PubMed

Nat Commun. 2022 Nov 17;13(1):7037. doi: 10.1038/s41467-022-34443-x.ABSTRACTCiliary neurotrophic factor (CNTF) acts as a potent neuroprotective cytokine in multiple models of retinal degeneration. To understand mechanisms underlying its broad neuroprotective effects, we have investigated the influence of CNTF on metabolism in a mouse model of photoreceptor degeneration. CNTF treatment improves the morphology of photoreceptor mitochondria, but also leads to reduced oxygen consumption and suppressed respiratory chain activities. Molecular analyses show elevated glycolytic pathway gene transcripts and active enzymes. Metabolomics analyses detect significantly higher levels of ATP and the energy currency phosphocreatine, elevated glycolytic pathway metabolites, increased TCA cycle metabolites, lipid biosynthetic pathway intermediates, nucleotides, and amino acids. Moreover, CNTF treatment restores the key antioxidant glutathione to the wild type level. Therefore, CNTF significantly impacts the metabolic status of degenerating retinas by promoting aerobic glycolysis and augmenting anabolic activities. These findings reveal cellular mechanisms underlying enhanced neuronal viability and suggest potential therapies for treating retinal degeneration.PMID:36396639 | DOI:10.1038/s41467-022-34443-x

Arch Dis Child Fetal Neonatal Ed. 2022 Nov 17:fetalneonatal-2022-324477. doi: 10.1136/archdischild-2022-324477. Online ahead of print.ABSTRACTOBJECTIVE: To determine the impact of supplemental bovine lactoferrin on the gut microbiome and metabolome of preterm infants.DESIGN: Cohort study nested within a randomised controlled trial (RCT). Infants across different trial arms were matched on several clinical variables. Bacteria and metabolite compositions of longitudinal stool and urine samples were analysed to investigate the impact of lactoferrin supplementation.SETTING: Thirteen UK hospitals participating in a RCT of lactoferrin.PATIENTS: 479 infants born <32 weeks' gestation between June 2016 and September 2017.RESULTS: 10 990 stool and 22 341 urine samples were collected. Analyses of gut microbiome (1304 stools, 201 infants), metabolites (171 stools, 83 infants; 225 urines, 90 infants) and volatile organic compounds (314 stools, 117 infants) were performed. Gut microbiome Shannon diversity at 34 weeks corrected age was not significantly different between infants in the lactoferrin (mean=1.24) or placebo (mean=1.06) groups (p=0.11). Lactoferrin receipt explained less than 1% variance in microbiome compositions between groups. Metabolomic analysis identified six discriminative features between trial groups. Hospital site (16%) and postnatal age (6%) explained the greatest variation in microbiome composition.CONCLUSIONS: This multiomic study identified minimal impacts of lactoferrin but much larger impacts of hospital site and postnatal age. This may be due to the specific lactoferrin product used, but more likely supports the findings of the RCT in which this study was nested, which showed no impact of lactoferrin on reducing rates of sepsis. Multisite mechanistic studies nested within RCTs are feasible and help inform trial interpretation and future trial design.PMID:36396443 | DOI:10.1136/archdischild-2022-324477

Life Sci. 2022 Nov 14:121189. doi: 10.1016/j.lfs.2022.121189. Online ahead of print.ABSTRACTAIMS: Obesity and its related metabolic disorders, including insulin resistance and fatty liver, have become a serious global public health problem. Previous studies show Methionine Enkephalin (MetEnk) has the potential on adipocyte browning, however, its effects on the potential mechanisms of its regulation in browning as well as its improvement in energy metabolic homeostasis remain to be deciphered.MAIN METHODS: C57BL/6J male mice were fed with high-fat diet (HFD) to induce obesity model, and MetEnk was injected subcutaneously to detect changes in the metabolic status of mice, adipocytes and HepG2 cells were also treated with MetEnk, and transcriptomic, metabolomic were used to detect the changes of lipid metabolism, mitochondrial function, inflammation and other related factors.KEY FINDINGS: We found that MetEnk effectively protected against obesity weight gain in HFD-induced C57BL/6J mice, significantly improved glucose tolerance and insulin sensitivity, reduced the expression level of interleukin 6 (IL-6), promoted white fat browning, moreover, using a combination of transcriptomic, metabolomic and inhibitors, it was found that MetEnk improved mitochondrial function, promoted thermogenesis and lipolysis by activating cAMP/PKA pathway in adipocytes, further analysis found that MetEnk also promoted lipolysis and alleviated inflammation through AMP-activated protein kinase (AMPK) pathway in mice liver and HepG2 cells.SIGNIFICANCE: Our study provides profound evidence for the role of MetEnk in improving lipid metabolism disorders. This study provides a mechanical foundation for investigating the potential of MetEnk to improve obesity and its associated metabolic disorders.PMID:36396109 | DOI:10.1016/j.lfs.2022.121189

