PubMed

Nat Commun. 2023 May 19;14(1):2876. doi: 10.1038/s41467-023-38403-x.ABSTRACTTumors are comprised of a multitude of cell types spanning different microenvironments. Mass spectrometry imaging (MSI) has the potential to identify metabolic patterns within the tumor ecosystem and surrounding tissues, but conventional workflows have not yet fully integrated the breadth of experimental techniques in metabolomics. Here, we combine MSI, stable isotope labeling, and a spatial variant of Isotopologue Spectral Analysis to map distributions of metabolite abundances, nutrient contributions, and metabolic turnover fluxes across the brains of mice harboring GL261 glioma, a widely used model for glioblastoma. When integrated with MSI, the combination of ion mobility, desorption electrospray ionization, and matrix assisted laser desorption ionization reveals alterations in multiple anabolic pathways. De novo fatty acid synthesis flux is increased by approximately 3-fold in glioma relative to surrounding healthy tissue. Fatty acid elongation flux is elevated even higher at 8-fold relative to surrounding healthy tissue and highlights the importance of elongase activity in glioma.PMID:37208361 | DOI:10.1038/s41467-023-38403-x

Fish Shellfish Immunol. 2023 May 17:108840. doi: 10.1016/j.fsi.2023.108840. Online ahead of print.ABSTRACTGrass carp reovirus genotype Ⅱ (GCRV Ⅱ) causes hemorrhagic disease in a variety fish, seriously affecting the aquaculture industry in China. However, the pathogenesis of GCRV Ⅱ is unclear. Rare minnow is an ideal model organism to study the pathogenesis of GCRV Ⅱ. Herein, we applied liquid chromatography-tandem mass spectrometry metabolomics to investigate metabolic responses in the spleen and hepatopancreas of rare minnow injected with virulent GCRV Ⅱ isolate DY197 and attenuated isolate QJ205. Results indicated that marked metabolic changes were identified in both the spleen and hepatopancreas after GCRV Ⅱ infection, and the virulent DY197 strain induced more significantly different metabolites (SDMs) than the attenuated QJ205 strain. Moreover, most SDMs were downregulated in the spleen and tend to be upregulated in hepatopancreas. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that tissue-specific metabolic responses were identified after viruses infection, and the virulent DY197 strain induced more SDMs involved in amino acid metabolism in the spleen, especially the tryptophan metabolism, cysteine and methionine metabolism, which were essential for immune regulation in host; Meanwhile, nucleotide metabolism, protein synthesis and metabolism related pathways were enriched in the hepatopancreas by both virulent and attenuated strains. Our findings revealed the large scale metabolic alterations in rare minnow in response to attenuated and virulent GCRV Ⅱ infection, which will lead to a better understanding of the pathogenesis of viruses and host-pathogens interactions.PMID:37207884 | DOI:10.1016/j.fsi.2023.108840

J Ethnopharmacol. 2023 May 17:116590. doi: 10.1016/j.jep.2023.116590. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: The skeletal complications associated with chronic kidney diseases from stages 3-5 in individuals are called Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD), which increases the incidence of cardiovascular diseases drastically and affects the quality of life of patients seriously. Eucommia cortex has the effect of tonifying kidneys and strengthening bones, and salt Eucommia cortex is one of the most commonly used traditional Chinese medicines in the clinical treatment of CKD-MBD instead of Eucommia cortex. However, its mechanism still remains unexplored.AIM OF THE STUDY: The aim of this study was to investigate the effects and mechanisms of salt Eucommia cortex on CKD-MBD by integrating network pharmacology, transcriptomics, and metabolomics.MATERIALS AND METHODS: The CKD-MBD mice induced by 5/6 nephrectomy and low calcium/high phosphorus diet were treated with salt Eucommia cortex. The renal functions and bone injuries were evaluated by serum biochemical detection, histopathological analyses, and femur Micro-CT examinations. Differentially expressed genes (DEGs) between the control group and model group, model group and high-dose Eucommia cortex group, model group and high-dose salt Eucommia cortex group were analyzed by transcriptomic analysis. The differentially expressed metabolites (DEMs) between the control group and model group, model group and high-dose Eucommia cortex group, model group and high-dose salt Eucommia cortex group were analyzed by metabolomics analysis.The common targets and pathways were obtained by integrating transcriptomics, metabolomics and network pharmacology, which were identified and verified by in vivo experiments.RESULTS: The negative impacts on the renal functions and bone injuries were alleviated with salt Eucommia cortex treatment effectively. Compared with CKD-MBD model mice, the levels of serum BUN, Ca and urine Upr were significantly decreased in the salt Eucommia cortex group. And the Integrated network pharmacology, transcriptomics and metabolomics analysis revealed that Peroxisome Proliferative Activated Receptor, Gamma (PPARG) was the only common target, mainly involved by AMPK signaling pathways. The activation of PPARG in the kidney tissue was significantly decreased in CKD-MBD mice but increased in the salt Eucommia cortex treatment. The AMPK signaling pathway were verified that AMPK expression levels were decreased in CKD-MBD mice but increased in the salt Eucommia cortex treatment.CONCLUSIONS: Our study presented that salt Eucommia cortex alleviated the negative impact of CKD-MBD on the renal injury and bone injury of mice induced by 5/6 nephrectomy with the low calcium/high phosphorus diet effectively, which is highly likely achieved through the PPARG/AMPK signaling pathway.PMID:37207881 | DOI:10.1016/j.jep.2023.116590

