PubMed

Poult Sci. 2024 Nov 10;104(1):104506. doi: 10.1016/j.psj.2024.104506. Online ahead of print.ABSTRACTThe use of bio-enzyme as feed additives holds significant potential. This study aimed to evaluate the impact of a kind of compound bio-enzyme supplementation (the main functional components are probiotics and astragalus polysaccharides) on the production performance, serum immunity, and intestinal health of Pekin ducks. A total of 126 male Pekin ducks were randomly assigned to three groups: a control group (CG, no additive), a low-dose group (LG, 0.1 % bio-enzyme), and a high-dose group (HG, 0.2 % bio-enzyme), with 6 replicates per group. Ducks were raised until 35 days of age, with weekly measurements of growth performance. At day 35, serum immunoglobulins were measured, carcass traits were recorded, and cecal contents were analyzed using 16S rRNA sequencing and metabolomics. Results indicated a significant increase in ADG (P = 0.049) and a decrease in feed-to-gain ratio (F:G) (P = 0.020) in LG and HG compared to CG during rearing. The HG showed a notable improvement in half eviscerated yield (HEY) (P = 0.023) and full eviscerated yield (FEY) (P = 0.008). No substantial changes were observed in immunological parameters (P > 0.05). The jejunal villus height to crypt depth ratio (VH/CD) significantly increased (P < 0.001) in LG, with notable improvements in duodenal (P = 0.001) and jejunal (P < 0.001) VH/CD in HG. The Shannon index (P = 0.042) and Pielou index (P = 0.038) of cecal microbiota were markedly lower in HG. Notable changes in the relative abundance of Firmicutes and Bacteroidota were observed in LG and HG. Differential bacteria and metabolites among the treatments were identified, and their correlations were analyzed. KEGG enrichment pathways of the metabolites were also identified. In conclusion, this bio-enzyme can improve production performance, intestinal wall structure, and microbiota in Pekin ducks. A 0.1 % concentration of this bio-enzyme is optimal for Pekin duck production.PMID:39700598 | DOI:10.1016/j.psj.2024.104506

J Exp Bot. 2024 Dec 19:erae506. doi: 10.1093/jxb/erae506. Online ahead of print.ABSTRACTUnderstanding how crop varieties acclimate to elevated temperatures is key to priming them for future climates. Here, we exposed two genotypes of Sorghum bicolor (one sensitive to heat shock (Sen) and one tolerant (Tol)) from multiple growth temperatures to a six-day heat shock (reaching 45°C), carrying out a suite of measurements before and during heat shock. Sen consistently reduced photosynthetic functioning during heat shock, while Tol increased its photosynthetic rate. Higher abundance of heat shock protein transcripts and metabolites related to heat tolerance were noted for Tol when compared to Sen both before and during heat shock, which can be attributed to constitutive and inducible responses to elevated temperatures. In addition, important changes in metabolic pathways were clearly identified for Tol during heat shock (including upregulation of raffinose family oligosaccharides and downregulation of the GABA catalytic pathway), even as the concentration of hexose sugars became depleted. We infer Tol was able to tolerate elevated temperatures due to an upregulation of osmoprotectants, chaperones and reactive oxygen species scavengers and by the suppression of SnRK1 via transcripts and metabolites during heat shock. Our results highlight potential targets for attributes of high temperature tolerance which can be utilised in future breeding trials.PMID:39700407 | DOI:10.1093/jxb/erae506

PLoS One. 2024 Dec 19;19(12):e0315330. doi: 10.1371/journal.pone.0315330. eCollection 2024.ABSTRACTMembrane transporters are responsible for moving a wide variety of molecules across biological membranes, making them integral to key biological pathways in all organisms. Identifying all membrane transporters within a (meta-)proteome, along with their specific substrates, provides important information for various research fields, including biotechnology, pharmacology, and metabolomics. Protein datasets are frequently annotated with thousands of molecular functions that form complex networks, often with partial or full redundancy and hierarchical relationships. This complexity, along with the low sample count for more specific functions, makes them unsuitable as classes for supervised learning methods, meaning that the creation of an optimal subset of annotations is required. However, selection of this subset requires extensive manual effort, along with knowledge about the biology behind the respective functions. Here, we present an automated pipeline to address this problem. Unlike previous approaches for reducing redundancy in GO datasets, we employ machine learning to identify a subset of functional annotations in a training dataset. Classes in the resulting predictive model meet four essential criteria: sufficient sample size for training predictive models, minimal redundancy, strong class separability, and relevance to substrate transport. Furthermore, we implemented a pipeline for creating training datasets of transmembrane transporters that cover a wide range of organisms, including plants, bacteria, mammals, and single-cell eukaryotes. For a dataset containing 98.1% of transporters from S. cerevisiae, the pipeline automatically reduced the number of functional annotations from 287 to 11 GO terms that could be classified with a median pairwise F1 score of 0.87±0.16. For a meta-organism dataset containing 96% of all transport proteins from S. cerevisiae, A. thaliana, E. coli and human, the number of classes was reduced from 695 to 49, with a median F1 score of 0.92±0.10 between pairs of GO terms. When lowering the percentage of covered proteins down to 67%, the pipeline found a subset of 30 GO terms with a median F1 score of 0.95±0.06.PMID:39700222 | DOI:10.1371/journal.pone.0315330