Free Radic Biol Med. 2022 Nov 14:S0891-5849(22)00977-7. doi: 10.1016/j.freeradbiomed.2022.11.014. Online ahead of print.ABSTRACTKeshan disease is an endemic fatal dilated cardiomyopathy that can cause heart enlargement, heart failure, and cardiogenic death. Selenium deficiency is considered to be the main cause of Keshan disease. However, the molecular mechanism underlying Keshan disease remains unclear. Our whole-exome sequencing from 68 patients with Keshan disease and 100 controls found 199 candidate genes by gene-level burden tests. Interestingly, using multiomics data, the selenium-related gene ALAD (δ-aminolevulinic acid dehydratase) was the only candidate causative gene identified by three different analysis approaches. Based on single-cell transcriptome data, ALAD was highly expressed in cardiomyocytes and double mutations of human ALAD dramatically reduced its enzyme activity in vitro compared to negative control. Functional analysis of ALAD inhibition in mice resulted in a Keshan phenotype with left ventricular enlargement and cardiac dysfunction, whereas administration of sodium selenite markedly reversed the changes caused by ALAD inhibition. In addition, sodium selenite reversed Keshan phenotypes by affecting energy metabolism and mitochondrial function in mice as shown by the transcriptomic and proteomic data and the ultrastructure of cardiac myocytes. Our findings are the first to demonstrate that the selenium-related gene ALAD is essential for cardiac function by maintaining normal mitochondrial activity, providing strong molecular evidence supporting the hypothesis of selenium deficiency in Keshan disease. These results identified ALAD as a novel target for therapeutic intervention in Keshan disease and Keshan disease-related dilated cardiomyopathy.PMID:36395956 | DOI:10.1016/j.freeradbiomed.2022.11.014

J Biol Chem. 2022 Nov 14:102706. doi: 10.1016/j.jbc.2022.102706. Online ahead of print.ABSTRACTThe Red Blood Cell (RBC)-Omics study, part of the larger NHLBI-funded Recipient Epidemiology and Donor Evaluation Study (REDS-III), aims to understand the genetic contribution to blood donor RBC characteristics. Previous work identified donor demographic, behavioral, genetic, and metabolic underpinnings to blood donation, storage, and (to a lesser extent) transfusion outcomes, but none have yet linked the genetic and metabolic bodies of work. We performed a Genome-Wide Association (GWA) analysis using RBC-Omics study participants with generated untargeted metabolomics data to identify metabolite quantitative trait loci (mQTL) in RBCs. We performed GWA analyses of 382 metabolites in 243 individuals imputed using the 1000 Genomes Project phase 3 all-ancestry reference panel. Analyses were conducted using ProbABEL and adjusted for sex, age, donation center, number of whole blood donations in the past two years, and first ten principal components of ancestry. Our results identified 423 independent genetic loci associated with 132 metabolites (p < 5x10-8). Potentially novel locus-metabolite associations were identified for the region encoding heme transporter FLVCR1 and choline, and for lysophosphatidylcholine acetyltransferase LPCAT3 and lysophosphatidylserine 16.0, 18.0, 18.1, and 18.2; these associations are supported by published rare disease and mouse studies. We also confirmed previous metabolite GWA results for associations including N(6)-Methyl-L-lysine and protein PYROXD2, and various carnitines and transporter SLC22A16. Association between pyruvate levels and G6PD polymorphisms was validated in an independent cohort and novel murine models of G6PD deficiency (African and Mediterranean variants). We demonstrate that it is possible to perform metabolomics-scale GWA analyses with a modest, trans-ancestry sample size.PMID:36395887 | DOI:10.1016/j.jbc.2022.102706

