PubMed

Nat Commun. 2024 Aug 13;15(1):6922. doi: 10.1038/s41467-024-51386-7.ABSTRACTCompensation and intracellular storage of PD-L1 may compromise the efficacy of antibody drugs targeting the conformational blockade of PD1/PD-L1 on the cell surface. Alternative therapies aiming to reduce the overall cellular abundance of PD-L1 thus might overcome resistance to conventional immune checkpoint blockade. Here we show by bioinformatics analysis that colon adenocarcinoma (COAD) with high microsatellite instability (MSI-H) presents the most promising potential for this therapeutic intervention, and that overall PD-L1 abundance could be controlled via HSC70-mediated lysosomal degradation. Proteomic and metabolomic analyses of mice COAD with MSI-H in situ unveil a prominent acidic tumor microenvironment. To harness these properties, an artificial protein, IgP β, is engineered using pH-responsive peptidic foldamers. This features customized peptide patterns and designed molecular function to facilitate interaction between neoplastic PD-L1 and HSC70. IgP β effectively reduces neoplastic PD-L1 levels via HSC70-mediated lysosomal degradation, thereby persistently revitalizing the action of tumor-infiltrating CD8 + T cells. Notably, the anti-tumor effect of lysosomal-degradation-based therapy surpasses that of antibody-based immune checkpoint blockade for MSI-H COAD in multiple mouse models. The presented strategy expands the use of peptidic foldamers in discovering artificial protein drugs for targeted cancer immunotherapy.PMID:39134545 | DOI:10.1038/s41467-024-51386-7

Nat Commun. 2024 Aug 12;15(1):6915. doi: 10.1038/s41467-024-51232-w.ABSTRACTProtein post-translational modifications (PTMs) are crucial for cancer cells to adapt to hypoxia; however, the functional significance of lysine crotonylation (Kcr) in hypoxia remains unclear. Herein we report a quantitative proteomics analysis of global crotonylome under normoxia and hypoxia, and demonstrate 128 Kcr site alterations across 101 proteins in MDA-MB231 cells. Specifically, we observe a significant decrease in K131cr, K156cr and K220cr of phosphoglycerate kinase 1 (PGK1) upon hypoxia. Enoyl-CoA hydratase 1 (ECHS1) is upregulated and interacts with PGK1, leading to the downregulation of PGK1 Kcr under hypoxia. Abolishment of PGK1 Kcr promotes glycolysis and suppresses mitochondrial pyruvate metabolism by activating pyruvate dehydrogenase kinase 1 (PDHK1). A low PGK1 K131cr level is correlated with malignancy and poor prognosis of breast cancer. Our findings show that PGK1 Kcr is a signal in coordinating glycolysis and the tricarboxylic acid (TCA) cycle and may serve as a diagnostic indicator for breast cancer.PMID:39134530 | DOI:10.1038/s41467-024-51232-w