J Cell Mol Med. 2024 Dec;28(24):e70277. doi: 10.1111/jcmm.70277.ABSTRACTLipid reprogramming in carcinoma is reported to have a role in carcinogenesis, prognosis and therapy response. The lipid reprogramming could be contributed by either autonomous or nonautonomous resources. Since the nonautonomous lipid resources contributed by lipoproteins and their receptors have been reported in epithelial ovarian cancer (EOC), the impact of autonomous lipid metabolites was unknown. This report revealed a unique lipid class, ether-linked phosphatidyl-ethanolamine (PE O-), which enhances chemo-insensitivity and progression in EOC and potentially cross carcinomas. Analysis of CCLEC/GDSCC database and in-house cell line lipidomes identified PE O- as the major lipid associated with cisplatin/paclitaxel sensitivity. In the testing of PE O- effect on cancer phenotypes, it enhanced cell growth, migratory activities and promoted cisplatin/paclitaxel insensitivity. In addition, treating AGPS inhibitor-sensitised chemo-cytotoxic upon cisplatin/paclitaxel treatments. Treating PE O- could reverse AGPS inhibitor chemosensitisation effect on EOC cells. At last, using TCGA-EOC transcriptome database, the PE O- related gene expressions were positive correlated with patient prognosis in general, or in whom were treated with platin- or taxel-based chemotherapies. The expressions of genes for the synthesis of PE O- aggravates therapy response in EOC patients. PE O- facilitates human carcinoma cell line growth, mobility and chemo-insensitivity.PMID:39700026 | DOI:10.1111/jcmm.70277

Anal Chem. 2024 Dec 19. doi: 10.1021/acs.analchem.4c04060. Online ahead of print.ABSTRACTMethods for assessing compound identification confidence in metabolomics and related studies have been debated and actively researched for the past two decades. The earliest effort in 2007 focused primarily on mass spectrometry and nuclear magnetic resonance spectroscopy and resulted in four recommended levels of metabolite identification confidence─the Metabolite Standards Initiative (MSI) Levels. In 2014, the original MSI Levels were expanded to five levels (including two sublevels) to facilitate communication of compound identification confidence in high resolution mass spectrometry studies. Further refinement in identification levels have occurred, for example to accommodate use of ion mobility spectrometry in metabolomics workflows, and alternate approaches to communicate compound identification confidence also have been developed based on identification points schema. However, neither qualitative levels of identification confidence nor quantitative scoring systems address the degree of ambiguity in compound identifications in the context of the chemical space being considered. Neither are they easily automated nor transferable between analytical platforms. In this perspective, we propose that the metabolomics and related communities consider identification probability as an approach for automated and transferable assessment of compound identification and ambiguity in metabolomics and related studies. Identification probability is defined simply as 1/N, where N is the number of compounds in a database that matches an experimentally measured molecule within user-defined measurement precision(s), for example mass measurement or retention time accuracy, etc. We demonstrate the utility of identification probability in an in silico analysis of multiproperty reference libraries constructed from a subset of the Human Metabolome Database and computational property predictions, provide guidance to the community in transparent implementation of the concept, and invite the community to further evaluate this concept in parallel with their current preferred methods for assessing metabolite identification confidence.PMID:39699939 | DOI:10.1021/acs.analchem.4c04060

