PubMed

Int J Biol Macromol. 2024 Dec 9:138625. doi: 10.1016/j.ijbiomac.2024.138625. Online ahead of print.ABSTRACTStilbenes constitute a class of naturally occurring polyphenolic compounds that have been identified in a wide range of plants. In wine, stilbenes play crucial roles in humans, exhibiting anti-cancer, anti-inflammatory, antioxidant properties, and aiding in the prevention of cardiovascular diseases. Therefore, studies on the synthesis and regulatory mechanisms of styrene compounds in grapes are of great economic importance. In this study, we discovered that BS (BSISTER) transcript factors, a member of the MADS-BOX gene family, regulate the biosynthesis of stilbenes in grapevine. Comprehensive transcriptome and phenolic metabolome analysis were conducted on wild-type grapevine callus, as well as on transgenic callus overexpressing 35S::VviBS1-GFP and 35S: VviBS2-GFP under the control of the 35S promoter. The results showed that VviBS1 and VviBS2 down-regulate the synthesis of stilbenes. We screened seven STS differential genes from the transcriptome and further examined the expression of these differential genes in grapevine callus by RT-qPCR, and found that VviSTS48 was the most highly expressed compared to other STS genes. In addition, yeast one-hybrid assay, dual luciferase assay, and Chip-qPCR assay were performed for validation. The results of these experiments indicate that VviBS1 and VviBS2 down-regulate astragalus synthesis by directly binding to the promoter of VviSTS48. In conclusion, our researches provide new insight into the regulatory mechanisms of stilbenes biosynthesis in grapevine, which could be effectively employed for metabolic engineering to regulate stilbenes content and represent a useful reference for further study of BS function.PMID:39662544 | DOI:10.1016/j.ijbiomac.2024.138625

Neurobiol Dis. 2024 Dec 9:106762. doi: 10.1016/j.nbd.2024.106762. Online ahead of print.ABSTRACTLipidomic alterations have been associated with various neurological diseases. Examining temporal changes in serum lipidomic profiles, irrespective of injury type, reveals promising prognostic indicators. In this longitudinal prospective observational study, serum samples were collected early (46 ± 24 h) and late (142 ± 52 h) post-injury from 70 patients with ischemic stroke, aneurysmal subarachnoid hemorrhage, and traumatic brain injury that had outcomes dichotomized as favorable (modified Rankin Scores (mRS) 0-3) and unfavorable (mRS 4-6) three months post-injury. Lipidomic profiling of 1153 lipids, analyzed using statistical and machine learning methods, identified 153 lipids with late-stage significant outcome differences. Supervised machine learning pinpointed 12 key lipids, forming a combinatory prognostic equation with high discriminatory power (AUC 94.7 %, sensitivity 89 %, specificity 92 %; p < 0.0001). Enriched functions of the identified lipids were related to sphingolipid signaling, glycerophospholipid metabolism, and necroptosis (p < 0.05, FDR-corrected). The study underscores the dynamic nature of lipidomic profiles in acute brain injuries, emphasizing late-stage distinctions and proposing lipids as significant prognostic markers, transcending injury types. These findings advocate further exploration of lipidomic changes for a comprehensive understanding of pathobiological roles and enhanced prediction for recovery trajectories.PMID:39662533 | DOI:10.1016/j.nbd.2024.106762

Ecotoxicol Environ Saf. 2024 Dec 10;289:117475. doi: 10.1016/j.ecoenv.2024.117475. Online ahead of print.ABSTRACTPerfluorodecanoic acid (PFDA) is a typical perfluoroalkyl substances frequently encountered in populations, posing significant risks to human health. However, research on the effects of PFDA exposure on organism metabolism and related pathogenic mechanisms is severely lacking. In this study, serum and liver samples of C57BL/6 J mice exposed to different doses of PFDA were analyzed by UPLC-HRMS-based metabolomics and lipidomics techniques. Both 1 mg/kg and 10 mg/kg PFDA exposure induced liver damage, while only 10 mg/kg PFDA exposure caused weight loss. Metabolomics analysis revealed that 330 and 515 metabolites were significantly altered in the serum and liver of mice after PFDA exposure, respectively. Most amino acids and peptides increased in the serum but decreased in the liver. Lipidomics analysis indicated that 281 and 408 lipids experienced significant alterations in the serum and liver after PFDA exposure, respectively. Most lipids, particularly multiple triacylglycerols, were downregulated in a dose-dependent manner in both serum and liver. Taken together, PFDA can induce changes in the amino acid metabolism pathway, disrupt fatty acid β-oxidation, and down-regulate glycolipid pathways in mice, resulting in disturbances in energy metabolism. These findings suggested that the liver is a critical target organ for PFDA exposure, and will also help inform future risk assessment.PMID:39662454 | DOI:10.1016/j.ecoenv.2024.117475

