PubMed

Anal Sci Adv. 2021 Aug 5;2(11-12):546-563. doi: 10.1002/ansa.202100010. eCollection 2021 Dec.ABSTRACTInborn errors of metabolism (IEMs) are a group of disorders caused by disruption of metabolic pathways, which leads to accumulation, decreased circulating levels, or increased excretion of metabolites as a consequence of the underlying genetic defects. These heterogeneous groups of disorders cause significant neonatal and infant mortality across the whole world and it is of utmost concern for developing countries like India owing to lack of awareness and standard preventive strategies like newborn screening (NBS). Though the predictive cumulative incidence of IEMs is said to be ∼1:800 newborns, data pertaining to the true prevalence of individual IEMs is not available in the context of Indian population. There is a need for a large population-based study to get a clear picture of the prevalence of different IEMs. One of the best ways to screen for IEMs is by applying advanced liquid chromatography-mass spectrometry (LC-MS) technology using a quantitative metabolomics approaches such as selected or multiple reaction monitoring (SRM or MRM). Recent developments in LC-MS/MRM based quantification of marker metabolites in newborns have opened a novel opportunity to screen multiple disorders simultaneously from a minuscule volume of biological fluids. In this review article, we have highlighted how LC-MS/MRM based metabolomics approach with its high sensitivity and diagnostic capability can make an impact on the nation's public health through NBS programs.PMID:38715861 | PMC:PMC10989570 | DOI:10.1002/ansa.202100010

Anal Sci Adv. 2021 Sep 30;2(11-12):579-593. doi: 10.1002/ansa.202100021. eCollection 2021 Dec.ABSTRACTMedicinal plant metabolomics has emerged as a goldmine for the natural product chemists. It provides a pool of bioactive phytoconstituents leading to accelerated novel discoveries and the elucidation of a variety of biosynthetic pathways. Further, it also acts as an innovative tool for herbal medicine's scientific validation and quality assurance. This review highlights different strategies and analytical techniques employed in the practice of metabolomics. Further, it also discusses several other applications and advantages of metabolomics in the area of natural product chemistry. Additional examples of integrating metabolomics with multivariate data analysis techniques for some Indian medicinal plants are also reviewed. Recent technical advances in mass spectrometry-based hyphenated techniques, nuclear magnetic resonance-based techniques, and comprehensive hyphenated technologies for phytometabolite profiling studies have also been reviewed. Mass Spectral Imaging (MSI) has been presented as a highly promising method for high precision in situ spatiotemporal monitoring of phytometabolites. We conclude by introducing GNPS (Global Natural Products Social Molecular Networking) as an emerging platform to make social networks of related molecules, to explore data and to annotate more metabolites, and expand the networks to novel "predictive" metabolites that can be validated.PMID:38715860 | PMC:PMC10989556 | DOI:10.1002/ansa.202100021

Anal Sci Adv. 2020 Oct 12;2(11-12):505-514. doi: 10.1002/ansa.202000081. eCollection 2021 Dec.ABSTRACTFrom the distinct wild locations of the Mumbai (India), dead Culex mosquito larvae were collected. The mid-gut micro-flora of these dead mosquito larvae was isolated on three different media that were selective for only the Gram-positive bacteria. These bacteria were tested against the third instar stage of Culex quinquefasciatus larvae, cultured in the laboratory, for their larvicidal activity. After performing the toxicity assay four times in duplicates, the average statistical values showed four bacteria exhibiting differential toxicities. Identification of these strains was done by 16S rRNA sequencing and their respective surface morphologies were studied by scanning electron microscopy (SEM). The differential toxicities of the four identified Bacillus strains were rationalized by performing differential proteomics and metabolomics approach using LC-MS and these results were analyzed against customized mosquito larvicidal toxin database which was further compared with the in silico p-BLAST data of that respective Bacillus sp. from the NCBI database. The presence and significance of the various mosquitocidal toxins in the identified Bacillus sp. are elucidated. The present study also attempted to identify new bacterial species exhibiting mosquitocidal toxicities that have not been reported earlier.PMID:38715859 | PMC:PMC10989537 | DOI:10.1002/ansa.202000081