BMJ Open. 2024 Aug 12;14(8):e081629. doi: 10.1136/bmjopen-2023-081629.ABSTRACTINTRODUCTION: Undernutrition during pregnancy is linked to adverse pregnancy and birth outcomes and has downstream effects on the growth and development of children. The gut microbiome has a profound influence on the nutritional status of the host. This phenomenon is understudied in settings with a high prevalence of undernutrition, and further investigation is warranted to better understand such interactions.METHODS AND ANALYSIS: This is a prospective, longitudinal observational study to investigate the relationship between prokaryotic and eukaryotic microbes in the gut and their association with maternal body mass index (BMI), gestational weight gain, and birth and infant outcomes among young mothers (17-24 years) in Matiari District, Pakistan. We aim to enrol 400 pregnant women with low and normal BMIs at the time of recruitment (<16 weeks of gestation). To determine the weight gain during pregnancy, maternal weight is measured in the first and third trimesters. Gut microbiome dynamics (bacterial and eukaryotic) will be assessed using 16S and 18S rDNA surveys applied to the maternal stool samples. Birth outcomes include birth weight, small for gestational age, large for gestational age, preterm birth and mortality. Infant growth and nutritional parameters include WHO z-scores for weight, length and head circumference at birth through infancy. To determine the impact of the maternal microbiome, including exposure to pathogens and parasites on the development of the infant microbiome, we will analyse maternal and infant microbiome composition, micronutrients in serum using metallomics (eg, zinc, magnesium and selenium) and macronutrients in the stool. Metatranscriptomics metabolomics and markers of inflammation will be selectively deployed on stool samples to see the variations in dietary intake and maternal nutritional status. We will also use animal models to explore the bacterial and eukaryotic components of the microbiome.ETHICS AND DISSEMINATION: The study is approved by the National Bioethics Committee (NBC) in Pakistan, the Ethics Review Committee (ERC) at Aga Khan University and the Research Ethics Board (REB) at the Hospital for Sick Children, and findings will be published in peer-reviewed journals.TRIAL REGISTRATION NUMBER: NCT05108675.PMID:39134435 | DOI:10.1136/bmjopen-2023-081629

Toxicology. 2024 Aug 10:153905. doi: 10.1016/j.tox.2024.153905. Online ahead of print.ABSTRACTGestating mice were exposed to three chemicals, tetrabromo-bisphenol A (TBBPA; 2mg/kg/day)), amitrole (25 and 50mg/kg/day) and pyraclostrobin (0.4 and 2mg/kg/day) to assess their capacity to act as thyroid hormone disruptors and compromise neurodevelopment. Propyl-thio-uracyl, a known pharmacological inhibitor of thyroid gland secretion, was used at both high and low dose as a reference thyroid hormone disruptor (1 ppm, 1500 ppm). A combination of plasma metabolomics and striatum transcriptomics revealed the induced change in pups at the postnatal stages. Although the underlying mechanism is unlikely to involve thyroid hormone disruption, these chemicals had a detectable effect on pups' neurodevelopment.PMID:39134236 | DOI:10.1016/j.tox.2024.153905

Int J Biol Macromol. 2024 Aug 10:134660. doi: 10.1016/j.ijbiomac.2024.134660. Online ahead of print.ABSTRACTCheckpoint blockades have emerged as a frontline approach in cancer management, designed to enhance the adaptive immune response against tumors. However, its clinical efficacy is limited to a narrow range of tumor types, which necessitates the exploration of novel strategies that target another main branch of the immune system. One such potential strategy is the therapeutic modulation of pattern recognition receptors (PRRs) pathways in innate immune cells, which have shown promise in tumor eradication. Previously, a β-1,3/1,6-glucan with high purity from Durvillaea antarctica (BG136) was reported by our group to exhibit pan-antitumor effects. In the current study, we systemically studied the antitumor activity of BG136 in combination with anti-PD1 antibody in MC38 syngeneic tumor model in vivo. Integrated transcriptomic and metabolomic analyses suggested that BG136 enhances the antitumor immunity of anti-PD1 antibody by reprogramming the tumor microenvironment to become more proinflammatory. In addition, an increase in innate and adaptive immune cell infiltration and activation, enhanced lipid metabolism, and a decreased in ascorbate and aldarate metabolism were also found. These findings provide mechanistic insights that support the potent antitumor efficacy of BG136 when combined with immune checkpoint inhibitor antibodies.PMID:39134196 | DOI:10.1016/j.ijbiomac.2024.134660