Sci Total Environ. 2024 Dec 10;958:177982. doi: 10.1016/j.scitotenv.2024.177982. Online ahead of print.ABSTRACTOxybenzone (BP-3), a common sunscreen ingredient, has been detected in marine ecosystems and shown to be toxic to various marine species, raising environmental concerns. However, its effects on macroalgae remain largely unknown. This study investigated the toxicity of BP-3 on two macroalgae species: Hormosira banksii and Ulva lactuca. A chronic germination-inhibition experiment with H. banksii and an acute study with mature U. lactuca were conducted using BP-3 concentrations ranging from 0.03 to 27 mg/L. Results revealed significant inhibition of H. banksii spore germination at 3, 9, and 27 mg/L BP-3 at 72 h, with a 10 % effect concentration of 0.363 mg/L (95 % confidence interval: 0.27-0.45 mg/L). For U. lactuca, relative growth rate decreased by 20-70 % compared to controls in treatments of 0.1, 3, 9, and 27 mg/L BP-3 after 72 h. Exposure to ≥0.3 mg/L BP-3 resulted in lower chlorophyll a and b concentrations and higher lipid peroxidation, with significant differences observed between the control and ≥9 mg/L BP-3 treatments. Exposure to 1 mg/L BP-3 induced significant alterations in several key metabolic pathways associated with stress response mechanisms, energy metabolism, and cellular signalling in U. lactuca. These findings suggest that BP-3 does not pose an acute risk to mature U. lactuca or a chronic risk to H. banksii at concentrations typically observed in the marine environment, as in both cases effect concentrations exceeded BP-3 concentrations typically observed in marine environmental water samples. However, further research is needed to assess potential risks associated with chronic exposure to environmentally relevant concentrations. These toxicity data contribute valuable information for future risk assessments of BP-3 and aid in setting water quality guidelines for this widely used organic UV filter.PMID:39662409 | DOI:10.1016/j.scitotenv.2024.177982

J Chromatogr A. 2024 Dec 6;1740:465588. doi: 10.1016/j.chroma.2024.465588. Online ahead of print.ABSTRACTThe analysis of ionic compounds by liquid chromatography is challenging due to the interaction of analytes with the metal surface of the instrument and the column, leading to poor peak shape and decreased sensitivity. The use of bioinert materials in the chromatographic system minimizes these unrequired interactions. In this work, the ultrahigh-performance liquid chromatography (UHPLC) with bioinert components was connected to a high-resolution mass spectrometer to develop a method for untargeted metabolomic analysis. 81 standards of metabolites were used for the development and optimization of the method. In comparison to the conventional chromatographic system, the application of bioinert technology resulted in significantly improved peak shapes and increased sensitivity, especially for metabolites containing phosphate groups. The calibration curves were constructed for the evaluation of the method performance, showing a wide dynamic range, low limit of detection, and linear regression coefficients higher than 0.99 for all standards. The optimized method was applied to the analysis of NIST SRM 1950 human plasma, which allowed the detection of 156 metabolites and polar lipids based on the combination of mass accuracy in the full-scan mass spectra in both polarity modes, characteristic fragment ions in MS/MS, and logical chromatographic behavior leading to the high confidence level of annotation/identification. We have demonstrated an improvement in the peak shapes and sensitivity of ionic metabolites using bioinert technology, which indicates the potential for the analysis of other ionic compounds, e.g., molecules containing phosphate groups.PMID:39662336 | DOI:10.1016/j.chroma.2024.465588