J Proteomics. 2023 May 17:104928. doi: 10.1016/j.jprot.2023.104928. Online ahead of print.ABSTRACTTuberous sclerosis complex (TSC) is a rare, multisystem genetic disorder that leads to the development of benign tumors in multiple organs and neurological symptoms. TSC clinical manifestations show a great heterogenicity, with most patients presenting severe neuropsychiatric and neurological disorders. TSC is caused by loss-of-function mutations in either Tsc1 or Tsc2 genes, leading to overexpression of the mechanistic target of rapamycin (mTOR) and, consequently, abnormal cellular growth, proliferation and differentiation as well as to cell migration defects. Beside the growing interest, TSC remains a disorder poorly understood, with limited perspectives in the field of therapeutic strategies. Here we used murine postnatal subventricular zone (SVZ) neural stem progenitor cells (NSPCs) deficient of Tsc1 gene as a TSC model to unravel novel molecular aspects of the pathophysiology of this disease. 2D-DIGE-based proteomic analysis detected 55 differently represented spots in Tsc1-deficient cells, compared to wild-type counterparts, which were associated with 36 protein entries after corresponding trypsinolysis and nanoLC-ESI-Q-Orbitrap-MS/MS analysis. Proteomic results were validated using various experimental approaches. Bioinformatics associated differently represented proteins with oxidative stress and redox pathways, methylglyoxal biosynthesis, myelin sheath, protein S-nitrosylation and carbohydrate metabolism. Because most of these cellular pathways have already been linked to TSC features, these results were useful to clarify some molecular aspects of TSC etiopathogenesis and suggested novel promising therapeutic protein targets. SIGNIFICANCE: Tuberous Sclerosis Complex (TSC) is a multisystemic disorder caused by inactivating mutations of TSC1 or TSC2 genes, which induce overactivation of the mTOR component. The molecular mechanisms underlying the pathogenesis of TSC remain unclear, probably due to complexity of mTOR signaling network. To have a picture of protein abundance changes occurring in TSC disorder, murine postnatal subventricular zone (SVZ) neural stem progenitor cells (NSPCs) deficient of Tsc1 gene were used as a model of disease. Thus, Tsc1-deficient SVZ NSPCs and wild-type cells were comparatively evaluated by proteomics. This analysis evidenced changes in the abundance of proteins involved in oxidative/nitrosative stress, cytoskeleton remodelling, neurotransmission, neurogenesis and carbohydrate metabolism. These proteins might clarify novel molecular aspects of TSC etiopathogenesis and constitute putative molecular targets for novel therapeutic management of TSC-related disorders.PMID:37207814 | DOI:10.1016/j.jprot.2023.104928

J Proteomics. 2023 May 17:104926. doi: 10.1016/j.jprot.2023.104926. Online ahead of print.ABSTRACTMetabolites are the final products of metabolism and provide insights into the biochemical balance of tissue systems. A cascade of reactions involving proteins, carbohydrates, and lipids affects meat color, tenderness, and flavor, specifically, metabolites that are key biomolecules in biochemical reactions associated with attainment of acceptable meat quality. Bioinformatics platforms, such as Kyoto Encyclopedia of Genes and Genomes (KEGG) databases and MetaboAnalyst, are utilized to help understanding the role of differentially abundant metabolites and characterizing their roles in cellular function/metabolism. However, the inability to identify all metabolites using a single platform and limited metabolite libraries specifically for meat/food remains a challenge. Therefore, the advances in metabolite separation, easy-to-use data processing, increased resolution of mass-spectrometry, and data analysis will help to make inferences or develop biomarkers related to meat quality. This review discusses how metabolomics can be exploited to characterize meat quality, the challenges, and current trends. SIGNIFICANCE: Metabolites are the final products of metabolism and provide insights into the biochemical balance of tissue systems. They play an important role in quality traits (i.e., color, texture, and flavor) and nutritive value of foods. Visual appearance of fresh foods, such as muscle foods, are utilized by consumers to assess the quality at the retail market before making purchases. Similarly, tenderness and flavor of meats influence eating satisfaction and re-purchase decisions. Inconsistencies in meat quality lead to huge economic losses to food industry. For instance, consumers often associate a bright-cherry red color with freshness, and the US beef industry loses $3.74 billion annually due to discoloration during storage. Both pre-and post-harvest factors influence the extent of meat quality changes. Metabolomics offer robust tools to get a snapshot of small molecules such as acids, amino acids, glycolytic- and tricarboxylic acids, fatty acids, and sugars present in post-mortem muscle tissue and their role in meat quality. Further, using bioinformatics platforms enables characterizing the role of differentially present metabolites in meat quality as well as identifying biomarkers for desirable quality traits such as tender meat or color-stable carcasses. Innovative applications of metabolomics can be exploited to elucidate the underpinnings of meat quality and to develop novel strategies to enhance marketability of retail fresh meats.PMID:37207813 | DOI:10.1016/j.jprot.2023.104926

Fitoterapia. 2023 May 17:105540. doi: 10.1016/j.fitote.2023.105540. Online ahead of print.ABSTRACTA comprehensive study of leaves, flowers, fruits, bark, and seeds' extracts of Gmelina arborea Roxb was performed for first time to investigate their anti-inflammatory, anti-Alzheimer, and antidiabetic activities. A thorough comparative phytochemical investigation of the five organs was performed using Tandem ESI-LC-MS. The biological investigation, further aided by multivariate data analysis and molecular docking proved the highly significant potential of using G.arborea organs' extracts as medicinal agents. Chemometric analysis of the obtained data revealed 4 distinct clusters among different samples of the 5 G.arborea (GA)organs and also confirmed that each organ was chemically distinct from the others, except for fruits and seeds which were closely correlated. Compounds anticipated to be responsible for activity were identified by LC-MS/MS. To clarify the differential chemical biomarkers of G. arborea organs, an orthogonal partial least squares discriminant analysis (OPLS-DA) was constructed. Bark exhibited it's in vitro anti-inflammatory activity through down regulation of COX-1 pro-inflammatory markers while fruits and leaves affected mainly DPP4 the marker for diabetes, and flowers were the most potent against Alzheimer maker acetylcholine (ACE) esterase. The metabolomic profiling of the 5 extracts lead to the identification of 27 compounds in negative ion mode and the differences in chemical composition were correlated to difference in activity. Iridoid glycosides were the major class of identified compounds. Molecular docking proved the different affinities of our metabolite towards different targets. Gmelina arborea Roxb. is a very important plant both economically and medicinally.PMID:37207792 | DOI:10.1016/j.fitote.2023.105540

Cancer Cell. 2023 May 6:S1535-6108(23)00141-1. doi: 10.1016/j.ccell.2023.04.015. Online ahead of print.ABSTRACTCalreticulin (CALR) exposure on the cell surface is known to deliver robust pro-phagocytic signals to myeloid cells. In Nature, Sen Santara et al. demonstrate that surface-exposed CALR also operates as an endogenous activator of natural killer (NK) cells. Collectively, these findings suggest that CALR exposure orchestrates multiple facets of innate immunosurveillance.PMID:37207656 | DOI:10.1016/j.ccell.2023.04.015

