PubMed

J Tradit Complement Med. 2024 Jan 5;14(4):403-413. doi: 10.1016/j.jtcme.2024.01.001. eCollection 2024 Jul.ABSTRACTINTRODUCTION: Guilingji, a famous traditional Chinese medicine (TCM) formula, has been used to combat aging and male sexual dysfunction in China for centuries. To date, there has been little evidence-based clinical research on the use of Guilingji to treat idiopathic oligo-asthenoteratozoospermia (OAT), and the therapeutic mechanism from a metabolic perspective needs to be investigated further.METHODS: This was a multicenter, double-blind, randomized controlled clinical study of 240 patients with idiopathic OAT recruited from four hospitals between January 2020 and January 2022. Patients were randomly assigned in a 1꞉1 ratio to receive oral Guilingji capsules or placebo for 12 weeks. The total progressive motile sperm count (TPMSC) was considered the primary outcome, and the other sperm parameters, seminal plasma parameters and serum hormones were considered the secondary outcome. A nontargeted metabolomics analysis of serum from OAT patients before and after Guilingji administration was performed by HPLC-MS to identify key metabolites. Furthermore, we used a rat model to show spermatogenesis phenotypes to validate the effect of the key metabolites screened from the patients.RESULTS: At weeks 4, 8 and 12, TPMSC and other sperm parameters were significantly improved in the Guilingji group compared with the placebo group (P < 0.05 for all comparisons). At week 4, superoxide dismutase (SOD) and acrosomal enzyme activity of seminal plasma were significantly elevated in the Guilingji group compared with the placebo group, while reactive oxygen species (ROS) levels were significantly reduced (P < 0.05). Lactate dehydrogenase-X (LDHX) levels appeared to be significantly increased after 12 weeks continuous medication compared with Placebo group (P = 0.032). The metabolomics analysis of serum from OAT patients before and after Guilingji administration showed that the glucose-6-phosphate (G6P) concentration in patients' serum was significantly elevated after Guilingji treatment. Compared to the control, when Kidney-Yang deficiency model rats were treated with Guilingji or its key intermediate metabolite G6P, their sperm concentration and spermatozoic activity were improved similarly, and their structural damage of rat's testicular and epididymal tissues were recovered.CONCLUSION: This study provided valuable clinical evidence for the utility of Guilingji as a treatment for OAT. These findings thus demonstrate that G6P is involved in the therapeutic mechanism of Guilingji in OAT treatment based on clinical and rat intervention studies.PMID:39035689 | PMC:PMC11259704 | DOI:10.1016/j.jtcme.2024.01.001

J Tradit Complement Med. 2024 Feb 20;14(4):456-466. doi: 10.1016/j.jtcme.2024.02.001. eCollection 2024 Jul.ABSTRACTBACKGROUND AND AIM: Interest in the safety of herbal medicine is growing rapidly regarding knowledge and challenges in natural products. Hence, this study aimed to reveal the toxicological profile of Ardisia elliptica, a traditional medicinal plant used in the treatment of various illnesses.EXPERIMENTAL PROCEDURE: Acute toxicity study was performed on female and male Sprague Dawley rats with a single oral administration of 2000 mg/kg BW of 70% ethanolic A. elliptica leaf extract, using a combination of conventional investigations and 1H-NMR-based metabolomics approaches.RESULTS: Physical, hematological, biochemical, and histopathological assessments demonstrated the usual rat profile, with no mortality and delayed toxicity 14 days after administration. 1H NMR serum metabolomics depicted similar metabolites between normal and treated groups. Nevertheless, 1H NMR of urinary metabolomics revealed perturbation in carbohydrate, amino acid, and energy metabolism within 24h after extract administration, while no accumulation of toxic biomarkers in the collected biological fluids on Day 14. A minor gender-based difference revealed the influence of sex hormones and different energy expenditure on response to extract treatment.CONCLUSION: This study suggested that 2000 mg/kg BW of 70% ethanolic A. elliptica leaf extract is considered as safe for consumption and offered a comprehensive overview of the response of physiological and metabolic aspects applicable to food and herbal product development.PMID:39035686 | PMC:PMC11259702 | DOI:10.1016/j.jtcme.2024.02.001

