean 7S globulin (β-conglycinin), a major soybean storage protein, has been demonstrated to exert remarkable triglyceride (TG) and cholesterol-lowering effects, yet the underlying mechanism remains controversial.METHODS AND RESULTS: A comparative investigation is performed to assess the contribution of different structural domains of soybean 7S globulin, including core region (CR) and extension region (ER) domains, to biological effects of soybean 7S globulin using a high-fat diet rat model. The results show that ER domain mainly contributes to the serum TG-lowering effect of soybean 7S globulin, but not for CR domain. Metabolomics analysis reveals that oral administration of ER peptides obviously influences the metabolic profiling of serum bile acids (BAs), as well as significantly increased the fecal excretion of total BAs. Meanwhile, ER peptides supplementation reshapes the composition of gut microbiota and impacts the gut microbiota-dependent biotransformation of BAs which indicate by a significantly increased secondary BAs concentration in fecal samples. These results highlight that TG-lowering effects of ER peptides mainly stem from their modulation of BAs homeostasis.CONCLUSION: Oral administration of ER peptides can effectively lower serum TG level by regulating BAs metabolism. ER peptides have potential to be used as a candidate pharmaceutical for the intervention of dyslipidemia.PMID:37423975 | DOI:10.1002/mnfr.202200883

Br J Haematol. 2023 Jul 9. doi: 10.1111/bjh.18939. Online ahead of print.ABSTRACTGrowth factor independence 1 (GFI1) is a transcriptional repressor protein that plays an essential role in the differentiation of myeloid and lymphoid progenitors. We and other groups have shown that GFI1 has a dose-dependent role in the initiation, progression, and prognosis of acute myeloid leukaemia (AML) patients by inducing epigenetic changes. We now demonstrate a novel role for dose-dependent GFI1 expression in regulating metabolism in haematopoietic progenitor and leukaemic cells. Using in-vitro and ex-vivo murine models of MLL::AF9-induced human AML and extra-cellular flux assays, we now demonstrate that a lower GFI1 expression enhances oxidative phosphorylation rate via upregulation of the FOXO1- MYC axis. Our findings underscore the significance of therapeutic exploitation in GFI1-low-expressing leukaemia cells by targeting oxidative phosphorylation and glutamine metabolism.PMID:37423893 | DOI:10.1111/bjh.18939

Anal Chim Acta. 2023 Sep 8;1273:341537. doi: 10.1016/j.aca.2023.341537. Epub 2023 Jun 21.ABSTRACTDespite the advances in low-field nuclear magnetic resonance (NMR), there are limited spectroscopic applications for untargeted analysis and metabolomics. To evaluate its potential, we combined high-field and low-field NMR with chemometrics for the differentiation between virgin and refined coconut oil and for the detection of adulteration in blended samples. Although low-field NMR has less spectral resolution and sensitivity compared to high-field NMR, it was still able to achieve a differentiation between virgin and refined coconut oils, as well as between virgin coconut oil and blends, using principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and random forest techniques. These techniques were not able to distinguish between blends with different levels of adulteration; however, partial least squares regression (PLSR) enabled the quantification of adulteration levels for both NMR approaches. Given the significant benefits of low-field NMR, including economic and user-friendly analysis and fitting in an industrial environment, this study establishes the proof of concept for its utilization in the challenging scenario of coconut oil authentication. Also, this method has the potential to be used for other similar applications that involve untargeted analysis.PMID:37423668 | DOI:10.1016/j.aca.2023.341537

Anal Chim Acta. 2023 Sep 8;1273:341495. doi: 10.1016/j.aca.2023.341495. Epub 2023 Jun 6.ABSTRACTLow-field nuclear magnetic resonance (NMR) has three general modalities: spectroscopy, imaging, and relaxometry. In the last twelve years, the modality of spectroscopy, also known as benchtop NMR, compact NMR, or just low-field NMR, has undergone instrumental development due to new permanent magnetic materials and design. As a result, benchtop NMR has emerged as a powerful analytical tool for use in process analytical control (PAC). Nevertheless, the successful application of NMR devices as an analytical tool in several areas is intrinsically linked to its coupling with different chemometric methods. This review focuses on the evolution of benchtop NMR and chemometrics in chemical analysis, including applications in fuels, foods, pharmaceuticals, biochemicals, drugs, metabolomics, and polymers. The review also presents different low-resolution NMR methods for spectrum acquisition and chemometric techniques for calibration, classification, discrimination, data fusion, calibration transfer, multi-block and multi-way.PMID:37423658 | DOI:10.1016/j.aca.2023.341495