J Breath Res. 2023 May 19. doi: 10.1088/1752-7163/acd715. Online ahead of print.ABSTRACTProlonged exposure to hyperbaric hyperoxia can lead to pulmonary oxygen toxicity (PO2tox). PO2tox is a mission limiting factor for special operations forces divers using closed-circuit rebreathing apparatus and a potential side effect for patients undergoing hyperbaric oxygen (HBO) treatment. In this study, we aim to determine if there is a specific breath profile of compounds in exhaled breath condensate (EBC) that is indicative of the early stages of pulmonary hyperoxic stress/PO2tox. 
Using a double-blind, randomized "sham" controlled, cross-over design 14 U.S. Navy trained diver volunteers breathed two different gas mixtures at an ambient pressure of 2 ATA (33 fsw, 10 msw) for 6.5 hours. One test gas consisted of 100% O2 (HBO) and the other was a gas mixture containing 30.6% O2 with the balance N2 (Nitrox). The high O2 stress dive (HBO) and low O2 stress dive (nitrox) were separated by at least seven days and were conducted dry and at rest inside a hyperbaric chamber. EBC samples were taken immediately before and after each dive and subsequently underwent a targeted and untargeted metabolomics analysis using liquid chromatography coupled to mass spectrometry (LC-MS). 
Following the HBO dive, 10 out of 14 subjects reported symptoms of the early stages of PO2tox and one subject terminated the dive early due to severe symptoms of PO2tox. No symptoms of PO2tox were reported following the nitrox dive. A Partial Least-Squares Discriminant Analysis of the normalized (relative to pre-dive) untargeted data gave good classification abilities between the HBO and nitrox EBC with an AUC of 0.99 (± 2%) and sensitivity and specificity of 0.93 (± 10%) and 0.94 (± 10%), respectively. The resulting classifications identified specific biomarkers that included human metabolites and lipids and their derivatives from different metabolic pathways that may explain metabolomic changes resulting from prolonged HBO exposure.
&#xD.PMID:37207635 | DOI:10.1088/1752-7163/acd715

Biochem Biophys Res Commun. 2023 May 4;667:34-42. doi: 10.1016/j.bbrc.2023.05.018. Online ahead of print.ABSTRACTIslet regeneration is a complex process involving multiple metabolic adaptions, but the specific characterization of the islet metabolome in relation to cell proliferation has not been established. This study aimed to investigate the metabolomic changes of regenerative islets from partial pancreatectomy (Ppx) mice and speculate underlying mechanisms. Islet samples were collected from C57/BL6 mice undergoing 70-80% Ppx or sham surgery, followed by analyses of glucose homeostasis, islet morphology, and untargeted metabolomics profiles using liquid chromatography-tandem mass spectrometry (LC-MS/MS). There is no difference in blood glucose and body weight between sham and Ppx mice. After surgery, the Ppx mice showed impaired glucose tolerance, increased Ki67 positive beta cells, and elevated beta-cell mass. LC-MS/MS analysis identified fourteen differentially changed metabolites in islets of Ppx mice, including long-chain fatty acids (e.g., docosahexaenoic acid) and amino acid derivatives (e.g., creatine). Pathway analysis based on the KEGG database revealed five significantly enriched signaling pathways including cAMP signaling pathway. Further immunostaining assay on pancreatic tissue sections showed the levels of p-CREB, a transcription factor downstream of cAMP, elevated in islets from Ppx mice. In conclusion, our results demonstrate that islet regeneration involves metabolic alterations in long-chain fatty acids and amino acid derivatives, as well as the activation of the cAMP signaling pathway.PMID:37207562 | DOI:10.1016/j.bbrc.2023.05.018