EBioMedicine. 2022 Nov 14;86:104359. doi: 10.1016/j.ebiom.2022.104359. Online ahead of print.ABSTRACTBACKGROUND: Arachidonate 5-lipoxygenase (Alox5) belongs to a class of nonheme iron-containing dioxygenases involved in the catalysis of leukotriene biosynthesis. However, the effects of Alox5 itself on pathological cardiac remodeling and heart failure remain elusive.METHODS: The role of Alox5 in pathological cardiac remodeling was investigated by Alox5 genetic depletion, AAV9-mediated overexpression in cardiomyocytes, and a bone marrow (BM) transplantation approach. Neonatal rat cardiomyocytes were used to explore the effects of Alox5 in vitro. Molecular and signaling pathways were revealed by CUT &Tag, IP-MS, RNA sequencing and bioinformatic analyses.FINDINGS: Untargeted metabolomics showed that serum 5-HETE (a primary product of Alox5) levels were little changed in patients with cardiac hypertrophy, while Alox5 expression was significantly upregulated in murine hypertensive cardiac samples and human cardiac samples of hypertrophy, which prompted us to test whether high Alox5 levels under hypertensive stimuli were directly associated with pathologic myocardium in an enzymatic activity-independent manner. Herein, we revealed that Alox5 deficiency significantly ameliorated transverse aortic constriction (TAC)-induced hypertrophy. Cardiomyocyte-specific Alox5 depletion attenuated hypertensive ventricular remodeling. Conversely, cardiac-specifical Alox5 overexpression showed a pro-hypertrophic cardiac phenotype. Ablation of Alox5 in bone marrow-derived cells did not affect pathological cardiac remodeling and heart failure. Mechanically, Runx2 was identified as a target of Alox5. In this regard, Alox5 PEST domain could directly bind to Runx2 PTS domain, promoting nuclear localization of Runx2 in an enzymatic activity-independent manner, simultaneously contributed to liquid-liquid phase separation (LLPS) of Runx2 at specific domain in the nucleus and increased transcription of EGFR in cardiomyocytes. Runx2 depletion alleviated hypertrophy in Ang II-pretreated Alox5-overexpressing cardiomyocytes.INTERPRETATION: Overall, our study demonstrated that targeting Alox5 exerted a protective effect against cardiac remodeling and heart failure under hypertensive stimuli by disturbing LLPS of Runx2 and substantial reduction of EGFR transcription activation in cardiomyocytes. Our findings suggest that negative modulation of Alox5-Runx2 may provide a therapeutic approach against pathological cardiac remodeling and heart failure.FUNDING: National Natural Science Foundation of China.PMID:36395739 | DOI:10.1016/j.ebiom.2022.104359

Mar Pollut Bull. 2022 Nov 14;185(Pt B):114326. doi: 10.1016/j.marpolbul.2022.114326. Online ahead of print.ABSTRACTParalytic shellfish poisoning is a global issue that would benefit from additional screening methods and rapid testing capacities. In this study, we applied 1H NMR spectroscopy-based metabolomics to identify biomarkers of Paralytic Shellfish Toxin (PST) exposure. We characterized the metabolic phenotypes of field-collected Alaskan mussels Mytilus trossulus across a wide range of bioaccumulated PST levels, from 0 to 1590 μg/100 g. A between-level grouping emerged for high (740-1590 μg/100 g) compared to low/non-detect (0-3.91 μg/100 g) PST levels. High levels of PST contamination in mussels were consistent with alterations to energy and amino acid metabolism, and disturbances in osmoregulation. This research demonstrates the effectiveness of 1H NMR-based metabolomics in elucidating the biological effects of paralytic shellfish toxin on the health of wild mussel populations, spatial variation, and identifies a metabolic signature indicative of PST contamination in Mytilus trossulus for potential use in a PSP biomarker panel.PMID:36395714 | DOI:10.1016/j.marpolbul.2022.114326