Nat Prod Res. 2024 Dec 19:1-6. doi: 10.1080/14786419.2024.2443490. Online ahead of print.ABSTRACTPhanera vahlii (Wight & Arn.) Benth., leaves are used traditionally in variety of diseases. Chemical examination of the leaves yielded Davinvolunol B (1) and Quercetin-3-O-rhamnoside (2). Compared with the other extracts, the aqueous methanol extract significantly inhibited Streptococcus aureus with an IC50 of 8 µg/mL. In the anticancer activity assay, the ethyl acetate extract was effective against HeLa cells (IC50 19 µg/mL), the methanol extract was effective against A549 cells (IC50 of 19 µg/mL), the aqueous methanol extract was effective against PANC-1 cells (IC50 of 17 µg/mL) and the chloroform extract was effective against HT1080 cells (IC50 of 19 µg/mL). The polar extracts which showed good antioxidant activity exhibited strong bioactivity. This finding was supported by untargeted phytometabolite profiling of extracts using UPLC-ESI-Q-TOF-MSE. The PCA score plot and the Ven diagram revealed that the extracts had a distinctive and adequate number of polar molecules that likely contributed to their observed inhibitory activity.PMID:39699566 | DOI:10.1080/14786419.2024.2443490

Food Funct. 2024 Dec 19. doi: 10.1039/d4fo04301d. Online ahead of print.ABSTRACTObesity-related metabolic syndrome is intimately associated with infiltrated adipose tissue macrophages (ATMs), gut microbiota, and metabolic disorders. Pediococcus acidilactici holds the potential to mitigate obesity; however, there exist strain-specific functionalities and diverse mechanisms, which deserve extensive exploration. This study aims to explore the potential of P. acidilactici Y01, isolated from traditional sour whey, in alleviating HFD-induced metabolic syndrome in mice and elucidating its underlying mechanism. The results showed that P. acidilactici Y01 could inhibit the increase of body weight gain, the deposition of fat, lipid disorders and chronic low-grade inflammation, improve glucose tolerance and insulin resistance, and could reduce adipose tissue inflammation by decreasing M1-type ATMs and increasing M2-type ATMs. Meanwhile, P. acidilactici Y01 significantly increased the abundance of potentially beneficial intestinal bacteria, such as Akkermansia, Alistipes, Bifidobacterium, Lachnospiraceae_NK4A136_group, Lactobacillus, norank_f__Muribaculaceae, and Parabacteroides, and partially restored the levels of metabolites, such as phosphatidylcholines, glycerophosphocholines, sphingolipids and unsaturated fatty acids. The fecal microbiota transplantation experiment demonstrated that P. acidilactici Y01 ameliorated obesity-related metabolic syndrome by modulating the polarization of M1/M2 ATMs mediated by gut microbiota. Overall, as a dietary supplement, P. acidilactici Y01 has good potential in the prevention and treatment of obesity.PMID:39699275 | DOI:10.1039/d4fo04301d

Microbiol Spectr. 2024 Dec 19:e0136824. doi: 10.1128/spectrum.01368-24. Online ahead of print.ABSTRACTMicrobiota-released extracellular vesicles (MEVs) have emerged as a key player in intercellular signaling. However, their involvement in the gut-brain axis has been poorly investigated. We hypothesize that MEVs cross host cellular barriers and deliver their cargoes of bioactive compounds to the brain. In this study, we aimed to investigate the cargo capacity of MEVs for bioactive metabolites and their interactions with the host cellular barriers. First, we conducted a multi-omics profiling of MEVs' contents from ex vivo and stool samples. Metabolomics analysis identified various neuro-related compounds encapsulated within MEVs, such as arachidonyl-dopamine, gabapentin, glutamate, and N-acylethanolamines. Metaproteomics unveiled an enrichment of enzymes involved in neuronal metabolism, primarily in the glutamine/glutamate/gamma-aminobutyric acid (GABA) pathway. These neuro-related proteins and metabolites were correlated with Bacteroides spp. We isolated 18 Bacteroides strains and assessed their GABA production capacity in extracellular vesicles (EVs) and culture supernatant. A GABA-producing Bacteroides finegoldii, released EVs with a high GABA content (4 µM) compared to Phocaeicola massiliensis. Upon testing the capacity of MEVs to cross host barriers, MEVs exhibited a dose-dependent paracellular transport and were endocytosed by Caco-2 and hCMEC/D3 cells. Exposure of Caco-2 cells to MEVs did not alter expression of genes related to intestinal barrier integrity, while affected immune pathways and cell apoptosis process as revealed by RNA-seq analyses. In vivo, MEVs biodistributed across mice organs, including the brain, liver, stomach, and spleen. Our results highlight the ability of MEVs to cross the intestinal and blood-brain barriers to deliver their cargoes to distant organs, with potential implication for the gut-brain axis.IMPORTANCE: Microbiota-released extracellular vesicles (MEVs) have emerged as a key player in intercellular signaling. In this study, a multi-level analysis revealed presence of a diverse array of biologically active molecules encapsulated within MEVs, including neuroactive metabolites, such as arachidonyl-dopamine, gabapentin, glutamate, and N-acylethanolamines, and gamma-aminobutyric acid (GABA). Metaproteomics also unveiled an enrichment of neural-related proteins, mainly the glutamine/glutamate/GABA pathway. MEVs were able to cross epithelial and blood-brain barriers in vitro. RNA-seq analyses showed that MEVs stimulate several immune pathways while suppressing cell apoptosis process. Furthermore, MEVs were able to traverse the intestinal barriers and reach distal organs, including the brain, thereby potentially influencing brain functionality and contributing to mental and behavior.PMID:39699251 | DOI:10.1128/spectrum.01368-24