Anal Sci Adv. 2021 Nov 28;2(11-12):594-610. doi: 10.1002/ansa.202000169. eCollection 2021 Dec.ABSTRACTMetabolomics is the comprehensive study of the metabolome and its alterations within biological fluids and tissues. Over the years, applications of metabolomics have been explored in several areas, including personalised medicine in diseases, metabolome-wide association studies (MWAS), pharmacometabolomics and in combination with other branches of omics such as proteomics, transcriptomics and genomics. Mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy are the major analytical techniques widely employed in metabolomics. In addition, MS is coupled with chromatography techniques like gas chromatography (GC) and liquid chromatography (LC) to separate metabolites before analysis. These analytical techniques have made possible identification and quantification of large numbers of metabolites, encompassing characterization of diseases and facilitating a systematic and rational therapeutic strategy based on metabolic patterns. In recent years, the metabolomics approach has been used to obtain a deeper insight into the underlying biochemistry of neurodegenerative disorders and the discovery of biomarkers of clinical implications. The current review mainly focuses on an Indian perspective of metabolomics for the identification of metabolites and metabolic alterations serving as potential diagnostic biomarkers for neurological diseases including acute spinal cord injury, amyotrophic lateral sclerosis, tethered cord syndrome, spina bifida, stroke, Parkinson's disease, glioblastoma and neurological disorders with inborn errors of metabolism.PMID:38715858 | PMC:PMC10989583 | DOI:10.1002/ansa.202000169

Anal Sci Adv. 2021 Dec 23;2(11-12):495-496. doi: 10.1002/ansa.202100064. eCollection 2021 Dec.NO ABSTRACTPMID:38715857 | PMC:PMC10989613 | DOI:10.1002/ansa.202100064

Anal Sci Adv. 2021 Jun 21;2(11-12):536-545. doi: 10.1002/ansa.202000167. eCollection 2021 Dec.ABSTRACTBACKGROUND: A recent study based on blood metabolomics analysis revealed inflammation-associated mitochondrial dysfunction as a potential mechanism underlying acute-on-chronic liver failure (ACLF) in cirrhotic patients. Serine, glycine, and methionine serve to maintain a healthy immune system and adequately sustain mitochondrial functionality in hepatocytes for regulating redox homeostasis through the production of antioxidant glutathione (GSH). Based on this, we hypothesized that the circulatory levels of serine, glycine and methionine will be altered in ACLF patients due to acute worsening of hepatic function and may provide novel insights into the mitochondrial dysfunction as well.METHODS: The circulatory concentrations of serine, glycine, and methionine were estimated in the sera of 40 ACLF patients and 49 normal controls (NC) subject using 1D 1H-CPMG NMR spectra recorded at 800 MHz NMR spectrometer. The resulting metabolite concentrations were compared using unpaired Student t-test and p-value < 0.05 was considered as the criterion of statistical significance. The diagnostic potential and statistical correlations were established using receiver-operating-characteristic (ROC) curve analysis and Pearson-r method, respectively.RESULTS: Circulating levels of serine and glycine were significantly decreased in ACLF patients (Ser = 23.06 ± 1.67 µM and Gly = 83.11±7.52 µM) compared to NC subjects (Ser = 55.61 ± 2.28 µM and Gly = 156.9±7.16 µM) with p-value < 0.0001, whereas those of methionine were significantly increased in ACLF (22.60 ± 2.49 µM) compared to NC subjects (=14.63 ± 0.85 µM) with p-value < 0.0015. Further, the ROC analysis yielded satisfactory sensitivity and specificity for serine, glycine, and methionine-to-glycine ratio (MGR) with area under ROC (AUROC) curve values equal to: 0.95 [95%CI = 0.91-0.99] for Ser; 0.87 [95%CI = 0.79-0.95] for Gly; and 0.90 [95%CI = 0.83-0.97] for MGR.CONCLUSION: Compared to NC subjects, the sera of ACLF patients were characterized by hypermethioninemia and aberrantly decreased levels of serine and glycine suggesting mitochondrial dysfunction as the possible mechanism for disturbed redox homeostasis and therefore depressed immune system in ACLF.PMID:38715854 | PMC:PMC10989557 | DOI:10.1002/ansa.202000167