Horm Metab Res. 2024 Aug 12. doi: 10.1055/a-2365-7521. Online ahead of print.ABSTRACTCongenital adrenal hyperplasia (CAH) manifests as an autosomal recessive disorder characterized by defects in the enzymes responsible for steroid synthesis. This work aims to perform metabolic profiling of patients with CAH, screen key differential metabolites compared to the control group, and discover the associated metabolic pathways implicated in CAH. Serum samples obtained from 32 pediatric male patients with CAH and 31 healthy control group candidates were subjected to analysis using non-targeted metabolomics strategy using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). A total of 278 differential metabolites were identified and annotated in KEGG. Operating characteristic curves (ROC) measurement exhibited 9 metabolites exhibiting high efficacy in differential diagnosis, as evidenced by an area under ROC curve (AUC) exceeding 0.85. Pathway analysis uncovered notable disruptions in steroid hormone biosynthesis (p <0.0001), purine metabolism and irregularities in lipid metabolism and amino acid metabolism, including tyrosine and alanine, in CAH patients. These findings demonstrate that metabolic pathways of purine, amino acid and lipid metabolism, apart from steroid hormone biosynthesis, may be disrupted and associated with CAH. This study helps provide insight into the metabolic profile of CAH patients and offers a new perspective for monitoring and administering follow-up care to CAH patients.PMID:39134036 | DOI:10.1055/a-2365-7521

Int Immunopharmacol. 2024 Aug 11;140:112895. doi: 10.1016/j.intimp.2024.112895. Online ahead of print.ABSTRACTOBJECTIVE: This study explores the therapeutic effects and mechanisms of DHA-enriched phosphatidylserine (DHA-PS) on liver injury induced by cyclophosphamide (CTX) in mice, focusing on the gut-liver axis.METHODS: A mouse model was established by administering CTX (80 mg/kg) intraperitoneally for 5 days. DHA-PS (50 or 100 mg/kg) was administered for the next 7 days to assess its reparative impact on liver damage.RESULTS: The findings revealed significant improvements in liver biochemical indices, inflammatory markers, and oxidative stress levels in the mice treated with DHA-PS. Through non-targeted metabolomics analysis, DHA-PS mitigated CTX-induced metabolic disruptions by modulating lipid, amino acid, and pyrimidine metabolism. Immunofluorescence analysis further confirmed that DHA-PS reduced the expression of liver-associated inflammatory proteins by inhibiting the TLR4/NF-κB pathway. Additionally, DHA-PS restored the intestinal barrier, evidenced by adjustments in the levels of intestinal lipopolysaccharide (LPS), secretory immunoglobulin A (sIgA), and tight junction proteins (Claudin-1, Occludin, and ZO-1). It also improved gut microbiota balance by enhancing microbial diversity, increasing beneficial bacteria, and altering community structures.CONCLUSION: These results suggest that DHA-PS could be a potential therapeutic agent or functional food for CTX-induced liver injury through its regulation of the gut-liver axis.PMID:39133957 | DOI:10.1016/j.intimp.2024.112895

Int Immunopharmacol. 2024 Aug 10;140:112912. doi: 10.1016/j.intimp.2024.112912. Online ahead of print.ABSTRACTOBJECTIVE: Lung adenocarcinoma (LA), the most prevalent type of lung cancer, is associated with a high mortality rate, especially among patients with cancer previously infected with coronavirus disease (COVID-19). Therefore, this study aimed to explore the mechanisms by which COVID-19 exacerbates LA progression in a clinical setting.METHODS: The experiment involved collecting serum samples from three groups: a healthy control group (Con, n = 20), a lung adenocarcinoma group (LA, n = 30), and a group of lung adenocarcinoma patients with first-time COVID-19 infection (C-LA, n = 58). Metabolites were analyzed using liquid chromatography-mass spectrometry, and differentially expressed metabolites were identified through bioinformatics analysis. The concentrations of glutathione (GSH), reactive oxygen species (ROS), and copper ions (Cu2+) in the serum of patients in the Con and C-LA groups were measured. Mitochondrial morphological changes in monocytes and lymphocytes were observed using electron microscopy.RESULTS: Metabolomic analysis revealed 142 distinct metabolites, among which glutamine (Gln) expression was significantly decreased in the C-LA group. Compared to the Con group, the C-LA group showed a significant decrease in GSH and a notable increase in ROS and Cu2+. Further research revealed that the mitochondria of monocytes and lymphocytes in the C-LA group exhibited corresponding alterations indicative of cuproptosis.CONCLUSIONS: SARS-CoV-2 infection may reduce Gln levels, leading to reduced GSH levels, copper overload, and increased death of immune cells, which may further exacerbate rapid tumor development. Thus, glutamine regulation plays an important role in LA progression in patients with COVID-19 and represents a potential therapeutic target.PMID:39133954 | DOI:10.1016/j.intimp.2024.112912