Tree Physiol. 2024 Dec 19:tpae166. doi: 10.1093/treephys/tpae166. Online ahead of print.ABSTRACTIron plaques on the root surface can promote or inhibit the absorption and accumulation of heavy metals by plants. However, the mechanism by which iron regulates the response of Robinia pseudoacacia to mercury (Hg) have not been elucidated which hinders its application in divalent Hg (Hg2+) removal from Hg-contaminated soil. In this study, association analyses between transcriptome and metabolome were used to investigate effects of iron on the rhizosphere microenvironment and performance of R. pseudoacacia to assess its potential for Hg2+ removal. The results showed that the addition of 10 mg kg-1 iron significantly increased the development of iron plaques on root surface, and reduced the secretion of low-molecular-weight organic acids by roots, thereby changing rhizosphere soil characteristics and decreasing total Hg in roots. In addition, the secretion of choline supported signal transduction and enhanced the interaction between R. pseudoacacia and rhizobia, thereby inducing resistance to Hg2+. Anti-oxidative enzyme activities were increased and Hg2+ exposure of plants was reduced. Enhanced Hg2+ resistance was indicated by improved photosynthesis and growth despite promoted xylem loading and transport of Hg2+, resulting in its accumulation in aboveground tissues that is essential for Hg2+ removal. These results indicate that iron addition has a great potential to improve the growth of R. pseudoacacia in Hg-contaminated soil and promote the accumulation of Hg2+ in aboveground tissues for phytoremediation approaches.PMID:39699123 | DOI:10.1093/treephys/tpae166

Curr Opin Pediatr. 2025 Feb 1;37(1):59-66. doi: 10.1097/MOP.0000000000001419. Epub 2024 Dec 2.ABSTRACTPURPOSE OF REVIEW: We provide an overview of the etiology of childhood cancer, the state of the literature, and highlight some opportunities for future research, including technological advancements that could be applied to etiologic studies of childhood cancer to accelerate our understanding.RECENT FINDINGS: Risk factors of childhood cancer were summarized based on demographics and perinatal factors, environmental risk factors, and genetic risk factors. Overall, demographics and perinatal factors are the most well studied in relation to childhood cancer. While environmental risk factors have been implicated, more work is needed to pinpoint specific exposures, identify window(s) of susceptibility, and understand mechanisms. With genome-wide association studies (GWAS), genetic risk factors of eight childhood cancers have emerged, and opportunities remain to conduct GWAS for other cancer types and determine whether risk variants are inherited or de novo. Technological advancements that can shed light into the susceptibility of childhood cancer include metabolomics, using primary teeth as an exposure matrix, and long-read sequencing.SUMMARY: The development of childhood cancer remains largely not well understood. Collaboration to increase sample size to conduct analyses by histology and/or molecular subtype and application of novel technologies will accelerate our understanding of childhood cancer.PMID:39699102 | DOI:10.1097/MOP.0000000000001419

Plant Cell Physiol. 2024 Dec 19:pcae149. doi: 10.1093/pcp/pcae149. Online ahead of print.ABSTRACTTrees in the genus Populus synthesize sticky and fragrant resins to protect dormant leaf buds during winter. These resins contain diverse phenolic metabolites, in particular hydroxycinnamate esters and methylated flavonoids. P. trichocarpa leaf bud resin is characterized by methylated dihydrochalcone aglycones. To determine how the resin profile is influenced by seasonal changes, P. trichocarpa lateral leaf bud extracts and secreted surface resin were collected monthly over a one-year cycle. The dihydrochalcones in both sets of extracts were quantified using ultrahigh pressure liquid chromatography - mass spectrometry (UPLC-MS) and other chemical changes monitored using non-targeted metabolomics by ultrahigh pressure liquid chromatography - high resolution mass spectrometry (UPLC-HRMS). The results indicate that the dihydrochalcone content changes over the seasons and that biosynthesis occurs concomitant with bud development in the summer months. Non-targeted metabolomics data confirmed a pattern of dramatic changes in the summer, and further suggested additional periods of substantive biochemical change in the resin. While overall patterns of surface-extracted resin matched that of whole bud extracts, some of the dynamics were shifted in the surface resin samples. This study provides the basis for the use of dihydrochalcones and other identified resin components as metabolic markers for more detailed investigations of resin biosynthesis, secretion and movement to the bud surface.PMID:39699046 | DOI:10.1093/pcp/pcae149