Poult Sci. 2024 Dec 5;104(1):104623. doi: 10.1016/j.psj.2024.104623. Online ahead of print.ABSTRACTEggshell translucency is the common problem on eggshell that become more severe with age. They are important because it influence consumer preferences and the economic value of eggs. The reason for the eggshell translucency is currently believed to be the eggshell membrane (ESM). In this study, we screened translucency eggs and normal eggs and used metabolomics to study liver metabolism in different eggshell translucency and discuss important liver lipids and phosphatidyl metabolites. Liver samples were taken for Liquid Chromatograph Mass Spectrometer (LC-MS) during the formation of eggshell membranes in hens, that is, when eggs form eggshell membranes in the oviduct isthmus. The results showed that we identified two essential metabolic pathways through differential metabolite pathway analysis, which were glycine, serine, and threonine metabolism related to amino acids metabolism and the PPAR metabolic pathway related to lipid metabolism. Furthermore, this study helps us understand the process of translucency egg production in poultry. This laid the foundation for in-depth research on eggshell translucency. These results may and provide support for future breeding.PMID:39662257 | DOI:10.1016/j.psj.2024.104623

Poult Sci. 2024 Dec 5;104(1):104643. doi: 10.1016/j.psj.2024.104643. Online ahead of print.ABSTRACTOmics techniques, including genomics, transcriptomics, proteomics, metabolomics, and lipidomics, analyze entire sets of biological molecules to seek comprehensive knowledge on a particular phenotype. These approaches have been extensively utilized to identify both biomarkers and biological mechanisms for various physiological conditions in livestock and poultry. The purpose of this symposium was not only to focus on how recent omics technologies can be used to gather, integrate, and interpret data produced by various methodologies in poultry research, but also to highlight how omics and bioinformatics have increased our understanding of poultry meat quality problems and other complex traits. This Poultry Science Association symposium paper includes 5 sections that cover: 1) functional annotation of cis-regulatory elements in the genome informs genetic control of complex traits in poultry, 2) mass spectrometry for proteomics, metabolomics, and lipidomics, 3) proteomic approaches to investigate meat quality, 4) spatial transcriptomics and metabolomics studies of wooden breast disease, and 5) multiomics analyses on chicken meat quality and spaghetti meat. These topics provide insights into the molecular components that contribute to the structure, function, and dynamics of the underlying mechanisms influencing meat quality traits, including chicken breast myopathies. This information will ultimately contribute to improving the quality and composition of poultry products.PMID:39662255 | DOI:10.1016/j.psj.2024.104643

J Photochem Photobiol B. 2024 Dec 8;262:113079. doi: 10.1016/j.jphotobiol.2024.113079. Online ahead of print.ABSTRACTDespite increasing evidence suggesting that red light photobiomodulation (R-PBM) and leonurus play important roles in analgesic and anti-inflammatory processes, data on their combined effect on primary dysmenorrhea (PD) are scarce. In this study, we reported the pain assessment of red light at various modes combined with leonurus on the oxytocin-induced model of PD mice. The combined intervention of pulsed R-PBM and leonurus decreased pain responses and PGF2α/PGE2 levels, alleviated uterine swelling and inflammatory infiltration, enhanced antioxidant levels (T-AOC, GSH-PX, SOD), and reduced lipid peroxidation (MDA, LPO) in the uterus, with its synergistic effect surpassing either treatment alone or the combination of continuous wave R-PBM with leonurus. Transcriptomic analysis demonstrated significant changes in differentially expressed genes associated with calcium signaling (Cav1, Cacna1c, Kcnmb1, Cnn1, and Myh11) and inflammatory response (Ptgs2, Jun, Fos, IL1rn, and IL17b) in the combination group, with concurrent downregulation of MLCK, COX-2, p-JNK/JNK, and IL17b protein levels, and upregulation of IL1rn, suggesting that the combined intervention of pulsed R-PBM and leonurus may alleviate pain through disruption of calcium homeostasis and induction of ROS-mediated inflammatory responses. Metabolomics studies of plasma revealed significant changes in lipid metabolism after the combined intervention, consistent with the transcriptomic findings. Hence, pulsed R-PBM combined leonurus has the potential to be an effective therapeutic approach for PD, as well as an alternative option for painful and inflammatory diseases; however, further exploration of its underlying mechanism is still necessary.PMID:39662253 | DOI:10.1016/j.jphotobiol.2024.113079

Food Chem. 2024 Dec 4;467:142368. doi: 10.1016/j.foodchem.2024.142368. Online ahead of print.ABSTRACTPecan (Carya illinoinensis) is a globally important nut crop, yet the processes of lipid biosynthesis and spatial lipid distribution within its embryo remain poorly understood. This study employed UHPLC-MS/MS and MALDI-MSI to profile lipids in developing pecan embryos, identifying 401 lipid molecules, including a high abundance of glycerolipids (148) and glycerophospholipids (144). Differential diacylglycerols showed gradual uptrends, highlighting their role in synthesizing glycerolipids and glycerophospholipids. Unsaturated fatty acids, especially oleic, linoleic, and linolenic acids, were enriched in triacylglycerols, diacylglycerols, phosphatidylethanolamines, and phosphatidylcholines. MALDI-MSI revealed the spatial distribution of phosphatidic acid (PA), phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylinositol (PI), suggesting heterogeneous lipid distribution within embryos. The proportion of linoleic and linolenic acids is higher in the kernel coat, whereas the proportion of oleic acid is relatively higher in the cotyledons. Differences in lipid content were also observed between the inner and outer cotyledons. This study provides the first comprehensive map of lipid distribution in pecan embryos, offering new insights into lipid metabolism regulation.PMID:39662248 | DOI:10.1016/j.foodchem.2024.142368

Clin Nutr. 2024 Dec 6;44:124. doi: 10.1016/j.clnu.2024.12.010. Online ahead of print.NO ABSTRACTPMID:39662117 | DOI:10.1016/j.clnu.2024.12.010

Kidney Blood Press Res. 2024 Dec 11:1-21. doi: 10.1159/000542263. Online ahead of print.ABSTRACTINTRODUCTION: Urolithiasis is characterized by a high morbidity and recurrence rate, primarily attributed to metabolic disorders. The identification of more metabolic biomarkers would provide valuable insights into the etiology of stone formation and the assessment of disease risk. The present study aimed to seek potential organic acid (OA) biomarkers from morning urine samples and explore new methods based on machine learning (ML) for metabolic risk prediction of urolithiasis.METHODS: Morning urine samples were collected from 117 healthy controls and 156 urolithiasis patients. Gas chromatography-mass spectrometry (GC-MS) was used to obtain metabolic profiles. Principal component analysis (PCA) and ML were carried out to screen robust markers and establish a prediction evaluation model.RESULTS: There were 25 differential metabolites identified, such as palmitic acid, L-pyroglutamic acid, glyoxylate, and ketoglutarate, mainly involving arginine and proline metabolism, fatty acid degradation, glycine, serine, and threonine metabolism, glyoxylate and dicarboxylic acid metabolism. The urinary organic acid markers significantly improved the performance of the ML model. The sensitivity and specificity were up to 87.50% and 84.38%, respectively. The area under the receiver operating characteristic curve (AUC) was significantly improved (AUC = 0.9248).CONCLUSION: The results suggest that OA profiles in morning urine can improve the accuracy of predicting urolithiasis risk, and possibly help to understand the involvement of metabolic perturbations in metabolic pathways of stone formation and to provide new insights.PMID:39662072 | DOI:10.1159/000542263

Clin Lab. 2024 Dec 1;70(12). doi: 10.7754/Clin.Lab.2024.240717.ABSTRACTBACKGROUND: Neonatal birth/perinatal asphyxia is a critical condition that can adversely affect many different bodily tissues, particularly the brain; depending on duration and severity of asphyxia, leading to difficulties and lifelong disabilities. These can be avoided by early detection of the biochemical derangements and prompt intervention. Serum alpha-ketoglutarate (α-KG) and cord blood lactate have been found to be associated with birth asphyxia and may have potential to act as biomarkers for birth asphyxia.METHODS: Serum levels of α-KG and cord blood lactate were estimated in 34 birth asphyxiated neonates with clinical evidence of asphyxia. The levels were also analyzed in 46 apparently healthy controls, and data was compared among different groups by using appropriate statistical analysis. Serum α-KG was estimated by enzyme-linked immunosorbent assay (ELISA) and cord blood lactate by blood gas autoanalyzer (BGA) in the serum samples.RESULTS: Serum α-KG levels were found to be increased in birth asphyxiated neonates as compared to healthy controls (p-value = 0.06). Correlation of serum α-ketoglutarate (ng/mL) levels with outcome (discharged/expired) in birth asphyxiated neonates was not found to be statistically significant (r value = 0.156, p-value = 0.384). A statisti-cally significant correlation was not found between severity of birth asphyxia and levels of serum α-ketoglutarate (ng/mL) (r value = 0.029, p-value = 0.86). Also, correlation of cord blood lactate levels (mmol/L) with severity in birth asphyxiated neonates was not found to be statistically significant (r value = 0.326, p-value = 0.10). Correlation between cord blood lactate levels (mmol/L) and outcome in birth asphyxiated neonates (discharged/ expired) was not found to be statistically significant (r value = 0.03, p-value = 0.87), while correlation of cord pH levels and severity of birth asphyxia in cases was found to be highly statistically significant (r value = -0.60, p-value < 0.01) Conclusions: Serum α-KG and cord blood lactate bear the potential to act as biomarkers in neonates with birth asphyxia.PMID:39662007 | DOI:10.7754/Clin.Lab.2024.240717