Arch Oral Biol. 2022 Nov 9;145:105583. doi: 10.1016/j.archoralbio.2022.105583. Online ahead of print.ABSTRACTOBJECTIVES: To evaluate the pathogenic role of colitis in experimental periodontitis and explore the potential serum metabolites of colitis exacerbating experimental periodontitis in mice model.DESIGN: C57BL/6 mice were divided into four groups (five mice in each group), including control, periodontitis, colitis and colitis+periodontitis group. Mice treated with 1.5 % dextran sulfate sodium for 14 days to induce colitis. On the seventh to fourteenth days, the experimental periodontitis model was established by installing a bacterially retentive ligature between two molars. Histological alteration of periodontium and colon was observed by hematoxylin and eosin staining. Tartrate-resistant acid phosphatase staining and micro-computed tomography was applied to evaluate alveolar bone loss. Gas chromatography-mass spectrometry was used to characterize serum metabolic profiles.RESULTS: Mice in colitis+periodontitis group displayed increased periodontal inflammation and alveolar bone loss when compared with the mice of periodontitis group, suggesting colitis aggravated periodontitis. Metabolomics analysis combined with enrichment analysis showed that colitis significantly (P＜0.05) altered the content of compounds associated with five metabolic pathways (e.g. fatty acid biosynthesis) of periodontitis mice. Notably, colitis significantly reduced the level of serum metabolites that inhibited the formation of osteoclasts (e.g. oleic acid) or anti-inflammatory metabolites (e.g. palmitoleic acid, palmitelaidic acid and chlorogenic acid) of periodontitis mice.CONCLUSIONS: Our findings showed that colitis might aggravate periodontitis and this might be associated with alteration of serum metabolic profiles.PMID:36395563 | DOI:10.1016/j.archoralbio.2022.105583

Anal Chem. 2022 Nov 17. doi: 10.1021/acs.analchem.2c03961. Online ahead of print.ABSTRACTLipidomic and metabolomic profiles of sporulated and vegetative Bacillus subtilis and Bacillus thuringiensis from irradiated lysates were recorded using a quadrupole ion trap mass spectrometer modified to perform two-dimensional tandem mass spectrometry (2D MS/MS). The 2D MS/MS data domains, acquired using a 1.2 s scan of negative ions generated by nanoelectrospray ionization of microwave irradiated spores, showed the presence of dipicolinic acid (DPA) as well as various lipids. Aside from microwave radiation to extract DPA and lipids from spores, sample preparation was minimal. Characteristic lipid and metabolic profiles were observed using 107─108 cells of the two Bacillus species. Major features of the lipid profiles observed for the vegetative states included sets of phosphatidylglycerol (PG) lipids. Product ion spectra were extracted from the 2D MS/MS data, and they provided structural information on the fatty acid components of the PG lipids. The study demonstrates the flexibility, speed, and informative power of metabolomic and lipidomic fingerprinting for identifying the presence of spore-forming biological agents using 2D MS/MS as a rapid profiling screening method.PMID:36395489 | DOI:10.1021/acs.analchem.2c03961

PLoS One. 2022 Nov 17;17(11):e0277808. doi: 10.1371/journal.pone.0277808. eCollection 2022.ABSTRACTStaphylococcus pseudintermedius is a urease-producing bacteria which is a major cause of magnesium ammonium phosphate (MAP) urolithiasis in canine. A positive urolith culture is an important risk factor for MAP urolithiasis in canine. The mechanism underlying the metabolic changes of S. pseudintermedius after crystallization in artificial urine (AU) needs more defined baseline metabolic information. Therefore, we extensively investigated the metabolic changes of S. pseudintermedius extensively after crystallization in AU. A high urease activity and positive biofilm formation strain, entitled the S. pseudintermedius (SPMAP09) strain, was isolated from canine MAP uroliths, and analyzed using nuclear magnetic resonance (NMR) spectroscopy-based metabolomics. The molecular mechanism-specific metabolic phenotypes were clearly observed after crystallization in AU at day 3. The crystals induced by SPMAP09 were also confirmed and the major chemical composition identified as struvite. Interestingly, our findings demonstrated that a total of 11 identified metabolites were significantly changed. The levels of formate, homocarnosine, tyrosine, cis-aconitate, glycolate, ethyl malonate, valine and acetate level were significantly higher, accompanied with decreased levels of inosine, glucose, and threonine at day 3 compared with the initial time-point (day 0). In addition, our results exhibited that the glyoxylate and dicarboxylate metabolism was significantly related to the SPMAP09 strain at day 3 in AU. Thus, metabolic changes of the SPMAP09 strain after crystallization in AU potentially helps to explain the preliminary molecular mechanism for the crystals induced by S. pseudintermedius.PMID:36395195 | DOI:10.1371/journal.pone.0277808