Heliyon. 2024 Jun 22;10(13):e33502. doi: 10.1016/j.heliyon.2024.e33502. eCollection 2024 Jul 15.ABSTRACTBACKGROUND: Better understanding of the interaction between metabolism and immune response will be key to understanding physiology and disease. Tumor Necrosis Factor-alpha (TNFα) has been studied widely. However, despite the extensive knowledge about TNFα, the cytokine appears to induce not only variable, but often contradictory, effects on inflammation and cell proliferation. Despite advancements in the metabolomics field, it is still difficult to analyze the types of multi-dose, multi-time point studies needed for elucidating the varied immunologic responses induced by TNFα.RESULTS: We studied the dose and time course effects of TNFα on murine fibroblast cultures and further elucidated these connections using selective blockade of the TNF receptors (TNFR1 and TNFR2). To streamline analysis, we developed a method to collate the metabolic pathway output from MetaboAnalyst into a single value for the Index of pathway significance (IPS). Using this metric, we tested dose-, time-, and receptor-dependent effects of TNFα signaling on cell metabolism. Guided by these results, we then demonstrate that alanine supplementation enriched TNFR1-related responses in both cell and mouse models.CONCLUSIONS: Our results suggest that TNFα, particularly when signaling through TNFR1, may preferentially use alanine metabolism for energy. These results are limited in by cell type used and immune outputs measured. However, we anticipate that our novel method may assist other researchers in identifying metabolic targets that influence their disease or model of interest through simplifying the analysis of multi-condition experiments. Furthermore, our results endorse the consideration of follow up studies in immunometabolism to improve outcomes in TNF-mediated diseases.PMID:39035522 | PMC:PMC11259870 | DOI:10.1016/j.heliyon.2024.e33502

Front Microbiol. 2024 Jul 5;15:1416734. doi: 10.3389/fmicb.2024.1416734. eCollection 2024.ABSTRACTTobacco, a crop of significant economic importance, was greatly influenced in leaf quality by protein content. However, current processing parameters fail to adequately meet the requirements for protein degradation. Microorganisms possess potential advantages for degrading proteins and enhancing the quality of tobacco leaves, and hold substantial potential in the process of curing. To effectively reduce the protein content in tobacco leaves, thereby improving the quality and safety of the tobacco leaves. In this study, tobacco leaf were used as experimental material. From these, the BSP1 strain capable of effectively degrading proteins was isolated and identified as Bacillus subtilis by 16S rDNA analysis. Furthermore, the mechanisms were analyzed by integrating microbiome, transcriptome, and metabolome. Before curing, BSP1 was applied to the surface of tobacco leaves. The results indicated that BSP1 effectively improves the activity of key enzymes and the content of related substances, thereby enhancing protein degradation. Additionally, protein degradation was achieved by regulating the diversity of the microbial community on the surface of the tobacco leaves and the ubiquitin-proteasome pathway. This study provided new strategies for extracting and utilizing functional strains from tobacco leaves, opening new avenues for enhancing the quality of tobacco leaves.PMID:39035444 | PMC:PMC11258012 | DOI:10.3389/fmicb.2024.1416734

Front Cell Infect Microbiol. 2024 Jul 5;14:1408569. doi: 10.3389/fcimb.2024.1408569. eCollection 2024.ABSTRACTA complex structure known as a biofilm is formed when a variety of bacterial colonies or a single type of cell in a group sticks to a surface. The extracellular polymeric compounds that encase these cells, often consisting of proteins, eDNA, and polysaccharides, exhibit strong antibiotic resistance. Concerns about biofilm in the pharmaceutical industry, public health, and medical fields have sparked a lot of interest, as antibiotic resistance is a unique capacity exhibited by these biofilm-producing bacteria, which increases morbidity and death. Biofilm formation is a complicated process that is controlled by several variables. Insights into the processes to target for the therapy have been gained from multiple attempts to dissect the biofilm formation process. Targeting pathogens within a biofilm is profitable because the bacterial pathogens become considerably more resistant to drugs in the biofilm state. Although biofilm-mediated infections can be lessened using the currently available medications, there has been a lot of focus on the development of new approaches, such as bioinformatics tools, for both treating and preventing the production of biofilms. Technologies such as transcriptomics, metabolomics, nanotherapeutics and proteomics are also used to develop novel anti-biofilm agents. These techniques help to identify small compounds that can be used to inhibit important biofilm regulators. The field of appropriate control strategies to avoid biofilm formation is expanding quickly because of this spurred study. As a result, the current article addresses our current knowledge of how biofilms form, the mechanisms by which bacteria in biofilms resist antibiotics, and cutting-edge treatment approaches for infections caused by biofilms. Furthermore, we have showcased current ongoing research utilizing the CRISPR/Cas9 gene editing system to combat bacterial biofilm infections, particularly those brought on by lethal drug-resistant pathogens, concluded the article with a novel hypothesis and aspirations, and acknowledged certain limitations.PMID:39035353 | PMC:PMC11257871 | DOI:10.3389/fcimb.2024.1408569