Neurology. 2024 Sep 10;103(5):e209749. doi: 10.1212/WNL.0000000000209749. Epub 2024 Aug 12.ABSTRACTBACKGROUND AND OBJECTIVES: Brain MRI abnormalities and increases in neurofilament light chain (NfL) have mostly been observed in cross-sectional studies before ataxia onset in polyglutamine spinocerebellar ataxias. Our study aimed to identify longitudinal changes in biological, clinical, and/or imaging biomarkers in spinocerebellar ataxia (SCA) 2 and SCA7 carriers over 1 year.METHODS: We studied SCA2 and SCA7 carriers and controls (expansion-negative relatives) at the Paris Brain Institute. Inclusion criteria included Scale for the Assessment and Rating of Ataxia (SARA) scores between 0 and 15. Assessments at baseline, 6 months, and 12 months comprised neurologic, quality of life, orofacial motor, neuropsychological, and ophthalmologic examinations, along with gait and oculomotor recordings, brain MRI, CSF, and blood sampling. The primary outcome was the longitudinal change in these assessments over 1 year.RESULTS: We included 15 SCA2 carriers, 15 SCA7 carriers, and 10 controls between May 2020 and April 2021. At baseline, the ages were similar (41 [37, 46] for SCA2, 38 [28.5, 39.8] for SCA7, and 39.5 [31, 54.5] for controls, p = 0.78), as well the sex (p = 0.61); SARA scores were low but different (4 [1.25, 6.5] in SCA2, 2 [0, 11.5] in SCA7, and 0 in controls, p < 0.01). Pons and medulla volumes were smaller in SCAs (p < 0.05) and cerebellum volume only in SCA2 (p = 0.01). Plasma NfL levels were higher in SCA participants (SCA2: 14.2 pg/mL [11.52, 15.89], SCA7: 15.53 [13.27, 23.23]) than in controls (4.88 [3.56, 6.17], p < 0.001). After 1-year follow-up, in SCA2, there was significant pons (-144 ± 60 mm3) and cerebellum (-1,508 ± 580 mm3) volume loss and a worsening of gait assessment; in SCA7, SARA score significantly increased (+1.3 ± 0.4) and outer retinal nuclear layer thickness decreased (-15.4 ± 1.6 μm); for both SCA groups, the orofacial motor assessment significantly worsened. For preataxic and early ataxic carriers, the strongest longitudinal deterioration on outcome measures was orofacial motility in SCA2 and retinal thickness in SCA7.DISCUSSION: Despite the limitation of the small sample size, we detected annual changes in preataxic and early ataxic SCA individuals across brain MRI imaging, clinical scores, gait parameters, and retinal thickness. These parameters could serve as potential end points for future therapeutic trials in the preataxic phase.TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT04288128.PMID:39133883 | DOI:10.1212/WNL.0000000000209749

