PubMed

Environ Toxicol Pharmacol. 2023 Apr 3:104120. doi: 10.1016/j.etap.2023.104120. Online ahead of print.ABSTRACTAmphipods are ideal indicators for biomonitoring and ecotoxicological studies of environmental contaminants because they are extensively distributed in aquatic environments, are easy to collect and are important in nutrient cycling. Marine amphipods (Allorchestes compressa) were exposed to two concentrations of copper and pyrene, and their mixtures, for 24 and 48h. Changes in polar metabolites were assessed using Gas Chromatography Mass Spectrometry (GC-MS)-based untargeted metabolomics. Generally, limited metabolite changes were observed for copper and pyrene single exposures (eight and two significant metabolites, respectively), while 28 metabolites had changed following exposures to mixtures. Furthermore, changes were mainly observed after 24hours but had seemingly returned to control levels after 48hours. Multiple types of metabolites were affected including amino acids, Tricarboxylic acid (TCA) cycle intermediates, sugars, fatty acids, and hormones. This study highlights the sensitivity of metabolomics in assessing the impacts of low concentrations of chemicals compared to traditional ecotoxicological endpoints.PMID:37019324 | DOI:10.1016/j.etap.2023.104120

Environ Pollut. 2023 Apr 3:121522. doi: 10.1016/j.envpol.2023.121522. Online ahead of print.ABSTRACTMounting evidence suggests that air pollution influences lipid metabolism and dyslipidemia. However, the metabolic mechanisms linking air pollutant exposure and altered lipid metabolism is not established. In year 2014-2018, we conducted a cross-sectional study on 136 young adults in southern California, and assessed lipid profiles (triglycerides, total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, very-low-density lipoprotein (VLDL)-cholesterol), and untargeted serum metabolomics using liquid chromatography-high-resolution mass spectrometry, and one-month and one-year averaged exposures to NO2, O3, PM2.5 and PM10 air pollutants at residential addresses. A metabolome-wide association analysis was conducted to identify metabolomic features associated with each air pollutant. Mummichog pathway enrichment analysis was used to assess altered metabolic pathways. Principal component analysis (PCA) was further conducted to summarize 35 metabolites with confirmed chemical identity. Lastly, linear regression models were used to analyze the associations of metabolomic PC scores with each air pollutant exposure and lipid profile outcome. In total, 9309 metabolomic features were extracted, with 3275 features significantly associated with exposure to one-month or one-year averaged NO2, O3, PM2.5 and PM10 (p < 0.05). Metabolic pathways associated with air pollutants included fatty acid, steroid hormone biosynthesis, tryptophan, and tyrosine metabolism. PCA of 35 metabolites identified three main PCs which together explained 44.4% of the variance, representing free fatty acids and oxidative byproducts, amino acids and organic acids. Linear regression indicated that the free fatty acids and oxidative byproducts-related PC score was associated with air pollutant exposure and outcomes of total cholesterol and LDL-cholesterol (p < 0.05). This study suggests that exposure to NO2, O3, PM2.5 and PM10 contributes to increased level of circulating free fatty acids, likely through increased adipose lipolysis, stress hormone and response to oxidative stress pathways. These alterations were associated with dysregulation of lipid profiles and potentially could contribute to dyslipidemia and other cardiometabolic disorders.PMID:37019258 | DOI:10.1016/j.envpol.2023.121522

