PubMed

Atherosclerosis. 2023 Apr 28:S0021-9150(23)00182-X. doi: 10.1016/j.atherosclerosis.2023.04.012. Online ahead of print.ABSTRACTIn 2022, the European Atherosclerosis Society (EAS) published a new consensus statement on lipoprotein(a) [Lp(a)], summarizing current knowledge about its causal association with atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. One of the novelties of this statement is a new risk calculator showing how Lp(a) influences lifetime risk for ASCVD and that global risk may be underestimated substantially in individuals with high or very high Lp(a) concentration. The statement also provides practical advice on how knowledge about Lp(a) concentration can be used to modulate risk factor management, given that specific and highly effective mRNA-targeted Lp(a)-lowering therapies are still in clinical development. This advice counters the attitude: "Why should I measure Lp(a) if I can't lower it?". Subsequent to publication, questions have arisen relating to how the recommendations of this statement impact everyday clinical practice and ASCVD management. This review addresses 30 of the most frequently asked questions about Lp(a) epidemiology, its contribution to cardiovascular risk, Lp(a) measurement, risk factor management and existing therapeutic options.PMID:37188555 | DOI:10.1016/j.atherosclerosis.2023.04.012

Front Nutr. 2023 Apr 28;10:1117460. doi: 10.3389/fnut.2023.1117460. eCollection 2023.ABSTRACTINTRODUCTION: Polydatin is a biologically active compound found in mulberries, grapes, and Polygonum cuspidatum, and it has uric acid-lowering effects. However, its urate-lowering effects and the molecular mechanisms underlying its function require further study.METHODS: In this study, a hyperuricemic rat model was established to assess the effects of polydatin on uric acid levels. The body weight, serum biochemical indicators, and histopathological parameters of the rats were evaluated. A UHPLC-Q-Exactive Orbitrap mass spectrometry-based metabolomics approach was applied to explore the potential mechanisms of action after polydatin treatment.RESULTS: The results showed a trend of recovery in biochemical indicators after polydatin administration. In addition, polydatin could alleviate damage to the liver and kidneys. Untargeted metabolomics analysis revealed clear differences between hyperuricemic rats and the control group. Fourteen potential biomarkers were identified in the model group using principal component analysis and orthogonal partial least squares discriminant analysis. These differential metabolites are involved in amino acid, lipid, and energy metabolism. Of all the metabolites, the levels of L-phenylalanine, L-leucine, O-butanoylcarnitine, and dihydroxyacetone phosphate decreased, and the levels of L-tyrosine, sphinganine, and phytosphingosine significantly increased in hyperuricemic rats. After the administration of polydatin, the 14 differential metabolites could be inverted to varying degrees by regulating the perturbed metabolic pathway.CONCLUSION: This study has the potential to enhance our understanding of the mechanisms of hyperuricemia and demonstrate that polydatin is a promising potential adjuvant for lowering uric acid levels and alleviating hyperuricemia-related diseases.PMID:37187876 | PMC:PMC10176606 | DOI:10.3389/fnut.2023.1117460

Physiol Mol Biol Plants. 2023 Apr;29(4):559-577. doi: 10.1007/s12298-023-01307-7. Epub 2023 Apr 19.ABSTRACTClimate change increases precipitation variability, particularly in savanna environments. We have used integrative strategies to understand the molecular mechanisms of drought tolerance, which will be crucial for developing improved genotypes. The current study compares the molecular and physiological parameters between the drought-tolerant Embrapa 48 and the sensitive BR16 genotypes. We integrated the root-shoot system's transcriptome, proteome, and metabolome to understand drought tolerance. The results indicated that Embrapa 48 had a greater capacity for water absorption due to alterations in length and volume. Drought tolerance appears to be ABA-independent, and IAA levels in the leaves partially explain the higher root growth. Proteomic profiles revealed up-regulated proteins involved in glutamine biosynthesis and proteolysis, suggesting osmoprotection and explaining the larger root volume. Dysregulated proteins in the roots belong to the phenylpropanoid pathways. Additionally, PR-like proteins involved in the biosynthesis of phenolics may act to prevent oxidative stress and as a substrate for modifying cell walls. Thus, we concluded that alterations in the root-shoot conductive vessel system are critical in promoting drought tolerance. Moreover, photosynthetic parameters from reciprocal grafting experiments indicated that the root system is more essential than the shoots in the drought tolerance mechanism. Finally, we provided a comprehensive overview of the genetic, molecular, and physiological traits involved in drought tolerance mechanisms.SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12298-023-01307-7.PMID:37187776 | PMC:PMC10172417 | DOI:10.1007/s12298-023-01307-7