Mov Disord. 2024 Dec 19. doi: 10.1002/mds.30083. Online ahead of print.ABSTRACTBACKGROUND: Recent studies have reported that expanded GCA repeats in the GLS gene can cause glutaminase deficiency with ataxia phenotype. However, to data, no studies have investigated the distribution and role of GCA repeats in the GLS gene of Chinese individuals.OBJECTIVE: The aim was to investigate the distribution of GCA repeats in Chinese individuals, including undiagnosed ataxia patients for identifying causal factors, healthy controls for determining the normal range, and ATX-ATXN3 (spinocerebellar ataxia type 3, SCA3) patients for exploring genetic modifiers.METHODS: We combined whole-genome sequencing (WGS), repeat-primed polymerase chain reaction, capillary electrophoresis (RP-PCR/CE), and ExpansionHunter to screen the GCA repeats in the GLS gene of 349 undiagnosed ataxia individuals, 1505 healthy controls, and 1236 ATX-ATXN3 (SCA3) patients from mainland China.RESULTS: No expanded GCA repeats in the GLS gene were detected across any of the samples. The average number of GCA repeats was 11 (range: 8-31), 12 (range: 6-33), and 11 (range: 6-33) for undiagnosed ataxia patients, healthy controls, and SCA3 patients, respectively. The intermediate repeat size (9 < repeat size ≤ 13) of the nonexpanded GCA allele in the GLS gene was associated with later disease onset in ATX-ATXN3 (SCA3) patients.CONCLUSIONS: Abnormal expansions of GLS GCA repeats are rare in the Chinese population. However, intermediate-length normal GCA repeat sizes may influence the age at onset (AAO) in ATX-ATXN3 (SCA3) patients. © 2024 International Parkinson and Movement Disorder Society.PMID:39699045 | DOI:10.1002/mds.30083

J Proteome Res. 2024 Dec 19. doi: 10.1021/acs.jproteome.4c00902. Online ahead of print.ABSTRACTThe prevalence rate of colorectal cancer (CRC) has dramatically increased in recent decades. However, robust CRC biomarkers with therapeutic value for early diagnosis are still lacking. To comprehensively reveal the molecular characteristics of CRC development, we employed a multiomics strategy to investigate eight different types of CRC samples. Proteomic analysis revealed 2022 and 599 differentially expressed tissue proteins between CRC and control groups in CRC patients and CRC mice, respectively. In patients with colorectal precancerous lesions, 25 and 34 significantly changed proteins were found between patients and healthy controls in plasma and white blood cells, respectively. Notably, vesicle-associated membrane protein-associated protein A (VAPA) was found to be consistently and significantly decreased in most types of CRC samples, and its level was also significantly correlated with increased overall survival of CRC patients. Furthermore, 37 significantly enriched pathways in CRC were further validated via metabolomics analysis. Ten VAPA-related pathways were found to be significantly enriched in CRC samples, among which PI3K-Akt signaling, central carbon metabolism in cancer, cholesterol metabolism, and ABC transporter pathways were also enriched in the premalignant stage. Our study identified VAPA and its associated pathways as key regulators, suggesting their potential applications in the early diagnosis and prognosis of CRC.PMID:39699012 | DOI:10.1021/acs.jproteome.4c00902