Gut Microbes. 2024 Jan-Dec;16(1):2387875. doi: 10.1080/19490976.2024.2387875. Epub 2024 Aug 12.ABSTRACTThe intestinal microbiome during infancy and childhood has distinct metabolic functions and microbial composition compared to adults. We recently published a gnotobiotic mouse model of the pre-weaning microbiome (PedsCom), which retains a pre-weaning configuration during the transition from a milk-based diet to solid foods, leads to a stunted immune system, and increases susceptibility to enteric infection. Here, we compared the phylogenetic and metabolic relationships of the PedsCom consortium to two adult-derived gnotobiotic communities, Altered Schaedler Flora and Oligo-Mouse Microbiota 12 (Oligo-MM12). We find that PedsCom contains several unique functions relative to these adult-derived mouse consortia, including differences in carbohydrate and lipid metabolism genes. Notably, amino acid degradation metabolic modules are more prevalent among PedsCom isolates, which is in line with the ready availability of these nutrients in milk. Indeed, metabolomic analysis revealed significantly lower levels of total free amino acids and lower levels of specific amino acids abundant in milk (e.g. glutamine and glutamic acid) in the intestinal contents of adult PedsCom colonized mice compared to Oligo-MM12 controls. Metabolomic analysis of pre-weaning intestinal contents also showed lower levels of amino acids that are replete in milk compared to germ-free controls. Thus, enhanced amino acid metabolism is a prominent feature of the pre-weaning microbiome that may facilitate design of early-life microbiome interventions.PMID:39133869 | DOI:10.1080/19490976.2024.2387875

J Am Soc Mass Spectrom. 2024 Aug 12. doi: 10.1021/jasms.4c00208. Online ahead of print.ABSTRACTUntargeted tandem mass spectrometry (MS/MS) is an essential technique in modern analytical chemistry, providing a comprehensive snapshot of chemical entities in complex samples and identifying unknowns through their fragmentation patterns. This high-throughput approach generates large data sets that can be challenging to interpret. Molecular Networks (MNs) have been developed as a computational tool to aid in the organization and visualization of complex chemical space in untargeted mass spectrometry data, thereby supporting comprehensive data analysis and interpretation. MNs group related compounds with potentially similar structures from MS/MS data by calculating all pairwise MS/MS similarities and filtering these connections to produce a MN. Such networks are instrumental in metabolomics for identifying novel metabolites, elucidating metabolic pathways, and even discovering biomarkers for disease. While MS/MS similarity metrics have been explored in the literature, the influence of network topology approaches on MN construction remains unexplored. This manuscript introduces metrics for evaluating MN construction, benchmarks state-of-the-art approaches, and proposes the Transitive Alignments approach to improve MN construction. The Transitive Alignment technique leverages the MN topology to realign MS/MS spectra of related compounds that differ by multiple structural modifications. Combining this Transitive Alignments approach with pseudoclique finding, a method for identifying highly connected groups of nodes in a network, resulted in more complete and higher-quality molecular families. Finally, we also introduce a targeted network construction technique called induced transitive alignments where we demonstrate effectiveness on a real world natural product discovery application. We release this transitive alignment technique as a high-throughput workflow that can be used by the wider research community.PMID:39133821 | DOI:10.1021/jasms.4c00208

PLoS One. 2024 Aug 12;19(8):e0308710. doi: 10.1371/journal.pone.0308710. eCollection 2024.ABSTRACTBACKGROUND: Late-onset breast milk jaundice (LBMJ) is a common form of hyperbilirubinemia, which can result in serious complications for newborns with persistently high bilirubin levels. The aim of this study was to investigate the differences in fecal metabolites between breastfed infants with and without LBMJ in order to elucidate potential biological mechanisms.METHODS: Biological samples were collected from 12 infants with LBMJ and 12 healthy individuals. Ultra-high performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UHPLC-Q-TOF/MS) was utilized for non-targeted determination of fecal metabolites. Principal components analysis (PCA), cluster analysis, and differential metabolite analysis were performed in both positive ion mode and negative ion mode for the two groups. Additionally, the KEGG database was employed to comprehensively analyze the pathways of differential metabolites.RESULTS: There were no significant differences in maternal and neonatal demographic characteristics between the two groups (p > 0.05). The results of PCA and cluster heat map analysis in both modes showed that there were significant differences in metabolites between the two groups. Among 751 differential metabolites (DMs) detected in positive ion mode, 720 were up-regulated in the case group while 31 were down-regulated. In negative ion mode, 1891 DMs were detected, including 817 up-regulated metabolites and 1074 down-regulated metabolites in the case group. Analysis of differential metabolic pathways showed that the DMs of the two groups were mainly annotated and enriched in Biotin metabolism, N-Glycan biosynthesis, Taurine and hypotaurine metabolism, Pyrimidine metabolism, and Pentose and glucuronate interconversions.CONCLUSION: Significant differences exist in fecal metabolites between LBMJ infants and healthy controls. The study of differential metabolic pathways provides insights into the mechanism of LBMJ.PMID:39133689 | DOI:10.1371/journal.pone.0308710