Front Immunol. 2022 Oct 18;13:993354. doi: 10.3389/fimmu.2022.993354. eCollection 2022.ABSTRACTImmunoglobulin G (IgG) antibodies play an important role in the immune response against viruses such as SARS-CoV-2. As the effector functions of IgG are modulated by N-glycosylation of the Fc region, the structure and possible function of the IgG N-glycome has been under investigation in relation to divergent COVID-19 disease courses. Through LC-MS analysis we studied both total IgG1 and spike protein-specific IgG1 Fc glycosylation of 129 German and 163 Brazilian COVID-19 patients representing diverse patient populations. We found that hospitalized COVID-19 patients displayed decreased levels of total IgG1 bisection and galactosylation and lowered anti-S IgG1 fucosylation and bisection as compared to mild outpatients. Anti-S IgG1 glycosylation was dynamic over the disease course and both anti-S and total IgG1 glycosylation were correlated to inflammatory markers. Further research is needed to dissect the possible role of altered IgG glycosylation profiles in (dys)regulating the immune response in COVID-19.PMID:36389824 | PMC:PMC9641981 | DOI:10.3389/fimmu.2022.993354

Front Immunol. 2022 Oct 27;13:971409. doi: 10.3389/fimmu.2022.971409. eCollection 2022.ABSTRACTBACKGROUND: Rhubarb is an important traditional Chinese medicine, and rhein is one of its most important active ingredients. Studies have found that rhein can improve ulcerative colitis by regulating gut microbes, but there are few reports on its effects on liver diseases. Therefore, this study aims to investigate these effects and underlying mechanisms.METHODS: Mice were given rhein (100 mg/kg), with both a normal control group and a model group receiving the same amount of normal saline for one week. Acute liver injury was induced in mice by intraperitoneal injection of D-GalN (800 mg/kg)/LPS (10 ug/kg). Samples (blood, liver, and stool) were then collected and assessed for histological lesions and used for 16S rRNA gene sequencing, high-performance liquid chromatography-mass spectrometry (LC-MS) and RNA-seq analysis.RESULTS: The levels of ALT and AST in the Model group were abnormal higher compared to the normal control group, and the levels of ALT and AST were significantly relieved in the rhein group. Hepatic HE staining showed that the degree of liver injury in the rhein group was lighter than that in the model group, and microbiological results showed that norank_o:Clostridia_UCG-014, Lachnoclostridium, and Roseburia were more abundant in the model group compared to the normal control group. Notably, the rhein treatment group showed reshaped disturbance of intestinal microbial community by D-GalN/LPS and these mice also had higher levels of Verrucomicrobia, Akkermansiaceae and Bacteroidetes. Additionally, There were multiple metabolites that were significantly different between the normal control group and the model group, such as L-α-amino acid, ofloxacin-N-oxide, 1-hydroxy-1,3-diphenylpropan-2-one,and L-4-hydroxyglutamate semialdehyde, but that returned to normal levels after rhein treatment. The gene expression level in the model group also changed significantly, various genes such as Cxcl2, S100a9, Tnf, Ereg, and IL-10 were up-regulated, while Mfsd2a and Bhlhe41 were down-regulated, which were recovered after rhein treatment.CONCLUSION: Overall, our results show that rhein alleviated D-GalN/LPS-induced acute liver injury in mice. It may help modulate gut microbiota in mice, thereby changing metabolism in the intestine. Meanwhile, rhein also may help regulate genes expression level to alleviate D-GalN/LPS-induced acute liver injury.PMID:36389730 | PMC:PMC9648667 | DOI:10.3389/fimmu.2022.971409

Front Immunol. 2022 Oct 25;13:983501. doi: 10.3389/fimmu.2022.983501. eCollection 2022.ABSTRACTWith the rapid aging of the population, the control of age-related disease susceptibility and prognosis faces greater challenges. There is an urgent need for a strategy to maintain the vitality of elderly people. In this study, the effect of Renshen Guben (RSGB) oral liquid was investigated on an accelerated aging mice model of thyrotoxicosis by conventional detection methods combined with multiomics technology. The results showed that RSGB increased the number of neutrophils and lymphocytes, enhanced the function of lymphocytes, and increased the levels of complement and antimicrobial peptides, which indicated that RSGB improved the immunity of thyrotoxicosis mice at the cellular and molecular levels. RSGB corrected malnutrition in thyrotoxicosis mice by improving anemia, hypoalbuminemia, ion transporters, and vitamin-binding proteins. RSGB significantly reduced the lipotoxicity by reducing the level of fatty acids, triglyceride, sphingolipids, and glucocorticoids, thus increasing the level of docosapentaenoic acid (DPA) and bile acids, which contributed to improve immunosenescence. The intestinal defense ability of thyrotoxicosis mice was enhanced with the increase of bile acids and lactic acid bacteria by the RSGB treatment. The plant metabolomics analysis showed that there were various active components in RSGB oral liquid and medicated serum, including terpenoids, phenolic acids, flavonoids, tannin, alkaloids, organic acids, phenolamines, amino acids, and others. They have antioxidant, immune regulation, and anti-aging effects, which was the material basis of RSGB. Totally, RSGB protected the thyrotoxicosis mice against aging by improving immunosenescence, hypoproteinemia, lipotoxicity, and the intestinal flora. It will be beneficial for improving the disease susceptibility and prognosis of the elderly.PMID:36389720 | PMC:PMC9640368 | DOI:10.3389/fimmu.2022.983501