FASEB J. 2024 Dec 13;38(24):e70250. doi: 10.1096/fj.202401747R.ABSTRACTSkeletal muscles are predominantly composed of long, multinucleated muscle fibers, classified according to their metabolic and contractile phenotype. The determination of fiber types is influenced by various factors (e.g., innervation, hormones, physical demand). Our laboratory and others showed that resolvins, lipid mediators derived from omega-3 fatty acids, promote muscle regeneration and function after an injury or in models of muscular dystrophies; however, the effect of resolvins on the determination of muscle phenotype remains unknown. Here, we investigated the impact of lipid mediators on muscle phenotype during myogenesis. Transcriptomics analysis of single-nuclei RNAseq data sets revealed that the enzymes responsible for bioactive lipids biosynthesis are differentially expressed in slow fibers versus fast fibers. Lipidomics analysis of slow-twitch muscle (soleus) versus fast-twitch muscle (tibialis anterior) showed that the levels of lipids derived from arachidonic acid are similar between muscle groups, but lipids derived from alpha-linolenic acid, linoleic acid, eicosapentaenoic acid, and docosahexaenoic acid are enriched in slow-twitch muscle. Screening for different lipids in vitro showed that resolvin-D2 enhances the formation of myotubes expressing the slow myosin heavy chain isoform. In vivo, the administration of resolvin-D2 enhances muscle strength, increases myofiber size, and affects fiber typing in injured muscles but not in uninjured muscles. Resolvin-D2 promoted the transition toward the dominant fiber types in regenerating muscle (i.e., type I in the slow-twitch soleus and type IIB in the fast-twitch tibialis anterior muscle), suggesting its participation in fiber typing in conjunction with other factors. Overall, these findings identified new roles of bioactive lipids in the regulation of fiber typing, which could have therapeutic applicability in muscle injuries or dystrophies.PMID:39698915 | DOI:10.1096/fj.202401747R

Curr Pharm Des. 2024 Dec 18. doi: 10.2174/0113816128349549241025150229. Online ahead of print.ABSTRACTINTRODUCTION: Dryopteris ramosa is a high-altitude plant of moist and shady habitat. Its aerial parts are edible and orally administered as an antibiotic and effective aphrodisiac. They are also used as pesticides, astringents, and febrifuges.AIM: The present study aimed to elucidate the plant's medicinal potential as an anticancer agent. Extracts of Dryopteris ramosa were examined for cytotoxic effects against AGS, A549, and HCT116 cell lines. The project also aimed to evaluate the phytochemical constitutents of the plant. For this purpose, GC-ToF-MS analysis was executed to identify the bioactive compounds in the aerial parts extract of Dryopteris ramosa. As a result, 93 different phytochemicals were identified from the spectral properties of GC-ToF-MS which contain 19 compounds of high peaks having reported anti-inflammatory, Anti-diabetic, Antibacterial, Analgesic, and antioxidant potential.METHODS: Three different cell lines have been treated against Ethanol, Methanol, Ethyl acetate, Water, Chloroform, Acetone, and n-hexane extracts from the aerial parts of Dryopteris ramosa. These cell lines were checked and were ranked in lethality based on IC50 value. The extract samples were processed as serial dilution from high concentrations (500 ug/ml). All the three cell lines were treated for 48 hours.RESULTS: Extracts showed a significant effect in different cell lines (based on IC50 less than 200 ug/ml). Performing the in-vitro anticancer activity against the three different cell lines in Ethyl Acetate, Methanol, nhexane, Chloroform and Acetone extract of Dryopteris indicated that anticancer activity of the plant is high against AGS and A549 cell line while less prominent in HTC116 cell lines through MTT Assay. Insilico drug-likeness and ADMET analysis were studied of the compounds, that exhibit considerable drug likenesses, phytochemical medicinal chemistry, and a promising ADMET score and no toxicity. The candidate compounds were chosen for further elucidation by Molecular Docking and dynamic simulations. Employing the molecular docking approach for virtual screening of the phytochemicals it was found that the compounds Germacrene showed remarkable results towards BCL2 with -7Kcal/Mol and a-D-(+)-Xylopyranose showed significant docking results towards 5P21 with -7.1Kcal/Mol.CONCLUSION: For multi-scale frames structural aberrations and fluctuations identification of the docked complexes, a molecular dynamics analysis was performed for a 100 ps simulation run by accessing the online tool of MDweb simulations. These molecular docking and simulation analyses also revealed that both the phytochemicals have a stable interaction with the cancer-related proteins BCL2 and 5P21.PMID:39698882 | DOI:10.2174/0113816128349549241025150229