Sci Total Environ. 2023 Apr 3:163254. doi: 10.1016/j.scitotenv.2023.163254. Online ahead of print.ABSTRACTDi-(2-ethylhexyl) phthalate (DEHP) as widely utilized plasticizer has aroused increasing concerns since its endocrine disrupting effects and continuous accumulation in biota. To date, the interaction mechanism between DEHP and rice plants has not been clearly illustrated at molecular level. Here, we investigated biological transformation and response of rice plants (Oryza sativa L.) to DEHP at realistic exposure concentrations. Nontargeted screening by UPLC-QTOF-MS was used to verify 21 transformation products derived from phase I metabolism (hydroxylation and hydrolysis) and phase II metabolism (conjugation with amino acids, glutathione, and carbohydrates) in rice. MEHHP-asp, MEHHP-tyr, MEHHP-ala, MECPP-tyr and MEOHP-tyr as the conjugation products with amino acids are observed for the first time. Transcriptomics analyses unraveled that DEHP exposure had strong negative effects on genes associated with antioxidative components synthesis, DNA binding, nucleotide excision repair, intracellular homeostasis, and anabolism. Untargeted metabolomics revealed that metabolic network reprogramming in rice roots was induced by DEHP, including nucleotide metabolism, carbohydrate metabolism, amino acid synthesis, lipid metabolism, synthesis of antioxidant component, organic acid metabolism and phenylpropanoid biosynthesis. The integrated analyses of interaction between differentially expressed genes (DEGs) and differentially expressed metabolites (DEMs) endorsed that metabolic network regulated by DEGs was significantly interfered by DEHP, resulting in cell dysfunction of roots and visible growth inhibition. Overall, these finding generated fresh perspective for crops security caused by plasticizer pollution and enhanced the public focus on dietary risk.PMID:37019237 | DOI:10.1016/j.scitotenv.2023.163254

Pharmacol Res. 2023 Apr 3:106755. doi: 10.1016/j.phrs.2023.106755. Online ahead of print.ABSTRACTChronic constipation (CC) is a common gastrointestinal condition associated with intestinal inflammation, and the condition considerably impairs patients' quality of life. We conducted a large-scale 42-day randomized, double-blind, placebo-controlled trial to investigate the effect of probiotics in alleviating CC. 163 patients diagnosed with CC (following Rome IV criteria) were randomly divided into probiotic (n = 78; received Lactiplantibacillus plantarum P9 [P9]; 1×1011 CFU/day) and placebo (n = 85; received placebo material) groups. Ingesting P9 significantly improved the weekly mean frequency of complete spontaneous bowel movements (CSBMs) and spontaneous bowel movements (SBMs), while significantly reducing the level of worries and concerns (WO; P < 0.05). Comparing with the placebo group, P9 group was significantly enriched in potentially beneficial bacteria (Lactiplantibacillus plantarum and Ruminococcus_B gnavus), while depriving of several bacterial and phage taxa (Oscillospiraceae sp., Lachnospiraceae sp., and Herelleviridae; P < 0.05). Interesting significant correlations were also observed between some clinical parameters and subjects' gut microbiome, including: negative correlation between Oscillospiraceae sp. and SBMs; positive correlation between WO and Oscillospiraceae sp., Lachnospiraceae sp. Additionally, P9 group had significantly (P < 0.05) more predicted gut microbial bioactive potential involved in the metabolism of amino acids (L-asparagine, L-pipecolinic), short-/medium-chain fatty acids (valeric acid and caprylic acid). Furthermore, several metabolites (p-cresol, methylamine, trimethylamine) related to the intestinal barrier and transit decreased significantly after P9 administration (P < 0.05). In short, the constipation relief effect of P9 intervention was accompanied by desirable changes in the fecal metagenome and metabolome. Our findings support the notion of applying probiotics in managing CC.PMID:37019193 | DOI:10.1016/j.phrs.2023.106755