Physiol Mol Biol Plants. 2023 Apr;29(4):459-469. doi: 10.1007/s12298-023-01306-8. Epub 2023 Apr 29.ABSTRACTBlumea balsamifera, a wooden plant belonging to the family Asteraceae, is a medicinal herb with anticancer, antiviral, and multiple pharmacological effects, which are believed to be caused by its essential oil. The essential oil from B. balsamifera is comprised of mono- and sesqui-terpenes as the majority. Unfortunately, this plant has been facing the challenge of resource shortage, which could be effectively alleviated by biological engineering. Therefore, the identification of key elements involved in the biosynthesis of active ingredients becomes an indispensable prerequisite. In this study, candidate genes encoding monoterpene synthase were screened by transcriptome sequencing combined with metabolomics profiling in the roots, stems, and leaves of B. balsamifera. Then, these candidates were successfully cloned and verified by heterologous expression and in vitro enzyme activity assays. As a result, six candidate BbTPS genes were isolated from B. balsamifera, of which three encoded single-product monoterpene synthases and one encoded a multi-product monoterpene synthase. Among them, BbTPS1, BbTPS3, and BbTPS4 could catalyze the formation of D-limonene, α-phellandrene, and L-borneol, respectively. Meanwhile, BbTPS5 functioned in catalyzing GPP into terpinol, β-phellandrene, β-myrcene, D-limonene, and 2-carene in vitro. In general, our results provided important elements for the synthetic biology of volatile terpenes in B. balsamifera, which laid a foundation for subsequent heterologous production of these terpenoids through metabolic engineering and increasing their yield, as well as promoting sustainable development and utilization of B. balsamifera.SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12298-023-01306-8.PMID:37187774 | PMC:PMC10172412 | DOI:10.1007/s12298-023-01306-8

PeerJ. 2023 May 9;11:e15386. doi: 10.7717/peerj.15386. eCollection 2023.ABSTRACTBACKGROUND: The liver fluke Opisthorchis viverrini (OV), which subsequently inhabits the biliary system and results in periductal fibrosis (PDF), is one of the primarily causes of cholangiocarcinoma (CCA), a bile duct cancer with an exceptionally high incidence in the northeast of Thailand and other Greater Mekong Subregion (GMS) countries. Insights in fecal metabolic changes associated with PDF and CCA are required for further molecular research related to gut health and potential diagnostic biological marker development.METHODS: In this study, nuclear magnetic resonance (NMR) metabolomics was applied for fecal metabolic phenotyping from 55 fecal water samples across different study groups including normal bile duct, PDF and CCA groups.RESULTS: By using NMR spectroscopy-based metabolomics, fecal metabolic profiles of patients with CCA or PDF and of individuals with normal bile duct have been established with a total of 40 identified metabolites. Further multivariate statistical analysis and hierarchical clustering heat map have demonstrated the PDF- and CCA-specific metabotypes through various altered metabolite groups including amino acids, alcohols, amines, anaerobic glycolytic metabolites, fatty acids, microbial metabolites, sugar, TCA cycle intermediates, tryptophan catabolism substrates, and pyrimidine metabolites. Compared to the normal bile duct group, PDF individuals showed the significantly elevated relative concentrations of fecal ethanol, glycine, tyrosine, and N-acetylglucosamine whereas CCA patients exhibited the remarkable fecal metabolic changes that can be evident through the increased relative concentrations of fecal uracil, succinate, and 5-aminopentanoate. The prominent fecal metabolic alterations between CCA and PDF were displayed by the reduction of relative concentration of methanol observed in CCA. The metabolic alterations associated with PDF and CCA progression have been proposed with the involvement of various metabolic pathways including TCA cycle, ethanol biogenesis, hexamine pathway, methanol biogenesis, pyrimidine metabolism, and lysine metabolism. Among them, ethanol, methanol, and lysine metabolism strongly reflect the association of gut-microbial host metabolic crosstalk in PDF and/or CCA patients.CONCLUSION: The PDF- and CCA-associated metabotypes have been investigated displaying their distinct fecal metabolic patterns compared to that of normal bile duct group. Our study also demonstrated that the perturbation in co-metabolism of host and gut bacteria has been involved from the early step since OV infection to CCA tumorigenesis.PMID:37187520 | PMC:PMC10178365 | DOI:10.7717/peerj.15386