Anal Sci Adv. 2020 Apr 22;1(1):46-55. doi: 10.1002/ansa.20190009. eCollection 2020 Jun.ABSTRACTPhospholipids are one of the most important lipid categories with multiple functions in biological systems. Their analysis can contribute to a better understanding of metabolomic and kinetic processes in living cells. Comprehensive methods based on liquid chromatography coupled to mass spectrometry are available for phospholipid identification and quantification. However, quantification of phospholipids using electrospray ionization-mass spectrometry with internal standards is still challenging due to several reasons. In particular, the detector response of phospholipid species differs with variation of the head group as well as the fatty acid chain length and double bond number. Inductively coupled plasma-tandem mass spectrometry (ICP-MS/MS) provides an alternative approach for their absolute quantification with universal detector response for phosphorus independent of its chemical form and proportional to its quantity. Therefore, a quantification method based on compound-independent calibration using hydrophilic interaction liquid chromatography (HILIC) coupled to ICP-MS/MS was developed. An inverse gradient system was implemented for constant mobile phase composition after HILIC separation, which provides steady plasma ionization conditions. Isobaric phosphorus interferences were decreased by using the oxygen reaction mode of the triple quadrupole based ICP-MS/MS instrument. Complementary molecular information was obtained by ESI-high-resolution MS and MS/MS. The applicability of this approach was demonstrated in a proof of concept by complementary analysis of a total lipid extract of baker's yeast.PMID:38715851 | PMC:PMC10989138 | DOI:10.1002/ansa.20190009

Am J Transl Res. 2024 Apr 15;16(4):1337-1352. doi: 10.62347/MJLN5908. eCollection 2024.ABSTRACTOBJECTIVES: Breast cancer is the most common cancer and the leading cause of cancer-related death among women. An Estrogen Receptor (ER) antagonist called tamoxifen is used as an adjuvant therapy for ER-positive breast cancers. Approximately 40% of patients develop tamoxifen resistance (TAMR) while receiving treatment. Cancer cells can rewire their metabolism to develop resistant phenotypes, and their metabolic state determines how receptive they are to chemotherapy.METHODS: Metabolite extraction from human MCF-7 and MCF-7/TAMR cells was done using the methanol-methanol-water extraction method. After treating the dried samples with methoxamine hydrochloride in pyridine, the samples were derivatized with 2,2,2-Trifluoro-N-methyl-N-(trimethylsilyl)-acetamide, and Chlorotrimethylsilane (MSTFA + 1% TMCS). The Gas chromatography/mass spectrometry (GC-MS) raw data were processed using MSdial and Metaboanalyst for analysis.RESULTS: Univariate analysis revealed that 35 metabolites were elevated in TAMR cells whereas 25 metabolites were downregulated. N-acetyl-D-glucosamine, lysine, uracil, tyrosine, alanine, and o-phosphoserine were upregulated in TAMR cells, while hydroxyproline, glutamine, N-acetyl-L-aspartic acid, threonic acid, pyroglutamic acid, glutamine, o-phosphoethanolamine, oxoglutaric acid, and myoinositol were found to be downregulated. Multivariate analysis revealed a distinct separation between the two cell lines, as evidenced by their metabolite levels. The enriched pathways of deregulated metabolites included valine, leucine, and isoleucine degradation, Citric Acid Cycle, Warburg effect, Malate-Aspartate shuttle, glucose-alanine cycle, propanoate metabolism, and Phospholipid biosynthesis.CONCLUSION: This study revealed dysregulation of various metabolic processes in TAMR cells, which may be crucial in elucidating the molecular basis of the mechanisms underlying acquired tamoxifen resistance.PMID:38715825 | PMC:PMC11070380 | DOI:10.62347/MJLN5908

Anal Sci Adv. 2021 Jan 21;2(1-2):47-67. doi: 10.1002/ansa.202000144. eCollection 2021 Feb.ABSTRACTThe packed column supercritical fluid chromatography has risen as a promising alternative separation technique to the conventional liquid chromatography and gas chromatography. Although the packed column supercritical fluid chromatography has many advantages compared to other chromatographic techniques, its separation mechanism is not fully understood due to the complex combination effects of many chromatographic parameters on separation quality and the lacking of global strategies for studying separation mechanisms. This review aims to provide recent information regarding the chromatographic behaviors and the effects of the parameters on the separation, discuss the results, and point out the remaining bottlenecks in the packed column supercritical fluid chromatography retention mechanism studies.PMID:38715740 | PMC:PMC10989630 | DOI:10.1002/ansa.202000144

