PubMed

Int J Mol Sci. 2023 Oct 31;24(21):15825. doi: 10.3390/ijms242115825.ABSTRACTThe aim of this research was to test the efficacy and potential clinical application of intranasal administration of galanin-like peptide (GALP) as an anti-obesity treatment under the hypothesis that GALP prevents obesity in mice fed a high-fat diet (HFD). Focusing on the mechanism of regulation of lipid metabolism in peripheral tissues via the autonomic nervous system, we confirmed that, compared with a control (saline), intranasally administered GALP prevented further body weight gain in diet-induced obesity (DIO) mice with continued access to an HFD. Using an omics-based approach, we identified several genes and metabolites in the liver tissue of DIO mice that were altered by the administration of intranasal GALP. We used whole-genome DNA microarray and metabolomics analyses to determine the anti-obesity effects of intranasal GALP in DIO mice fed an HFD. Transcriptomic profiling revealed the upregulation of flavin-containing dimethylaniline monooxygenase 3 (Fmo3), metallothionein 1 and 2 (Mt1 and Mt2, respectively), and the Aldh1a3, Defa3, and Defa20 genes. Analysis using the DAVID tool showed that intranasal GALP enhanced gene expression related to fatty acid elongation and unsaturated fatty acid synthesis and downregulated gene expression related to lipid and cholesterol synthesis, fat absorption, bile uptake, and excretion. Metabolite analysis revealed increased levels of coenzyme Q10 and oleoylethanolamide in the liver tissue, increased levels of deoxycholic acid (DCA) and taurocholic acid (TCA) in the bile acids, increased levels of taurochenodeoxycholic acid (TCDCA), and decreased levels of ursodeoxycholic acid (UDCA). In conclusion, intranasal GALP administration alleviated weight gain in obese mice fed an HFD via mechanisms involving antioxidant, anti-inflammatory, and fatty acid metabolism effects and genetic alterations. The gene expression data are publicly available at NCBI GSE243376.PMID:37958806 | DOI:10.3390/ijms242115825

Int J Mol Sci. 2023 Oct 27;24(21):15668. doi: 10.3390/ijms242115668.ABSTRACTThe human CERS2 gene encodes a ceramide synthase enzyme, known as CERS2 (ceramide synthase 2). This protein is also known as LASS2 (LAG1 longevity assurance homolog 2) and TMSG1 (tumor metastasis-suppressor gene 1). Although previously described as a tumor suppressor for different types of cancer, such as prostate or liver cancer, it has also been observed to promote tumor growth in adenocarcinoma. In this review, we focus on the influence of CERS2 in bladder cancer (BC), approaching the existing literature about its structure and activity, as well as the miRNAs regulating its expression. From a mechanistic point of view, different explanations for the role of CERS2 as an antitumor protein have been proposed, including the production of long-chain ceramides, interaction with vacuolar ATPase, and its function as inhibitor of mitochondrial fission. In addition, we reviewed the literature specifically studying the expression of this gene in both BC and biopsy-derived tumor cell lines, complementing this with an analysis of public gene expression data and its association with disease progression. We also discuss the importance of CERS2 as a biomarker and the presence of CERS2 mRNA in extracellular vesicles isolated from urine.PMID:37958652 | DOI:10.3390/ijms242115668

