PubMed

Heliyon. 2023 Nov 19;9(12):e22611. doi: 10.1016/j.heliyon.2023.e22611. eCollection 2023 Dec.ABSTRACTTuberculosis has been a public health crisis since the 1900, which has caused the highest mortalities due to a single bacterial infection worldwide, that was recently further complicated by the Coronavirus disease 2019 pandemic. The causative agent of Tuberculosis, Mycobacterium tuberculosis, belongs to a genetically well-characterized family of strains known as the Mycobacterium tuberculosis complex, which has complicated progress made towards eradicating Tuberculosis due to pathogen-specific phenotypic differences in the members of this complex. Mycobacterium tuberculosis complex strains are genetically diverse human- and animal-adapted pathogens belonging to 7 lineages (Indo-Oceanic, East-Asian, East-African Indian, Euro-American, M. africanum West Africa 1, M. africanum West Africa 2 and Ethopia), respectively and the recently identified Lineage 8 and M. africanum Lineage 9. Genomic studies have revealed that Mycobacterium tuberculosis complex members are ∼99 % similar, however, due to selective pressure and adaptation to human host, they are prone to mutations that have resulted in development of drug resistance and phenotypic heterogeneity that impact strain virulence. Furthermore, members of the Mycobacterium tuberculosis complex have preferred geographic locations and possess unique phenotypic characteristics that is linked to their pathogenicity. Due to the recent advances in development next generation sequencing platforms, several studies have revealed epigenetic changes in genomic regions combined with "unique" gene regulatory mechanisms through non-coding RNAs that are responsible for strain-specific behaviour on in vitro and in vivo infection models. The current review provides up to date epigenetic patterns, gene regulation through non-coding RNAs, together with implications of these mechanisms in down-stream proteome and metabolome, which may be responsible for "unique" responses to infection by members of the Mycobacterium tuberculosis complex. Understanding lineage-specific molecular mechanisms during infection may provide novel drug targets and disease control measures towards World Health organization END-TB strategy.PMID:38046135 | PMC:PMC10686871 | DOI:10.1016/j.heliyon.2023.e22611

Front Genet. 2023 Nov 17;14:1259674. doi: 10.3389/fgene.2023.1259674. eCollection 2023.ABSTRACTAcanthopanax senticosus (Rupr. et Maxim.) Harms is a perennial shrub of the Acanthopanax genus in the Araliaceae family and has a high medicinal value. The application of zinc fertilizer can improve the yield and quality of medicinal materials. However, there are limited reports on approaches to increase the content of medicinal components in A. senticosus, hindering the improvement of its medicinal quality. In this study, A. senticosus was treated with 0.1% (LZn) and 0.4% (HZn) zinc sprayed on the leaf surface. The effects of zinc treatment on the medicinal components in the roots of A. senticosus were analyzed by comprehensive metabolomics and transcriptomics analyses. A total of 316 metabolites were detected, with a prevailing occurrence of terpenoids and phenylpropanoids. We identified metabolites related to the medicinal components that were upregulated after Zn treatment, including 43 terpenoids, 19 phenylpropanoids, eight phenols, and three flavonoids. Combining differential gene expression and K-means analysis, we found 95, 65, and 25 upregulated genes related to phenylpropanoid biosynthesis, terpenoid biosynthesis, and flavonoid biosynthesis, respectively. Under different concentrations of Zn treatment, the upregulated metabolite biosynthesis-related genes and differentially expressed transcription factors varied. Pearson correlation network analysis revealed significant correlations among terpenoids, phenylpropanoids, flavonoids biosynthetic genes, and several transcription factors (ERFs, WRKYs, bHLHs, NACs, and MYBs). This study lays the foundation for understanding the metabolic processes in response to varying levels of zinc foliar spray and provides a theoretical basis for enhancing the efficiency of zinc fertilizer utilization in A. senticosus.PMID:38046048 | PMC:PMC10690782 | DOI:10.3389/fgene.2023.1259674