Anal Sci Adv. 2023 Mar 21;4(11-12):319-323. doi: 10.1002/ansa.202200055. eCollection 2023 Dec.ABSTRACTSince the late 1970s, many 'omics-style investigations have advanced our understanding of systems at all levels, from community level, through organismal, to individual cellular processes. Beginning with genomics and progressing through transcriptomics, proteomics and finally to metabolomics, the scope of interest shifts significantly from what is genetically possible to what is currently expressed, produced and measurable in a system. While the ideal goal of any 'omics investigation is to fully describe a system, loss of information occurs at each decision-making juncture. These losses are often not considered in the experimental planning stage but, when combined, they drastically affect the power of an investigation and the conclusions that can be drawn from it. Herein we discuss through the analogy of photography many of the decision-making junctures of metabolomics investigations and the resultant losses of information occurring at each.PMID:38715650 | PMC:PMC10989593 | DOI:10.1002/ansa.202200055

Front Immunol. 2024 Apr 23;15:1385896. doi: 10.3389/fimmu.2024.1385896. eCollection 2024.ABSTRACTINTRODUCTION: Peripartal cows are susceptible to a negative energy balance due to inadequate nutrient intake and high energy requirements for lactation. Improving the energy metabolism of perinatal dairy cows is crucial in increasing production in dairy cows.METHODS: In this study, we investigated the impact of rumen-protected branched-chain amino acid (RPBCAA) on the production performance, energy and lipid metabolism, oxidative stress, and immune function of primiparous dairy cows using metabolomics through a single-factor experiment. Twenty healthy primiparous Holstein cows were selected based on body condition scores and expected calving date, and were randomly divided into RPBCAA (n = 10) and control (n = 10) groups. The control group received a basal diet from calving until 21 d in milk, and the RPBCAA group received the basal diet and 44.6 g/d RPLeu, 25.14 g/d RPIle, and 25.43 g/d RPVal.RESULTS: In comparison to the control group, the supplementation of RPBCAA had no significant effect on milk yield and milk composition of the dairy cows. Supplementation with RPBCAA significantly increased the concentrations of insulin, insulin growth factor 1, glucagon, and growth hormones, which are indicators of energy metabolism in postpartum cows. The very low density lipoprotein, fatty acid synthase, acetyl coenzyme A carboxylase, and hormone-sensitive lipase contents of the RPBCAA group were significantly greater than that of the control group; these metrics are related to lipid metabolism. In addition, RPBCAA supplementation significantly increased serum glutathione peroxidase and immunoglobulin G concentrations and decreased malondialdehyde concentrations. Liquid chromatography-mass spectrometry (LC-MS) analysis revealed 414 serum and 430 milk metabolic features. Supplementation with RPBCAA primarily increased concentrations of amino acid and lipid metabolism pathways and upregulated the abundance of serotonin, glutamine, and phosphatidylcholines.DISCUSSION: In summary, adding RPBCAA to the daily ration can influence endocrine function and improve energy metabolism, regulate amino acid and lipid metabolism, mitigate oxidative stress and maintain immune function on primiparous cows in early lactation.PMID:38715606 | PMC:PMC11075066 | DOI:10.3389/fimmu.2024.1385896

Anal Sci Adv. 2022 Nov 8;4(1-2):1-3. doi: 10.1002/ansa.202200901. eCollection 2023 Feb.NO ABSTRACTPMID:38715587 | PMC:PMC10989530 | DOI:10.1002/ansa.202200901

Anal Sci Adv. 2023 Feb 5;4(1-2):37-48. doi: 10.1002/ansa.202200039. eCollection 2023 Feb.ABSTRACTMetabolomics and lipidomics techniques are capable of comprehensively measuring hundreds to thousands of small molecules in single analytical runs and have been used to characterize responses to exercise traditionally using venipuncture-produced liquid samples. Advanced microsampling devices offer an alternative by circumventing the requirement to maintain frozen samples. This approach combines a microneedle puncture for blood draw with microfluidic sample collection onto a dried carrier and has thus far been employed for targeted measurements of a few analytes. To demonstrate the utility of advanced dried microsampling to characterize metabolomic and lipidomic changes during exercise, we obtained samples before and after a 2-mile run from twelve (8 male, 4 female) healthy volunteers with various ranges in activity levels. Results highlighted significant changes in whole blood levels of several metabolites associated with energy (glycolysis and Tricarboxylic Acid cycle) and redox (Pentose Phosphate Pathway) metabolism. Lipid changes during this same period were individualized and less uniform. Sex-based differences in response to running highlighted reliance on carbohydrate or fat substrate utilization in males or females, respectively. The results presented herein illustrate the ability of this approach to monitor circulating metabolome and lipidome profiles from field sampled blood in response to exercise.PMID:38715582 | PMC:PMC10989637 | DOI:10.1002/ansa.202200039