J Ethnopharmacol. 2023 Apr 3:116453. doi: 10.1016/j.jep.2023.116453. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Gastrointestinal nematodes (GIN) control in small ruminants has relied on the systematic use of synthetic anthelmintics (AH), their effectiveness has been progressively decreasing due to the rise and diffusion of anthelmintic resistances. The most prevalent genera affecting small ruminants were Haemonchus spp., and Trichostrongylus spp. The investigation of new anthelmintics in plants is a highly studied option, especially when it is linked to ethnobotanical knowledge and phenolic compounds.THE AIMS OF OUR STUDY: Four medicinal plants mentioned in traditional medicine were selected to evaluate their anthelmintic proprieties at different stages of the life cycle of GIN, namely: Kyllinga odorata Valh., Cassia occidentalis L., Artemisia absinthium L, and Verbena litoralis Kunth and to explore the role of polyphenols in the AH activity.MATERIALS AND METHODS: To evaluate the anthelmintic activity in this study, two models of GIN species, namely Haemonchus contortus (Hc) and Trichostrongylus colubriformis (Tc) were selected and tested on two in vitro assays: 1) Larval Exsheathment Inhibition Assay (LEIA) and, 2) Egg Hatch Assay (EHA). To explore the role of tannins and polyphenols in AH activity by comparing the effects of LEIA and EHA with or without polyvinylpolypyrrolidone (PVPP) and to characterize the phytochemical composition of the most active plants using ultra-high performance liquid chromatography (UHPLC) coupled with high-resolution mass spectrometry (HRMS).RESULTS: C. occidentalis exhibited the highest activity on LEIA (EC50 = 250.42-41.80 μg/mL) and A. absinthium on egg hatching processes (EC50 = 121.70-137.34 μg/mL) in both species of GIN. The inhibition in the development of eggs was from 67.70% to 96.36% on H. contortus, and from 78.87% to 99.65% on T. colubriformis. At the maximal dose, Additionally, it was observed that the AH on eggs varies according to the GIN species: on H. contortus the extracts tested blocked the formation of larvae Ovicidal Effect (% higher OE) and on T. colubriformis they blocked the appearance of L1 larvae, Larvae Failing Eclosion (% higher LFE). After PVPP, a reduction in AH activity on LEIA and EHA was noted, especially with C. occidentalis (87.20-67.00% of larvae exsheathment, (p < 0.05) and 40.51-24.96% of egg hatching, (p > 0.05) of both parasite species. Nine putative features were identified using HRMS and MS/MS after addition of PVPP.CONCLUSIONS: The present study demonstrated that C. occidentalis, A. absinthium, and K. odorata, which parts have been traditionally used as medicinal plants are a valuable source of active compounds with anthelmintic activity. The medicinal use of these plants against GIN parasites was proven by in vitro analysis. Therefore exploration of the secondary metabolites of these plant extracts and testing of isolated fractions of active compounds under in vivo experiments are planned and represent a specific challenge for alternative drug research. Regarding the PVPP, in this study we hypotheses about the standard doses it was not able to completely absorb the polyphenols of extracts of K. odorata, C. occidentalis, and A. absinthium, which would lead to more studies to evaluate the role of this product in the absorption of phenolic compounds.PMID:37019160 | DOI:10.1016/j.jep.2023.116453

Redox Biol. 2023 Mar 29;62:102691. doi: 10.1016/j.redox.2023.102691. Online ahead of print.ABSTRACTThe activation of stimulator of interferon genes (STING) and NOD-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis signaling pathways represent two distinct central mechanisms in liver disease. However, the interconnections between these two pathways and the epigenetic regulation of the STING-NLRP3 axis in hepatocyte pyroptosis during liver fibrosis remain unknown. STING and NLRP3 inflammasome signaling pathways are activated in fibrotic livers but are suppressed by Sting knockout. Sting knockout ameliorated hepatic pyroptosis, inflammation, and fibrosis. In vitro, STING induces pyroptosis in primary murine hepatocytes by activating the NLRP3 inflammasome. H3K4-specific histone methyltransferase WD repeat-containing protein 5 (WDR5) and DOT1-like histone H3K79 methyltransferase (DOT1L) are identified to regulate NLRP3 expression in STING-overexpressing AML12 hepatocytes. WDR5/DOT1L-mediated histone methylation enhances interferon regulatory transcription factor 3 (IRF3) binding to the Nlrp3 promoter and promotes STING-induced Nlrp3 transcription in hepatocytes. Moreover, hepatocyte-specific Nlrp3 deletion and downstream Gasdermin D (Gsdmd) knockout attenuate hepatic pyroptosis, inflammation, and fibrosis. RNA-sequencing and metabolomics analysis in murine livers and primary hepatocytes show that oxidative stress and metabolic reprogramming might participate in NLRP3-mediated hepatocyte pyroptosis and liver fibrosis. The STING-NLRP3-GSDMD axis inhibition suppresses hepatic ROS generation. In conclusion, this study describes a novel epigenetic mechanism by which the STING-WDR5/DOT1L/IRF3-NLRP3 signaling pathway enhances hepatocyte pyroptosis and hepatic inflammation in liver fibrosis.PMID:37018971 | DOI:10.1016/j.redox.2023.102691

J Pharm Biomed Anal. 2023 Mar 25;229:115355. doi: 10.1016/j.jpba.2023.115355. Online ahead of print.ABSTRACTOBJECTIVE: To investigate the metabolic mechanisms of Chinese and Western medicines on the metabolic network of striatal injury in a copper-loaded rat model of Wilson disease (WD) from a metabolomic perspective.METHODS: We divided 60 rats into 4 groups of 15 rats each according to a random number table, namely the control group, the model group, the Bushen Huoxue Huazhuo Recipe group, and the penicillamine group, and subsequently replicated the WD copper-loaded rat model according to the literature method for a total of 12 weeks. From the 7th week onwards, each intervention group was given an equivalent dose of the corresponding drug, and the control and model groups were given an equal volume of saline gavage until the end of the model replication. We used 1H NMR metabolomics techniques combined with multivariate statistical methods to describe the changes in the striatal metabolic profile of nerve injury in Wilson's disease and to analyze the effect of different treatments on their biomarker interventions.RESULTS: Nerve cell damage was evident in the WD copper-loaded rat model and could be reduced to varying degrees by different methods of intervention in the striatal nerve cells. The content of glycine, serine metabolism, and valine metabolism decreased in WD copper-loaded rat model; aspartate content increased after penicillamine intervention; glycolytic metabolism, valine metabolism, taurine metabolism, and tyrosine metabolism increased in the group of Bushen Huoxue Huazhuo Recipe.CONCLUSION: Different intervention methods of Chinese and Western medicine affect aspartate, glycolysis, taurine, tyrosine, valine, and carbon metabolism in striatal tissues of WD copper-loaded rats, and can regulate the metabolism of small molecules, which in turn have certain repairing effects on nerve damage in WD copper-loaded rats.PMID:37018958 | DOI:10.1016/j.jpba.2023.115355

Comp Biochem Physiol Part D Genomics Proteomics. 2023 Mar 21;46:101073. doi: 10.1016/j.cbd.2023.101073. Online ahead of print.ABSTRACTRaw materials or bioactive ingredients trigger mechanisms to assimilate nutrients and activate metabolic pathways that promote growth, immune function, or energy storage. Our understanding of these processes at a molecular level remains limited in aquaculture, especially in shrimp. Here, hepatopancreas proteomics and haemolymph metabolomics were used to investigate the post-prandial response of black tiger shrimps (Penaeus monodon) fed a conventional fishmeal diet (FM); a diet supplemented with the microbial biomass Novacq™ (NV); krill meal (KM); or, fasted (FS). Using FM as a control, a 2-fold change in abundance threshold was implemented to determine the significance of proteins and metabolites. NV fed shrimp showed preference for energy derived from carbohydrates indicated by a strong signature of glycoconjugate metabolism and activation of the amino- and nucleotide sugar metabolic pathway. KM activated the glyoxylate and dicarboxylate pathway that denoted shrimp preference for lipidic energy. KM also influenced energy generation by the TCA cycle inferred from higher abundance of the metabolites succinic semialdehyde, citric acid, isocitrate, alpha ketoglutarate and ATP and downregulation of the enzyme isocitrate dehydrogenase that catalyses oxidative decarboxylation of isocitrate. FS shrimp displayed down-regulation of oxidative phosphorylation and resorted to internal lipid reserves for energy homeostasis displaying a strong signature of autophagy. Pyrimidine metabolism was the preferred energy strategy in this group. Our study also provided evidence that during fasting or consumption of specific ingredients, shrimp share common pathways to meet their energy requirements, however, the intensity at which these pathways were impacted was diet dependent.PMID:37018937 | DOI:10.1016/j.cbd.2023.101073