Cancer Lett. 2023 Jul 7:216305. doi: 10.1016/j.canlet.2023.216305. Online ahead of print.ABSTRACTAs essential modulators of transcription and translation, RNA-binding proteins (RBPs) are frequently dysregulated in cancer. Bioinformatics study reveals that the RNA-binding protein hexokinase domain component 1 (HKDC1) is overexpressed in gastric cancer (GC). As HKDC1 plays a role in lipid homeostasis in the liver and glucose metabolism in certain cancers, the exact mechanism of action of HKDC1 in GC remains largely unknown. Upregulation of HKDC1 correlates with chemoresistance and poor prognosis in GC patients. HKDC1 enhances invasion, migration and resistance to cisplatin (CDDP) in GC cells in vitro and in vivo. Comprehensive transcriptomic sequencing and metabolomic analysis reveal that HKDC1 mediates abnormal lipid metabolism in GC cells. Herein, we identify a number of HKDC1-binding endogenous RNAs in GC cells, including protein kinase, DNA-activated, catalytic subunit (PRKDC) mRNA. We further validate that PRKDC is a crucial downstream effector of HKDC1 induced-GC tumorigenesis depends on lipid metabolism. Interestingly, G3BP1, a well-known oncoprotein, can be bound by HKDC1. HKDC1 cooperates with G3BP1 to enhance the stability of PRKDC transcript. Our results reveal a novel HKDC1/G3BP1-PRKDC regulatory axis that induces GC metastasis and chemoresistance via reprogramming lipid metabolism, which may provide an effective therapeutic strategy for a subset of GC with HKDC1 overexpression.PMID:37423558 | DOI:10.1016/j.canlet.2023.216305

J Ethnopharmacol. 2023 Jul 7:116893. doi: 10.1016/j.jep.2023.116893. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Buyang Huanwu decoction (BHD), a famous traditional Chinese medicine (TCM) formula, was first recorded in Qing Dynasty physician Qingren Wang's Yi Lin Gai Cuo. BHD has been widely utilized in the treatment of patients with neurological disorders, including Parkinson's disease (PD). However, the underlying mechanism has not been fully elucidated. In particular, little is known about the role of gut microbiota.AIM OF THE STUDY: We aimed to reveal the alterations and functions of gut microbiota and its correlation with the liver metabolome in the process of improving PD with BHD.MATERIALS AND METHODS: The cecal contents were collected from PD mice treated with or without BHD. 16S rRNA gene sequencing was performed on an Illumina MiSeq-PE250 platform, and the ecological structure, dominant taxa, co-occurrence patterns, and function prediction of the gut microbial community were analyzed by multivariate statistical methods. The correlation between differential microbial communities in the gut and differentially accumulated metabolites in the liver was analyzed using Spearman's correlation analysis.RESULTS: The abundance of Butyricimonas, Christensenellaceae, Coprococcus, Peptococcaceae, Odoribacteraceae, and Roseburia was altered significantly in the model group, which was by BHD. Ten genera, namely Dorea, unclassified_Lachnospiraceae, Oscillospira, unidentified_Ruminococcaceae, unclassified_Clostridiales, unidentified_Clostridiales, Bacteroides, unclassified_Prevotellaceae, unidentified_Rikenellaceae, and unidentified_S24-7, were identified as key bacterial communities. According to the function prediction of differential genera, the mRNA surveillance pathway might be a target of BHD. Integrated analysis of gut microbiota and the liver metabolome revealed that several gut microbiota genera such as Parabacteroides, Ochrobactrum, Acinetobacter, Clostridium, and Halomonas, were positively or negatively correlated with some nervous system-related metabolites, such as L-carnitine, L-pyroglutamic acid, oleic acid, and taurine.CONCLUSIONS: Gut microbiota might be a target of BHD in the process of ameliorating PD. Our findings provide novel insight into the mechanisms underlying the effects of BHD on PD and contribute to the development of TCM.PMID:37423520 | DOI:10.1016/j.jep.2023.116893