Sci Adv. 2024 Dec 13;10(50):eadp4033. doi: 10.1126/sciadv.adp4033. Epub 2024 Dec 11.ABSTRACTA method is presented for high-precision chemical detection that integrates quantum sensing with droplet microfluidics. Using nanodiamonds (ND) with fluorescent nitrogen-vacancy (NV) centers as quantum sensors, rapidly flowing microdroplets containing analyte molecules are analyzed. A noise-suppressed mode of optically detected magnetic resonance is enabled by pairing controllable flow with microwave control of NV electronic spins, to detect analyte-induced signals of a few hundredths of a percent of the ND fluorescence. Using this method, paramagnetic ions in droplets are detected with low limit-of-detection using small analyte volumes, with exceptional measurement stability over >103 s. In addition, these droplets are used as microconfinement chambers by co-encapsulating ND quantum sensors with various analytes such as single cells, suggesting wide-ranging applications including single-cell metabolomics and real-time intracellular measurements from bioreactors. Important advances are enabled by this work, including portable chemical testing devices, amplification-free chemical assays, and chemical imaging tools for probing reactions within microenvironments.PMID:39661672 | DOI:10.1126/sciadv.adp4033

Sci Adv. 2024 Dec 13;10(50):eadq4274. doi: 10.1126/sciadv.adq4274. Epub 2024 Dec 11.ABSTRACTDirect targeting of the KRAS-G12C-mutant protein using covalent inhibitors (G12Ci) acts on human non-small cell lung cancer (NSCLC). However, drug resistance is an emerging concern in this approach. Here, we show that MRTX849, a covalent inhibitor targeting the KRAS-G12C mutation, leads to the reactivation of the mitogen-activated protein kinase signaling pathway in MRTX849-resistant NSCLC and pancreatic ductal adenocarcinoma. A genome-wide CRISPR screen revealed that the adenosine triphosphate binding cassette transporter ABCC1 mediates MRTX849 resistance. Functional studies demonstrated that the transcription factor JUN drives ABCC1 expression, resulting in multidrug resistance. An unbiased drug screen identified the tyrosine kinase inhibitor dasatinib that potentiates MRTX849 efficacy by inhibiting SRC-dependent JUN activation, avoiding multidrug resistance and tumor suppression in vitro as well as in suitable preclinical mouse models and patient-derived organoids. SRC inhibitors (DGY-06-116, dasatinib, and bosutinib) also exhibit synergistic effects with MRTX849 in eliminating various tumor cell lines carrying KRAS-G12C mutations. Thus, SRC inhibitors amplify the therapeutic utility of G12Ci.PMID:39661665 | DOI:10.1126/sciadv.adq4274

PLoS One. 2024 Dec 11;19(12):e0311971. doi: 10.1371/journal.pone.0311971. eCollection 2024.ABSTRACTUric acid (UA) is a final product of purine metabolism and has neuroprotective effects. It has not been established whether serum UA levels are associated with depressive disorder. Thus, we investigated whether serum UA levels are associated with depressive symptoms in a Japanese general population. We used the Iwaki Health Promotion Project 2022 data (737 subjects) in this cross-sectional study. The Center for Epidemiologic Studies Depression Scale (CES-D) was used to assess the prevalence of depressive symptoms. Subjects with CES-D scores ≥16 were assigned to the Depression group. We compared characteristics and laboratory data (including serum UA) between the Depression and Non-depression groups and performed a multivariable logistic regression analysis to investigate whether their serum UA levels were associated with depressive symptoms, after adjusting for possible confounding factors. We analyzed the cases of 705 subjects: the Depression group (n = 142) and the Non-depression group (n = 563). The Depression group's serum UA levels were significantly lower than those of the Non-depression group. The multivariable logistic regression analysis demonstrated that lower serum UA levels were significantly associated with the depressive symptoms. In conclusion, lower serum UA levels in this Japanese general population were significantly associated with the depressive symptoms.PMID:39661619 | DOI:10.1371/journal.pone.0311971

Cell Rep. 2024 Dec 10;43(12):115069. doi: 10.1016/j.celrep.2024.115069. Online ahead of print.ABSTRACTLysine metabolism converges at α-aminoadipic semialdehyde dehydrogenase (ALDH7A1). Rare loss-of-function mutations in ALDH7A1 cause a toxic accumulation of lysine catabolites, including piperideine-6-carboxylate (P6C), that are thought to cause fatal seizures in children unless strictly managed with dietary lysine reduction. In this study, we perform metabolomics and expression analysis of tissues from Aldh7a1-deficient mice, which reveal tissue-specific differences in lysine metabolism and other metabolic pathways. We also develop a fluorescent biosensor to characterize lysine transporter activity and identify competitive substrates that reduce the accumulation of lysine catabolites in ALDH7A1-deficient HEK293 cells. Lastly, we show that intravenous administration of lysine α-oxidase from Trichoderma viride reduces lysine and P6C levels by >80% in mice. Our results improve our understanding of lysine metabolism and make inroads toward improving therapeutic strategies for lysine catabolic disorders.PMID:39661514 | DOI:10.1016/j.celrep.2024.115069

Plant Physiol. 2024 Dec 11:kiae642. doi: 10.1093/plphys/kiae642. Online ahead of print.ABSTRACTThe SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complex is involved in various aspects of plant development and stress responses. Here, we investigated the role of BRM (BRAHMA), a core catalytic subunit of the SWI/SNF complex, in Arabidopsis thaliana seed biology. brm-3 seeds exhibited enlarged size, reduced yield, increased longevity, and enhanced secondary dormancy, but did not show changes in primary dormancy or salt tolerance. Some of these phenotypes depended on the expression of DOG1, a key regulator of seed dormancy, as they were restored in the brm-3 dog1-4 double mutant. Transcriptomic and metabolomic analyses revealed that BRM and DOG1 synergistically modulate the expression of numerous genes. Some of the changes observed in the brm-3 mutant, including increased glutathione levels, depended on a functional DOG1. We demonstrated that the BRM-containing chromatin remodeling complex directly controls secondary dormancy through DOG1 by binding and remodeling its 3' region, where the promoter of the long non-coding RNA asDOG1 is located. Our results suggest that BRM and DOG1 cooperate to control seed physiological properties and that BRM regulates DOG1 expression through asDOG1. This study reveals chromatin remodeling at the DOG1 locus as a molecular mechanism controlling the interplay between seed viability and dormancy.PMID:39661382 | DOI:10.1093/plphys/kiae642

Anal Chem. 2024 Dec 11. doi: 10.1021/acs.analchem.4c03808. Online ahead of print.ABSTRACTVarious rounded turn designs in Structures for Lossless Ion Manipulation (SLIM) were explored via ion trajectory simulations. The optimized design was integrated into a SLIM ion mobility (IM) system coupled with a time-of-flight (TOF) mass spectrometer (MS) for further experimental investigation. The SLIM-TOF IM-MS system was assessed for IM resolution and ion transmission efficiency across a wide m/z range using various RF frequencies and buffer gas combinations. High ion transmission efficiency and high resolution ion mobility (HRIM) separation were achieved for Agilent tune mix ions through a ∼12.8 m serpentine separation path in both nitrogen and helium. In helium, ion transmission for low m/z ions was enhanced at higher RF trapping frequency, enabling the detection of ions with m/z below 50 and all 17 amino acids from a standard mixture. Lossless ion transmission was observed for glycine (m/z 76) in both passthrough and HRIM modes. HRIM resolution was benchmarked using L-isoleucine, L-leucine, and various other isobaric and isomeric metabolites with m/z values of 60-89. This work demonstrates a rounded turn SLIM design that enables HRIM measurements for small molecule analytes, with a particular focus on metabolomics, where IM offers a means to enhance the speed, robustness, and specificity of analytical workflows.PMID:39661157 | DOI:10.1021/acs.analchem.4c03808

Ann Hematol. 2024 Dec 11. doi: 10.1007/s00277-024-06089-w. Online ahead of print.ABSTRACTAcute myeloid leukemia (AML) with FLT3-ITD mutation represents a quarter of AML patients and is associated with high relapse rate and dismal prognosis. FLT3 tyrosine kinase inhibitors (TKIs) were developed in order to target this genetic alteration and among these TKIs, AC220 (quizartinib) combined with chemotherapy has already shown an increased overall survival for patients with AML with FLT3-ITD mutation. Even though this increase in overall survival was significant, it remains discrete, and relapse rate is still high, so there is an unmet medical need. All-trans retinoic acid (ATRA) is well known for its effectiveness in acute promyelocytic leukemia (APL) treatment and has already been shown to have synergistic effects combined with another TKI, sorafenib. In this study, quizartinib, a more potent FLT3-TKI, was tested in combination with ATRA in the AML FLT3-ITD positive cell lines MOLM-13 and MV4-11. ATRA has effectively improved AC220 induced cell death via caspase activation. In addition, ATRA in combination with AC220 treatment notably enhanced BECN1 cleavage compared to AC220 treatment alone. Finally, in a xenotransplantation model ATRA plus AC220 was more efficient to reduce the leukemic burden than monotherapy with ATRA or AC220. Taken together, our results are a proof of the concept that ATRA and AC220 have synergistic anti-leukemic effects.PMID:39661129 | DOI:10.1007/s00277-024-06089-w

mSystems. 2024 Dec 11:e0045724. doi: 10.1128/msystems.00457-24. Online ahead of print.ABSTRACTEmerging evidence highlights the potential impact of intratumoral microbiota on cancer. However, the microbial composition and function in glioma remains elusive. Consequently, our study aimed to investigate the microbial community composition in glioma tissues and elucidate its role in glioma development. We parallelly performed microbial profiling, transcriptome sequencing, and metabolomics detection on tumor and adjacent normal brain tissues obtained from 50 glioma patients. We employed immunohistochemistry, multicolor immunofluorescence, and fluorescence in situ hybridization (FISH) staining to observe the presence and location of bacteria. Furthermore, an animal model was employed to validate the impact of key bacteria on glioma development. Six genera were found to be significantly enriched in glioma tissues compared to adjacent normal brain tissues, including Fusobacterium, Longibaculum, Intestinimonas, Pasteurella, Limosilactobacillus, and Arthrobacter. Both bacterial RNA and lipopolysaccharides (LPS) were observed in glioma tissues. Integrated microbiomics, transcriptomics, and metabolomics revealed that genes associated with intratumoral microbes were enriched in multiple synapse-associated pathways and that metabolites associated with intratumoral microbes were (R)-N-methylsalsolinol, N-acetylaspartylglutamic acid, and N-acetyl-l-aspartic acid. Further mediation analysis suggested that the intratumoral microbiome may affect the expression of neuron-related genes through bacteria-associated metabolites. In addition, both in vivo and in vitro models of glioma show that Fusobacterium nucleatum promotes glioma proliferation and upregulates CCL2, CXCL1, and CXCL2 levels. Our findings shed light on the intricate interplay between intratumoral bacteria and glioma.IMPORTANCE: Our study adopted a multi-omics approach to unravel the impact of intratumoral microbes on neuron-related gene expression through bacteria-associated metabolites. Importantly, we found bacterial RNA and LPS signals within glioma tissues, which were traditionally considered sterile. We identified key microbiota within glioma tissues, including Fusobacterium nucleatum (Fn). Through in vivo and in vitro experiments, we identified the crucial role of Fn in promoting glioma progression, suggesting that Fn could be a potential diagnostic and therapeutic target for glioma patients. These findings offer valuable insights into the intricate interplay between intratumoral bacteria and glioma, offering novel inspiration to the realm of glioma biology.PMID:39660865 | DOI:10.1128/msystems.00457-24