Cancer Treat Res. 2024;191:191-216. doi: 10.1007/978-3-031-55622-7_8.ABSTRACTDiet play an important role in the development of cancer. A lot of research has been done on the role of individual nutrients or phytochemicals and cancer risk. Both harmful and beneficial associations of this nutrient have been observed with cancer. However, there is an interaction of individual dietary constituents to influence disease risk. On the other hand, examining the diet as a whole as is done in dietary patterns research may produce more accurate estimates and data that can be more easily translated into dietary recommendations. Dietary patterns and cancer research are becoming increasingly common in the epidemiology literature, and novel dietary patterns are being generated at a rapid pace. However, major issues remain over whether one general "healthy" dietary pattern can be suggested for cancer prevention or whether several diets should be advocated for different forms of cancer protection. It is challenging to study typical human diet in animal model that is appropriate for cancer prevention. Some dietary patterns, such as the ketogenic diet or macronutrient composition alteration, have been investigated more extensively in animal models than in humans in terms of cancer prevention, and bigger human observational studies are now needed to advise dietary guidelines. The question of whether to adapt nutritional guidelines to population subgroups based on susceptibility factors (for example, family history, sex, age, other lifestyle factors or comorbidities, metabolomics signatures, or microbiota-based profiles) is still open and will be crucial in moving the field forward.PMID:39133409 | DOI:10.1007/978-3-031-55622-7_8

Anim Biotechnol. 2024 Nov;35(1):2388704. doi: 10.1080/10495398.2024.2388704. Epub 2024 Aug 12.ABSTRACTThe flavour, tenderness and juiciness of the beef are all impacted by the composition of the intramuscular fat (IMF), which is a key determinant of beef quality. Thus, enhancing the IMF composition of beef cattle has become a major area of research. Consequently, the aim of this paper was to provide insight and synthesis into the emerging technologies, nutritional practices and management strategies to improve IMF composition in beef cattle. This review paper examined the current knowledge of management techniques and nutritional approaches relevant to cattle farming in the beef industry. It includes a thorough investigation of animal handling, weaning age, castration, breed selection, sex determination, environmental factors, grazing methods, slaughter weight and age. Additionally, it rigorously explored dietary energy levels and optimization of fatty acid profiles, as well as the use of feed additives and hormone implant techniques with their associated regulations. The paper also delved into emerging technologies that are shaping future beef production, such as genomic selection methods, genome editing techniques, epigenomic analyses, microbiome manipulation strategies, transcriptomic profiling approaches and metabolomics analyses. In conclusion, a holistic approach combining genomic, nutritional and management strategies is imperative for achieving targeted IMF content and ensuring high-quality beef production.PMID:39133095 | DOI:10.1080/10495398.2024.2388704

Lab Chip. 2024 Aug 12. doi: 10.1039/d4lc00269e. Online ahead of print.ABSTRACTThe interactions of proteins, membranes, nucleic acid, and metabolites shape a cell's phenotype. These interactions are stochastic, and each cell develops differently, making it difficult to synchronize cell populations. Consequently, studying biological processes at the single- or few-cell level is often necessary to avoid signal dilution below the detection limit or averaging over many cells. We have developed a method to study metabolites and proteins from a small number of or even a single adherent eukaryotic cell. Initially, cells are lysed by short electroporation and aspirated with a microcapillary under a fluorescent microscope. The lysate is placed on a carrier slide for further analysis using liquid-chromatography mass spectrometry (LC-MS) and/or reverse-phase protein (RPPA) approach. This method allows for a correlative measurement of (i) cellular structures and metabolites and (ii) cellular structures and proteins on the single-cell level. The correlative measurement of cellular structure by light-microscopy, metabolites by LC-MS, and targeted protein detection by RPPA was possible on the few-cell level. We discuss the method, potential applications, limitations, and future improvements.PMID:39132885 | DOI:10.1039/d4lc00269e