Front Neurosci. 2022 Oct 28;16:1030694. doi: 10.3389/fnins.2022.1030694. eCollection 2022.ABSTRACTWhat is the effect of our gut microbial flora on brain? Does the gut microbiome have any role in the causation of psychiatric and neurodegenerative diseases? Does the effect of gut microbiota traverse the gut-brain axis? Questions like these have captured the interest and imagination of the scientific community for quite some time now. Research in the quest for answers to these questions, to unravel the potential role of the microbiota inhabiting the gut in controlling brain functions, has progressed manifold over the last two decades. Although the possibility of microbiome as a key susceptibility factor for neurological disorders viz. Parkinson's disease, Alzheimer's disease, multiple sclerosis, and autism spectrum disorder has bolstered by an increase in the clinical and preclinical evidence, the field is still in its infancy. Given the fact that the diversity of the gut microbiota is affected by various factors including the diet and exercise, the interpretation of such data becomes all the more difficult. Also, such studies have been mostly conducted on animal models, so there is a need for randomized controlled trials in human subjects, corroborated by longitudinal studies, to establish if modulating the gut microbiota can unravel novel therapeutic interventions. Exploring the genomic, metagenomic and metabolomic data from clinical subjects with psychiatric and neurological diseases can prove to be a helpful guide in individual treatment selection.PMID:36389228 | PMC:PMC9650127 | DOI:10.3389/fnins.2022.1030694

Front Cell Infect Microbiol. 2022 Oct 26;12:1023806. doi: 10.3389/fcimb.2022.1023806. eCollection 2022.ABSTRACTAccumulating evidence suggests that selected microbiota-derived metabolites play a significant role in both tumor prevention and supportive treatment of cancer. Short-chain fatty acids (SCFAs), i.e., mainly acetate, proprionate, and butyrate, are one of them. Nowadays, it is known that butyrate is a key microbial metabolite. Therefore, in the current review, we focused on butyrate and sodium butyrate (NaB) in the context of colorectal cancer. Notably, butyrate is characterized by a wide range of beneficial properties/activities. Among others, it influences the function of the immune system, maintains intestinal barrier integrity, positively affects the efficiency of anti-cancer treatment, and may reduce the risk of mucositis induced by chemotherapy. Taking into consideration these facts, we analyzed NaB (which is a salt of butyric acid) and its impact on gut microbiota as well as anti-tumor activity by describing molecular mechanisms. Overall, NaB is available as, for instance, food with special medical purposes (depending on the country's regulation), and its administration seems to be a promising option for colorectal cancer patients.PMID:36389140 | PMC:PMC9643746 | DOI:10.3389/fcimb.2022.1023806