Pediatr Neurol. 2023 Mar 4;143:68-76. doi: 10.1016/j.pediatrneurol.2023.02.016. Online ahead of print.ABSTRACTBACKGROUND: Kearns-Sayre syndrome (KSS) is caused by duplications and/or deletions of mitochondrial DNA (mtDNA) and is typically diagnosed based on a classic triad of symptoms with chronic progressive external ophthalmoplegia (CPEO), retinitis pigmentosa, and onset before age 20 years. The present study aimed to diagnose two patients, on suspicion of KSS.METHODS: One of the patients went through a diagnostic odyssey, with normal results from several mtDNA analyses, both in blood and muscle, before the diagnosis was confirmed genetically.RESULTS: Two patients presented increased tau protein and low 5-methyltetrahydrofolate (5-MTHF) levels in the cerebrospinal fluid (CSF). Untargeted metabolomics on CSF samples also showed an increase in the levels of free sialic acid and sphingomyelin C16:0 (d18:1/C16:0), compared with four control groups (patients with mitochondrial disorders, nonmitochondrial disorders, low 5-MTHF, or increased tau proteins).CONCLUSIONS: It is the first time that elevated sphingomyelin C16:0 (d18:1/C16:0) and tau protein in KSS are reported. Using an untargeted metabolomics approach and standard laboratory methods, the study could shed new light on metabolism in KSS to better understand its complexity. In addition, the findings may suggest the combination of elevated free sialic acid, sphingomyelin C16:0 (d18:1/C16:0), and tau protein as well as low 5-MTHF as new biomarkers in the diagnostics of KSS.PMID:37018879 | DOI:10.1016/j.pediatrneurol.2023.02.016

Anal Chem. 2023 Apr 5. doi: 10.1021/acs.analchem.2c05810. Online ahead of print.ABSTRACTIn untargeted metabolomics, multiple ions are often measured for each original metabolite, including isotopic forms and in-source modifications, such as adducts and fragments. Without prior knowledge of the chemical identity or formula, computational organization and interpretation of these ions is challenging, which is the deficit of previous software tools that perform the task using network algorithms. We propose here a generalized tree structure to annotate ions in relationships to the original compound and infer neutral mass. An algorithm is presented to convert mass distance networks to this tree structure with high fidelity. This method is useful for both regular untargeted metabolomics and stable isotope tracing experiments. It is implemented as a Python package (khipu) and provides a JSON format for easy data exchange and software interoperability. By generalized preannotation, khipu makes it feasible to connect metabolomics data with common data science tools and supports flexible experimental designs.PMID:37018697 | DOI:10.1021/acs.analchem.2c05810

J Proteome Res. 2023 Apr 5. doi: 10.1021/acs.jproteome.3c00047. Online ahead of print.ABSTRACTNuclear magnetic resonance (NMR) metabolomics was used for identification of metabolic changes in pancreatic cancer (PC) blood plasma samples when compared to healthy controls or diabetes mellitus patients. An increased number of PC samples enabled a subdivision of the group according to individual PC stages and the construction of predictive models for finer classification of at-risk individuals recruited from patients with recently diagnosed diabetes mellitus. High-performance values of orthogonal partial least squares (OPLS) discriminant analysis were found for discrimination between individual PC stages and both control groups. The discrimination between early and metastatic stages was achieved with only 71.5% accuracy. A predictive model based on discriminant analyses between individual PC stages and the diabetes mellitus group identified 12 individuals out of 59 as at-risk of development of pathological changes in the pancreas, and four of them were classified as at moderate risk.PMID:37018516 | DOI:10.1021/acs.jproteome.3c00047

Proc Natl Acad Sci U S A. 2023 Apr 11;120(15):e2221508120. doi: 10.1073/pnas.2221508120. Epub 2023 Apr 5.ABSTRACTSoil-dwelling microbes are the principal inoculum for the root microbiota, but our understanding of microbe-microbe interactions in microbiota establishment remains fragmentary. We tested 39,204 binary interbacterial interactions for inhibitory activities in vitro, allowing us to identify taxonomic signatures in bacterial inhibition profiles. Using genetic and metabolomic approaches, we identified the antimicrobial 2,4-diacetylphloroglucinol (DAPG) and the iron chelator pyoverdine as exometabolites whose combined functions explain most of the inhibitory activity of the strongly antagonistic Pseudomonas brassicacearum R401. Microbiota reconstitution with a core of Arabidopsis thaliana root commensals in the presence of wild-type or mutant strains revealed a root niche-specific cofunction of these exometabolites as root competence determinants and drivers of predictable changes in the root-associated community. In natural environments, both the corresponding biosynthetic operons are enriched in roots, a pattern likely linked to their role as iron sinks, indicating that these cofunctioning exometabolites are adaptive traits contributing to pseudomonad pervasiveness throughout the root microbiota.PMID:37018204 | DOI:10.1073/pnas.2221508120

Cell Rep. 2023 Apr 3;42(4):112333. doi: 10.1016/j.celrep.2023.112333. Online ahead of print.ABSTRACTMosaic symptoms are commonly observed in virus-infected plants. However, the underlying mechanism by which viruses cause mosaic symptoms as well as the key regulator(s) involved in this process remain unclear. Here, we investigate maize dwarf mosaic disease caused by sugarcane mosaic virus (SCMV). We find that the manifestation of mosaic symptoms in SCMV-infected maize plants requires light illumination and is correlated with mitochondrial reactive oxidative species (mROS) accumulation. The transcriptomic and metabolomic analyses results together with the genetic and cytopathological evidence indicate that malate and malate circulation pathways play essential roles in promoting mosaic symptom development. Specifically, at the pre-symptomatic infection stage or infection front, SCMV infection elevates the enzymatic activity of pyruvate orthophosphate dikinase by decreasing the phosphorylation of threonine527 under light, resulting in malate overproduction and subsequent mROS accumulation. Our findings indicate that activated malate circulation contributes to the manifestation of light-dependent mosaic symptoms via mROS.PMID:37018076 | DOI:10.1016/j.celrep.2023.112333

Liver Int. 2023 Apr 5. doi: 10.1111/liv.15575. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is characterized by the pathological accumulation of triglycerides in hepatocytes and is associated with insulin resistance, atherogenic dyslipidaemia and cardiometabolic diseases. Thus far, the extent of metabolic dysregulation associated with hepatic triglyceride accumulation has not been fully addressed. In this study, we aimed to identify metabolites associated with hepatic triglyceride content (HTGC) and map these associations using network analysis.METHODS: To gain insight in the spectrum of metabolites associated with hepatic triglyceride accumulation, we performed a comprehensive plasma metabolomics screening of 1363 metabolites in apparently healthy middle aged (age 45-65) individuals (N = 496) in whom HTGC was measured by proton magnetic resonance spectroscopy. An atlas of metabolite-HTGC associations, based on univariate results, was created using correlation-based Gaussian graphical model (GGM) and genome scale metabolic model network analyses. Pathways associated with the clinical prognosis marker fibrosis 4 (FIB-4) index were tested using a closed global test.RESULTS: Our analyses revealed that 118 metabolites were univariately associated with HTGC (p-value <6.59 × 10-5 ), including 106 endogenous, 1 xenobiotic and 11 partially characterized/uncharacterized metabolites. These associations were mapped to several biological pathways including branched amino acids (BCAA), diglycerols, sphingomyelin, glucosyl-ceramide and lactosyl-ceramide. We also identified a novel possible HTGC-related pathway connecting glutamate, metabolonic lactone sulphate and X-15245 using the GGM network. These pathways were confirmed to be associated with the FIB-4 index as well. The full interactive metabolite-HTGC atlas is provided online: https://tofaquih.github.io/AtlasLiver/.CONCLUSIONS: The combined network and pathway analyses indicated extensive associations between BCAA and the lipids pathways with HTGC and the FIB-4 index. Moreover, we report a novel pathway glutamate-metabolonic lactone sulphate-X-15245 with a potential strong association with HTGC. These findings can aid elucidating HTGC metabolomic profiles and provide insight into novel drug targets for fibrosis-related outcomes.PMID:37017544 | DOI:10.1111/liv.15575

mSphere. 2023 Apr 5:e0062522. doi: 10.1128/msphere.00625-22. Online ahead of print.ABSTRACTBacteria are known to cope with amino acid starvation by the stringent response signaling system, which is mediated by the accumulation of the (p)ppGpp alarmones when uncharged tRNAs stall at the ribosomal A site. While a number of metabolic processes have been shown to be regulatory targets of the stringent response in many bacteria, the global impact of amino acid starvation on bacterial metabolism remains obscure. This work reports the metabolomic profiling of the human pathogen Streptococcus pneumoniae under methionine starvation. Methionine limitation led to the massive overhaul of the pneumococcal metabolome. In particular, methionine-starved pneumococci showed a massive accumulation of many metabolites such as glutamine, glutamic acid, lactate, and cyclic AMP (cAMP). In the meantime, methionine-starved pneumococci showed a lower intracellular pH and prolonged survival. Isotope tracing revealed that pneumococci depend predominantly on amino acid uptake to replenish intracellular glutamine but cannot convert glutamine to methionine. Further genetic and biochemical analyses strongly suggested that glutamine is involved in the formation of a "prosurvival" metabolic state by maintaining an appropriate intracellular pH, which is accomplished by the enzymatic release of ammonia from glutamine. Methionine starvation-induced intracellular pH reduction and glutamine accumulation also occurred to various extents under the limitation of other amino acids. These findings have uncovered a new metabolic mechanism of bacterial adaptation to amino acid limitation and perhaps other stresses, which may be used as a potential therapeutic target for infection control. IMPORTANCE Bacteria are known to cope with amino acid starvation by halting growth and prolonging survival via the stringent response signaling system. Previous investigations have allowed us to understand how the stringent response regulates many aspects of macromolecule synthesis and catabolism, but how amino acid starvation promotes bacterial survival at the metabolic level remains largely unclear. This paper reports our systematic profiling of the methionine starvation-induced metabolome in S. pneumoniae. To the best of our knowledge, this represents the first reported bacterial metabolome under amino acid starvation. These data have revealed that the significant accumulation of glutamine and lactate enables S. pneumoniae to form a "prosurvival" metabolic state with a lower intracellular pH, which inhibits bacterial growth for prolonged survival. Our findings have provided insightful information on the metabolic mechanisms of pneumococcal adaptation to nutrient limitation during the colonization of the human upper airway.PMID:37017541 | DOI:10.1128/msphere.00625-22

Adv Biol (Weinh). 2023 Apr 5:e2200318. doi: 10.1002/adbi.202200318. Online ahead of print.ABSTRACTEven in this post genomic era, no national level newborn screening (NBS) programs for inborn errors of metabolism (IEMs) are yet available in several developing countries including Pakistan. Through NBS, various IEMs can be screened using minute quantities of biofluids. Targeted metabolomics and genomic techniques are the main approaches used for NBS. However, lack of technical expertise and such high-end "omics" based analytical facilities, and meager funding for healthcare in developing countries are the major reasons for unavailability of NBS programs. As it is reflected by only a handful reports about IEMs from Pakistan with population of ≈220 million and consanguinity rate of about 70%, which suggests an unmet need for an NBS program owing to reasonably high prevalence of inherited diseases. Around 200 IEMs are potentially treatable if diagnosed at an earlier stage through biochemical marker and genetic screening, so such patients can get benefit from the NBS program. This overview will help to persuade the stakeholders to setup NBS programs in developing countries including Pakistan, due to multitude of benefits for IEMs; timely diagnosis and early treatment can help the patients to live a nearly healthy life, reduced suffering of the family and minimal burden on society or national healthcare system.PMID:37017505 | DOI:10.1002/adbi.202200318

Alzheimers Dement. 2023 Apr 5. doi: 10.1002/alz.13007. Online ahead of print.ABSTRACTINTRODUCTION: The ketogenic diet (KD) is an intriguing therapeutic candidate for Alzheimer's disease (AD) given its protective effects against metabolic dysregulation and seizures. Gut microbiota are essential for KD-mediated neuroprotection against seizures as well as modulation of bile acids, which play a major role in cholesterol metabolism. These relationships motivated our analysis of gut microbiota and metabolites related to cognitive status following a controlled KD intervention compared with a low-fat-diet intervention.METHODS: Prediabetic adults, either with mild cognitive impairment (MCI) or cognitively normal (CN), were placed on either a low-fat American Heart Association diet or high-fat modified Mediterranean KD (MMKD) for 6 weeks; then, after a 6-week washout period, they crossed over to the alternate diet. We collected stool samples for shotgun metagenomics and untargeted metabolomics at five time points to investigate individuals' microbiome and metabolome throughout the dietary interventions.RESULTS: Participants with MCI on the MMKD had lower levels of GABA-producing microbes Alistipes sp. CAG:514 and GABA, and higher levels of GABA-regulating microbes Akkermansia muciniphila. MCI individuals with curcumin in their diet had lower levels of bile salt hydrolase-containing microbes and an altered bile acid pool, suggesting reduced gut motility.DISCUSSION: Our results suggest that the MMKD may benefit adults with MCI through modulation of GABA levels and gut-transit time.PMID:37017243 | DOI:10.1002/alz.13007

Chronobiol Int. 2023 Apr 5:1-8. doi: 10.1080/07420528.2023.2197063. Online ahead of print.ABSTRACTBipolar disorder (BD) is a common mental condition with a seasonal pattern (SP) of onset. In the spring, there is a higher incidence rate of mania or mixed onset and suicide. However, the underlying mechanism of this SP remains unclear. In this study, targeted metabolomics was used to understand metabolic changes in patients with BD before and after the spring equinox. Nine patients with BD and matched healthy controls were tested for serum metabolomics at the spring equinox and 15 days before and after the spring equinox. The results showed that 27 metabolite levels changed significantly, three of which interacted between three time points and groups involving triglyceride (TG, 20:4_34:2), TG (20:4_34:3) and TG (16:0_36:6). The identified metabolic pathways mainly involved arginine biosynthesis, D-glutamine and D-glutamate metabolism, and nitrogen metabolism. Changes in solar radiation and lunar cycle during spring may be the external causes of metabolic changes. These findings help to further explore seasonal metabolic changes in patients with BD and provide insights into the mechanisms of patients' emotional changes in spring.PMID:37017129 | DOI:10.1080/07420528.2023.2197063

Biosci Microbiota Food Health. 2023;42(2):124-130. doi: 10.12938/bmfh.2022-057. Epub 2023 Jan 13.ABSTRACTClostridium butyricum TO-A, Enterococcus faecium T-110, and Bacillus subtilis TO-A are sold as oral probiotic preparations and reportedly exhibit many beneficial effects on the health of hosts, including humans and livestock. In this study, we compared the ability of these clinically applied probiotic bacteria with Escherichia coli OP50 in extending the lifespan of Caenorhabditis elegans. To compare the C. elegans lifespan-extending effects of the three bacteria, experiments were performed using a nematode growth medium containing a small amount of trypticase soy agar. The maximum lifespans of worms fed C. butyricum TO-A, E. faecium T-110, or B. subtilis TO-A increased by 11, 12, and 26%, respectively, compared with worms fed E. coli OP50. In addition, we conducted a metabolomic analysis of methanol extracts of B. subtilis TO-A cells, which exhibited the strongest lifespan-extending effect on C. elegans among the probiotic bacteria tested in this study. As a result, 59 candidate substances involved in extending the lifespan of C. elegans were identified in B. subtilis TO-A cells.PMID:37016687 | PMC:PMC10067327 | DOI:10.12938/bmfh.2022-057

Curr Med Chem. 2023 Apr 3. doi: 10.2174/0929867330666230403100008. Online ahead of print.ABSTRACTCancer is a complex and debilitating disease that is one of the leading causes of death in the modern world. Computational methods have contributed to the successful design and development of several drugs. The recent advances in computational methodology, coupled with the avalanche of data being acquired through high throughput genomics, proteomics, and metabolomics, are likely to increase the contribution of computational methods toward the development of more effective treatments for cancer. Recent advances in the application of neural networks for the prediction of the native conformation of proteins have provided structural information regarding the complete human proteome. In addition, advances in machine learning and network pharmacology have provided novel methods for target identification and for the utilization of biological, pharmacological, and clinical databases for the design and development of drugs. This is a review of the key advances in computational methods that have the potential for application in the design and development of drugs for cancer.PMID:37016530 | DOI:10.2174/0929867330666230403100008