Int J Gen Med. 2023 Nov 28;16:5587-5595. doi: 10.2147/IJGM.S438364. eCollection 2023.ABSTRACTThe metabolic system and immunology used to be seen as distinct fields of study. Recent developments in our understanding of how the immune system operates in health and disease have connected these fields to complex systems. An effective technique for identifying probable abnormalities of metabolic homeostasis brought on by disease is metabolomics, which is defined as the thorough study of small molecule metabolic intermediates within a biological system that collectively make up the metabolome. A prognostic metabolic biomarker with adequate prognostic accuracy for tuberculosis progression has recently been created. The rate-limiting host enzyme for the conversion of tryptophan to kynurenine, indoleamine 2,3-dioxygenase (IDO), is greatly elevated in the lungs of tuberculosis disease patients. Targeted study on tryptophan in tuberculosis disease indicates that such decreases may also resembled this upregulation. Although tuberculosis diagnosis has improved with the use of interferon release assay and tuberculosis nucleic acid amplification, tuberculosis control is made difficult by the lack of a biomarker to diagnose active tuberculosis disease. We hope that the reader of this work can develop an understanding of the advantages of metabolomics testing, particularly as a sort of testing that can be used for both diagnosing and monitoring a patient's response to treatment for tuberculosis.PMID:38045904 | PMC:PMC10693202 | DOI:10.2147/IJGM.S438364

Open Med (Wars). 2023 Nov 29;18(1):20230849. doi: 10.1515/med-2023-0849. eCollection 2023.ABSTRACTThe gut microbiota and microbial metabolites influence the enteric nervous system and the central nervous system via the microbial-gut-brain axis. Increasing body of evidence suggests that disturbances in the metabolism of peripheral branched-chain amino acids (BCAAs) can contribute to the development of neurodegenerative diseases through neuroinflammatory signaling. Preliminary research has shown that longitudinal changes in serum amino acid levels in mouse models of Parkinson's disease (PD) are negatively correlated with disease progression. Therefore, the aim of the present study was to determine the changes in serum levels of short-chain fatty acids (SCFAs) in a mouse model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD after dietary BCAA supplementation. In our research, gas chromatography-mass spectrometry was used to detect serum SCFA concentrations. The data were then analyzed with principal component analysis and orthogonal partial least squares discriminant analysis. Finally, the correlations of serum SCFA levels with gut and motor function in MPTP-induced PD mice were explored. Propionic acid, acetic acid, butyric acid, and isobutyric acid concentrations were elevated in MPTP + H-BCAA mice compared with MPTP mice. Propionic acid concentration was increased the most, while the isovaleric acid concentration was decreased. Propionic acid concentration was positively correlated with fecal weight and water content and negatively correlated with the pole-climbing duration. In conclusion, these results not only suggest that propionic acid may be a potential biomarker for PD, but also indicate the possibility that PD may be treated by altering circulating levels of SCFA.PMID:38045857 | PMC:PMC10693015 | DOI:10.1515/med-2023-0849

Microbiome Res Rep. 2022 Mar 5;1(2):11. doi: 10.20517/mrr.2021.12. eCollection 2022.ABSTRACTIrritable bowel syndrome (IBS) affects approximately one tenth of the general population and is characterized by abdominal pain associated with abnormalities in bowel habits. Visceral hypersensitivity, abnormal intestinal motor function, mucosal immune activation, and increased intestinal permeability concur to its pathophysiology. Psychological factors can influence symptom perception at the central nervous system level. In addition, recent evidence suggests that dysbiosis may be a key pathophysiological factor in patients with IBS. Increasing understanding of the pathophysiological mechanisms translates into new and more effective therapeutic approaches. Indeed, in line with this evidence, IBS therapies nowadays include agents able to modulate gut microbiota function and composition, such as diet, prebiotics, probiotics, and antibiotics. In addition, in the last decade, an increasing interest in fecal microbiota transplantation has been paid. An in-depth understanding of the intestinal microenvironment through accurate faucal microbiota and metabolite analysis may provide valuable insights into the pathophysiology of IBS, finally shaping new tailored IBS therapies.PMID:38045643 | PMC:PMC10688783 | DOI:10.20517/mrr.2021.12

Curr Res Food Sci. 2023 Nov 13;7:100638. doi: 10.1016/j.crfs.2023.100638. eCollection 2023.ABSTRACTHyperlipidaemia, which is characterized by an excess of lipids or fats in the bloodstream, is a high-risk factor and critical indicator of many metabolic diseases. This study used 16 S rRNA gene sequencing and metabolomics to determine that stachyose (ST) has a therapeutic effect and is a mechanism of hyperlipidaemia. These results show that ST significantly attenuated high-fat diet-induced weight gain and fat deposition while also adjusting the gut microbial composition. Untargeted serum metabolomics identified 12 biomarkers, which suggests that ST may function by regulating metabolic pathways. These results highlight the potential of ST in treating hyperlipidaemia and provides directions for future research including an in-depth investigation of the bioactive components, dosage, and treatment strategies of ST.PMID:38045511 | PMC:PMC10692757 | DOI:10.1016/j.crfs.2023.100638