Anal Chem. 2024 Dec 19. doi: 10.1021/acs.analchem.4c05341. Online ahead of print.ABSTRACTWe report the first implementation of ion mobility mass spectrometry combined with an ultrahigh throughput sample introduction technology for high-throughput screening (HTS). The system integrates differential mobility spectrometry (DMS) with acoustic ejection mass spectrometry (AEMS), termed DAEMS, enabling the simultaneous quantitation of structural isomers that are the substrates and products of isomerase-mediated reactions in intermediary metabolism. We demonstrate this potential by comparing DAEMS to a luminescence assay for the isoform of phosphoglycerate mutase (iPGM) distinctively present in pathogens, offering an opportunity as a drug target for a variety of microbial and parasite borne diseases. The metabolome consists of many structural isomers that require for separation a mobility resolving power of more than 300. Resolving powers measured in collision cross-section space of 1588 and 1948 for 2- and 3-phosphoglycerate and the citrate/isocitrate isomeric pairs, respectively, are shown. These are the highest reported ion mobility resolving powers for molecules from the metabolome reported to date. The potential for DAEMS as a generalized screening tool is demonstrated with the separation of the substrates and products of two additional isomerases that present as potential therapeutic targets, chorismate mutase and triosephosphate isomerase. The separations are achieved at speeds compatible with the sample introduction rates of AEMS providing sufficient data points to integrate the peaks for quantitation without the use of internal standards. DMS hyphenated with acoustic sample ejection MS provides a unique solution to high-throughput mass spectrometry applications where separation of isomers and other types of isobaric overlaps are required.PMID:39698870 | DOI:10.1021/acs.analchem.4c05341

Front Cell Dev Biol. 2024 Dec 4;12:1496884. doi: 10.3389/fcell.2024.1496884. eCollection 2024.ABSTRACTBACKGROUND: Mechanical stress and pathological signaling trigger the activation of fibroblasts to myofibroblasts, which impacts extracellular matrix composition, disrupts normal wound healing, and can generate deleterious fibrosis. Myocardial fibrosis independently promotes cardiac arrhythmias, sudden cardiac arrest, and contributes to the severity of heart failure. Fibrosis can also alter cell-to-cell communication and increase myocardial stiffness which eventually may lead to lusitropic and inotropic cardiac dysfunction. Human induced pluripotent stem cell derived cardiac fibroblasts (hiPSC-CFs) have the potential to enhance clinical relevance in precision disease modeling by facilitating the study of patient-specific phenotypes. However, it is unclear whether hiPSC-CFs can be activated to become myofibroblasts akin to primary cells, and the key signaling mechanisms in this process remain unidentified.OBJECTIVE: We aim to explore the notable changes in fibroblast phenotype upon passage-mediated activation of hiPSC-CFs with increased mitochondrial metabolism, like primary cardiac fibroblasts.METHODS: We activated the hiPSC-CFs with serial passaging from passage 0 to 3 (P0 to P3) and treatment of P0 with TGFβ1.RESULTS: Passage-mediated activation of hiPSC-CFs was associated with a gradual induction of genes to initiate the activation of these cells to myofibroblasts, including collagen, periostin, fibronectin, and collagen fiber processing enzymes with concomitant downregulation of cellular proliferation markers. Most importantly, canonical TGFβ1 and Hippo signaling component genes including TAZ were influenced by passaging hiPSC-CFs. Seahorse assay revealed that passaging and TGFβ1 treatment increased mitochondrial respiration, consistent with fibroblast activation requiring increased energy production, whereas treatment with the glutaminolysis inhibitor BPTES completely attenuated this process.CONCLUSION: Our study highlights that the hiPSC-CF passaging enhanced fibroblast activation, activated fibrotic signaling pathways, and enhanced mitochondrial metabolism approximating what has been reported in primary cardiac fibroblasts. Thus, hiPSC-CFs may provide an accurate in vitro preclinical model for the cardiac fibrotic condition, which may facilitate the identification of putative anti-fibrotic therapies, including patient-specific approaches.PMID:39698493 | PMC:PMC11653212 | DOI:10.3389/fcell.2024.1496884

ACS Pharmacol Transl Sci. 2024 Nov 26;7(12):4096-4111. doi: 10.1021/acsptsci.4c00533. eCollection 2024 Dec 13.ABSTRACTFTO, an N 6-methyladenosine (m6A) and N 6,2'-O-dimethyladenosine (m6Am) RNA demethylase, is a promising target for treating acute myeloid leukemia (AML) due to the significant anticancer activity of its inhibitors in preclinical models. Here, we demonstrate that the FTO inhibitor FB23-2 suppresses proliferation across both AML and CML cell lines, irrespective of FTO dependency, indicating an alternative mechanism of action. Metabolomic analysis revealed that FB23-2 induces the accumulation of dihydroorotate (DHO), a key intermediate in pyrimidine nucleotide synthesis catalyzed by human dihydroorotate dehydrogenase (hDHODH). Notably, structural similarities between the catalytic pockets of FTO and hDHODH enabled FB23-2 to inhibit both enzymes. In contrast, the hDHODH-inactive FB23-2 analog, ZLD115, required FTO for its antiproliferative activity. Similarly, the FTO inhibitor CS2 (brequinar), known as one of the most potent hDHODH inhibitors, exhibited FTO-independent antileukemic effects. Uridine supplementation fully rescued leukemia cells from FB23-2 and CS2-induced growth inhibition, but not ZLD115, confirming the inhibition of pyrimidine synthesis as the primary mechanism of action underlying their antileukemic activity. These findings underscore the importance of considering off-target effects on hDHODH in the development of FTO inhibitors to optimize their therapeutic potential and minimize unintended consequences.PMID:39698280 | PMC:PMC11651170 | DOI:10.1021/acsptsci.4c00533