J Pharm Anal. 2024 Jun;14(6):100956. doi: 10.1016/j.jpha.2024.02.010. Epub 2024 Feb 27.ABSTRACTOxalate is an organic dicarboxylic acid that is a common component of plant foods. The kidneys are essential organs for oxalate excretion, but excessive oxalates may induce kidney stones. Jupiter microtubule associated homolog 2 (JPT2) is a critical molecule in Ca2+ mobilization, and its intrinsic mechanism in oxalate exposure and kidney stones remains unclear. This study aimed to reveal the mechanism of JPT2 in oxalate exposure and kidney stones. Genetic approaches were used to control JPT2 expression in cells and mice, and the JPT2 mechanism of action was analyzed using transcriptomics and untargeted metabolomics. The results showed that oxalate exposure triggered the upregulation of JPT2, which is involved in nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated Ca2+ mobilization. Transcriptomic analysis revealed that cell adhesion and macrophage inflammatory polarization were inhibited by JPT2 knockdown, and these were dominated by phosphatidylinositol 3-kinase (PI3K)/AKT signaling, respectively. Untargeted metabolomics indicated that JPT2 knockdown inhibited the production of succinic acid semialdehyde (SSA) in macrophages. Furthermore, JPT2 deficiency in mice inhibited kidney stones mineralization. In conclusion, this study demonstrates that oxalate exposure facilitates kidney stones by promoting crystal-cell adhesion, and modulating macrophage metabolism and inflammatory polarization via JPT2/PI3K/AKT signaling.PMID:39035219 | PMC:PMC11259813 | DOI:10.1016/j.jpha.2024.02.010

PeerJ. 2024 Jul 18;12:e17364. doi: 10.7717/peerj.17364. eCollection 2024.ABSTRACTDue to the emergence of drug-resistant microorganisms, the search for broad-spectrum antimicrobial compounds has become extremely crucial. Natural sources like plants and soils have been explored for diverse metabolites with antimicrobial properties. This study aimed to identify microorganisms from agricultural soils exhibiting antimicrobial effects against known human pathogens, and to highlight the chemical space of the responsible compounds through the computational metabolomics-based bioprospecting approach. Herein, bacteria were extracted from soil samples and their antimicrobial potential was measured via the agar well diffusion method. Methanolic extracts from the active bacteria were analyzed using the liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) technique, and the subsequent data was further analyzed through molecular networking approach which aided in identification of potential anti-microbial compounds. Furthermore, 16S rRNA gene sequencing enabled identification of the active bacterial isolates, where isolate 1 and 2 were identified as strains of Bacillus pumilus, whilst isolate 3 was found to be Bacillus subtilis. Interestingly, isolate 3 (Bacillus subtilis) displayed wide-ranging antimicrobial activity against the tested human pathogens. Molecular networking revealed the presence of Diketopiperazine compounds such as cyclo (D-Pro-D-Leu), cyclo (L-Tyr-L-Pro), cyclo (L-Pro-D-Phe), and cyclo (L-Pro-L-Val), alongside Surfactin C, Surfactin B, Pumilacidin E, and Isarrin D in the Bacillus strains as the main anti-microbial compounds. The application of the molecular networking approach represents an innovation in the field of bio-guided bioprospection of microorganisms and has proved to be an effective and feasible towards unearthing potent antimicrobial compounds. Additionally, the (computational metabolomics-based) approach accelerates the discovery of bioactive compounds and isolation of strains which offer a promising avenue for discovering new clinical antimicrobials. Finally, soil microbial flora could serve an alternative source of anti-microbial compounds which can assist in the fight against emergence of multi-drug resistance bacterial pathogens.PMID:39035159 | PMC:PMC11260408 | DOI:10.7717/peerj.17364

Kidney Res Clin Pract. 2024 Jul 5. doi: 10.23876/j.krcp.23.334. Online ahead of print.ABSTRACTChronic kidney disease (CKD) has been increasing over the last years, with a rate between 0.49% to 0.87% new cases per year. Currently, the number of affected people is around 850 million worldwide. CKD is a slowly progressive disease that leads to irreversible loss of kidney function, end-stage kidney disease, and premature death. Therefore, CKD is considered a global health problem, and this sets the alarm for necessary efficient prediction, management, and disease prevention. At present, modern computer analysis, such as in silico medicine (ISM), denotes an emergent data science that offers interesting promise in the nephrology field. ISM offers reliable computer predictions to suggest optimal treatments in a case-specific manner. In addition, ISM offers the potential to gain a better understanding of the kidney physiology and/or pathophysiology of many complex diseases, together with a multiscale disease modeling. Similarly, -omics platforms (including genomics, transcriptomics, metabolomics, and proteomics), can generate biological data to obtain information on gene expression and regulation, protein turnover, and biological pathway connections in renal diseases. In this sense, the novel patient-centered approach in CKD research is built upon the combination of ISM analysis of human data, the use of in vitro models, and in vivo validation. Thus, one of the main objectives of CKD research is to manage the disease by the identification of new disease drivers, which could be prevented and monitored. This review explores the wide-ranging application of computational medicine and the application of -omics strategies in evaluating and managing kidney diseases.PMID:39034863 | DOI:10.23876/j.krcp.23.334

Kidney Res Clin Pract. 2024 Jul 3. doi: 10.23876/j.krcp.23.218. Online ahead of print.ABSTRACTBACKGROUND: Fabry disease (FD) is an X-linked lysosomal disorder caused by α-galactosidase A enzyme activity deficiency. Although glycosphingolipid analogs have been identified in the plasma or urine of patients with FD, there is a limited understanding of altered metabolomics profiles beyond the globotriaosylceramide accumulation in FD.METHODS: Metabolomics study was performed for monitoring of biomarker and altered metabolism related with disease progression in serum and urine from male α-galactosidase A knockout mice and age-matched wild-type mice at 20 and 40 weeks. Profiling analysis for metabolites, including organic acids, amino acids, fatty acids, kynurenine pathway metabolites, and nucleosides in the serum and urine was performed using gas chromatography-tandem mass spectrometry and liquid chromatography-tandem mass spectrometry combined with star symbol patterns and partial least squares discriminant analysis (PLS-DA).RESULTS: A total of 27 and 23 metabolites from the serum and urine of Fabry mice were distinguished from those of wild-type mice, respectively, based on p-value (<0.05) and variable importance in projection scores (>1.0) of PLS-DA. In the serum, metabolites of the glutathione, glutathione disulfide, citrulline, and kynurenine pathways that are related to oxidative stress, nitric oxide biosynthesis, and inflammation were increased, whereas those involved in pyruvate and tyrosine metabolism and the tricarboxylic acid cycle were altered in the 20- and 40-week-old urine of FD model mice.CONCLUSION: Altered metabolic signatures associated with disease progression by oxidative stress, inflammation, nitric oxide biosynthesis, and immune regulation in the early and late stages of FD.PMID:39034862 | DOI:10.23876/j.krcp.23.218

Biochim Biophys Acta Mol Cell Biol Lipids. 2024 Jul 19:159535. doi: 10.1016/j.bbalip.2024.159535. Online ahead of print.ABSTRACTBACKGROUND: APOH plays an essential role in lipid metabolism and the transport of lipids in the circulation. Previous studies have shown that APOH deficiency causes fatty liver and gut microbiota dysbiosis in mouse models. However, the role and potential mechanisms of APOH deficiency in the pathogenesis of alcoholic liver disease remain unclear.METHODS: C57BL/6 WT and ApoH-/- mice were used to construct the binge-on-chronic alcohol feeding model. Mouse liver transcriptome, targeted bile acid metabolome, and 16S gut bacterial taxa were assayed and analyzed. Open-source human liver transcriptome dataset was analyzed.RESULTS: ApoH-/- mice fed with alcohol showed severe hepatic steatosis. Liver RNAseq and RT-qPCR data indicated that APOH deficiency predominantly impacts hepatic lipid metabolism by disrupting de novo lipogenesis, cholesterol processing, and bile acid metabolism. A targeted bile acid metabolomics assay indicated significant changes in bile acid composition, including increased percentages of TCA in the liver and DCA in the gut of alcohol-fed ApoH-/- mice. The concentrations of CA, NorCA, and HCA in the liver were higher in ApoH-/- mice on an ethanol diet compared to the control mice (p < 0.05). Additionally, APOH deficiency altered the composition of gut flora, which correlated with changes in the liver bile acid composition in the ethanol-feeding mouse model. Finally, open-source transcript-level data from human ALD livers highlighted a remarkable link between APOH downregulation and steatohepatitis, as well as bile acid metabolism.CONCLUSION: APOH deficiency aggravates alcohol induced hepatic steatosis through the disruption of gut microbiota homeostasis and bile acid metabolism in mice.PMID:39033850 | DOI:10.1016/j.bbalip.2024.159535

Food Chem. 2024 Jul 17;460(Pt 1):140505. doi: 10.1016/j.foodchem.2024.140505. Online ahead of print.ABSTRACTThe flavor alterations in bighead carp subjected to varying storage temperatures and the underlying metabolic mechanism were elucidated. Analysis of volatile flavor compounds, electronic nose, free amino acids, ATP-related compounds, and sensory evaluations uncovered a progressive flavor deterioration during storage, especially at 25 °C. Metabolomics-based flavor relating component profiling analysis showed that free fatty acids formed various fatty aldehydes including (E, E)-2,4-heptadienal and nonanal under lipoxygenase catalysis. Alcohol dehydrogenase and alcohol acyltransferases were intimately involved in alcohol and ester generation, while alkaline phosphatase, 5'-nucleotidase, and acid phosphatase were closely associated with IMP, Hx, and HxR conversion, respectively. Aeromonas, Serratia, Lactococcus, Pseudomonas, and Peptostreptococcus notably influenced flavor metabolism and enzyme activities. The metabolism disparities of valine, leucine, isoleucine, lysine, and α-linolenic acid could be the primary factors contributing to flavor metabolism distinctions. This study offers novel insights into the flavor change mechanisms and potential regulation strategies of bighead carp during storage.PMID:39033638 | DOI:10.1016/j.foodchem.2024.140505

Food Chem. 2024 Jul 17;460(Pt 1):140400. doi: 10.1016/j.foodchem.2024.140400. Online ahead of print.ABSTRACTTo investigate the impact of low temperature on the quality and flavor of ripe red tomatoes, we analyzed transcriptomes and volatile metabolomes of ripe red fruits stored at 0 °C and 20 °C for 8 days. The results showed that 0 °C maintained the sugar content by increasing the expression of sucrose synthetase (SUS) and sucrose transporter (SUT). Low expression of aroma synthesis-related genes, such as alcohol dehydrogenase 1 (ADH1), amino acid decarboxylase 1 A (AADC1A), and branched-chain amino acid aminotransferase 2 (BCAT2), were associated with reduced levels of pentanal, hexanal, 3-methylbutanal, 2-methylbutanal, and 2-phenylethanol. Additionally, the expression of pectinesterase (PE), beta-galactosidase (β-GAL), and beta-glucosidase (β-Glu), as well as phytoene synthase1 (PSY1) involved in carotenoid synthesis, was inhibited, thereby maintaining fruits texture and color. Furthermore, storage at 0 °C induced the expression of numerous genes regulating antioxidant and heat shock proteins, which further preserved the postharvest quality of tomatoes.PMID:39033633 | DOI:10.1016/j.foodchem.2024.140400

Phytochem Anal. 2024 Jul 21. doi: 10.1002/pca.3414. Online ahead of print.ABSTRACTINTRODUCTION: Untargeted metabolomics is a powerful tool that provides strategies for gaining a systematic understanding of quantitative changes in the levels of metabolites, especially when combining different metabolomic platforms. Vanilla is one of the world's most popular flavors originating from cured pods of the orchid Vanilla planifolia. However, only a few studies have investigated the metabolome of V. planifolia, and no LC-MS or GC-MS metabolomics studies with respect to leaves have been performed.OBJECTIVE: The aim of the study was to comprehensively characterize the metabolome of different organs (leaves, internodes, and aerial roots) of V. planifolia.MATERIAL AND METHODS: Characterization of the metabolome was achieved using two complementary platforms (GC × GC-MS, LC-QToF-MS), and metabolite identification was based on a comparison with in-house databases or curated external spectral libraries.RESULTS: In total, 127 metabolites could be identified with high certainty (confidence level 1 or 2) including sugars, amino acids, fatty acids, organic acids, and amines/amides but also secondary metabolites such as vanillin-related metabolites, flavonoids, and terpenoids. Ninty-eight metabolites showed significantly different intensities between the plant organs. Most strikingly, aglycons of flavonoids and vanillin-related metabolites were elevated in aerial roots, whereas its O-glycoside forms tended to be higher in leaves and/or internodes. This suggests that the more bioactive aglycones may accumulate where preferably needed, e.g. for defense against pathogens.CONCLUSION: The results derived from the study substantially expand the knowledge regarding the vanilla metabolome forming a valuable basis for more targeted investigations in future studies, e.g. towards an optimization of vanilla plant cultivation.PMID:39034429 | DOI:10.1002/pca.3414

Cell Rep. 2024 Jul 20;43(8):114416. doi: 10.1016/j.celrep.2024.114416. Online ahead of print.ABSTRACTMetabolism oscillates between catabolic and anabolic states depending on food intake, exercise, or stresses that change a multitude of metabolic pathways simultaneously. We present the HuMet Repository for exploring dynamic metabolic responses to oral glucose/lipid loads, mixed meals, 36-h fasting, exercise, and cold stress in healthy subjects. Metabolomics data from blood, urine, and breath of 15 young, healthy men at up to 56 time points are integrated and embedded within an interactive web application, enabling researchers with and without computational expertise to search, visualize, analyze, and contextualize the dynamic metabolite profiles of 2,656 metabolites acquired on multiple platforms. With examples, we demonstrate the utility of the resource for research into the dynamics of human metabolism, highlighting differences and similarities in systemic metabolic responses across challenges and the complementarity of metabolomics platforms. The repository, providing a reference for healthy metabolite changes to six standardized physiological challenges, is freely accessible through a web portal.PMID:39033506 | DOI:10.1016/j.celrep.2024.114416

J Autism Dev Disord. 2024 Jul 20. doi: 10.1007/s10803-024-06485-1. Online ahead of print.ABSTRACTAutism spectrum disorder (ASD) is a complex neurodevelopmental condition with a wide range of behavioral and cognitive impairments. While genetic and environmental factors are known to contribute to its etiology, metabolic perturbations associated with ASD, which can potentially connect genetic and environmental factors, remain poorly understood. Therefore, we conducted a metabolomic case-control study and performed a comprehensive analysis to identify significant alterations in metabolite profiles between children with ASD and typically developing (TD) controls in order to identify specific metabolites that may serve as biomarkers for the disorder. We conducted metabolomic profiling on plasma samples from participants in the second phase of Epidemiological Research on Autism in Jamaica, an age and sex-matched cohort of 200 children with ASD and 200 TD controls (2-8 years old). Using high-throughput liquid chromatography-mass spectrometry techniques, we performed a targeted metabolite analysis, encompassing amino acids, lipids, carbohydrates, and other key metabolic compounds. After quality control and missing data imputation, we performed univariable and multivariable analysis using normalized metabolites while adjusting for covariates, age, sex, socioeconomic status, and child's parish of birth. Our findings revealed unique metabolic patterns in children with ASD for four metabolites compared to TD controls. Notably, three metabolites were fatty acids, including myristoleic acid, eicosatetraenoic acid, and octadecenoic acid. The amino acid sarcosine exhibited a significant association with ASD. These findings highlight the role of metabolites in the etiology of ASD and suggest opportunities for the development of targeted interventions.PMID:39033254 | DOI:10.1007/s10803-024-06485-1

Arch Microbiol. 2024 Jul 20;206(8):359. doi: 10.1007/s00203-024-04082-5.ABSTRACTIn this experiment, the eutrophication system was established by adding sucrose and yeast powder, and the pH and dissolved oxygen were measured in a bioreactor in real time to study the effect of aerobic environment on the fermentation process of Polygonati Rhizoma extract by Lactiplantibacillus plantarum. To further analyze metabolic changes, UPLC-Q-Exactive MS was used for metabolomic analysis and metabolic profiling. Multivariate analysis was performed using principal component analysis and Orthogonal projections to latent structures discriminant analysis. Finally, 313 differential metabolites were selected, 196 of which were annotated through database matching. After fermentation, the content of short-chain fatty acids, lactic acid, and their derivatives increased significantly, and there were 13 kinds and 4 kinds, respectively. Both compounds and their derivatives are beneficial to the intestinal flora. Consequently, incorporating L. plantarum into the aerobic fermentation process of Polygonati Rhizoma extract within the eutrophic system is potentially advantageous in enhancing the impact of its fermentation solution on the gut microbiota and its effects on human health. Our findings for this kind of edible and medicinal material research and development offer useful insights.PMID:39033087 | DOI:10.1007/s00203-024-04082-5

J Immunother Cancer. 2024 Jul 20;12(7):e008717. doi: 10.1136/jitc-2023-008717.ABSTRACTBACKGROUND: Human and mouse natural killer (NK) cells have been shown to develop memory-like function after short-term exposure to the cocktail of IL-12/15/18 or to overnight co-culture with some tumor cell lines. The resulting cells retain enhanced lytic ability for up to 7 days as well as after cryopreservation, and memory-like NK cells (mlNK) have been shown to induce complete remissions in patients with hematological malignancies. No single phenotype has been described for mlNK and the physiological changes induced by the short-term cytokine or tumor-priming which are responsible for these enhanced functions have not been fully characterized. Here, we have generated mlNK by cytokine and tumor-priming to find commonalities to better define the nature of NK cell "memory" in vitro and, for the first time, in vivo.METHODS: We initiated mlNK in vitro from healthy donors with cytokines (initiated cytokine-induced memory-like (iCIML)-NK) and by tumor priming (TpNK) overnight and compared them by high-dimensional flow cytometry, proteomic and metabolomic profiling. As a potential mechanism of enhanced cytolytic function, we analyzed the avidity of binding of the mlNK to NK-resistant tumors (z-Movi). We generated TpNK from healthy donors and from cancer patients to determine whether mlNK generated by interaction with a single tumor type could enhance lytic activity. Finally, we used a replication-incompetent tumor cell line (INKmune) to treat patients with myeloid leukaemias to potentiate NK cell function in vivo.RESULTS: Tumor-primed mlNK from healthy donors and patients with cancer showed increased cytotoxicity against multiple tumor cell lines in vitro, analogous to iCIML-NK cells. Multidimensional cytometry identified distinct memory-like profiles of subsets of cells with memory-like characteristics; upregulation of CD57, CD69, CD25 and ICAM1. Proteomic profiling identified 41 proteins restricted to mlNK cells and we identified candidate molecules for the basis of NK memory which can explain how mlNK overcome inhibition by resistant tumors. Finally, of five patients with myelodysplastic syndrome or refractory acute myeloid leukemia treated with INKmune, three responded to treatment with measurable increases in NK lytic function and systemic cytokines.CONCLUSIONS: NK cell "memory" is a physiological state associated with resistance to MHC-mediated inhibition, increased metabolic function, mitochondrial fitness and avidity to NK-resistant target cells.PMID:39032940 | DOI:10.1136/jitc-2023-008717

J Proteomics. 2024 Jul 18:105261. doi: 10.1016/j.jprot.2024.105261. Online ahead of print.ABSTRACTBACKGROUND: Ovarian cancer is insidious and usually detected in advanced stages of the disease. As the ovaries are pelvic organs, changes in their pelvic fluid metabolites may be associated with ovarian cancer.METHODS: Metabolomic changes in the pelvic fluid were detected using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in patients with ovarian cancer, ovarian cysts and uterine fibroids. Area under the curve (AUC) analysis was used to assess the diagnostic performance of lipid metabolites and blood tumor indices. The Pearson correlation algorithm was used to analyze the correlation between clinical characteristics and lipid metabolites in ovarian cancer patients.RESULTS: There were 24 lipid metabolites significantly changed in the pelvic fluid of ovarian cancer patients (p < 0.05). Palmitoylcarnitine, lipoamide, lipid metabolites, and blood tumor indices (CA15-3 and CA125) showed AUC > 0.8, with palmitoylcarnitine reaching a high of 0.942. In addition, we found that some lipid metabolites were significantly associated with the clinical stage, abdominal water volume, lymphatic metastasis, and recurrence (p < 0.05, r > 0.5).CONCLUSION: Levels of specific lipid metabolites are potential biomarkers of ovarian cancer and may play a key role in the early diagnosis and prognostic assessment of ovarian cancer.SIGNIFICANCE: Our results showed that pelvic metabolites, especially some lipid metabolites, play an important role in the diagnosis of ovarian cancer. Meanwhile, partial lipid metabolites were closely associated with the clinical presentation and prognosis of patients with ovarian cancer. We believe that our study makes a significant contribution to the literature because it provides a potential approach that is more effective for ovarian cancer detection.PMID:39032862 | DOI:10.1016/j.jprot.2024.105261

Mol Metab. 2024 Jul 18:101994. doi: 10.1016/j.molmet.2024.101994. Online ahead of print.ABSTRACTRetinitis pigmentosa (RP) is a hereditary retinal disease characterized by progressive photoreceptor degeneration, leading to vision loss. The best hope for a cure for RP lies in gene therapy. However, given that RP patients are most often diagnosed in the midst of ongoing photoreceptor degeneration, it is important to determine how the retinal proteome changes as RP disease progresses, and to identify which changes can be prevented, halted, or reversed by gene therapy. Here, we used our Pde6b-deficient RP gene therapy mouse model and demonstrated that Pde6b gene restoration led to a novel form of homeostatic plasticity in rod phototransduction which functionally compensates for the decreased number of rods. By profiling protein levels of metabolic genes and measuring metabolites, we observed an upregulation of proteins associated with oxidative phosphorylation in mutant and treated photoreceptors. Thus, the metabolic demands of the retina differ in our Pde6b-deficient RP mouse model and are not rescued by gene therapy treatment. These findings provide novel insights into features of both RP disease progression and long-term rescue with gene therapy.PMID:39032643 | DOI:10.1016/j.molmet.2024.101994

Brain Behav Immun. 2024 Jul 18:S0889-1591(24)00489-6. doi: 10.1016/j.bbi.2024.07.020. Online ahead of print.ABSTRACTThe developing central nervous system is highly sensitive to nutrient changes during the perinatal period, emphasising the potential impact of alterations of maternal diet on offspring brain development and behaviour. A growing body of research implicates the gut microbiota in neurodevelopment and behaviour. Maternal overweight and obesity during the perinatal period has been linked to changes in neurodevelopment, plasticity and affective disorders in the offspring, with implications for microbial signals from the maternal gut. Here we investigate the impact of maternal high-fat diet (mHFD)-induced changes in microbial signals on offspring brain development, and neuroimmune signals, and the enduring effects on behaviour into adolescence. We first demonstrate that maternal caecal microbiota composition at term pregnancy (embryonic day 18: E18) differs significantly in response to maternal diet. Moreover, mHFD resulted in the upregulation of microbial genes in the maternal intestinal tissue linked to alterations in quinolinic acid synthesis and elevated kynurenine levels in the maternal plasma, both neuronal plasticity mediators related to glutamate metabolism. Metabolomics of mHFD embryonic brains at E18 also detected molecules linked to glutamate-glutamine cycle, including glutamic acid, glutathione disulphide and kynurenine. During adolescence, the mHFD offspring exhibited increased locomotor activity and anxiety-like behaviour in a sex-dependent manner, along with upregulation of glutamate-related genes compared to controls. Overall, our results demonstrate that maternal exposure to high-fat diet results in microbiota changes, behavioural imprinting, altered brain metabolism and glutamate signalling during critical developmental windows during the perinatal period.PMID:39032541 | DOI:10.1016/j.bbi.2024.07.020