bioRxiv. 2023 Nov 21:2023.11.21.568033. doi: 10.1101/2023.11.21.568033. Preprint.ABSTRACTOccupational exposure to manganese (Mn) induces manganism and has been widely linked as a contributing environmental factor to Parkinson's disease (PD), featuring dramatic signature overlaps between the two in motor symptoms and clinical hallmarks. However, the molecular mechanism underlying such link remains elusive, and for combating PD, effective mechanism-based therapies are lacking. Here, we developed an adult Drosophila model of Mn toxicity to recapitulate key parkinsonian features, spanning behavioral deficits, neuronal loss, and dysfunctions in lysosome and mitochondria. We performed global metabolomics on flies at an early stage of toxicity and identified metabolism of the B vitamin, biotin (vitamin B 7 ), as a master pathway underpinning Mn toxicity with systemic, body-brain increases in Mn-treated groups compared to the controls. Using Btnd RNAi mutant flies, we show that biotin depletion exacerbates Mn-induced neurotoxicity, parkinsonism, and mitochondrial dysfunction; while in Mn-exposed wild-type flies, biotin feeding dramatically ameliorates these pathophenotypes. We further show in human induced stem cells (iPSCs)- differentiated midbrain dopaminergic neurons that the supplemented biotin protects against Mn-induced neuronal loss, cytotoxicity, and mitochondrial dysregulation. Finally, human data profiling biotin-related proteins show for PD cases elevated circulating levels of biotin transporters but not of metabolic enzymes compared to healthy controls, suggesting humoral biotin transport as a key event involved in PD. Taken together, our findings identified compensatory biotin pathway as a convergent, systemic driver of Mn toxicity and parkinsonian pathology, providing new basis for devising effective countermeasures against manganism and PD.SIGNIFICANCE STATEMENT: Environmental exposure to manganese (Mn) may increase the risk for Parkinson's disease (PD); however, the mechanistic basis linking the two remains unclear. Our adult fruit fly ( Drosophila ) model of Mn toxicity recapitulated key Parkinson's hallmarks in vivo spanning behavioral deficits, neuronal loss, and mitochondrial dysfunction. Metabolomics identified the biotin (vitamin B 7 ) pathway as a key mediator, featuring systemic biotin increases in the flies. Rescue trials leveraging biotin-deficient flies, wild-type flies, and human iPSC-derived dopaminergic neurons determined biotin as a driver of manganism, with the parkinsonian phenotypes dramatically reversed through biotin supplementation. Our findings, in line with overexpressed circulating biotin transporters observed in PD patients, suggest compensatory biotin pathway as a key to untangle the Mn-PD link for combating neurodegenerative disease.PMID:38045419 | PMC:PMC10690230 | DOI:10.1101/2023.11.21.568033

bioRxiv. 2023 Nov 23:2023.11.22.568379. doi: 10.1101/2023.11.22.568379. Preprint.ABSTRACTBACKGROUND: Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) is a critical glycolytic regulator responsible for upregulation of glycolysis in response to insulin and adrenergic signaling. PFKFB2, the cardiac isoform of PFK-2, is degraded in the heart in the absence of insulin signaling, contributing to diabetes-induced cardiac metabolic inflexibility. However, previous studies have not examined how the loss of PFKFB2 affects global cardiac metabolism and function.METHODS: To address this, we have generated a mouse model with a cardiomyocyte-specific knockout of PFKFB2 (cKO). Using 9-month-old cKO and control (CON) mice, we characterized impacts of PFKFB2 on cardiac metabolism, function, and electrophysiology.RESULTS: cKO mice have a shortened lifespan of 9 months. Metabolically, cKO mice are characterized by increased glycolytic enzyme abundance and pyruvate dehydrogenase (PDH) activity, as well as decreased mitochondrial abundance and beta oxidation, suggesting a shift toward glucose metabolism. This was supported by a decrease in the ratio of palmitoyl carnitine to pyruvate-dependent mitochondrial respiration in cKO relative to CON animals. Metabolomic, proteomic, and western blot data support the activation of ancillary glucose metabolism, including pentose phosphate and hexosamine biosynthesis pathways. Physiologically, cKO animals exhibited impaired systolic function and left ventricular (LV) dilation, represented by reduced fractional shortening and increased LV internal diameter, respectively. This was accompanied by electrophysiological alterations including increased QT interval and other metrics of delayed ventricular conduction.CONCLUSIONS: Loss of PFKFB2 results in metabolic remodeling marked by cardiac ancillary pathway activation. This could delineate an underpinning of pathologic changes to mechanical and electrical function in the heart.CLINICAL PERSPECTIVE: What is New?: We have generated a novel cardiomyocyte-specific knockout model of PFKFB2, the cardiac isoform of the primary glycolytic regulator Phosphofructokinase-2 (cKO).The cKO model demonstrates that loss of cardiac PFKFB2 drives metabolic reprogramming and shunting of glucose metabolites to ancillary metabolic pathways.The loss of cardiac PFKFB2 promotes electrophysiological and functional remodeling in the cKO heart.What are the Clinical Implications?: PFKFB2 is degraded in the absence of insulin signaling, making its loss particularly relevant to diabetes and the pathophysiology of diabetic cardiomyopathy.Changes which we observe in the cKO model are consistent with those often observed in diabetes and heart failure of other etiologies.Defining PFKFB2 loss as a driver of cardiac pathogenesis identifies it as a target for future investigation and potential therapeutic intervention.PMID:38045353 | PMC:PMC10690253 | DOI:10.1101/2023.11.22.568379

bioRxiv. 2023 Nov 21:2023.11.20.567897. doi: 10.1101/2023.11.20.567897. Preprint.ABSTRACTEctomycorrhizal fungi establish mutually beneficial relationships with trees, trading nutrients for carbon. Suillus are ectomycorrhizal fungi that are critical to the health of boreal and temperate forest ecosystems. Comparative genomics has identified a high number of non-ribosomal peptide synthetase and terpene biosynthetic gene clusters (BGC) potentially involved in fungal competition and communication. However, the functionality of these BGCs is not known. This study employed co-culture techniques to activate BGC expression and then used metabolomics to investigate the diversity of metabolic products produced by three Suillus species ( S. hirtellus EM16, S. decipiens EM49, and S. cothurnatus VC1858), core members of the Pine microbiome. After 28 days of growth on solid media, liquid chromatography-tandem mass spectrometry identified a diverse range of extracellular metabolites (exometabolites) along the interaction zone between Suillus co-cultures. Prenol lipids were among the most abundant chemical classes. Out of the 62 unique terpene BGCs predicted by genome mining, 116 putative terpenes were identified across the three Suillus species using metabolomics. Notably, some terpenes were significantly more abundant in co-culture conditions. For example, we identified a metabolite matching to isomers isopimaric acid, sandaracopimaric acid, and abietic acid, which can be found in pine resin and play important roles in host defense mechanisms and Suillus spore germination. This research highlights the importance of combining genomics and metabolomics to advance our understanding of the chemical diversity underpinning fungal signaling and communication.IMPORTANCE: Using a combination of genomics and metabolomics, this study's findings offer new insights into the signaling and communication of Suillus fungi, which serve a critical role in forest ecosystems.PMID:38045323 | PMC:PMC10690165 | DOI:10.1101/2023.11.20.567897

bioRxiv. 2023 Nov 23:2023.11.22.568320. doi: 10.1101/2023.11.22.568320. Preprint.ABSTRACTHumans and animals encounter a summation of exposures during their lifetime (the exposome). In recent years, the scope of the exposome has begun to include microplastics. Microplastics (MPs) have increasingly been found in locations where there could be an interaction with Salmonella enterica Typhimurium, one of the commonly isolated serovars from processed chicken. In this study, the microbiota response to a 24-hour co-exposure to Salmonella enterica Typhimurium and/or low-density polyethylene (PE) microplastics in an in vitro broiler cecal model was determined using 16S rRNA amplicon sequencing (Illumina) and untargeted metabolomics. Community sequencing results indicated that PE fiber with and without S. Typhimurium yielded a lower Firmicutes/Bacteroides ratio compared to other treatment groups, which is associated with poor gut health, and overall had greater changes to the cecal microbial community composition. However, changes in the total metabolome were primarily driven by the presence of S. Typhimurium. Additionally, the co-exposure to PE Fiber and S . Typhimurium caused greater cecal microbial community and metabolome changes than either exposure alone. Our results indicate that polymer shape is an important factor in effects resulting from exposure. It also demonstrates that microplastic-pathogen interactions cause metabolic alterations to the chicken cecal microbiome in an in vitro chicken cecal model.IMPORTANCE: Researching the exposome, a summation of exposure of one's lifespan, will aid in determining the environmental factors that contribute to disease states. There is an emerging concern that microplastic-pathogen interactions in the gastrointestinal tract of broiler chickens may lead to an increase in Salmonella infection across flocks and eventually increased incidence of human salmonellosis cases. In this research article, we elucidated the effects of co-exposure to polyethylene microplastics and Salmonella enterica serovar Typhimurium on the ceca microbial community. Salmonella presence caused strong shifts in the cecal metabolome but not the microbiome. The inverse was true for polyethylene fiber. Polyethylene powder had almost no effect. The co-exposure had worse effects than either alone. This demonstrates that exposure effects to the gut microbial community are contaminant specific. When combined, the interactions between exposures exacerbate changes to the gut environment. The results herein support current Salmonella mitigation efforts and understanding microplastics-pathogen interactions.PMID:38045247 | PMC:PMC10690274 | DOI:10.1101/2023.11.22.568320

Heliyon. 2023 Nov 10;9(11):e22151. doi: 10.1016/j.heliyon.2023.e22151. eCollection 2023 Nov.ABSTRACTNon-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver disorders worldwide and had no approved pharmacological treatments. Diwuyanggan prescription (DWYG) is a traditional Chinese medicine preparation composed of 5 kinds of herbs, which has been used for treating chronic liver diseases in clinic. Whereas, the synergistic mechanism of this prescription for anti-NAFLD remains unclear. In this study, we aimed to demonstrate the synergetic effect of DWYG by using the disassembled prescriptions and untargeted metabolomics research strategies. The therapeutic effects of the whole prescription of DWYG and the individual herb were divided into six groups according to the strategy of disassembled prescriptions, including DWYG, Artemisia capillaris Thunb. (AC), Curcuma longa L. (CL), Schisandra chinensis Baill. (SC), Rehmannia glutinosa Libosch. (RG) and Glycyrrhiza uralensis Fisch. (GU) groups. The high fat diets-induced NAFLD mice model was constructed to evaluate the efficacy effects of DWYG. An untargeted metabolomics based on the UPLC-QTOF-MS/MS approach was carried out to make clear the synergetic effect on the regulation of metabolites dissecting the united mechanisms. Experimental results on animals revealed that the anti-NAFLD effect of DWYG prescription was better than the individual herb group in reducing liver lipid deposition and restoring the abnormality of lipidemia. In addition, further metabolomics analysis indicated that 23 differential metabolites associated with the progression of NAFLD were identified and 19 of them could be improved by DWYG. Compared with five single herbs, DWYG showed the most extensive regulatory effects on metabolites and their related pathways, which were related to lipid and amino acid metabolisms. Besides, each individual herb in DWYG was found to show different degrees of regulatory effects on NAFLD and metabolic pathways. SC and CL possessed the highest relationship in the regulation of NAFLD. Altogether, these results provided an insight into the synergetic mechanisms of DWYG from the metabolic perspective, and also supported a scientific basis for the rationality of clinical use of this prescription.PMID:38045182 | PMC:PMC10692813 | DOI:10.1016/j.heliyon.2023.e22151

Plant J. 2023 Dec 4. doi: 10.1111/tpj.16572. Online ahead of print.ABSTRACTCells save their energy during nitrogen starvation by selective autophagy of ribosomes and degradation of RNA to ribonucleotides and nucleosides. Nucleosides are hydrolyzed by nucleoside N-ribohydrolases (nucleosidases, NRHs). Subclass I of NRHs preferentially hydrolyzes the purine ribosides while subclass II is more active towards uridine and xanthosine. Here, we performed a crystallographic and kinetic study to shed light on nucleoside preferences among plant NRHs followed by in vivo metabolomic and phenotyping analyses to reveal the consequences of enhanced nucleoside breakdown. We report the crystal structure of Zea mays NRH2b (subclass II) and NRH3 (subclass I) in complexes with the substrate analog forodesine. Purine and pyrimidine catabolism are inseparable because nucleobase binding in the active site of ZmNRH is mediated via a water network and is thus unspecific. Dexamethasone-inducible ZmNRH overexpressor lines of Arabidopsis thaliana, as well as double nrh knockout lines of moss Physcomitrium patents, reveal a fine control of adenosine in contrast to other ribosides. ZmNRH overexpressor lines display an accelerated early vegetative phase including faster root and rosette growth upon nitrogen starvation or osmotic stress. Moreover, the lines enter the bolting and flowering phase much earlier. We observe changes in the pathways related to nitrogen-containing compounds such as β-alanine and several polyamines, which allow plants to reprogram their metabolism to escape stress. Taken together, crop plant breeding targeting enhanced NRH-mediated nitrogen recycling could therefore be a strategy to enhance plant growth tolerance and productivity under adverse growth conditions.PMID:38044809 | DOI:10.1111/tpj.16572

J Inherit Metab Dis. 2023 Dec 4. doi: 10.1002/jimd.12691. Online ahead of print.ABSTRACTArgininosuccinate lyase (ASL) is integral to the urea cycle detoxifying neurotoxic ammonia and the nitric oxide (NO) biosynthesis cycle. Inherited ASL deficiency causes argininosuccinic aciduria (ASA), a rare disease with hyperammonemia and NO deficiency. Patients present with developmental delay, epilepsy and movement disorder, associated with NO-mediated downregulation of central catecholamine biosynthesis. A neurodegenerative phenotype has been proposed in ASA. To better characterise this neurodegenerative phenotype in ASA, we conducted a retrospective study in six paediatric and adult metabolic centres in the UK in 2022. We identified 60 patients and specifically looked for neurodegeneration-related symptoms: movement disorder such as ataxia, tremor and dystonia, hypotonia/fatigue and abnormal behaviour. We analysed neuroimaging with diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) in an individual with ASA with movement disorders. We assessed conventional and DTI MRI alongside single photon emission computer tomography (SPECT) with dopamine analogue radionuclide 123 I-ioflupane, in Asl-deficient mice treated by hASL mRNA with normalised ureagenesis. Movement disorders in ASA appear in the second and third decades of life, becoming more prevalent with ageing and independent from the age of onset of hyperammonemia. Neuroimaging can show abnormal DTI features affecting both grey and white matter, preferentially basal ganglia. ASA mouse model with normalised ureagenesis did not recapitulate these DTI findings and showed normal 123 I-ioflupane SPECT and cerebral dopamine metabolomics. Altogether these findings support the pathophysiology of a late-onset movement disorder with cell-autonomous functional central catecholamine dysregulation but without or limited neurodegeneration of dopaminergic neurons, making these symptoms amenable to targeted therapy.PMID:38044746 | DOI:10.1002/jimd.12691

J Clin Endocrinol Metab. 2023 Dec 4:dgad672. doi: 10.1210/clinem/dgad672. Online ahead of print.ABSTRACTCONTEXT: Atherosclerosis is a dominant cause of cardiovascular disease (CVD), including myocardial infarction and stroke.OBJECTIVE: To investigate metabolic states that are associated with the development of atherosclerosis.METHODS: Cross-sectional cohort study at a university hospital in the Netherlands. A total of 302 adult subjects with a body mass index (BMI) ≥ 27 kg/m2 were included. We integrated plasma metabolomics with clinical metadata to quantify the "atherogenic state" of each individual, providing a continuous spectrum of atherogenic states that ranges between nonatherogenic states to highly atherogenic states.RESULTS: Analysis of groups of individuals with different clinical conditions-such as metabolically healthy individuals with obesity, and individuals with metabolic syndrome-confirmed the generalizability of this spectrum; revealed a wide variation of atherogenic states within each condition; and allowed identification of metabolites that are associated with the atherogenic state regardless of the particular condition, such as gamma-glutamyl-glutamic acid and homovanillic acid sulfate. The analysis further highlighted metabolic pathways such as catabolism of phenylalanine and tyrosine and biosynthesis of estrogens and phenylpropanoids. Using validation cohorts, we confirmed variation in atherogenic states in healthy subjects (before atherosclerosis plaques become visible), and showed that metabolites associated with the atherogenic state were also associated with future CVD.CONCLUSION: Our results provide a global view of atherosclerosis risk states using plasma metabolomics.PMID:38044551 | DOI:10.1210/clinem/dgad672

Gut Microbes. 2023 Dec;15(2):2287073. doi: 10.1080/19490976.2023.2287073. Epub 2023 Dec 3.ABSTRACTLoss of response to therapy in inflammatory bowel disease (IBD) has led to a surge in research focusing on precision medicine. Three systematic reviews have been published investigating the associations between gut microbiota and disease activity or IBD therapy. We performed a systematic review to investigate the microbiome predictors of response to advanced therapy in IBD. Unlike previous studies, our review focused on predictors of response to therapy; so the included studies assessed microbiome predictors before the proposed time of response or remission. We also provide an update of the available data on mycobiomes and viromes. We highlight key themes in the literature that may serve as future biomarkers of treatment response: the abundance of fecal SCFA-producing bacteria and opportunistic bacteria, metabolic pathways related to butyrate synthesis, and non-butyrate metabolomic predictors, including bile acids (BAs), amino acids, and lipids, as well as mycobiome predictors of response.PMID:38044504 | DOI:10.1080/19490976.2023.2287073

Environ Res. 2023 Dec 1:117776. doi: 10.1016/j.envres.2023.117776. Online ahead of print.ABSTRACTINTRODUCTION: Exposure to metals is associated with increased risk of type 2 diabetes (T2D). Potential mechanisms for metals-T2D associations involve biological processes including oxidative stress and disruption of insulin-regulated glucose uptake. In this study, we assessed whether associations between metal exposure and metabolite profiles relate to biological pathways linked to T2D.MATERIALS AND METHODS: We used data from 29 adults rural Colorado residents enrolled in the San Luis Valley Diabetes Study. Urinary concentrations of arsenic, cadmium, cobalt, lead, manganese, and tungsten were measured. Metabolic effects were evaluated using untargeted metabolic profiling, which included 61,851 metabolite signals detected in serum. We evaluated cross-sectional associations between metals and metabolites present in at least 50% of samples. Primary analyses adjusted urinary heavy metal concentrations for creatinine. Metabolite outcomes associated with each metal exposure were evaluated using pathway enrichment to investigate potential mechanisms underlying the relationship between metals and T2D.RESULTS: Participants had a mean age of 58.5 years (standard deviation = 9.2), 48.3% were female, 48.3% identified as Hispanic/Latino, 13.8% were current smokers, and 65.5% had T2D. Of the detected metabolites, 455 were associated with at least one metal, including 42 associated with arsenic, 22 with cadmium, 10 with cobalt, 313 with lead, 66 with manganese, and two with tungsten. The metabolic features were linked to 25 pathways including linoleate metabolism, butanoate metabolism, and arginine and proline metabolism. Several of these pathways have been previously associated with T2D, and our results were similar when including only participants with T2D.CONCLUSIONS: Our results support the hypothesis that metals exposure may be associated with biological processes related to T2D, including amino acid, co-enzyme, and sugar and fatty acid metabolism. Insight into biological pathways could influence interventions to prevent adverse health outcomes due to metal exposure.PMID:38043890 | DOI:10.1016/j.envres.2023.117776

J Ethnopharmacol. 2023 Dec 1:117519. doi: 10.1016/j.jep.2023.117519. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Ficus benghalensis, commonly known as Banyan Fig, is the national tree of India and its aerial roots are used traditionally to treat female reproductive disorders. However, despite this traditional use, no pharmacological evidence could be traced supporting this use. Additionally, no comprehensive metabolite profiling was reported for F. benghalensis aerial roots.AIM OF THE STUDY: This study attempts to justify biochemically the traditional use of F. benghalensis aerial roots in treatment of female reproductive disorders and in relation to its secondary metabolite profile.MATERIALS AND METHODS: Total ethanol extract (TEE) and subfractions [petroleum ether (PEF), chloroform (CHF), ethyl acetate (EAF) and n-butanol (BUF] were prepared from air-dried powdered aerial roots of F. benghalensis. Detailed in-vivo investigation of the hormonal activity and action mechanism of the total ethanol extract and subfractions was carried out through evaluation of estrogenic and gonadotropic activities. The estrogenic activity was evaluated on ovariectomized immature female rats through estimating uterine weight, vaginal cornification and serum estradiol level along with histological examination of uteri. The gonadotropic activity was measured by assay of follicle stimulating hormone (FSH) and luteinizing hormone (LH) like activities. Total follicular and corpora lutea counts in immature female rats were used to determine FSH and LH like activities, respectively in addition to histological picture of the genitalia. Comprehensive non-targeted metabolite profiling was carried out for the TEE and subfractions using UPLC-HRMS in negative and positive ionization modes. UPLC-MS fingerprint was subjected to principal component analysis (PCA) and partial least squares analyses to correlate the bioactivities to specific chemical constituents in F. benghalensis different subfractions. GC-MS was further used for non-polar silylated fractions.RESULTS: Results revealed that only the non-polar PEF and CHF displayed moderate estrogenic and FSH-like activities but with no LH-like activity. Metabolites profiling via (UPLC-HRMS) and multivariate PCA analysis enabled identification and comparison of various chemical classes in F. benghalensis extract and fractions. The active non-polar fractions revealed nearly similar metabolites profile being composed of isoflavonoids, triterpenes, sterols, fatty acids and cyclic peptides. In contrast, polar fractions were more abundant in apocarotenoids, fatty acyl amides, hydroxybenzoates and hydroxycinnamates in addition to two lignans. PLS analysis revealed strong correlation between hydroxylated fatty acids and pyranoisoflavones with estrogenic and FSH-like activities. GC-MS analysis was further employed for non-polar fractions profiling revealing for their enrichment in fatty acids/esters, terpenes, organic acids and phenolics.CONCLUSION: This is the first study to rationalize the use of F. benghalensis aerial root traditionally in treatment of gynecological disorders, revealing that the petroleum ether and chloroform non-polar subfractions of F. benghalensis showed estrogenic and FSH-like activity with absence of LH-like activity. This biological activity could possibly be attributed to its metabolites profile of isoflavonoids, fatty acids, triterpenes, sterols and cyclic peptides identified via UPLC-MS and GC-MS techniques. Consequently, F. benghalensis aerial roots should be used with caution in traditional treatment of female infertility or other reproductive disorders.PMID:38043752 | DOI:10.1016/j.jep.2023.117519

Metab Eng. 2023 Dec 1:S1096-7176(23)00172-6. doi: 10.1016/j.ymben.2023.11.008. Online ahead of print.ABSTRACTKynurenine pathway has a potential to convert L-tryptophan into multiple medicinal molecules. This study aims to explore the biosynthetic potential of kynurenine pathway for the efficient production of actinocin, an antitumor precursor selected as a proof-of-concept target molecule. Kynurenine pathway is first constructed in Escherichia coli by testing various combinations of biosynthetic genes from four different organisms. Metabolic engineering strategies are next performed to improve the production by inhibiting a competing pathway, and enhancing intracellular supply of a cofactor S-adenosyl-L-methionine, and ultimately to produce actinocin from glucose. Metabolome analysis further suggests additional gene overexpression targets, which finally leads to the actinocin titer of 719 mg/L. E. coli strain engineered to produce actinocin is further successfully utilized to produce 350 mg/L of kynurenic acid, a neuroprotectant, and 1401 mg/L of 3-hydroxyanthranilic acid, an antioxidant, also from glucose. These competitive production titers demonstrate the biosynthetic potential of kynurenine pathway as a source of multiple medicinal molecules. The approach undertaken in this study can be useful for the sustainable production of molecules derived from kynurenine pathway, which are otherwise chemically synthesized.PMID:38043641 | DOI:10.1016/j.ymben.2023.11.008

Ecotoxicol Environ Saf. 2023 Dec 2;269:115753. doi: 10.1016/j.ecoenv.2023.115753. Online ahead of print.ABSTRACTTriphenyltin is an environmental contaminant widely used in antifouling paints and can cause toxicity in various organs in living organisms. However, its effects on intestinal function and the microbiome of the gut remain unknown. The objective of this study was to explore the intestinal toxicity of triphenyltin in mice by orally administering 0, 1.875, 3.75, and 7.5 mg/Kg to adult male mice for 8 weeks. Results showed that triphenyltin caused ileum tissue damage, induced oxidative stress, upregulated inflammation-related gene expression and increased serum tumor-necrosis factor α (TNF-α) levels in mice. Triphenyltin impaired ileum barrier function by downregulating Muc2, ZO-1, Occludin and their protein levels at 3.75 and 7.5 mg/Kg. TPT exposure led to partial inflammation and decreased mucin mRNA expression in the colon. Triphenyltin altered intestinal micro-ecological balance and fecal metabolome in mice. In conclusion, triphenyltin alters the mouse gut microbiota and fecal metabolome.PMID:38043414 | DOI:10.1016/j.ecoenv.2023.115753

Food Chem. 2023 Nov 28;439:138086. doi: 10.1016/j.foodchem.2023.138086. Online ahead of print.ABSTRACTDehulled hempseed (DHS), fermented dehulled hempseed (FDHS), hempseed cake (HSC), and fermented HSC (FHSC) were examined for their phytochemical composition, health benefits, and rheological characteristics. At 500 µg/mL concentration, DHS, FDHS, HSC, and FHSC extracts exhibited the ability to inhibit DPPH radicals, with 32.46 %, 47.35 %, 33.85 %, and 47.41 %, respectively. Similarly, they demonstrated potential to scavenge ABTS radicals by 13.7 %, 27.87 %, 14.40 % and 25.70 %, respectively. For lipase inhibition activity, FDHS (72.92 %) and FDHS (85.89 %) outperformed DHS (52.94 %) and HSC (43.08 %). Furthermore, FHSC enhanced the survival and reduced fat accumulation in glucose-supplemented Caenorhabditis elegans. We used HPLC and UHPLC-ESI-QTOF-MS for metabolite analysis, quantifying eight polyphenols using HPLC and identifying thirty-four metabolites with UHPLC-ESI-QTOF-MS. Generally, metabolomics indicated an improved metabolite profile after fermentation. Fermentation also showed impact on rheological characteristics, modifying viscosity, loss modulus, and storage modulus. These findings collectively demonstrate the ability of fermentation in enhancing overall value of hempseed.PMID:38043281 | DOI:10.1016/j.foodchem.2023.138086