J Agric Food Chem. 2024 Aug 12. doi: 10.1021/acs.jafc.4c05187. Online ahead of print.ABSTRACTSprouting of stored oilseeds due to improper storage can lead to quality defects of cold-pressed oils obtained from them. This study aimed to evaluate the effect of seed sprouting on volatile organic compounds (VOCs), aroma-active compounds, and the content of nonvolatile metabolites in cold-pressed false flax oil obtained from sprouted seeds. In this study, 88 unique VOCs were detected in sprouted oils, whereas only 42 were found in the control oils. The control oils were characterized by a higher abundance of alcohols, while all other groups of compounds were associated with sprouted seeds. The formation of many VOCs was reflected in changes in the nonvolatile precursors. Fifteen aroma-active compounds were identified in sprouted oil, with five compounds playing a significant role (FD ≥ 128) in aroma formation. The presented approach allowed identification of differences caused by seed sprouting, resulting in oils with a much stronger aroma and a richer profile of VOCs due to intensive metabolic changes. The origin of many VOCs can be explained by alterations in the content of nonvolatile metabolites.PMID:39132846 | DOI:10.1021/acs.jafc.4c05187

Ren Fail. 2024 Dec;46(2):2387429. doi: 10.1080/0886022X.2024.2387429. Epub 2024 Aug 12.ABSTRACTObjectives: To investigate the role of the intestinal flora and metabolites in the development of hyperuricemic renal injury in chronic kidney disease (CKD).Methods: Unilaterally nephrectomized mice were fed with adenine and potassium oxonate for 9 weeks. HE staining combined with plasma biochemical indicators was used to evaluate renal pathological and functional changes. We conducted 16S rRNA sequencing and untargeted metabolomics on feces and plasma samples to reveale changes in intestinal microbiota and metabolites.Result: Our analysis revealed significant differences in 15 bacterial genera, with 7 being upregulated and 8 being downregulated. Furthermore, metabolomic analysis revealed changes in the distribution of amino acid and biotin metabolites in basic metabolic pathways in both feces and serum. Specifically, differentially abundant metabolites in feces were associated primarily with histidine metabolism; the biosynthesis of phenylalanine, tyrosine, and tryptophan; and tyrosine metabolism. In plasma, the differentially abundant metabolites were involved in multiple metabolic pathways, including aminoacyl-tRNA biosynthesis; glycine, serine, and threonine amino acid metabolism; valine, leucine, and isoleucine biosynthesis; tyrosine biosynthesis and metabolism; biotin metabolism; and taurine and hypotaurine metabolism. Furthermore, correlation analysis revealed that Akkermansia, UCG-005, Lachnospiraceae_NK4A136_group, Lactococcus, and Butymonas were associated with various differentially abundant metabolites as well as renal function, oxidative stress, and mitophagy. The changes in the intestinal flora observed in hyperuricemia may lead to imbalances in amino acid and biotin metabolism in both the intestine and host, ultimately affecting oxidative stress and mitophagy in mice and accelerating the progression of CKD.Conclusion: Our findings provide insights into a potential pathogenic mechanism by which hyperuricemia exacerbates renal injury in mice with renal insufficiency. Understanding these pathways may offer new therapeutic strategies for managing hyperuricemic renal injury in CKD patients.PMID:39132829 | DOI:10.1080/0886022X.2024.2387429