Front Nutr. 2024 Dec 4;11:1495346. doi: 10.3389/fnut.2024.1495346. eCollection 2024.ABSTRACTINTRODUCTION: Hyperuricemia (HUA) is a metabolic disease caused by purine metabolism disorders in the body. Lactic acid bacteria (LAB) and their fermentation broth have the potential to alleviate hyperuricemia, but the potential mechanism of action is still unclear.METHODS: The LAB with high inhibitory activity against xanthine oxidase (XOD) were screened out. Then the fermentation broth, fermentation supernatant and fermentation bacteria after fermentation of these LAB were administered into HUA mice, respectively.RESULTS: Lactobacillus reuteri NCUF203.1 and Lactobacillus brevis NCUF207.7, of which fermentation supernatant had high inhibitory activity against XOD, were screened out and administered into HUA mice. Among them, L. reuteri strain, L. reuteri fermentation broth, L. brevis fermentation broth and L. brevis fermentation supernatant could significantly reduce serum uric acid levels and inhibited the liver XOD activity in HUA mice. The GC-MS metabolomics analysis of colon contents showed that supplementation of these four substances could partially reverse the down-regulation of energy metabolism pathways such as ketone body metabolism, pyruvate metabolism and citric acid cycle in HUA mice. It could also regulate amino acid metabolism pathways such as alanine metabolism, arginine and proline metabolism, glycine and serine metabolism, and repair the disorders of amino acid metabolism caused by HUA. In addition, the intervention of L. brevis fermentation broth and L. brevis fermentation supernatant may also accelerate the catabolism of uric acid in the intestine by up-regulating the urea cycle pathway. Fecal 16S rRNA sequencing analysis showed that their intervention increased the diversity of gut microbiota in HUA mice and alleviated the gut microbiota dysregulation caused by HUA.DISCUSSION: These results indicated that the LAB and their fermentation broth may play a role in alleviating HUA by regulating intestinal metabolism and gut microbiota.PMID:39698246 | PMC:PMC11652139 | DOI:10.3389/fnut.2024.1495346

J Diabetes Metab Disord. 2024 Dec 16;24(1):4. doi: 10.1007/s40200-024-01508-1. eCollection 2025 Jun.ABSTRACTOBJECTIVES: SGLT-2 inhibitors have been shown to exert cardio- and renoprotective actions. We aimed to investigate the underlying mechanisms using 1H-NMR based metabolomics in patients with type-2 diabetes mellitus who received dapagliflozin.METHODS: 50 patients with type 2 diabetes mellitus, inadequately controlled on metformin monotherapy (HbA1c > 7%) received dapagliflozin for 3 months and 30 matched patients received insulin degludec for 3 months. Clinical and laboratory values, as well as 1H-NMR based metabolomics were assessed before treatment and after completion of 3 months of treatment.RESULTS: Dapagliflozin reduced weight, body mass index, systolic and diastolic blood pressure significantly. Using 1H-NMR based metabolomics, the dapagliflozin group showed a good separation with a degree of overlap before and after treatment initiation. Regarding targeted metabolomics, dapagliflozin increased serum ketone, citrate and tryptophan levels compared with insulin. On the other hand, serum taurine, threonine and mannose levels were significantly decreased following dapagliflozin administration.CONCLUSIONS: Dapagliflozin led to a small, but significant change in serum metabolome. The observed changes may indicate improvement in energy metabolism, reduction in inflammatory activity and decreased insulin resistance which may provide further evidence of the agent's observed cardiac and renal protection. The study was registered with ClinicalTrials.gov (identifier: NCT02798757).SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40200-024-01508-1.PMID:39697865 | PMC:PMC11649604 | DOI:10.1007/s40200-024-01508-1