Plant Physiol Biochem. 2023 May 12;200:107742. doi: 10.1016/j.plaphy.2023.107742. Online ahead of print.ABSTRACTAnthocyanins and selenium (Se) play critical roles in antioxidant, anticancer, antibacterial, and antiviral treatments. Previous studies indicate that colored-grain wheat accumulates more Se than regular wheat, and Se synergistically promotes anthocyanin synthesis. However, the mechanism through which Se regulates anthocyanin synthesis remains unclear. We studied anthocyanin accumulation during the grain-filling stage of colored-grain wheat development by employing transcriptomics and metabolomics. We show that Se biofortification increased the concentrations of Se, anthocyanin, chlorophyll a and b, and carotenoids in colored-grain wheat. Genes related to biosynthesis of anthocyanins, phenylpropanoids biosynthesis, and flavonoids biosynthesis were significantly upregulated after Se treatment, which led to the accumulation of anthocyanin metabolites in colored-grain wheat. Genetic alterations in the expression profiles of several genes and transcription factors were observed, which slowed down lignin and proanthocyanidin biosynthesis and accelerated anthocyanin synthesis. Our results deepen the understanding of anthocyanin metabolism in Se-treated colored-grain wheat, which will likely promote harvest of these varieties.PMID:37207492 | DOI:10.1016/j.plaphy.2023.107742

Aquat Toxicol. 2023 May 17;260:106569. doi: 10.1016/j.aquatox.2023.106569. Online ahead of print.ABSTRACTCarbonate alkalinity (CA) is one of the environmental factors affecting the survival and growth of aquatic animals. However, the toxic effects of CA stress on Pacific white shrimp Litopenaeus vannamei at the molecular level are completely unclear. In this study, we investigated the changes of the survival and growth, and hepatopancreas histology of L. vannamei under different levels of CA stress, and integrated transcriptomics and metabolomics to explore major functional changes in the hepatopancreas and identify biomarkers. After CA exposure for 14 days, the survival and growth of the shrimp were reduced, and the hepatopancreas showed obvious histological damage. A total of 253 genes were differentially expressed in the three CA stress groups, and immune-related genes such as pattern recognition receptors, phenoloxidase system and detoxification metabolism were affected; substance transport-related regulators and transporters were mostly downregulated. Furthermore, the metabolic pattern of the shrimp was also altered by CA stress, especially amino acids, arachidonic acid and B-vitamin metabolites. The integration analysis of differential metabolites and genes further showed that the functions of ABC transporters, protein digestion and absorption, and amino acid biosynthesis and metabolism were highly altered by CA stress. The results of this study revealed that CA stress caused immune, substance transport, and amino acid metabolic variations in L. vannamei, and identified several potential biomarkers related to stress response.PMID:37207485 | DOI:10.1016/j.aquatox.2023.106569

J Neuroimmunol. 2023 May 11;379:578105. doi: 10.1016/j.jneuroim.2023.578105. Online ahead of print.ABSTRACTTo prioritize circulating metabolites that likely play causal roles in the pathogenesis of multiple sclerosis (MS). Two-sample Mendelian randomization analysis was performed to estimate the causal effects of 571 circulating metabolites on the risk of MS. Genetic instruments for circulating metabolites were obtained from three previous genome-wide association studies (GWAS) of the blood metabolome (N = 7824; 24,925; and 115,078; respectively), while genetic associations with MS were from a large GWAS by the International Multiple Sclerosis Genetics Consortium (14,802 cases and 26,703 control). The primary analysis was performed with the multiplicative random-effect inverse variance-weighted method, while multiple sensitivity analyses were conducted with the weighted median, weighted mode, MR-Egger, and MR-PRESSO. A total of 29 metabolites had suggestive evidence of causal associations with MS. Genetically instrumented levels of serine (OR = 1.56, 95% CI = 1.25-1.95), lysine (OR = 1.18, 95% CI = 1.01-1.38), acetone (OR = 2.45, 95% CI = 1.02-5.90), and acetoacetate (OR = 2.47, 95% CI = 1.14-5.34) were associated with a higher MS risk. Total cholesterol and phospholipids in large very-low-density lipoprotein were associated with a lower MS risk (OR = 0.83, 95% CI = 0.69-1.00; OR = 0.80, 95% CI = 0.68-0.95), but risk-increasing associations (OR = 1.20, 95% CI = 1.04-1.40; OR = 1.13, 95% CI = 1.00-1.28) were observed for the same two lipids in very large high-density lipoprotein. Our metabolome-wide Mendelian randomization study prioritized a list of circulating metabolites, such as serine, lysine, acetone, acetoacetate, and lipids, that likely have causal associations with MS.PMID:37207441 | DOI:10.1016/j.jneuroim.2023.578105