medRxiv [Preprint]. 2024 Jul 30:2024.07.29.24311176. doi: 10.1101/2024.07.29.24311176.ABSTRACTStudying relationships between longitudinal changes in omics variables and risks of events requires specific methodologies for joint analyses of longitudinal and time-to-event outcomes. We applied two such approaches (joint models [JM], stochastic process models [SPM]) to longitudinal metabolomics data from the Long Life Family Study focusing on understudied associations of longitudinal changes in lysophosphatidylcholines (LPC) with mortality and aging-related outcomes (23 LPC species, 5,790 measurements of each in 4,011 participants, 1,431 of whom died during follow-up). JM analyses found that higher levels of the majority of LPC species were associated with lower mortality risks, with the largest effect size observed for LPC 15:0/0:0 (hazard ratio: 0.715, 95% CI (0.649, 0.788)). SPM applications to LPC 15:0/0:0 revealed how the association found in JM reflects underlying aging-related processes: decline in robustness to deviations from optimal LPC levels, better ability of males' organisms to return to equilibrium LPC levels (which are higher in females), and increasing gaps between the optimum and equilibrium levels leading to increased mortality risks with age. Our results support LPC as a biomarker of aging and related decline in robustness/resilience, and call for further exploration of factors underlying age-dynamics of LPC in relation to mortality and diseases.PMID:39132492 | PMC:PMC11312646 | DOI:10.1101/2024.07.29.24311176

Front Behav Neurosci. 2024 Jul 25;18:1397284. doi: 10.3389/fnbeh.2024.1397284. eCollection 2024.ABSTRACTDietary phospholipids (PLs) are promising supplements that are commonly found as natural food ingredients and emulsifier additives. The present study aimed to evaluate the effect of major PLs found in food supplements on social behavior in mice. In this study, the effect of short-term high dietary PL content was studied in terms of social odor discrimination and social interactions with male and female intruders in male mice. We used odor discrimination and habituation tests to demonstrate that PL-fed male mice tend to lose preference toward female odor and fail to discriminate against socially significant scents. At the same time, test animals recognize non-social odors. We also found that PL affected the social behavior of the test males, who tend to behave indiscriminately toward male and female intruders during direct contact. Brain metabolomic profiling revealed no major changes in the intermediary metabolism or neurotransmitter biosynthesis. At the same time, intranasal PL application resembled the effects of dietary supplementation. These data suggest that certain PL might suppress pheromone perception in the olfactory system and affect the sense of socially important odor cues.PMID:39132447 | PMC:PMC11310928 | DOI:10.3389/fnbeh.2024.1397284

Front Microbiol. 2024 Jul 25;15:1279536. doi: 10.3389/fmicb.2024.1279536. eCollection 2024.ABSTRACTINTRODUCTION: Cistanche salsa (C.A.Mey.) G. Beck is a perennial holoparasitic herb recognized for its medicinal properties, particularly in kidney-tonifying and laxative treatments. Despite its therapeutic potential, little is known about the endophyte communities inhabiting C. salsa and its host plants, and how these microorganisms may impact the production and accumulation of metabolites in C. salsa.METHODS: We conducted a dual analysis focusing on metabolomics of wild C. salsa and microbiome characterization of both C. salsa and its host plant, Kalidium foliatum (Pall.) Moq. The metabolomics analysis revealed variations in metabolite composition across different parts of C. salsa. Additionally, the microbiome analysis involved studying endophytic bacteria and fungi, comparing their community structures between parasitic C. salsa and its host plant.RESULTS: Significant variations in metabolite composition were observed through metabolomic profiling, which identified 93 secondary metabolites and 398 primary metabolites across various parts of C. salsa. Emphasis was placed on differences in metabolite composition within the flowers. Microbiome analysis revealed differential community compositions of endophytic bacteria between the parasitic and host plants, whereas differences in endophytic fungi were less pronounced. Certain endophytes, such as Bacteroidota, Proteobacteria, