PubMed

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

Front Microbiol. 2024 Nov 29;15:1474071. doi: 10.3389/fmicb.2024.1474071. eCollection 2024.ABSTRACTINTRODUCTION: Tuberculosis (TB) treatment typically involves a tailored combination of four antibiotics based on the drug resistance profile of the infecting strain. The increasing drug resistance of Mycobacterium tuberculosis (Mtb) requires the development of novel antibiotics to ensure effective treatment regimens. Gallium (Ga) is being explored as a repurposed drug against TB due to its ability to inhibit Mtb growth and disrupt iron metabolism. Given the potential interactions between Ga and established antibiotics, we investigated how a combination of Ga with levofloxacin (Lfx) or linezolid (Lzd) affects the growth and metabolome of a multidrug-resistant (MDR) Mtb clinical strain.METHODS: Mtb was cultured using a BACTEC 960 system with concentrations of Ga ranging from 125 to 1,000 μM and with 250 to 500 μM of Ga combined with 0.125 mg/L of Lfx or Lzd. For metabolome analysis, the antibacterials were used at concentrations that inhibited the growth of bacteria without causing cell death. Metabolites were extracted from Mtb cells and analyzed using chromatography-mass spectrometry.RESULTS: The MDR Mtb strain exhibited a dose-dependent response to Ga. Notably, the enhancement in growth inhibition was statistically significant for the Ga/Lfx combination compared to Ga alone, while no such significance was observed for Ga/Lzd. Moreover, exposure to Ga/Lfx or Ga/Lzd resulted in distinct metabolite profiles. Ga treatment increased the level of aconitate, fumarate, and glucose in the cells, suggesting the inhibition of iron-dependent aconitase and fumarate hydratase, as well as disruption of the pentose phosphate pathway. The levels of glucose, succinic acid, citric acid, and hexadecanoic acid followed a similar pattern in cells exposed to Ga and Ga/Lfx at 500 μM Ga but exhibited different trends at 250 μM Ga.DISCUSSION: In the presence of Lfx, the Mtb metabolome changes induced by Ga are more pronounced compared to those observed with Lzd. Lfx affects nucleic acids and transcription, which may enhance Ga-dependent growth inhibition by preventing the metabolic redirection that bacteria typically use to bypass iron-dependent enzymes.PMID:39697659 | PMC:PMC11654424 | DOI:10.3389/fmicb.2024.1474071

J Circ Biomark. 2024 Dec 16;13:36-44. doi: 10.33393/jcb.2024.3146. eCollection 2024 Jan-Dec.ABSTRACTINTRODUCTION: Prostate cancer (PCa) management presents a multifaceted clinical challenge, intricately linking oncological considerations with cardiovascular health. Despite the recognized importance of lipid metabolism and hypertension in this interwoven relationship, their involvement in PCa development remains partially understood. This study aimed to explore variations in plasma metabolome among Sudanese PCa patients and their associated comorbidities.METHODS: Plasma samples were collected from 50 patients across four hospitals in Sudan and profiled by nuclear magnetic resonance (NMR) spectroscopy. One-dimensional proton NMR spectra were acquired for each sample using standard nuclear Overhauser effect spectroscopy pulse sequence presat on a 500 MHz Bruker Avance III HD NMR spectrometer. Metabolite concentrations were quantified using R scripts developed in-house. Univariate and multivariate analyses were generated in the R software.RESULTS: Patients were categorized into four distinct metabotypes based on their metabolic profiles, and statistical analyses were conducted to evaluate the significance of observed differences. Our findings revealed high levels of fatty acids, phospholipids, cholesterol, valine, leucine, and isoleucine associated with non-hypertensive patients. In contrast, hypertensive patients were associated with high GlycA and GlycB levels and altered amino acid metabolism.CONCLUSION: These findings underscore the intricate interplay between metabolic dysregulation and hypertension in PCa patients. Further research is warranted to elucidate the precise molecular pathways underlying lipid metabolism in PCa and to explore the therapeutic potential of targeting these pathways. In conclusion, our study contributes to a deeper understanding of the metabolic landscape of PCa in Sudanese patients, emphasizing the importance of personalized approaches in cancer management.PMID:39697480 | PMC:PMC11653783 | DOI:10.33393/jcb.2024.3146

Tob Induc Dis. 2024 Dec 18;22. doi: 10.18332/tid/196677. eCollection 2024.ABSTRACTINTRODUCTION: This study aimed to evaluate the metabolomic profiles of urine samples obtained from smokers who smoked cigarettes with low and high nicotine content.METHODS: Three smokers participated in this study. They were given low-nicotine (LN) cigarettes, and urine was collected at the end of the third day for the LN group. After 1 week of not smoking, they were given high-nicotine (HN) cigarettes, and urine was collected for the HN group. Untargeted metabolomics and bioinformatic analysis methods were used for urine analysis.RESULTS: PCA showed a high degree of similarity between samples within the group and a large distance between samples between groups, indicating a significant difference between the two groups. A total of 1150 significantly differential metabolites were selected between the HN and LN groups, such as cotinine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol-N-glucuronide. Two-way hierarchical clustering analysis also suggested noticeable differences between the two comparison groups Enrichment analysis indicates that the differential metabolites between the two groups were mainly enriched in 19 pathways, such as the protein kinase G (cGMP)-protein kinase G (PKG) signaling pathway, adenosine monophosphate (AMP)-activated protein kinase signaling pathway, mammalian target of rapamycin signaling pathway, and Parkinson's disease.CONCLUSIONS: Cigarettes with different nicotine content may alter the metabolism of smokers. A total of 1150 significantly different metabolites were identified between the HN and LN groups, which were mainly enriched in ABC transporters, protein kinase G (cGMP)-protein kinase G (PKG) signaling pathway, caffeine metabolism, and arginine biosynthesis pathways.PMID:39697303 | PMC:PMC11653067 | DOI:10.18332/tid/196677

Crit Rev Clin Lab Sci. 2024 Dec 19:1-28. doi: 10.1080/10408363.2024.2430775. Online ahead of print.ABSTRACTPolycystic ovary syndrome (PCOS) is a complex multifactorial endocrinopathy affecting reproductive aged women globally, whose presentation is strongly influenced by genetic makeup, ethnic, and geographic diversity leaving these affected women substantially predisposed to reproductive and metabolic perturbations. Sophisticated techniques spanning genomics, proteomics, epigenomics, and transcriptomics have been harnessed to comprehensively understand the enigmatic pathophysiology of PCOS, however, conclusive markers for PCOS are still lacking today. Metabolomics represents a paradigm shift in biotechnological advances enabling the simultaneous identification and quantification of metabolites and the use of this approach has added yet another dimension to help unravel the strong metabolic component of PCOS. Reports dissecting the metabolic signature of PCOS have revealed disparate levels of metabolites such as pyruvate, lactate, triglycerides, free fatty acids, carnitines, branched chain and essential amino acids, and steroid intermediates in major biological compartments. These metabolites have been shown to be altered in women with PCOS overall, after phenotypic subgrouping, in animal models of PCOS, and also following therapeutic intervention. This review seeks to supplement previous reviews by highlighting the aforementioned aspects and to provide easy, coherent and elementary access to significant findings and emerging trends. This will in turn help to delineate the metabolic plot in women with PCOS in various biological compartments including plasma, urine, follicular microenvironment, and gut. This may pave the way to design additional studies on the quest of unraveling the etiology of PCOS and delving into novel biomarkers for its diagnosis, prognosis and management.PMID:39697160 | DOI:10.1080/10408363.2024.2430775

Plant Physiol. 2024 Dec 19:kiae615. doi: 10.1093/plphys/kiae615. Online ahead of print.ABSTRACTCollections of insertional mutants have been instrumental for characterizing the functional relevance of genes in different model organisms, including Arabidopsis (Arabidopsis thaliana). However, mutations may often result in subtle phenotypes, rendering it difficult to pinpoint the function of a knocked-out gene. Here, we present a data-integrative modeling approach that enables predicting the effects of mutations on metabolic traits and plant growth. To test the approach, we gathered lipidomics data and physiological read-outs for a set of 64 Arabidopsis lines with mutations in lipid metabolism. Use of flux sums as a proxy for metabolite concentrations allowed us to integrate the relative abundance of lipids and facilitated accurate predictions of growth and biochemical phenotype in approximately 73% and 76% of the mutants, respectively, for which phenotypic data were available. Likewise, we showed that this approach can pinpoint alterations in metabolic pathways related to silent mutations. Therefore, our study paves the way for coupling model-driven characterization of mutant lines from different mutagenesis approaches with metabolomic technologies, as well as for validating knowledge structured in large-scale metabolic networks of plants and other species.PMID:39696931 | DOI:10.1093/plphys/kiae615

Oncoimmunology. 2025 Dec;14(1):2432726. doi: 10.1080/2162402X.2024.2432726. Epub 2024 Dec 18.ABSTRACTOver the last decade, the annual Immunorad Conference, held under the joint auspicies of Gustave Roussy (Villejuif, France) and the Weill Cornell Medical College (New-York, USA) has aimed at exploring the latest advancements in the fields of tumor immunology and radiotherapy-immunotherapy combinations for the treatment of cancer. Gathering medical oncologists, radiation oncologists, physicians and researchers with esteemed expertise in these fields, the Immunorad Conference bridges the gap between preclinical outcomes and clinical opportunities. Thus, it paves a promising way toward optimizing radiotherapy-immunotherapy combinations and, from a broader perspective, improving therapeutic strategies for patients with cancer. Herein, we report on the topics developed by key-opinion leaders during the 7th Immunorad Conference held in Paris-Les Cordeliers (France) from September 27th to 29th 2023, and set the stage for the 8th edition of Immunorad which will be held at Weill Cornell Medical College (New-York, USA) in October 2024.PMID:39696783 | DOI:10.1080/2162402X.2024.2432726

Environ Microbiome. 2024 Dec 18;19(1):103. doi: 10.1186/s40793-024-00656-4.ABSTRACTBACKGROUND: Pollen is a crucial source of nutrients and energy for pollinators. It also provides a unique habitat and resource for microbiota. Previous research on the microbiome of pollen has largely focused on angiosperm systems, with limited research into coniferous gymnosperms. This study characterises the pollen microbiome and metabolome associated with one of the world's most widely grown tree species, Pinus radiata. Trees were sampled from locations across Canterbury, New Zealand. Repeated collections were undertaken in 2020 and 2021.RESULTS: Metabolomic analysis revealed the main compounds present on P. radiata pollen to be amino acids (principally proline), and carbohydrates (fructose, glucose, and sucrose). Although phenolic compounds such as ρ-coumaric acid and catechin, and terpenoids such as dehydroabietic acid, were present at low concentrations, their strong bioactive natures mean they may be important in ecological filtering of microbiome communities on pollen. The P. radiata pollen microbiome was richer in fungal taxa compared with bacteria, which differs from many angiosperm species. Geographic range and annual variation were evaluated as drivers of microbiome assembly. Neither sampling location (geographic range) nor annual variation significantly influenced the fungal community which exhibited remarkable conservation across samples. However, some bacterial taxa exhibited sensitivity to geographic distances and yearly variations, suggesting a secondary role of these factors for some taxa. A core microbiome was identified in P. radiata pollen, characterized by a consistent presence of specific fungal and bacterial taxa across samples. While the dominant phyla, Proteobacteria and Ascomycota, align with findings from other pollen microbiome studies, unique core members were unidentified at genus level.CONCLUSION: This tree species-specific microbiome assembly emphasizes the crucial role of the host plant in shaping the pollen microbiome. These findings contribute to a deeper understanding of pollen microbiomes in gymnosperms, shedding light on the need to look further at their ecological and functional roles.PMID:39696657 | DOI:10.1186/s40793-024-00656-4

Stem Cell Res Ther. 2024 Dec 18;15(1):467. doi: 10.1186/s13287-024-04109-0.ABSTRACTBACKGROUND: Mesenchymal stem cells (MSCs) are widely applied in the treatment of various clinical diseases and in the field of medical aesthetics. However, MSCs exhibit greater heterogeneity limited stability, and more complex molecular and mechanistic characteristics compared to conventional drugs, making rapid and precise monitoring more challenging.METHODS: Surface-enhanced Raman spectroscopy (SERS) is an ultrasensitive, tractable and low-cost fingerprinting technique capable of identifying a wide range of molecules related to biological processes. Here, we employed SERS for reproducible quantification of ultralow concentrations of molecules and utilized spectral sets, termed SERSomes, for robust and comprehensive intracellular multi-metabolite profiling.RESULTS: We revealed that with increasing passage number, there is a gradual decline in cell expansion efficiency, accompanied by significant changes in intracellular amino acids, purines, and pyrimidines. By integrating these metabolic features detected by SERS with transcriptomic data, we established a correlation between SERS signals and biological changes, as well as differentially expressed genes.CONCLUSION: In this study, we explore the application of SERS technique to provide robust metabolic characteristics of MSCs across different passages and donors. These results demonstrate the effectiveness of SERSome in reflecting biological characteristics. Due to its sensitivity, adaptability, low cost, and feasibility for miniaturized instrumentation throughout pretreatment, measurement, and analysis, the label-free SERSome technique is suitable for monitoring MSC expansion and offers significant advantages for large-scale MSC manufacturing.PMID:39696645 | DOI:10.1186/s13287-024-04109-0

BMC Vet Res. 2024 Dec 18;20(1):563. doi: 10.1186/s12917-024-04417-w.ABSTRACTMarbling is a key indicator of the meat quality of ruminants. Gastrointestinal microbiota may regulate the formation of marbling by influencing the nutritional metabolism of animals. This study analyzed the composition and functional differences of microbiota in the rumen and cecum, the differences in volatile fatty acids (VFAs) content in the longissimus thoracis muscle, and the differences in protein abundance in the longissimus thoracis muscle of ruminants with different marbling grades through microbiome-proteome analysis. The results showed that the diversity of gastrointestinal microbiota in high-marbling ruminants was significantly higher than that in low-marbling ruminants. The relative abundance of Firmicutes and Akkermansia in the gastrointestinal of high-marbling ruminants was higher than that in low-marbling ruminants, while the relative abundance of Bacteroidetes and Prevotella was lower. In addition, PICRUST2 functional prediction results of the microbiota revealed that the gastrointestinal microbiota of high-marbling ruminants was mainly involved in the biosynthesis pathways of fat and lipids. The metabolomics results showed that the content of VFAs (acetic acid, propionic acid, butyric acid, isovaleric acid, valeric acid, and hexanoic acid) in the rumen of high-marbling ruminants was significantly higher than that in low-marbling ruminants. The proteome analysis results indicated that the differential proteins in the longissimus thoracis muscle of high-marbling ruminants were mainly involved in lipid transport and metabolism compared to low-marbling ruminants. In summary, the differences in the composition and function of the gastrointestinal microbiota led to higher levels of VFAs in the gastrointestinal tract of high-marbling ruminants, which provides the basis for lipid/fat synthesis. The proteome results of the longissimus thoracis muscle support the view that high-marbling ruminants have richer lipid transport and metabolic functions in their muscle.PMID:39696486 | DOI:10.1186/s12917-024-04417-w

Stem Cell Res Ther. 2024 Dec 18;15(1):485. doi: 10.1186/s13287-024-04072-w.ABSTRACTBACKGROUND: Adipose-derived stem cells (ADSCs) are widely used in the field of regenerative medicine because of their various functions, including anti-inflammatory effects. ADSCs are considered to exert their anti-inflammatory effects by secreting anti-inflammatory cytokines and extracellular vesicles. Although recent studies have reported that metabolites have a variety of physiological activities, whether those secreted by ADSCs have anti-inflammatory properties remains unclear. Here, we performed multiomics analyses to examine the effect of ADSC-derived metabolites on M1-like macrophages, which play an important role in inflammatory responses.METHODS: The concentration of metabolites in the culture supernatant of ADSCs was quantified using capillary electrophoresis time-of-flight mass spectrometry. To evaluate their effects on inflammatory responses, M1-like macrophages were exposed to the conditioned ADSC medium or their metabolites, and RNA sequencing was used to detect gene expression changes. Immunoblotting was performed to examine how the metabolite suppresses inflammatory processes. To clarify the contribution of the metabolite in the conditioned medium to its anti-inflammatory effects, metabolite uptake was pharmacologically inhibited, and gene expression and the tumor necrosis factor-α concentration were measured by quantitative PCR and enzyme-linked immunosorbent assay, respectively.RESULTS: Metabolomic analysis showed large amounts of lactate in the culture supernatant. The conditioned medium and lactate significantly suppressed or increased the pro-inflammatory and anti-inflammatory gene expressions. However, sequencing and immunoblotting analysis revealed that lactate did not induce polarization from M1- to M2-like macrophages. Based on a recent report that the immunosuppressive effect of lactate depends on epigenetic reprogramming, histone acetylation was investigated, and H3K27ac expression was upregulated. In addition, 7ACC2, which specifically inhibits the monocarboxylate transporter 1, significantly inhibited the anti-inflammatory effect of the conditioned ADSC medium on M1-like macrophages.CONCLUSIONS: Our results showed that ADSCs suppress pro-inflammatory effects of M1-like macrophages by secreting lactate. This study adds to our understanding of the importance of metabolites and is also expected to elucidate new mechanisms of ADSC treatments.PMID:39696485 | DOI:10.1186/s13287-024-04072-w

Cancer Metab. 2024 Dec 18;12(1):37. doi: 10.1186/s40170-024-00366-y.ABSTRACTBACKGROUND: The efficacy of tyrosine kinase inhibitors (TKIs) targeting the EGFR is limited due to the persistence of drug-tolerant cell populations, leading to therapy resistance. Non-genetic mechanisms, such as metabolic rewiring, play a significant role in driving lung cancer cells into the drug-tolerant state, allowing them to persist under continuous drug treatment.METHODS: Our study employed a comprehensive approach to examine the impact of the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) on the adaptivity of lung cancer cells to EGFR TKI therapies. We conducted metabolomics to trace glucose rerouting in response to PFKFB3 inhibition during TKI treatment. Live cell imaging and DCFDA oxidation were used to quantify levels of oxidation stress. Immunocytochemistry and Neutral Comet assay were employed to evaluate DNA integrity in response to therapy-driven oxidative stress.RESULTS: Our metabolic profiling revealed that PFKFB3 inhibition significantly alters the metabolic profile of TKI-treated cells. It limited glucose utilization in the polyol pathway, glycolysis, and TCA cycle, leading to a depletion of ATP levels. Furthermore, pharmacological inhibition of PFKFB3 overcome TKI-driven redox capacity by diminishing the expression of glutathione peroxidase 4 (GPX4), thereby exacerbating oxidative stress. Our study also unveiled a novel role of PFKFB3 in DNA oxidation and damage by controlling the expression of DNA-glycosylases involved in base excision repair. Consequently, PFKFB3 inhibition improved the cytotoxicity of EGFR-TKIs by facilitating ROS-dependent cell death.CONCLUSIONS: Our results suggest that PFKFB3 inhibition reduces glucose utilization and DNA damage repair, limiting the adaptivity of the cells to therapy-driven oxidative stress and DNA integrity insults. Inhibiting PFKFB3 can be an effective strategy to eradicate cancer cells surviving under EGFR TKI therapy before they enter the drug-resistant state. These findings may have potential implications in the development of new therapies for drug-resistant cancer treatment.PMID:39696407 | DOI:10.1186/s40170-024-00366-y

Lipids Health Dis. 2024 Dec 18;23(1):402. doi: 10.1186/s12944-024-02380-x.ABSTRACTBACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely associated with many aspects of disturbed metabolic health. MASLD encompasses a wide spectrum of liver diseases, ranging from isolated steatosis to metabolic dysfunction-associated steatohepatitis (MASH), up to fibrosis, cirrhosis, and ultimately hepatocellular carcinoma. Limited noninvasive diagnostic tools are currently available to distinguish the various stages of MASLD and as such liver biopsy remains the gold standard for MASLD diagnostics. We aimed to explore whether the plasma lipidome and its variations can serve as a biomarker for MASLD stages.METHODS: We investigated the plasma lipidome of 7 MASLD-free subjects and 32 individuals with MASLD, of whom 11 had MASH based on biopsy scoring.RESULTS: Compared with the MASLD-free subjects, individuals with MASLD had higher plasma concentrations of sphingolipids, glycerolipids, and glycerophospholipids. Only plasma concentrations of ceramide-1-phosphate C1P(d45:1) and phosphatidylcholine PC(O-36:3), PC(O-38:3), and PC(36:2) differed significantly between presence of MASH in individuals with MASLD. Of these lipids, the first three have a very low relative plasma abundance, thus only PC(36:2) might serve as a biomarker with higher plasma concentrations in MASLD individuals without MASH compared to those with MASH.CONCLUSIONS: Plasma lipids hold promise as biomarkers of MASLD stages, whereas plasma PC(36:2) concentrations would be able to distinguish individuals with MASH from those with MASLD without MASH.PMID:39696394 | DOI:10.1186/s12944-024-02380-x

J Nanobiotechnology. 2024 Dec 19;22(1):768. doi: 10.1186/s12951-024-03034-x.ABSTRACTBACKGROUND: Sleep disorder is widespread and involves a variety of intricate factors in its development. Sleep deprivation is a manifestation of sleep disorder, can lead to energy metabolism disturbances, weakened immune system, and compromised body functions. In extreme situations, sleep deprivation can cause organ failure, presenting significant risks to human health.PURPOSE: This study aimed to investigate the efficacy and mechanisms of Astragalus Radix vesicles-like nanoparticles (AR-VLNs) in counteracting the deleterious effects of sleep deprivation.METHODS: The ICR mice were divided into control, model, AR-VLNs high dose (equivalent to 20 g/kg crude drug), AR-VLNs low dose (equivalent to 10 g/kg crude drug), AR high dose (equivalent to 20 g/kg crude drug), and AR low dose (equivalent to 10 g/kg crude drug). The REM (rapid eye movement) sleep-deprivation model was established, and evaluations were conducted for motor function, antioxidant capacity, and energy metabolism indices. Moreover, CACO-2 cells damage was induced with lipopolysaccharide to evaluate the repairing ability of AR-VLNs on the intestinal cell mucosa by measuring permeability. Furthermore, metabolomics was employed to elucidate the mechanisms of AR-VLNs action.RESULTS: AR-VLNs were demonstrated to enhance the motor efficiency and antioxidant capacity in REM sleep-deprived mice, while also minimized pathological damage and restored the integrity of the intestinal mucosal barrier. In vitro experiments indicated the anti-inflammatory effect of AR-VLNs against LPS-induced cell damage. Additionally, metabolomic analysis linked these effects with regulation of the amino acid metabolic pathways. Further confirmation from molecular biology experiments revealed that the protective effects of AR-VLNs against the deleterious effects of REM sleep deprivation were associated with the restoration of the intestinal mucosal barrier and the enhancement of amino acid metabolism.CONCLUSION: AR-VLNs administration effectively improved energy metabolism disorders in REM sleep deprived mice, by facilitating the repair of the intestinal mucosal barrier and regulating the amino acid metabolism.PMID:39696385 | DOI:10.1186/s12951-024-03034-x