Curr Opin Chem Biol. 2023 May 17;75:102324. doi: 10.1016/j.cbpa.2023.102324. Online ahead of print.ABSTRACTWith the rapid progress in metabolomics and sequencing technologies, more data on the metabolome of single microbes and their communities become available, revealing the potential of microorganisms to metabolize a broad range of chemical compounds. The analysis of microbial metabolomics datasets remains challenging since it inherits the technical challenges of metabolomics analysis, such as compound identification and annotation, while harboring challenges in data interpretation, such as distinguishing metabolite sources in mixed samples. This review outlines the recent advances in computational methods to analyze primary microbial metabolism: knowledge-based approaches that take advantage of metabolic and molecular networks and data-driven approaches that employ machine/deep learning algorithms in combination with large-scale datasets. These methods aim at improving metabolite identification and disentangling reciprocal interactions between microbes and metabolites. We also discuss the perspective of combining these approaches and further developments required to advance the investigation of primary metabolism in mixed microbial samples.PMID:37207402 | DOI:10.1016/j.cbpa.2023.102324

Adv Mater. 2023 May 19:e2301623. doi: 10.1002/adma.202301623. Online ahead of print.ABSTRACTDrug combination provides an efficient pathway to combat drug resistance in bacteria and bacterial biofilms. However, the facile methodology to construct the drug combinations and their applications in nanocomposites is still lacking. Here we report the two-tailed antimicrobial amphiphiles (T2 A2 ) composed of nitric oxide (NO)-donor (diethylenetriamine NONOate, DN) and various natural aldehydes. T2 A2 self-assemble into nanoparticles due to their amphiphilic nature, with remarkably low critical aggregation concentration. The representative cinnamaldehyde (Cin)-derived T2 A2 (Cin-T2 A2 ) assemblies demonstrate excellent bactericidal efficacy, notably higher than free Cin and free DN. Cin-T2 A2 assemblies kill multidrug-resistant staphylococci and eradicate their biofilms via multiple mechanisms, as proved by mechanism studies, molecular dynamics simulations, proteomics, and metabolomics. Furthermore, Cin-T2 A2 assemblies rapidly eradicate bacteria and alleviate inflammation in the subsequent murine infection models. Together, our Cin-T2 A2 assemblies may provide an efficient, non-antibiotic alternative in combating the ever-increasing threat of drug-resistant bacteria and their biofilms. This article is protected by copyright. All rights reserved.PMID:37207289 | DOI:10.1002/adma.202301623

iScience. 2023 Apr 25;26(5):106744. doi: 10.1016/j.isci.2023.106744. eCollection 2023 May 19.ABSTRACTEmerging studies demonstrate that inflammation plays a crucial role in the pathogenesis of bipolar disorder (BD), but the underlying mechanism remains largely unclear. Given the complexity of BD pathogenesis, we performed high-throughput multi-omic profiling (metabolomics, lipidomics, and transcriptomics) of the BD zebrafish brain to comprehensively unravel the molecular mechanism. Our research proved that in BD zebrafish, JNK-mediated neuroinflammation altered metabolic pathways involved in neurotransmission. On one hand, disturbed metabolism of tryptophan and tyrosine limited the participation of the monoamine neurotransmitters serotonin and dopamine in synaptic vesicle recycling. On the other hand, dysregulated metabolism of the membrane lipids sphingomyelin and glycerophospholipids altered the synaptic membrane structure and neurotransmitter receptors (chrnα7, htr1b, drd5b, and gabra1) activity. Our findings revealed that disturbance of serotonergic and dopaminergic synaptic transmission mediated by the JNK inflammatory cascade was the key pathogenic mechanism in a zebrafish model of BD, provides critical biological insights into the pathogenesis of BD.PMID:37207274 | PMC:PMC10189518 | DOI:10.1016/j.isci.2023.106744

Life Metab. 2023 Apr;2(2):load014. doi: 10.1093/lifemeta/load014. Epub 2023 Apr 4.ABSTRACTWeight loss from an overweight state is associated with a disproportionate decrease in whole-body energy expenditure that may contribute to the heightened risk for weight regain. Evidence suggests that this energetic mismatch originates from lean tissue. Although this phenomenon is well documented, the mechanisms have remained elusive. We hypothesized that increased mitochondrial energy efficiency in skeletal muscle is associated with reduced expenditure under weight loss. Wildtype (WT) male C57BL6/N mice were fed with high fat diet for 10 weeks, followed by a subset of mice that were maintained on the obesogenic diet (OB) or switched to standard chow to promote weight loss (WL) for additional 6 weeks. Mitochondrial energy efficiency was evaluated using high-resolution respirometry and fluorometry. Mass spectrometric analyses were employed to describe the mitochondrial proteome and lipidome. Weight loss promoted ~50% increase in the efficiency of oxidative phosphorylation (ATP produced per O2 consumed, or P/O) in skeletal muscle. However, weight loss did not appear to induce significant changes in mitochondrial proteome, nor any changes in respiratory supercomplex formation. Instead, it accelerated the remodeling of mitochondrial cardiolipin (CL) acyl-chains to increase tetralinoleoyl CL (TLCL) content, a species of lipids thought to be functionally critical for the respiratory enzymes. We further show that lowering TLCL by deleting the CL transacylase tafazzin was sufficient to reduce skeletal muscle P/O and protect mice from diet-induced weight gain. These findings implicate skeletal muscle mitochondrial efficiency as a novel mechanism by which weight loss reduces energy expenditure in obesity.PMID:37206438 | PMC:PMC10195096 | DOI:10.1093/lifemeta/load014

Front Physiol. 2023 May 3;14:1211911. doi: 10.3389/fphys.2023.1211911. eCollection 2023.NO ABSTRACTPMID:37206364 | PMC:PMC10189146 | DOI:10.3389/fphys.2023.1211911

Front Microbiol. 2023 May 3;14:1160821. doi: 10.3389/fmicb.2023.1160821. eCollection 2023.ABSTRACTOBJECTIVE: Bile reflux plays a key role in the development of gastric intestinal metaplasia (GIM), an independent risk factor of gastric cancer. Here, we aimed to explore the biological mechanism of GIM induced by bile reflux in a rat model.METHODS: Rats were treated with 2% sodium salicylate and allowed to freely drink 20 mmol/L sodium deoxycholate for 12 weeks, and GIM was confirmed by histopathological analysis. Gastric microbiota was profiled according to the 16S rDNA V3-V4 region, gastric transcriptome was sequenced, and serum bile acids (BAs) were analyzed by targeted metabolomics. Spearman's correlation analysis was used in constructing the network among gastric microbiota, serum BAs, and gene profiles. Real-time polymerase chain reaction (RT-PCR) measured the expression levels of nine genes in the gastric transcriptome.RESULTS: In the stomach, deoxycholic acid (DCA) decreased the microbial diversity but promoted the abundances of several bacterial genera, such as Limosilactobacillus, Burkholderia-Caballeronia-Paraburkholderia, and Rikenellaceae RC9 gut group. Gastric transcriptome showed that the genes enriched in gastric acid secretion were significantly downregulated, whereas the genes enriched in fat digestion and absorption were obviously upregulated in GIM rats. The GIM rats had four promoted serum BAs, namely cholic acid (CA), DCA, taurocholic acid, and taurodeoxycholic acid. Further correlation analysis showed that the Rikenellaceae RC9 gut group was significantly positively correlated with DCA and RGD1311575 (capping protein-inhibiting regulator of actin dynamics), and RGD1311575 was positively correlated with Fabp1 (fatty acid-binding protein, liver), a key gene involved in fat digestion and absorption. Finally, the upregulated expression of Dgat1 (diacylglycerol acyltransferase 1) and Fabp1 related to fat digestion and absorption was identified by RT-PCR and IHC.CONCLUSION: DCA-induced GIM enhanced gastric fat digestion and absorption function and impaired gastric acid secretion function. The DCA-Rikenellaceae RC9 gut group-RGD1311575/Fabp1 axis might play a key role in the mechanism of bile reflux-related GIM.PMID:37206332 | PMC:PMC10188980 | DOI:10.3389/fmicb.2023.1160821

Front Microbiol. 2023 May 3;14:1164877. doi: 10.3389/fmicb.2023.1164877. eCollection 2023.ABSTRACTMicroorganisms and their hosts communicate with each other by secreting numerous components. This cross-kingdom cell-to-cell signaling involves proteins and small molecules, such as metabolites. These compounds can be secreted across the membrane via numerous transporters and may also be packaged in outer membrane vesicles (OMVs). Among the secreted components, volatile compounds (VOCs) are of particular interest, including butyrate and propionate, which have proven effects on intestinal, immune, and stem cells. Besides short fatty acids, other groups of volatile compounds can be either freely secreted or contained in OMVs. As vesicles might extend their activity far beyond the gastrointestinal tract, study of their cargo, including VOCs, is even more pertinent. This paper is devoted to the VOCs secretome of the Bacteroides genus. Although these bacteria are highly presented in the intestinal microbiota and are known to influence human physiology, their volatile secretome has been studied relatively poorly. The 16 most well-represented Bacteroides species were cultivated; their OMVs were isolated and characterized by NTA and TEM to determine particle morphology and their concentration. In order to analyze the VOCs secretome, we propose a headspace extraction with GC-MS analysis as a new tool for sample preparation and analysis of volatile compounds in culture media and isolated bacterial OMVs. A wide range of released VOCs, both previously characterized and newly described, have been revealed in media after cultivation. We identified more than 60 components of the volatile metabolome in bacterial media, including fatty acids, amino acids, and phenol derivatives, aldehydes and other components. We found active butyrate and indol producers among the analyzed Bacteroides species. For a number of Bacteroides species, OMVs have been isolated and characterized here for the first time as well as volatile compounds analysis in OMVs. We observed a completely different distribution of VOC in vesicles compared to the bacterial media for all analyzed Bacteroides species, including almost complete absence of fatty acids in vesicles. This article provides a comprehensive analysis of the VOCs secreted by Bacteroides species and explores new perspectives in the study of bacterial secretomes in relation the intercellular communication.PMID:37206326 | PMC:PMC10189065 | DOI:10.3389/fmicb.2023.1164877

Front Cardiovasc Med. 2023 May 3;10:1161761. doi: 10.3389/fcvm.2023.1161761. eCollection 2023.ABSTRACTBACKGROUND: The intermediate metabolites associated with the development of atherosclerotic cardiovascular disease (ASCVD) remain largely unknown. Thus, we conducted a large panel of metabolomics profiling to identify the new candidate metabolites that were associated with 10-year ASCVD risk.METHODS: Thirty acylcarnitines and twenty amino acids were measured in the fasting plasma of 1,102 randomly selected individuals using a targeted FIA-MS/MS approach. The 10-year ASCVD risk score was calculated based on 2013 ACC/AHA guidelines. Accordingly, the subjects were stratified into four groups: low-risk (n = 620), borderline-risk (n = 110), intermediate-risk (n = 225), and high-risk (n = 147). 10 factors comprising collinear metabolites were extracted from principal component analysis.RESULTS: C4DC, C8:1, C16OH, citrulline, histidine, alanine, threonine, glycine, glutamine, tryptophan, phenylalanine, glutamic acid, arginine, and aspartic acid were significantly associated with the 10-year ASCVD risk score (p-values ≤ 0.044). The high-risk group had higher odds of factor 1 (12 long-chain acylcarnitines, OR = 1.103), factor 2 (5 medium-chain acylcarnitines, OR = 1.063), factor 3 (methionine, leucine, valine, tryptophan, tyrosine, phenylalanine, OR = 1.074), factor 5 (6 short-chain acylcarnitines, OR = 1.205), factor 6 (5 short-chain acylcarnitines, OR = 1.229), factor 7 (alanine, proline, OR = 1.343), factor 8 (C18:2OH, glutamic acid, aspartic acid, OR = 1.188), and factor 10 (ornithine, citrulline, OR = 1.570) compared to the low-risk ones; the odds of factor 9 (glycine, serine, threonine, OR = 0.741), however, were lower in the high-risk group. "D-glutamine and D-glutamate metabolism", "phenylalanine, tyrosine, and tryptophan biosynthesis", and "valine, leucine, and isoleucine biosynthesis" were metabolic pathways having the highest association with borderline/intermediate/high ASCVD events, respectively.CONCLUSIONS: Abundant metabolites were found to be associated with ASCVD events in this study. Utilization of this metabolic panel could be a promising strategy for early detection and prevention of ASCVD events.PMID:37206107 | PMC:PMC10188945 | DOI:10.3389/fcvm.2023.1161761