Front Cell Infect Microbiol. 2023 Apr 28;13:1179967. doi: 10.3389/fcimb.2023.1179967. eCollection 2023.ABSTRACTINTRODUCTION: The protozoan parasite Babesia microti is the primary cause of human babesiosis. This parasite invades and multiplies inside red blood cells (RBCs), and infections differ significantly based on the age and immune competency of the host. The aim of this study was to investigate the use of serum metabolic profiling to identify systemic metabolic variations between B. microti-infected mice and noninfected controls.METHODS: A serum metabolomics analysis of BALB/c mice that had been intraperitoneally injected with 107 B. microti-infected RBCs was performed. Serum samples from the early infected group (2 days postinfection), the acutely infected group (9 days postinfection), and the noninfected group were collected and evaluated using a liquid chromatography-mass spectrometry (LC-MS) platform. Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal partial least squares discriminant analysis (OPLS-DA) identified metabolomic profiles that differentiated the B. microti-infected and noninfected groups.RESULTS: Our results confirm that the serum metabolome is significantly influenced by acute B. microti infection and show that infection results in dysregulation of metabolic pathways and perturbation of metabolites. Acutely infected mice displayed perturbations in metabolites associated with taurine and hypotaurine metabolism, histidine metabolism, and arachidonic acid metabolism. Taurocholic acid, anserine, and arachidonic acid may be potential candidates as serological biomarkers for diagnosing B. microti infection at the acute stage. These metabolites could be further examined for their role in disease complexity.DISCUSSION: Our findings demonstrate that the acute stage of B. microti infection induces abnormalities in the metabolites present in mouse serum and provide new insight into the mechanisms involved in systemic metabolic changes that occur during B. microti infection.PMID:37187473 | PMC:PMC10176453 | DOI:10.3389/fcimb.2023.1179967

Clin Chim Acta. 2023 May 13:117390. doi: 10.1016/j.cca.2023.117390. Online ahead of print.ABSTRACTComprehensive elucidation of humoral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination is critical for understanding coronavirus disease 2019 (COVID-19) pathogenesis in general and developing antibody-based diagnostic and therapeutic strategies specifically. Following the emergence of SARS-CoV-2, significant scientific research has been conducted worldwide using omics, sequencing and immunologic approaches. These studies have been critical to the successful development of vaccines. Here, the current understanding of SARS-CoV-2 immunogenic epitopes, humoral immunity to SARS-CoV-2 structural proteins and non-structural proteins, SARS-CoV-2-specific antibodies, and T-cell responses in convalescents and vaccinated individuals are reviewed. Additionally, we explore the integrated analysis of proteomic and metabolomic data to examine mechanisms of organ injury and identify potential biomarkers. Insight into the immunologic diagnosis of COVID-19 and improvements of laboratory methods are highlighted.PMID:37187222 | DOI:10.1016/j.cca.2023.117390

Phytomedicine. 2023 Apr 12;115:154818. doi: 10.1016/j.phymed.2023.154818. Online ahead of print.ABSTRACTBACKGROUND: Atopic dermatitis (AD) is a chronic, relapsing skin disease accompanied by itchy and dry skin. AD is caused by complex interactions between innate and adaptive immune response. AD treatment include glucocorticoids and immunosuppressants. However, long-term treatment can have serious side effects. Thus, an effective AD treatment with fewer side effects is required. Natural materials, including herbal medicines, have potential applications.PURPOSE: This study evaluated the in vivo and in vitro therapeutic effects of BS012, a mixture of Asarum sieboldii, Platycodon grandiflorum, and Cinnamomum cassia extracts, on AD and investigated the underlying metabolic mechanisms.METHODS: The anti-inflammatory effects of BS012 were assessed using a mouse model of AD induced by 1‑chloro-2,4-dinitrobenzene (DNCB) and in tumor necrosis factor-alpha/interferon-gamma (TNF-α/IFN-γ) stimulated normal human epidermal keratinocytes (NHEKs). In DNCB-induced mice, total dermatitis score, histopathological analysis, and immune cell factors were assessed to evaluate the anti-atopic activity. In TNF-α/IFN-γ-stimulated NHEKs, pro-inflammatory cytokines, chemokines, and related signaling pathways were investigated. Serum and intracellular metabolomics were performed to identify the metabolic mechanism underlying the therapeutic effects of BS012 treatment.RESULTS: In DNCB-induced mice, BS012 showed potent anti-atopic activity, including reducing AD-like skin lesions and inhibiting the expression of Th2 cytokines and thymic stromal lymphopoietin. In TNF-α/IFN-γ-stimulated keratinocytes, BS012 dose-dependently inhibited the expression of pro-inflammatory cytokines and chemokines by blocking nuclear factor-kappa B and signal transducer and activator of transcription signaling pathways. Serum metabolic profiles of mice revealed significant changes in lipid metabolism related to inflammation in AD. Intracellular metabolome analysis revealed that BS012 treatment affected the metabolism associated with inflammation, skin barrier function, and lipid organization of the stratum corneum.CONCLUSION: BS012 exerts anti-atopic activity by reducing the Th2-specific inflammatory response and improving skin barrier function in AD in vivo and in vitro. These effects are mainly related to the inhibition of inflammation and recovery of metabolic imbalance in lipid organization. BS012, a novel combination with strong activity in suppressing the Th2-immune response, could be a potential alternative for AD treatment. Furthermore, the metabolic mechanism in vivo and in vitro using a metabolomics approach will provide crucial information for the development of natural products for AD treatment.PMID:37187105 | DOI:10.1016/j.phymed.2023.154818

Proc Natl Acad Sci U S A. 2023 May 23;120(21):e2301215120. doi: 10.1073/pnas.2301215120. Epub 2023 May 15.ABSTRACTPlasma metabolite concentrations and labeling enrichments are common measures of organismal metabolism. In mice, blood is often collected by tail snip sampling. Here, we systematically examined the effect of such sampling, relative to gold-standard sampling from an in-dwelling arterial catheter, on plasma metabolomics and stable isotope tracing. We find marked differences between the arterial and tail circulating metabolome, which arise from two major factors: handling stress and sampling site, whose effects were deconvoluted by taking a second arterial sample immediately after tail snip. Pyruvate and lactate were the most stress-sensitive plasma metabolites, rising ~14 and ~5-fold. Both acute handling stress and adrenergic agonists induce extensive, immediate production of lactate, and modest production of many other circulating metabolites, and we provide a reference set of mouse circulatory turnover fluxes with noninvasive arterial sampling to avoid such artifacts. Even in the absence of stress, lactate remains the highest flux circulating metabolite on a molar basis, and most glucose flux into the TCA cycle in fasted mice flows through circulating lactate. Thus, lactate is both a central player in unstressed mammalian metabolism and strongly produced in response to acute stress.PMID:37186827 | DOI:10.1073/pnas.2301215120

Biomed Chromatogr. 2023 Apr 25:e5661. doi: 10.1002/bmc.5661. Online ahead of print.ABSTRACTAnise fruit (Aniseed) has been used for many years as a traditional medicine in various countries throughout the world, however, the chemical material basis of Aniseed water extract (AWE) has not been examined in detail, limiting our understanding of its pharmacological mechanism and methods for practical quality control. A high-efficiency and high-sensitivity LC-Triple TOF MS/MS analysis method, using data processing method combined with product ion (PI) and neutral loss (NL) filtering for systematic screening and identification of the constituents of AWE was established. A quantitative method was established by using LC-MS/MS with multiple reaction monitoring (MRM) for 10 minutes to determine the concentration of 17 representative constituents. A total of 89 compounds were discovered in AWE, of which 31 were confirmed by reference standards, while 24 were found in Aniseed for the first time. The qualification analysis results showed that chlorogenic acids (CGAs) and luteolin derivatives were the major compounds. The linearity, sensitivity, precision, stability, repeatability and accuracy of the method were verified, which demonstrated that the method could meet the requirements for quantification. This work contributes to a better understanding of the chemical material basis of Aniseed and assists in the development of effective analytical methods for natural medicines.PMID:37186388 | DOI:10.1002/bmc.5661

Cell Prolif. 2023 Apr 26:e13488. doi: 10.1111/cpr.13488. Online ahead of print.ABSTRACTThis study aimed to investigate the role of the gut microbiota (GM)-bile acid (BA)-fibroblast growth factor (FGF) 19 axis in patients with atrial fibrillation (AF). Gut bacterial metabolisms of BAs were determined in an AF metagenomic dataset. The composition of faecal BAs pools was characterized by targeted metabolomics in an independent AF cross-sectional cohort. Circulating levels of FGF19 were measured by ELISA. In vitro cell experiments were conducted to validate the regulatory role of FGF19 in atrial cardiomyocytes stimulated with palmitic acid. First, metagenomic profiling revealed that gut microbial biotransformation from primary to secondary BAs was dysregulated in AF patients. Second, the proportion of secondary BAs decreased in the faeces of patients with AF. Also, eight BAs were identified as AF-associated BAs, including seven AF-enriched BAs (ursodeoxycholic acid, chenodeoxycholic acid, etc.), and AF-decreased dehydrolithocholic acid. Third, reduced levels of circulating FGF19 were observed in patients with AF. Subsequently, FGF19 was found to protect against palmitic acid-induced lipid accumulation and dysregulated signalling in atrial cardiomyocytes, including attenuated phosphorylation of YAP and Ca2+ /calmodulin-dependent protein kinases II and secretion of interleukin-1β, mediated via peroxisome proliferator-activated receptor α. Our data found decreased levels of secondary BAs and circulating FGF19, resulting in the impaired protective function of FGF19 against lipid accumulation in atrial cardiomyocytes.PMID:37186335 | DOI:10.1111/cpr.13488

Zhen Ci Yan Jiu. 2023 Apr 25;48(4):339-46. doi: 10.13702/j.1000-0607.20211242.ABSTRACTOBJECTIVE: To investigate the effect of acupuncture-moxibustion with "Biao-Ben" acupoint combination (BB) on the serum metabolites and metabolic pathway in irritable bowel syndrome (IBS) model rats, so as to explore the mechanisms of BB in the prevention and treatment of IBS.METHODS: Thirty SD rats were randomly divided into three groups: control group, model group, and BB group, with 10 rats in each group. The IBS model was established by the combination of acute stress method and chronic stress method, and the success of the model establishment was evaluated by abdominal wall reflex (AWR). BB group received acupuncture-moxibustion treatment at "Neiguan" (PC6), "Zusanli" (ST36), and "Guanyuan" (CV4) for 15 min, once a day, for a total of 28 days. Bristol's fecal character score was evaluated, and intestinal propulsion rate was calculated. The open-field experiment was used to observe the behaviour of rats. Pathological changes in the colon were observed by H.E. staining. TM widely targeted metabolomics technology was used to detect the metabolic profile of serum samples from 3 groups of rats. Principal component analysis and orthogonal partial least-squares discrimination analysis techniques were combined with database screening to screen differential metabolites, and the KEGG database was utilized to map the enriched metabolic pathway.RESULTS: Compared with the control group, AWR, and the total distance, speed, duration traveled autonomously, the distance of central grid traveling, the number of central grid crossings of the open-field experiment were significantly decreased (P<0.01，P<0.05), while Bristol's fecal character score, intestinal propulsion rate and rest duration in the open-field experiment were significantly increased(P<0.01) in the model group. Compared with the model group, Bristol's fecal character score, the intestinal propulsion rate, rest duration, and rest episode were significantly decreased(P<0.01, P<0.05), while AWR, the total distance, speed, duration traveled autonomously, the distance of central grid traveling, the number of central grid crossings, and the residence time of the central grid were significantly increased(P<0.01，P<0.05) in the BB group. H.E. staining showed a discontinuous mucosal layer of colon tissue, a slightly disordered arrangement of glands, and more inflammatory cell infiltration in the submucosa and muscle layer in the model group, which was relatively milder in the BB group. After comparing the model and control group, 123 differential metabolites were screened, while 57 were screened after comparing the model and BB group. Six differential metabolic pathways were acquired when comparing the model and the control group, while 8 were acquired when comparing the model and BB group using KEGG enrichment analysis, both of which included the arachidonic acid metabolism pathway.CONCLUSION: "Biao-Ben" acupoint combination can improve symptoms of IBS by regulating metabolites of the arachidonic acid metabolism pathway, which may be a potential target for the treatment of IBS.PMID:37186197 | DOI:10.13702/j.1000-0607.20211242

Helicobacter. 2023 Apr 25:e12984. doi: 10.1111/hel.12984. Online ahead of print.ABSTRACTPURPOSE: To characterize the serum metabolism in patients with Helicobacter pylori-positive and H. pylori-negative gastritis.METHODS: Clinical data and serum gastric function parameters, PGI (pepsinogen I), PGII, PGR (PGI/II), and G-17 (gastrin-17) of 117 patients with chronic gastritis were collected, including 57 H. pylori positive and 60 H. pylori negative subjects. Twenty cases in each group were randomly selected to collect intestinal mucosa specimens and serum samples. The gut microbiota profiles were generated by 16S rRNA gene sequencing, and the serum metabolites were analyzed by a targeted metabolomics approach based on liquid chromatography-mass spectrometry (LC-MS) technology.RESULTS: Altered expression of 20 metabolites, including isovaleric acid, was detected in patients with HPAG. Some taxa of Bacteroides, Fusobacterium, and Prevotella in the gut microbiota showed significant correlations with differentially expressed metabolites between H. pylori positive and H. pylori negative individuals. As a result, an H. pylori-gut microbiota-metabolism (HGM) axis was proposed.CONCLUSION: Helicobacter pylori infection may influence the progression of mucosal diseases and the emergence of other complications in the host by altering the gut microbiota, and thus affecting the host serum metabolism.PMID:37186092 | DOI:10.1111/hel.12984

Mol Omics. 2023 Apr 26. doi: 10.1039/d3mo00026e. Online ahead of print.ABSTRACTThe infection rate of syphilis continues to rise globally, and the difficulty in diagnosis of neurosyphilis promptly needs to be resolved. More specific and sensitive diagnostic markers for latent syphilis and neurosyphilis should be found. Here the metabolic profiles of 88 cerebrospinal fluid samples from syphilis patients and controls were analyzed by LC/MS-based untargeted metabolomics. In total, 272 metabolites based on 3937 features obtained in ESI- mode and 252 metabolites based on 3799 features in ESI+ mode were identified. The experimental process was evaluated by principal component analysis, partial least squares discriminant analysis, and hierarchical cluster analysis. A clear separation between latent syphilis and neurosyphilis was found. Levels of lipid and linoleic acid metabolites, such as 9-oxo-octadecadienoic acid and 9,10,13-trihydroxyoctadecenoic acid, were increased in syphilis patients. In patients with neurosyphilis, significant changes in levels of 5-hydroxy-L-tryptophan (5-HTP) and acetyl-N-formyl-5-methoxykynurenamine (AFMK) in the tryptophan-kynurenine pathway were also detected. Only one metabolite, theophylline, differed significantly between symptomatic and asymptomatic neurosyphilis patients. Additionally, KEGG analysis revealed significant enrichment of tryptophan metabolism pathways, indicating a high correlation between tryptophan metabolism and syphilis symptoms. Levels of linoleic acid metabolites, 5-HTP, AFMK and theophylline were significantly altered in different patients. The role of these differential metabolites in the development of syphilis is worthy of further exploration. Our results may promote the development of biomarkers for diagnosis of latent syphilis from neurosyphilis, and for that of asymptomatic neurosyphilis from symptomatic neurosyphilis in the future.PMID:37185577 | DOI:10.1039/d3mo00026e

Oncogene. 2023 Apr 25. doi: 10.1038/s41388-023-02700-y. Online ahead of print.ABSTRACTColorectal cancer (CRC) ranks third in incidence and second in mortality worldwide. Metabolic disorders are known to be closely associated with CRC. Functional metabolomics aims to translate metabolomics-derived biomarkers to disease mechanisms. Previous work based on untargeted liquid chromatography identified 30 differential metabolites of CRC. Among them, only β-hydroxybutyrate (BHB) was elevated in CRC. Here, we first confirm the increased level of β-hydroxybutyrate by targeted metabolomic analysis using an independent cohort of 400 serum samples by UPLC-QQQ-MS/MS analysis. Using appropriate cell and animal models, we find that treatment with pathological levels of β-hydroxybutyrate expedites CRC proliferation and metastasis. Out of four major rate-limiting enzymes of ketolysis, only acetyl-coenzyme A acetyltransferase1 (ACAT1) expression is increased in paired human CRC tissues. These findings suggest probable clinical relevance for the functional implications of β-hydroxybutyrate in CRC. We demonstrate that β-hydroxybutyrate may exert its tumorigenic effects via regulation of ACAT1, due to induction of downstream isocitrate dehydrogenase1 (IDH1) acetylation. Genetic silencing of ACAT1 significantly suppresses the progression of CRC and abrogates the effects of β-hydroxybutyrate both in vitro and in vivo. Overall, this study suggests that targeting β-hydroxybutyrate and its major rate-limiting enzyme ACAT1 may provide a new avenue for therapeutic intervention in CRC.PMID:37185457 | DOI:10.1038/s41388-023-02700-y

Ann Surg. 2023 Apr 27. doi: 10.1097/SLA.0000000000005886. Online ahead of print.ABSTRACTOBJECTIVE: Determine preoperative gut microbiota metabolites that may be associated with postoperative delirium (POD) development in patients and further study in rodents.SUMMARY BACKGROUND DATA: POD occurs in 9-50% of older patients undergoing anesthesia/surgery but lacks effective treatments or prevention. High throughput metabolomics using liquid chromatography with tandem mass spectrometry have accelerated disease-related biomarkers discovery. We performed metabolomic studies in humans to identify potential metabolite biomarkers linked to POD and examined potential mechanisms in rodents.METHODS: We performed a prospective observational cohort study to examine the metabolomic changes that were associated with the development of POD. Then the gut microbiota-related metabolomic changes were recapitulated by gut microbiota perturbation in rodents. POD was assessed in mice using a battery of behavioral tests including novel objective test, Y maze test, open field test, and buried food test. The mechanisms through which gut microbiota-related metabolomic changes influenced POD were examined using chemogenetics.RESULTS: IPA is a gut microbiota metabolite that belongs to the indole family. Baseline plasma levels of IPA were significantly inversely correlated with the onset of POD in 103 (17 cases) human individuals. This relationship was validated in preclinical mouse models for POD: reducing IPA levels through gut microbiota perturbation promoted POD-like behavior. More importantly, IPA administration deterred POD-like behavior. Colonization of germ-free mice with mutant Clostridium sporogenes that did not produce IPA promoted POD-like behavior. Chemogenetic studies revealed that the protective effect of IPA in mice was mediated, in part, by peroxisome proliferator-activated receptor gamma coactivator 1-alpha in hippocampal interneurons.CONCLUSIONS: Gut microbiota-derived IPA is an important molecule implicated in the pathogenesis of POD, which could potentially be harnessed for POD prevention. (270 words).PMID:37185230 | DOI:10.1097/SLA.0000000000005886

Hepatol Commun. 2023 Apr 26;7(5):e0114. doi: 10.1097/HC9.0000000000000114. eCollection 2023 May 1.ABSTRACTBACKGROUND: Macrophage-inducible C-type lectin (Mincle) is expressed on hepatic macrophages and senses ethanol (EtOH)-induced danger signals released from dying hepatocytes and promotes IL-1β production. However, it remains unclear what and how EtOH-induced Mincle ligands activate downstream signaling events to mediate IL-1β release and contribute to alcohol-associated liver disease (ALD). In this study, we investigated the association of circulating β-glucosylceramide (β-GluCer), an endogenous Mincle ligand, with severity of ALD and examined the mechanism by which β-GluCer engages Mincle on hepatic macrophages to release IL-1β in the absence of cell death and exacerbates ALD.METHOD AND RESULTS: Concentrations of β-GluCer were increased in serum of patients with severe AH and correlated with disease severity. Challenge of hepatic macrophages with lipopolysaccharide and β-GluCer induced formation of a Mincle and Gsdmd-dependent secretory complex containing chaperoned full-length gasdermin D (Hsp90-CDC37-NEDD4) with polyubiquitinated pro-IL-1β and components of the Caspase 8-NLRP3 inflammasome loaded as cargo in small extracellular vesicles (sEVs). Gao-binge EtOH exposure to wild-type, but not Mincle-/- and Gsdmd-/-, mice increased release of IL-1β-containing sEVs from liver explant cultures. Myeloid-specific deletion of Gsdmd similarly decreased the formation of sEVs by liver explant cultures and protected mice from EtOH-induced liver injury. sEVs collected from EtOH-fed wild-type, but not Gsdmd-/-, mice promoted injury of cultured hepatocytes and, when injected into wild-type mice, aggravated Gao-binge EtOH-induced liver injury.CONCLUSION: β-GluCer functions as a danger-associated molecular pattern activating Mincle-dependent gasdermin D-mediated formation and release of IL-1β-containing sEVs, which in turn exacerbate hepatocyte cell death and contribute to the pathogenesis of ALD.PMID:37185170 | DOI:10.1097/HC9.0000000000000114

Acta Diabetol. 2023 May 15. doi: 10.1007/s00592-023-02094-z. Online ahead of print.ABSTRACTAIMS: Diabetic kidney disease (DKD) is the one of the leading causes of end-stage kidney disease. Unraveling novel biomarker signatures capable to identify patients with DKD is favorable for tackle the burden. Here, we investigated the possible association between urinary metabolites and the presence of DKD in type 2 diabetes (T2D), and further, whether the associated metabolites improve discrimination of DKD and mediate the effect of inflammation on kidney involvement was evaluated.METHODS: Two independent cohorts comprising 192 individuals (92 DKD) were analyzed. Urinary metabolites were analyzed by targeted metabolome profiling and inflammatory cytokine IL-18 were measured by ELISA. Differentially expressed metabolites were selected and mediation analysis was carried out.RESULTS: Seven potential metabolite biomarkers (i.e., S-Adenosyl-L-homocysteine, propionic acid, oxoadipic acid, leucine, isovaleric acid, isobutyric acid, and indole-3-carboxylic acid) were identified using the discovery and validation design. In the pooled analysis, propionic acid, oxoadipic acid, leucine, isovaleric acid, isobutyric acid, and indole-3-carboxylic acid were markedly and independently associated with DKD. The composite index of 7 potential metabolite biomarkers (CMI) mediated 32.99% of the significant association between the inflammatory IL-18 and DKD. Adding the metabolite biomarkers improved the discrimination of DKD.CONCLUSIONS: In T2D, several associated urinary metabolites were identified to improve the prediction of DKD. Whether interventions aimed at reducing CMI also reduce the risk of DKD especially in patients with high IL-18 needs further investigations.PMID:37184672 | DOI:10.1007/s00592-023-02094-z

J Neurol. 2023 May 15. doi: 10.1007/s00415-023-11741-y. Online ahead of print.ABSTRACTBACKGROUND: The longitudinal dynamics of neurofilament light chain (NfL) in multiple system atrophy (MSA) were incompletely illuminated. This study aimed to explore whether the plasma NfL (pNfL) could serve as a potential biomarker of clinical diagnosis and disease progression for MSA.METHODS: We quantified pNfL concentrations in both a large cross-sectional cohort with 214 MSA individuals, 65 PD individuals, and 211 healthy controls (HC), and a longitudinal cohort of 84 MSA patients. Propensity score matching (PSM) was used to balance the age between the three groups. The pNfL levels between groups were compared using Kruskal-Wallis test. Linear mixed models were performed to explore the disease progression-associated factors in longitudinal MSA cohort. Random forest model as a complement to linear models was employed to quantify the importance of predictors.RESULTS: Before and after matching the age by PSM, the pNfL levels could reliably differentiate MSA from HC and PD groups, but only had mild potential to distinguish PD from HC. By combining linear and nonlinear models, we demonstrated that pNfL levels at baseline, rather than the change rate of pNfL, displayed potential prognostic value for progression of MSA. The combination of baseline pNfL levels and other modifiers, such as subtypes, Hoehn-Yahr stage at baseline, was first shown to improve the diagnosis accuracy.CONCLUSIONS: Our study contributed to a better understanding of longitudinal dynamics of pNfL in MSA, and validated the values of pNfL as a non-invasive sensitive biomarker for the diagnosis and progression. The combination of pNfL and other factors is recommended for better monitoring and prediction of MSA progression.PMID:37184660 | DOI:10.1007/s00415-023-11741-y

Metabolomics. 2023 May 15;19(5):51. doi: 10.1007/s11306-023-02015-9.ABSTRACTINTRODUCTION: This study aimed to assess the associations between the relative abundance (RA) of blood metabolites and growth rate (i.e., live weight change, LWC) calculated using different intervals of time between live weight (LW) measurements from the metabolome assessment.METHODS: Grazing beef cattle were raised for 56 days and blood samples from each animal were taken on day 57. Live weight was continuously measured using an automatic in-paddock weighing scale. The RA of plasma metabolites were determined using proton nuclear magnetic resonance (NMR). Live weight data were filtered for outliers and one LW record was selected every 1, 7, 14, 21, 28, 35, 42, 49 and 56 days before the metabolome assessment (LWC1 to LWC56, respectively). Live weight change was then re-calculated for each interval between LW data selected.RESULTS: Associations between LWC calculations and the RA of metabolites were greatly affected by the interval of time between LW data selected. Thus, the number of significant associations decreased from 9 for LWC1 to 5 for LWC35 whereas no significant associations were found for LWC56 (P > 0.05). There were 7 metabolites negatively associated with LWC1 including leucine, 2-hydroxybutyrate, valine, creatinine, creatine, phenylalanine and methylhistidine; however, correlations were positive for 2 lipids. The strength of the correlation coefficients decreased as the length of the interval between LW measures increased although this reduction was greater for some metabolites such as leucine compared to others such as lipids. Our findings suggest that the time frame in which a particular response variable, such as LWC, is measured and metabolomic samples are taken could largely impact associations and thus conclusions drawn.CONCLUSIONS: Depending on the variable to be explored, rapid changes in cattle metabolome may not be reflected in correlations if they are not assessed close in time. Our findings suggest that LWC should be measured for a period shorter than 28 days before the metabolome assessment as the number of significant associations decreases when LWC is measured for longer periods.PMID:37184621 | DOI:10.1007/s11306-023-02015-9