Front Cell Infect Microbiol. 2022 Oct 28;12:1011254. doi: 10.3389/fcimb.2022.1011254. eCollection 2022.ABSTRACTChildren are at high risk for influenza A virus (IAV) infections, which can develop into severe illnesses. However, little is known about interactions between the microbiome and respiratory tract metabolites and their impact on the development of IAV pneumonia in children. Using a combination of liquid chromatography tandem mass spectrometry (LC-MS/MS) and 16S rRNA gene sequencing, we analyzed the composition and metabolic profile of the oropharyngeal microbiota in 49 pediatric patients with IAV pneumonia and 42 age-matched healthy children. The results indicate that compared to healthy children, children with IAV pneumonia exhibited significant changes in the oropharyngeal macrobiotic structure (p = 0.001), and significantly lower microbial abundance and diversity (p < 0.05). These changes came with significant disturbances in the levels of oropharyngeal metabolites. Intergroup differences were observed in 204 metabolites mapped to 36 metabolic pathways. Significantly higher levels of sphingolipid (sphinganine and phytosphingosine) and propanoate (propionic acid and succinic acid) metabolism were observed in patients with IAV pneumonia than in healthy controls. Using Spearman's rank-correlation analysis, correlations between IAV pneumonia-associated discriminatory microbial genera and metabolites were evaluated. The results indicate significant correlations and consistency in variation trends between Streptococcus and three sphingolipid metabolites (phytosphingosine, sphinganine, and sphingosine). Besides these three sphingolipid metabolites, the sphinganine-to-sphingosine ratio and the joint analysis of the three metabolites indicated remarkable diagnostic efficacy in children with IAV pneumonia. This study confirmed significant changes in the characteristics and metabolic profile of the oropharyngeal microbiome in pediatric patients with IAV pneumonia, with high synergy between the two factors. Oropharyngeal sphingolipid metabolites may serve as potential diagnostic biomarkers of IAV pneumonia in children.PMID:36389138 | PMC:PMC9651038 | DOI:10.3389/fcimb.2022.1011254

Front Cell Infect Microbiol. 2022 Oct 27;12:1026627. doi: 10.3389/fcimb.2022.1026627. eCollection 2022.ABSTRACTGastrodia elata Blume was used to treat stroke and headaches caused by "Feng" for thousands of years. The present study has shown a significant effect of G. elata Blume in improving cerebral ischemia-reperfusion injury (CIRI). However, the mechanism of G. elata Blume in improving CIRI by regulating the intestinal flora has not been reported until now. This research aimed to comprehensively evaluate the mechanism of G. elata Blume in CIRI based on fecal metabolomics and 16S rDNA sequencing. The rat model with CIRI was created based on the Zea Longa method. Enzyme-linked immunosorbent assay (ELISA) was used to monitor the inflammatory factors in rat serum. Damages of brain tissues were observed using hematoxylin and eosin (H&E) staining. Cerebral infarction was observed by 2,3,5-triphenyltetrazolium chloride (TTC) staining. The balance of intestinal flora in cecal contents of rats was evaluated by high-throughput sequencing. Changes of metabolites in the intestinal flora were evaluated by fecal metabolomics through Ultra high performance liquid chromatography-orbitrap exploris-mass spectrometer (UHPLC-OE-MS). The area of brain necrosis, cerebral infarction volume, and the contents of inflammatory factors in CIRI rats can be effectively reduced after oral administration of G. elata Blume. CIRI can cause disturbances in the intestinal flora and its associated metabolites. G. elata Blume can significantly regulate the composition of the intestinal microflora. It reversed CIRI-induced changes in the levels of multiple intestinal bacteria, including Prevotellaceae, Coriobacteriaceae; Prevotella, Gamma proteobacteria unclassified, Barnesiella, Escherichia, Shigella; uncultured Shigella sp., Flavonifractor sp., Escherichia sp. enrichment culture clone NBAR004, Veillonella sp. R-32, and Lactobacillus intestinalis. The levels of metabolites in cecal contents were disturbed in rats with CIRI, including amino acid, purine, and sphingolipid metabolism. The changes in the level of biomarkers in amino acid metabolism induced by CIRI were significantly reversed after treatment with G. elata Blume. Correlation studies show that Prevotellaceae was significantly positively correlated with interleukin (IL)-6, and L. intestinalis and L-phenylalanine were negatively interrelated to IL-1β. Beta-glycerophosphoric acid was significantly negatively interrelated to high-sensitivity C-reactive protein (hs-CRP). There were significantly negative correlations between L-phenylalanine and L. intestinalis, beta-glycerophosphoric acid and Prevotellaceae. G. elata Blume protected against CIRI, which may be related to improved intestinal microflora composition and metabolism, resulting in decreased inflammation.PMID:36389137 | PMC:PMC9648199 | DOI:10.3389/fcimb.2022.1026627

Biomed Res Int. 2022 Nov 3;2022:6207701. doi: 10.1155/2022/6207701. eCollection 2022.ABSTRACTHigh-risk human papillomavirus (HR-HPV) is the main etiological factor for cervical cancer. Accumulating evidence has suggested the active role of metabolites in the initiation and progression of cancers. This study explored the plasma metabolic profiles of HPV-16 positive (HPV16 (+)), HPV-18 positive (HPV18 (+)), and HPV negative (CTL) individuals using a nontargeted metabolomics approach. C8 ceramide-1-Phosphate (d18 : 1/8 : 0) was found to inhibit cervical cancer cell proliferation and migration in vitro, evidenced by CCK8 experiments, a cell migration test, RT-qPCR, and western blotting. The underlying mechanism demonstrated that C8 inhibited proliferation and migration in cervical cancer cells via the MAPK/JNK1 signaling pathway. These findings may contribute to the clinical treatment of HR-HPV-induced cervical cancer by intervening in its initiation and progression.PMID:36389117 | PMC:PMC9649303 | DOI:10.1155/2022/6207701

Front Aging Neurosci. 2022 Oct 31;14:1026688. doi: 10.3389/fnagi.2022.1026688. eCollection 2022.ABSTRACTINTRODUCTION: Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, are heavy burdens to global health and economic development worldwide. Mounting evidence suggests that exercise, a type of non-invasive intervention, has a positive impact on the life quality of elderly with neurodegenerative diseases. X-omics are powerful tools for mapping global biochemical changes in disease and treatment.METHOD: Three major databases were searched related to current studies in exercise intervention on neurodegenerative diseases using omics tools, including metabolomics, metagenomics, genomics, transcriptomics, and proteomics.RESULT: We summarized the omics features and potential mechanisms associated with exercise and neurodegenerative diseases in the current studies. Three main mechanisms by which exercise affects neurodegenerative diseases were summed up, including adult neurogenesis, brain-derived neurotrophic factor (BDNF) signaling, and short-chain fatty acids (SCFAs) metabolism.CONCLUSION: Overall, there is compelling evidence that exercise intervention is a feasible way of preventing the onset and alleviating the severity of neurodegenerative diseases. These studies highlight the importance of exercise as a complementary approach to the treatment and intervention of neurodegenerative diseases in addition to traditional treatments. More mechanisms on exercise interventions for neurodegenerative diseases, the specification of exercise prescriptions, and differentiated exercise programs should be explored so that they can actually be applied to the clinic.PMID:36389059 | PMC:PMC9659972 | DOI:10.3389/fnagi.2022.1026688

Front Aging Neurosci. 2022 Oct 28;14:1023493. doi: 10.3389/fnagi.2022.1023493. eCollection 2022.ABSTRACTThe APOE ε2, ε3, and ε4 alleles differentially impact various complex diseases and traits. We examined whether these alleles modulated associations of 94 single-nucleotide polymorphisms (SNPs) harbored by 26 genes in 19q13.3 region with 217 plasma metabolites using Framingham Heart Study data. The analyses were performed in the E2 (ε2ε2 or ε2ε3 genotype), E3 (ε3ε3 genotype), and E4 (ε3ε4 or ε4ε4 genotype) groups separately. We identified 31, 17, and 22 polymorphism-metabolite associations in the E2, E3, and E4 groups, respectively, at a false discovery rate P FDR < 0.05. These entailed 51 and 19 associations with 20 lipid and 12 polar analytes. Contrasting the effect sizes between the analyzed groups showed 20 associations with group-specific effects at Bonferroni-adjusted P < 7.14E-04. Three associations with glutamic acid or dimethylglycine had significantly larger effects in the E2 than E3 group and 12 associations with triacylglycerol 56:5, lysophosphatidylethanolamines 16:0, 18:0, 20:4, or phosphatidylcholine 38:6 had significantly larger effects in the E2 than E4 group. Two associations with isocitrate or propionate and three associations with phosphatidylcholines 32:0, 32:1, or 34:0 had significantly larger effects in the E4 than E3 group. Nine of 70 SNP-metabolite associations identified in either E2, E3, or E4 groups attained P FDR < 0.05 in the pooled sample of these groups. However, none of them were among the 20 group-specific associations. Consistent with the evolutionary history of the APOE alleles, plasma metabolites showed higher APOE-cluster-related variations in the E4 than E2 and E3 groups. Pathway enrichment mainly highlighted lipids and amino acids metabolism and citrate cycle, which can be differentially impacted by the APOE alleles. These novel findings expand insights into the genetic heterogeneity of plasma metabolites and highlight the importance of the APOE-allele-stratified genetic analyses of the APOE-related diseases and traits.PMID:36389057 | PMC:PMC9650319 | DOI:10.3389/fnagi.2022.1023493