Int J Mol Sci. 2023 Oct 26;24(21):15627. doi: 10.3390/ijms242115627.ABSTRACTThe red imported fire ant (RIFA), Solenopsis invicta, is an invasive pest that causes damage to agricultural and ecological environments worldwide. Fluralaner is a new isoxazoline pesticide with the potential to become a control agent against RIFA. However, it is not clear whether S. invicta responds the same way to fluralaner at different reproductive stages. The present study firstly evaluated the toxicity of fluralaner to S. invicta at different developmental stages, finding that fourth instar larvae (LD50, 1744.23 mg/kg) and worker ants (LD50, 8.62 mg/kg) were differently susceptible to fluralaner, while the mortality rate of fourth instar larvae was significantly lower at the same concentration of 10 mg/L (5.56 ± 3.14%) than that of worker ants (62.22 ± 3.14%), demonstrating a greater tolerance to fluralaner. Subsequently, the metabolic responses of worker and larval ants to fluralaner stress (10 mg/L) were investigated using non-targeted metabolomics, which indicated that the amount of differential metabolites and the KEGG metabolic pathways enriched were different between workers and larvae when exposed to the same dose (10 mg/L) of fluralaner. Differential metabolites of larvae and worker ants under fluralaner stress were mainly concentrated in organic acids and their derivatives, lipids and lipid-like molecules, nucleosides, nucleotides, and analogues, combined with the enriched metabolic pathways, revealed that the differential metabolic responses of larvae and worker ants were mainly in energy metabolism, detoxification metabolism, and neurotransmitter ligands. Workers consumed more substrates in the arginine synthesis pathway (l-glutamic acid, l-aspartic acid, and fumaric acid) to provide energy for the detoxification (glutathione) of pesticides when exposed to fluralaner stress, and the high accumulation of l-aspartic acid induced excitotoxicity in the worker ants. Larval ants consumed more arachidonic acid to synthesize PG D2, and changes in the metabolism of antioxidants such as catechins, hesperidin, and l-ascorbic acid suggested that larvae were more capable of scavenging the ROS response than worker ants. The results of non-targeted metabolomics successfully revealed differences in the sensitivity of larvae and workers to fluralaner agents, providing insights into the fluralaner control of Solenopsis invicta.PMID:37958611 | DOI:10.3390/ijms242115627

Int J Mol Sci. 2023 Oct 26;24(21):15615. doi: 10.3390/ijms242115615.ABSTRACTCancer researchers are fascinated by the chemistry of diverse natural products that show exciting potential as anticancer agents. In this study, we aimed to investigate the anticancer properties of watermelon rind extract (WRE) by examining its effects on cell proliferation, apoptosis, senescence, and global gene expression in human renal cell adenocarcinoma cells (HRAC-769-P) in vitro. Our metabolome data analysis of WRE exhibited untargeted phyto-constituents and targeted citrulline (22.29 µg/mg). HRAC-769-P cells were cultured in RPMI-1640 media and treated with 22.4, 44.8, 67.2, 88.6, 112, 134.4, and 156.8 mg·mL-1 for 24, 48, and 72 h. At 24 h after treatment, (88.6 mg·mL-1 of WRE) cell proliferation significantly reduced, more than 34% compared with the control. Cell viability decreased 48 and 72 h after treatment to 45% and 37%, respectively. We also examined poly caspase, SA-beta-galactosidase (SA-beta-gal), and wound healing activities using WRE. All treatments induced an early poly caspase response and a significant reduction in cell migration. Further, we analyzed the transcript profile of the cells grown at 44.8 mg·mL-1 of WRE after 6 h using RNA sequencing (RNAseq) analysis. We identified 186 differentially expressed genes (DEGs), including 149 upregulated genes and 37 downregulated genes, in cells treated with WRE compared with the control. The differentially expressed genes were associated with NF-Kappa B signaling and TNF pathways. Crucial apoptosis-related genes such as BMF, NPTX1, NFKBIA, NFKBIE, and NFKBID might induce intrinsic and extrinsic apoptosis. Another possible mechanism is a high quantity of citrulline may lead to induction of apoptosis by the production of increased nitric oxide. Hence, our study suggests the potential anticancer properties of WRE and provides insights into its effects on cellular processes and gene expression in HRAC-769-P cells.PMID:37958599 | DOI:10.3390/ijms242115615

Cancers (Basel). 2023 Nov 3;15(21):5271. doi: 10.3390/cancers15215271.ABSTRACTMetabolites associated with microbes regulate human immunity, inhibit bacterial colonization, and promote pathogenicity. Integrating microbe and metabolome research in GC provides a direction for understanding the microbe-associated pathophysiological process of metabolic changes and disease occurrence. The present study included 30 GC patients with 30 cancerous tissues and paired non-cancerous tissues (NCs) as controls. LC-MS/MS metabolomics and 16S rRNA sequencing were performed to obtain the metabolic and microbial characteristics. Integrated analysis of the microbes and metabolomes was conducted to explore the coexistence relationship between the microbial and metabolic characteristics of GC and to identify microbial-related metabolite diagnostic markers. The metabolic analysis showed that the overall metabolite distribution differed between the GC tissues and the NC tissues: 25 metabolites were enriched in the NC tissues and 42 metabolites were enriched in the GC tissues. The α and β microbial diversities were higher in the GC tissues than in the NC tissues, with 11 differential phyla and 52 differential genera. In the correlation and coexistence integrated analysis, 66 differential metabolites were correlated and coexisted, with specific differential microbes. The microbes in the GC tissue likely regulated eight metabolic pathways. In the efficacy evaluation of the microbial-related differential metabolites in the diagnosis of GC, 12 differential metabolites (area under the curve [AUC] >0.9) exerted relatively high diagnostic efficiency, and the combined diagnostic efficacy of 5 to 6 microbial-related differential metabolites was higher than the diagnostic efficacy of a single feature. Therefore, microbial diversity and metabolite distribution differed between the GC tissues and the NC tissues. Microbial-related metabolites may be involved in eight major metabolism-based biological processes in GC and represent potential diagnostic markers.PMID:37958446 | DOI:10.3390/cancers15215271

Cancers (Basel). 2023 Oct 28;15(21):5182. doi: 10.3390/cancers15215182.ABSTRACTHepatoblastoma (HB) is a rare childhood tumour with an evolving molecular landscape. We present the first comprehensive metabolomic analysis using untargeted and targeted liquid chromatography coupled to high-resolution tandem mass spectrometry (LC-MS/MS) of paired tumour and non-tumour surgical samples in HB patients (n = 8 pairs). This study demonstrates that the metabolomic landscape of HB is distinct from that of non-tumour (NT) liver tissue, with 35 differentially abundant metabolites mapping onto pathways such as fatty acid transport, glycolysis, the tricarboxylic acid (TCA) cycle, branched-chain amino acid degradation and glutathione synthesis. Targeted metabolomics demonstrated reduced short-chain acylcarnitines and a relative accumulation of branched-chain amino acids. Medium- and long-chain acylcarnitines in HB were similar to those in NT. The metabolomic changes reported are consistent with previously reported transcriptomic data from tumour and non-tumour samples (49 out of 54 targets) as well as metabolomic data obtained using other techniques. Gene set enrichment analysis (GSEA) from RNAseq data (n = 32 paired HB and NT samples) demonstrated a downregulation of the carnitine metabolome and immunohistochemistry showed a reduction in CPT1a (n = 15 pairs), which transports fatty acids into the mitochondria, suggesting a lack of utilisation of long-chain fatty acids in HB. Thus, our findings suggest a reduced metabolic flux in HB which is corroborated at the gene expression and protein levels. Further work could yield novel insights and new therapeutic targets.PMID:37958356 | DOI:10.3390/cancers15215182

Diagnostics (Basel). 2023 Oct 30;13(21):3345. doi: 10.3390/diagnostics13213345.ABSTRACTObjective: Metabolomics has growing importance in the research of inflammatory processes. Chronic subdural hematoma (cSDH) is considered to be, at least in part, of inflammatory nature, but no metabolic analyses yet exist. Therefore, a mass spectrometry untargeted metabolic analysis was performed on hematoma samples from patients with cSDH. Methods: A prospective analytical cross-sectional study on the efficacy of subperiosteal drains in cSDH was performed. Newly diagnosed patients had the option of granting permission for the collection of a hematoma sample upon its removal. The samples were analyzed using liquid chromatography-mass spectrometry to obtain different types of metabolites from diverse biochemical classes. The statistical analysis included data cleaning, imputation, and log transformation, followed by PCA, PLS-DA, HCA, and ANOVA. The postoperative course of the disease was followed for 3 months. The metabolite concentrations in the hematoma fluid were compared based on whether a recurrence of the disease was recorded within this time frame. Results: Fifty-nine samples from patients who were operated on because of a cSDH were gathered. Among those, 8 samples were eliminated because of missing metabolites, and only 51 samples were analyzed further. Additionally, 39 samples were from patients who showed no recurrence over the course of a 3-month follow-up, and 12 samples were from a group with later recurrence. We recorded a noticeable drop (35%) in the concentration of acylcarnitines in the "recurrence group", where 10 of the 22 tested metabolites showed a significant reduction (p < 0.05). Furthermore, a noticeable reduction in different Acyl-CoA-dehydrogenases was detected (VLCAD-deficiency p < 0.05, MCAD-deficiency p = 0.07). No further changes were detected between both populations. Conclusions: The current study presents a new approach to the research of cSDH. The measurements presented us with new data, which, to date, are without any reference values. Therefore, it is difficult to interpret the information, and our conclusions should be considered to be only speculative. The results do, however, point in the direction of impaired fatty acid oxidation for cases with later recurrence. As fatty acid oxidation plays an important role in inflammatory energy metabolism, the results suggest that inflammatory processes could be aggravated in cases with recurrence. Because our findings are neither proven through further analyses nor offer an obvious therapy option, their implications would not change everyday practice in the management of cSDH. They do, however, present a further possibility of research that might, in the future, be relevant to the therapy.PMID:37958242 | DOI:10.3390/diagnostics13213345

Animals (Basel). 2023 Oct 29;13(21):3356. doi: 10.3390/ani13213356.ABSTRACTPalm oil (PO) is currently the most widely used fat source for food production, but insect fat from Hermetia illucens larvae (HF) might be a suitable alternative fat source, because its production is less harmful to the environment. The present study investigated the effect of HF, as compared to PO and soybean oil (SO), on the hepatic lipid metabolism and the plasma metabolome of healthy rats, which were randomly assigned to three groups (n = 10 rats/group), and fed three different semi-synthetic diets containing either SO, PO, or HF as the main fat source for 4 weeks. Feed intake, body weight gain, liver and plasma lipid concentrations, and the hepatic mRNA levels of genes involved in lipid metabolism and inflammation did not differ between groups. Targeted plasma metabolomics revealed 294 out of 630 metabolites analyzed to be different between groups. Principal component analysis showed a clear separation of the plasma metabolomes of the SO group and the other two groups, but no separation of those of the PO and the HF groups. The present study shows that HF exerts no adverse metabolic effects in healthy rats, compared to PO or SO, indicating that HF is a safe alternative fat source to PO for food production.PMID:37958111 | DOI:10.3390/ani13213356

Animals (Basel). 2023 Oct 27;13(21):3349. doi: 10.3390/ani13213349.ABSTRACTAnoxia is a significant challenge for most animals, as it can lead to tissue damage and death. Among amphibians, the Siberian frog Rana amurensis is the only known species capable of surviving near-zero levels of oxygen in water for a prolonged period. In this study, we aimed to compare metabolomic profiles of the liver, brain, and heart of the Siberian frog exposed to long-term oxygen deprivation (approximately 0.2 mg/L water) with those of the susceptible Far Eastern frog (Rana dybowskii) subjected to short-term hypoxia to the limits of its tolerance. One of the most pronounced features was that the organs of the Far Eastern frog contained more lactate than those of the Siberian frog despite a much shorter exposure time. The amounts of succinate were similar between the two species. Interestingly, glycerol and 2,3-butanediol were found to be significantly accumulated under hypoxia in the Siberian frog, but not in the Far Eastern frog. The role and biosynthesis of these substances are still unclear, but they are most likely formed in certain side pathways of glycolysis. Based on the obtained data, we suggest a pathway for metabolic changes in the Siberian frog under anoxia.PMID:37958105 | DOI:10.3390/ani13213349

Plant Genome. 2023 Nov 13:e20402. doi: 10.1002/tpg2.20402. Online ahead of print.ABSTRACTTemperatures below or above optimal growth conditions are among the major stressors affecting productivity, end-use quality, and distribution of key staple crops including rice (Oryza sativa), wheat (Triticum aestivum), and maize (Zea mays L.). Among temperature stresses, cold stress induces cellular changes that cause oxidative stress and slowdown metabolism, limit growth, and ultimately reduce crop productivity. Perception of cold stress by plant cells leads to the activation of cold-responsive transcription factors and downstream genes, which ultimately impart cold tolerance. The response triggered in crops to cold stress includes gene expression/suppression, the accumulation of sugars upon chilling, and signaling molecules, among others. Much of the information on the effects of cold stress on perception, signal transduction, gene expression, and plant metabolism are available in the model plant Arabidopsis but somewhat lacking in major crops. Hence, a complete understanding of the molecular mechanisms by which staple crops respond to cold stress remain largely unknown. Here, we make an effort to elaborate on the molecular mechanisms employed in response to low-temperature stress. We summarize the effects of cold stress on the growth and development of these crops, the mechanism of cold perception, and the role of various sensors and transducers in cold signaling. We discuss the progress in cold tolerance research at the genome, transcriptome, proteome, and metabolome levels and highlight how these findings provide opportunities for designing cold-tolerant crops for the future.PMID:37957947 | DOI:10.1002/tpg2.20402

Comb Chem High Throughput Screen. 2023 Nov 7. doi: 10.2174/0113862073244102231020050502. Online ahead of print.ABSTRACTBACKGROUND: Ginseng-ophiopogon injection (GOI) is a clinically commonly used drug for Qi deficiency syndrome characterized by decreased physical function in China. This study aimed to clarify common pharmacological mechanisms of GOI in enhancing physical function.METHODS: We performed an integrative strategy of weight-loaded swimming tests in cold water (5.5 °C), hepatic glycogen and superoxide dismutase (SOD) detections, GC-TOF/MS-based metabolomics, multivariate statistical techniques, network pharmacology of known targets and constituents, and KEGG pathway analysis of GOI.RESULTS: Compared with the control group, GOI showed significant increases in the weightloaded swimming time, hepatic levels of glycogen and SOD. Additionally, 34 significantly differential serum metabolites referred to glycolysis, gluconeogenesis and arginine biosynthesis were affected by GOI. The target collection revealed 98 metabolic targets and 50 experimentreported drug targets of ingredients in GOI involved in enhancing physical function. Further, the PPI network analysis revealed that 8 ingredients of GOI, such as ginsenoside Re, ginsenoside Rf, ginsenoside Rg1, and notoginsenoside R1, were well-associated with 48 hub targets, which had good ability in enhancing physical function. Meanwhile, nine hub proteins, such as SOD, mechanistic target of Rapamycin (mTOR), and nitric oxide synthases, were confirmed to be affected by GOI. Finally, 98 enriched KEGG pathways (P<0.01 and FDR<0.001) of GOI were obtained from 48 hub targets of the PPI network. Among them, pathways in cancer, Chagas disease, lipid and atherosclerosis, and PI3K-Akt signaling pathway ranked top four.CONCLUSIONS: This study provided an integrative and efficient approach to understanding the molecular mechanism of GOI in enhancing physical function.PMID:37957852 | DOI:10.2174/0113862073244102231020050502

Biomark Res. 2023 Nov 13;11(1):97. doi: 10.1186/s40364-023-00536-y.ABSTRACTCongenital heart disease (CHD) represents a significant contributor to both morbidity and mortality in neonates and children. There's currently no analogous dried blood spot (DBS) screening for CHD immediately after birth. This study was set to assess the feasibility of using DBS to identify reliable metabolite biomarkers with clinical relevance, with the aim to screen and classify CHD utilizing the DBS. We assembled a cohort of DBS datasets from the California Department of Public Health (CDPH) Biobank, encompassing both normal controls and three pre-defined CHD categories. A DBS-based quantitative metabolomics method was developed using liquid chromatography with tandem mass spectrometry (LC-MS/MS). We conducted a correlation analysis comparing the absolute quantitated metabolite concentration in DBS against the CDPH NBS records to verify the reliability of metabolic profiling. For hydrophilic and hydrophobic metabolites, we executed significant pathway and metabolite analyses respectively. Logistic and LightGBM models were established to aid in CHD discrimination and classification. Consistent and reliable quantification of metabolites were demonstrated in DBS samples stored for up to 15 years. We discerned dysregulated metabolic pathways in CHD patients, including deviations in lipid and energy metabolism, as well as oxidative stress pathways. Furthermore, we identified three metabolites and twelve metabolites as potential biomarkers for CHD assessment and subtypes classifying. This study is the first to confirm the feasibility of validating metabolite profiling results using long-term stored DBS samples. Our findings highlight the potential clinical applications of our DBS-based methods for CHD screening and subtype classification.PMID:37957758 | DOI:10.1186/s40364-023-00536-y