Med Sci Monit. 2024 May 8;30:e943360. doi: 10.12659/MSM.943360.ABSTRACTBACKGROUND Aberrant lipid metabolism alterations in skin tissue, blood, or urine have been implicated in psoriasis. Here, we examined lipid metabolites related to psoriasis and their association with the age of disease onset. MATERIAL AND METHODS Differences in lipid metabolites before and after methotrexate (MTX) treatment were evaluated. The discovery cohort and validation cohort consisted of 50 and 46 patients, respectively, with moderate-to-severe psoriasis. After MTX treatment, the patients were divided into response (Psoriasis Area and Severity Index [PASI] 75 and above) and non-response (PASI below 75) groups, blood was collected for serum metabolomics, and multivariate statistical analysis was performed. RESULTS We detected 1546 lipid metabolites. The proportion of the top 3 metabolites was as follows: triglycerides (TG, 34.8%), phospholipids (PE, 14.5%), phosphatidylcholine (PC, 12.4%); diglycerides (DG) (16: 1/18: 1), and DG (18: 1/18: 1) showed strong positive correlations with onset age. There were marked changes in TG (16: 0/18: 0/20: 0), TG (18: 0/18: 0/22: 0), TG (14: 0/18: 0/22: 0), TG (14: 0/20: 0/20: 0), lysophosphatidylcholine (LPC) (16: 0/0: 0), LPC (18: 0/0: 0), LPC (14: 0/0: 0), and LPC (18: 1/0: 0) levels before and after 12 weeks of MTX treatment. The glycerophospholipid metabolic pathway was implicated in psoriasis development. Of the 96 recruited patients, 35% were MTX responders and 65% non-responders. PE (34: 4) and PE (38: 1) levels were significantly different between the groups. Obvious differences in lipid metabolism were found between early-onset (<40 years) and late-onset (≥40 years) psoriasis. Significant changes in serum lipid profile before and after MTX treatment were observed. CONCLUSIONS The specific lipid level changes in responders may serve as an index for MTX treatment efficacy evaluation.PMID:38715343 | DOI:10.12659/MSM.943360

Biotechnol Bioeng. 2024 May 7. doi: 10.1002/bit.28730. Online ahead of print.ABSTRACTThe human microbiota impacts a variety of diseases and responses to therapeutics. Due to a lack of robust in vitro models, detailed mechanistic explanations of host-microbiota interactions cannot often be recapitulated. We describe the design and development of a novel, versatile and modular in vitro system that enables indirect coculture of human epithelial cells with anaerobic bacteria for the characterization of host-microbe secreted metabolite interactions. This system was designed to compartmentalize anaerobes and human cells in separate chambers conducive to each organism's requisite cell growth conditions. Using perfusion, fluidic mixing, and automated sample collection, the cells continuously received fresh media, while in contact with their corresponding compartments conditioned supernatant. Supernatants from each chamber were collected in a cell-free time-resolved fashion. The system sustained low oxygen conditions in the anaerobic chamber, while also supporting the growth of a representative anaerobe (Bacteroides thetaiotaomicron) and a human colonic epithelial cell line (Caco-2) in the aerobic chamber. Caco-2 global gene expression changes in response to coculture with B. thetaiotaomicron was characterized using RNA sequencing. Extensive, targeted metabolomics analysis of over 150 central carbon metabolites was performed on the serially collected supernatants. We observed broad metabolite changes in host-microbe coculture, compared to respective mono-culture controls. These effects were dependent both on sampling time and the compartment probed (apical vs. basolateral). Coculturing resulted in the depletion of several important metabolites, including guanine, uridine 5'-monophosphate, asparagine, and thiamine. Additionally, while Caco-2 cells cultured alone predominantly affected the basolateral metabolite milieu, increased abundance of 2,3-dihydroxyisovalerate and thymine on the basolateral side, occurred when the cells were cocultured with B. thetaiotaomicron. Thus, our system can capture the dynamic, competitive and cooperative processes between host cells and gut microbes.PMID:38715197 | DOI:10.1002/bit.28730

Trials. 2024 May 7;25(1):307. doi: 10.1186/s13063-024-08130-9.ABSTRACTBACKGROUND: Aging has been associated with a progressive loss of skeletal muscle quality, quantity and strength, which may result in a condition known as sarcopenia, leading to a decline in physical performance, loss of independence and reduced quality of life. While the cause of impaired physical functioning observed in elderly populations appears to be multifactorial, recent evidence suggests that age-associated alterations in gut microbiota could be a contributing factor. The primary objective will be to assess the effects of a dietary synbiotic formulation on sarcopenia-related functional outcomes such as handgrip strength, gait speed and physical performance within older individuals living independently. The secondary objective will be to examine associations between changes in gut microbiota composition, functional performance and lean muscle mass.METHODS: Seventy-four elderly (60-85 years) participants will be randomized in a double-blind, placebo-controlled fashion to either an intervention or control group. The intervention group (n = 37) will receive oral synbiotic formulation daily for 16 weeks. The control group (n = 37) will receive placebo. Assessments of physical performance (including Short Physical Performance Battery, handgrip strength and timed up-and-go tests) and muscle ultrasonography will be performed at 4 time points (baseline and weeks 8, 16 and 20). Likewise, body composition via bioelectric impedance analysis and blood and stool samples will be collected at each time point. Dual-energy X-ray absorptiometry will be performed at baseline and week 16. The primary outcomes will be between-group changes in physical performance from baseline to 16 weeks. Secondary outcomes include changes in body composition, muscle mass and architecture, fecal microbiota composition and diversity, and fecal and plasma metabolomics.DISCUSSION: Gut-modulating supplements appear to be effective in modifying gut microbiota composition in healthy older adults. However, it is unclear whether these changes translate into functional and/or health improvements. In the present study, we will investigate the effects of a synbiotic formulation on measures of physical performance, strength and muscle health in healthy older populations.TRIAL REGISTRATION: This study was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12622000652774) in May 2022.PMID:38715143 | DOI:10.1186/s13063-024-08130-9

Microbiome. 2024 May 7;12(1):80. doi: 10.1186/s40168-024-01795-z.ABSTRACTBACKGROUND: Antibiotic exposure can occur in medical settings and from environmental sources. Long-term effects of brief antibiotic exposure in early life are largely unknown.RESULTS: Post a short-term treatment by ceftriaxone to C57BL/6 mice in early life, a 14-month observation was performed using 16S rRNA gene-sequencing technique, metabolomics analysis, and metagenomics analysis on the effects of ceftriaxone exposure. Firstly, the results showed that antibiotic pre-treatment significantly disturbed gut microbial α and β diversities (P < 0.05). Both Chao1 indices and Shannon indices manifested recovery trends over time, but they didn't entirely recover to the baseline of control throughout the experiment. Secondly, antibiotic pre-treatment reduced the complexity of gut molecular ecological networks (MENs). Various network parameters were affected and manifested recovery trends over time with different degrees, such as nodes (P < 0.001, R2 = 0.6563), links (P < 0.01, R2 = 0.4543), number of modules (P = 0.0672, R2 = 0.2523), relative modularity (P = 0.6714, R2 = 0.0155), number of keystones (P = 0.1003, R2 = 0.2090), robustness_random (P = 0.79, R2 = 0.0063), and vulnerability (P = 0.0528, R2 = 0.28). The network parameters didn't entirely recover. Antibiotic exposure obviously reduced the number of key species in gut MENs. Interestingly, new keystones appeared during the recovery process of network complexity. Changes in network stability might be caused by variations in network complexity, which supports the ecological theory that complexity begets stability. Besides, the metabolism profiles of the antibiotic group and control were significantly different. Correlation analysis showed that antibiotic-induced differences in gut microbial metabolism were related to MEN changes. Antibiotic exposure also caused long-term effects on gut microbial functional networks in mice.CONCLUSIONS: These results suggest that short-term antibiotic exposure in early life will cause long-term negative impacts on gut microbial diversity, MENs, and microbial metabolism. Therefore, great concern should be raised about children's brief exposure to antibiotics if the results observed in mice are applicable to humans. Video Abstract.PMID:38715137 | DOI:10.1186/s40168-024-01795-z

J Transl Med. 2024 May 7;22(1):431. doi: 10.1186/s12967-024-05150-6.ABSTRACTBACKGROUND: In humans, two ubiquitously expressed N-myristoyltransferases, NMT1 and NMT2, catalyze myristate transfer to proteins to facilitate membrane targeting and signaling. We investigated the expression of NMTs in numerous cancers and found that NMT2 levels are dysregulated by epigenetic suppression, particularly so in hematologic malignancies. This suggests that pharmacological inhibition of the remaining NMT1 could allow for the selective killing of these cells, sparing normal cells with both NMTs.METHODS AND RESULTS: Transcriptomic analysis of 1200 NMT inhibitor (NMTI)-treated cancer cell lines revealed that NMTI sensitivity relates not only to NMT2 loss or NMT1 dependency, but also correlates with a myristoylation inhibition sensitivity signature comprising 54 genes (MISS-54) enriched in hematologic cancers as well as testis, brain, lung, ovary, and colon cancers. Because non-myristoylated proteins are degraded by a glycine-specific N-degron, differential proteomics revealed the major impact of abrogating NMT1 genetically using CRISPR/Cas9 in cancer cells was surprisingly to reduce mitochondrial respiratory complex I proteins rather than cell signaling proteins, some of which were also reduced, albeit to a lesser extent. Cancer cell treatments with the first-in-class NMTI PCLX-001 (zelenirstat), which is undergoing human phase 1/2a trials in advanced lymphoma and solid tumors, recapitulated these effects. The most downregulated myristoylated mitochondrial protein was NDUFAF4, a complex I assembly factor. Knockout of NDUFAF4 or in vitro cell treatment with zelenirstat resulted in loss of complex I, oxidative phosphorylation and respiration, which impacted metabolomes.CONCLUSIONS: Targeting of both, oxidative phosphorylation and cell signaling partly explains the lethal effects of zelenirstat in select cancer types. While the prognostic value of the sensitivity score MISS-54 remains to be validated in patients, our findings continue to warrant the clinical development of zelenirstat as cancer treatment.PMID:38715059 | DOI:10.1186/s12967-024-05150-6

Nat Commun. 2024 May 7;15(1):3796. doi: 10.1038/s41467-024-47897-y.ABSTRACTThe metabolic implications in Alzheimer's disease (AD) remain poorly understood. Here, we conducted a metabolomics study on a moderately aging Chinese Han cohort (n = 1397; mean age 66 years). Conjugated bile acids, branch-chain amino acids (BCAAs), and glutamate-related features exhibited strong correlations with cognitive impairment, clinical stage, and brain amyloid-β deposition (n = 421). These features demonstrated synergistic performances across clinical stages and subpopulations and enhanced the differentiation of AD stages beyond demographics and Apolipoprotein E ε4 allele (APOE-ε4). We validated their performances in eight data sets (total n = 7685) obtained from Alzheimer's Disease Neuroimaging Initiative (ADNI) and Religious Orders Study and Memory and Aging Project (ROSMAP). Importantly, identified features are linked to blood ammonia homeostasis. We further confirmed the elevated ammonia level through AD development (n = 1060). Our findings highlight AD as a metabolic disease and emphasize the metabolite-mediated ammonia disturbance in AD and its potential as a signature and therapeutic target for AD.PMID:38714706 | DOI:10.1038/s41467-024-47897-y

Nat Commun. 2024 May 7;15(1):3805. doi: 10.1038/s41467-024-47514-y.ABSTRACTGenomic alterations that activate Fibroblast Growth Factor Receptor 2 (FGFR2) are common in intrahepatic cholangiocarcinoma (ICC) and confer sensitivity to FGFR inhibition. However, the depth and duration of response is often limited. Here, we conduct integrative transcriptomics, metabolomics, and phosphoproteomics analysis of patient-derived models to define pathways downstream of oncogenic FGFR2 signaling that fuel ICC growth and to uncover compensatory mechanisms associated with pathway inhibition. We find that FGFR2-mediated activation of Nuclear factor-κB (NF-κB) maintains a highly glycolytic phenotype. Conversely, FGFR inhibition blocks glucose uptake and glycolysis while inciting adaptive changes, including switching fuel source utilization favoring fatty acid oxidation and increasing mitochondrial fusion and autophagy. Accordingly, FGFR inhibitor efficacy is potentiated by combined mitochondrial targeting, an effect enhanced in xenograft models by intermittent fasting. Thus, we show that oncogenic FGFR2 signaling drives NF-κB-dependent glycolysis in ICC and that metabolic reprogramming in response to FGFR inhibition confers new targetable vulnerabilities.PMID:38714664 | DOI:10.1038/s41467-024-47514-y