Anal Chem. 2023 Nov 13. doi: 10.1021/acs.analchem.3c03626. Online ahead of print.ABSTRACTCell surface glycans are essential for establishing cell communication, adhesion, and migration. However, it remains challenging to obtain cell surface-specific information about glycoconjugate structures. Acquiring this information is essential for unraveling the functional role of glycans and for exploiting them as clinical targets. To specifically analyze the N-glycoprotein forms expressed at the cell surface, we developed a C18 liquid chromatography (LC)-mass spectrometry (MS)-based glycoproteomics method in combination with highly specific cell surface protein labeling and enrichment using a biotin label. The surface-specificity of the method was validated by MS-based proteomics of subcellular component marker proteins. Using the human keratinocytes N/TERT-1 as a model system, we identified and quantified the glycosylation of hundreds of cell surface N-glycosylation sites. This approach allowed us to study the glycoforms present at the functional relevant cell surface, omitting immaturely glycosylated proteins present in the secretory pathway. Interestingly, the different stages of N-glycan processing at individual sites displayed at the cell surface were found to correlate with their accessibility for ER-residing processing enzymes, as investigated through molecular dynamics simulations. Using the new approach, we compared N-glycosylation sites of proteins expressed on the cell surface to their counterparts in a total cell lysate, showing profound differences in glycosylation between the subcellular components and indicating the relevance of the method for future studies in understanding contextual glycan functions.PMID:37956981 | DOI:10.1021/acs.analchem.3c03626

Bioresour Technol. 2023 Nov 11:130002. doi: 10.1016/j.biortech.2023.130002. Online ahead of print.ABSTRACT2,3-Butanediol is an essential renewable fuel. The synthesis of 2,3-butanediol using Paenibacillus polymyxa has attracted increasing attention. In this study, the glucose-derived 2,3-butanediol pathway and its related genes were identified in P. polymyxa using combined transcriptome and metabolome analyses. The functions of two distinct genes ldh1 and ldh3 encoding lactate dehydrogenase, the gene bdh encoding butanediol dehydrogenase, and the spore-forming genes spo0A and spoIIE were studied and directly knocked out or overexpressed in the genome sequence to improve the production of 2,3-butanediol. A raw hydrolysate of poplar wood containing 27 g/L glucose and 15 g/L xylose was used to produce 2,3-butanediol with a maximum yield of 0.465 g/g and 93 % of the maximum theoretical value, and the total production of 2,3-butanediol and ethanol reached 21.7 g/L. This study provides a new scheme for engineered P. polymyxa to produce renewable fuels using raw poplar wood hydrolysates.PMID:37956945 | DOI:10.1016/j.biortech.2023.130002

Microb Pathog. 2023 Nov 11:106445. doi: 10.1016/j.micpath.2023.106445. Online ahead of print.ABSTRACTFoliar fungal blast and bacterial leaf blight have significant impacts on rice production, and their management through host resistance and agrochemicals has proven inadequate. To achieve their sustainable management, innovative approaches like leveraging the foliar microbiome, which collaborates with plants and competes against pathogens, are essential. In our study, we isolated three Pantoea bacterial strains (P. agglomerans Os-Ep-PPA-1b, P. vagans Os-Ep-PPA-3b, and P. deleyi Os-Ep-VPA-9a) from the rice phylloplane. These isolates exhibited antimicrobial action through their metabolome and volatilome, while also promoting rice growth.Our analysis, using Gas Chromatography-Mass Spectrometry (GC-MS), revealed the presence of various antimicrobial compounds such as esters and fatty acids produced by these Pantoea isolates. Inoculating rice seedlings with P. agglomerans and P. vagans led to increased root and shoot growth. Additionally, bacterized seedlings displayed enhanced immunocompetence, as evidenced by upregulated expressions of defense genes (OsEDS1, OsFLS2, OsPDF2.2, ACO4, ICS OsPR1a, OsNPR1.3, OsPAD4, OsCERK1.1), along with heightened activities of defense enzymes like Polyphenol Oxidase and Peroxidase. These plants also exhibited elevated levels of total phenols.In field trials, the Pantoea isolates contributed to improved plant growth, exemplified by increased flag-leaf length, panicle number, and grains per panicle, while simultaneously reducing the incidence of chaffy grains. Hypersensitivity assays performed on a model plant, tobacco, confirmed the non-pathogenic nature of these Pantoea isolates.In summary, our study underscores the potential of Pantoea bacteria in combatting rice foliar diseases. Coupled with their remarkable growth-promoting and biostimulant capabilities, these findings position Pantoea as promising agents for enhancing rice cultivation.PMID:37956936 | DOI:10.1016/j.micpath.2023.106445

Biochem Pharmacol. 2023 Nov 11:115922. doi: 10.1016/j.bcp.2023.115922. Online ahead of print.ABSTRACTInfantile hemangioma (IH) is the most common benign tumor in children. Propranolol is the first-line treatment for IH, but the underlying mechanism of propranolol treatment in IH is not completely understood. Integrated transcriptional and metabolic analyses were performed to investigate the metabolic changes in hemangioma-derived endothelial cells (HemECs) after propranolol treatment. The findings were then further validated through independent cell experiments using a Seahorse XFp analyzer, Western blotting, immunohistochemistry and mitochondrial functional assays. Thirty-four differentially expressed metabolites, including the glycolysis metabolites glucose 6-phosphate, fructose 6-phosphate and fructose 1,6-bisphosphate, were identified by targeted metabolomics. A KEGG pathway enrichment analysis showed that the disturbances in these metabolites were highly related to glucose metabolism-related pathways, including the pentose phosphate pathway, the Warburg effect, glycolysis and the citric acid cycle. Transcriptional analysis revealed that metabolism-related pathways, including glycine, serine and threonine metabolism, tyrosine metabolism, and glutathione metabolism, were highly enriched. Moreover, integration of the metabolomic and transcriptomic data revealed that glucose metabolism-related pathways, particularly glycolysis, were altered after propranolol treatment. Cell experiments demonstrated that HemECs exhibited higher levels of glycolysis than human umbilical vein ECs (HUVECs) and that propranolol suppressed glycolysis in HemECs. In conclusion, propranolol inhibited glucose metabolism in HemECs by suppressing glucose metabolic pathways, particularly glycolysis.PMID:37956892 | DOI:10.1016/j.bcp.2023.115922

Neurobiol Dis. 2023 Nov 11:106348. doi: 10.1016/j.nbd.2023.106348. Online ahead of print.ABSTRACT3,4-Methylenedioxymethamphetamine (MDMA) is the most widely used illicit substance worldwide. Nevertheless, recent observational studies demonstrated that lifetime MDMA use among U.S. adults was associated with a lower risk of depression and suicide thoughts. We recently reported that the gut-brain axis may contribute to MDMA-induced stress resilience in mice. To further explore this, we investigated the effects of subdiaphragmatic vagotomy (SDV) in modulating the stress resilience effects of MDMA in mice subjected to chronic restrain stress (CRS). Pretreatment with MDMA (10 mg/kg/day for 14 days) blocked anhedonia-like behavior and reduced expression of synaptic proteins and brain-derived neurotrophic factor in the prefrontal cortex (PFC) of CRS-exposed mice. Interestingly, SDV blocked the beneficial effects of MDMA on these alterations in CRS-exposed mice. Analysis of gut microbiome revealed alterations in four measures of α-diversity between the sham + MDMA + CRS group and the SDV + MDMA + CRS group. Moreover, specific microbes differed between the vehicle + CRS group and the MDMA + CRS group, and further differences in microbial composition were observed among all four groups. Untargeted metabolomics analysis showed that SDV prevented the increase in plasma levels of three compounds [lactic acid, 1-(2-hydroxyethyl)-2,2,6-tetramethyl-4-piperidinol, 8-acetyl-7-hydroxyvumaline] observed in the sham + MDMA + CRS group. Interestingly, positive correlations were found between the plasma levels of two of these compounds and the abundance of several microbes across all groups. In conclusion, our data suggest that the gut-brain axis via the subdiaphragmatic vagus nerve might contribute to the stress resilience of MDMA.PMID:37956855 | DOI:10.1016/j.nbd.2023.106348

Sci Total Environ. 2023 Nov 11:168422. doi: 10.1016/j.scitotenv.2023.168422. Online ahead of print.ABSTRACTSeagrass ecosystems provide crucial ecosystem services for coastal environments and were shown to reduce the abundance of pathogens linked to infections in humans and marine organisms. Among potential drivers, seagrass phenolics released into seawater have been linked to pathogen suppression, but the potential involvement of the seagrass microbiome has not been investigated. We hypothesized that the microbiome of the eelgrass Zostera marina, especially the leaf epiphytes that are at direct interface between the seagrass host and surrounding seawater, inhibit waterborne pathogens thereby contributing to their removal. Using a culture-dependent approach, we isolated 88 bacteria and fungi associated with the surfaces and inner tissues of the eelgrass leaves (healthy and decaying) and the roots. We assessed the antibiotic activity of microbial extracts against a large panel of common aquatic, human (fecal) and plant pathogens, and mined the metabolome of the most active extracts. The healthy leaf epibiotic bacteria, particularly Streptomyces sp. strain 131, displayed broad-spectrum antibiotic activity superior to some control drugs. Gram-negative bacteria abundant on healthy leaf surfaces, and few endosphere-associated bacteria and fungi also displayed remarkable activities. UPLC-MS/MS-based untargeted metabolomics analyses showed rich specialized metabolite repertoires with low annotation rates, indicating the presence of many undescribed antimicrobials in the extracts. This study contributes to our understanding on microbial and chemical ecology of seagrasses, implying potential involvement of the seagrass microbiome in suppression of pathogens in seawater. Such effect is beneficial for the health of ocean and human, especially in the context of climate change that is expected to exacerbate all infectious diseases. It may also assist future seagrass conservation and management strategies.PMID:37956849 | DOI:10.1016/j.scitotenv.2023.168422

Prog Neuropsychopharmacol Biol Psychiatry. 2023 Nov 11:110896. doi: 10.1016/j.pnpbp.2023.110896. Online ahead of print.ABSTRACTAcid sphingomyelinase deficiency is a neurodegenerative lysosomal storage disorder caused by mutations in the sphingomyelin-degrading enzyme acid sphingomyelinase (ASM) gene. Upregulated neuroinflammation has been well-characterized in an ASM knockout mouse model of acid sphingomyelinase deficiency disease, but lipid mediator pathways involved in 'mediating' inflammation and inflammation-resolution have yet to be characterized. In this study, we 1) measured free (bioactive) and esterified (inactive) lipid mediators involved in inflammation and inflammation resolution in cerebellum and neuronal cultures of ASM knockout (ASMko) mice and wildtype (WT) controls, and 2) tested the incorporation of labeled pro-resolving free d11-14(15)-epoxyeicosatrienoic acid into culture neurons from ASMko and WT mice. We found elevated concentrations of esterified pro-resolving lipid mediators and hydroxyeicosatrienoic acids typically destined for pro-resolving lipid mediator synthesis (e.g. lipoxins) in the cerebellum and neurons of ASMko mice compared to controls. Free d11-14(15)-epoxyeicosatrienoic acid incorporation into neurons of ASMko mice was significantly elevated compared to WT. Our findings show evidence of increased inactivation of free pro-resolving lipid mediators through esterification, suggesting impaired resolution as a new pathway underlying ASM deficiency pathogenesis.PMID:37956788 | DOI:10.1016/j.pnpbp.2023.110896

Toxicology. 2023 Nov 11:153672. doi: 10.1016/j.tox.2023.153672. Online ahead of print.ABSTRACTHuman lifetime exposure to arsenic through drinking water, food supply or industrial pollution leads to its accumulation in many organs such as liver, kidneys, lungs or pancreas but also adipose tissue. Recently, population-based studies revealed the association between arsenic exposure and the development of metabolic diseases such as obesity and type 2 diabetes. To shed light on the molecular bases of such association, we determined the concentration that inhibited 17% of cell viability and investigated the effects of arsenic acute exposure on adipose-derived human mesenchymal stem cells differentiated in vitro into mature adipocytes and treated with sodium arsenite (NaAsO2, 10nM to 10µM). Untargeted metabolomics and gene expression analyses revealed a strong dose-dependent inhibition of lipogenesis and lipolysis induction, reducing the cellular ability to store lipids. These dysregulations were emphasized by the inhibition of the cellular response to insulin, as shown by the perturbation of several genes and metabolites involved in the mentioned biological pathways. Our study highlighted the activation of an adaptive oxidative stress response with the strong induction of metallothioneins and increased glutathione levels in response to arsenic accumulation that could exacerbate the decreased insulin sensitivity of the adipocytes. Arsenic exposure strongly affected the expression of arsenic transporters, responsible for arsenic influx and efflux, and induced a pro-inflammatory state in adipocytes by enhancing the expression of the inflammatory interleukin 6 (IL6). Collectively, our data showed that an acute exposure to low levels of arsenic concentrations alters key adipocyte functions, highlighting its contribution to the development of insulin resistance and the pathogenesis of metabolic disorders.PMID:37956786 | DOI:10.1016/j.tox.2023.153672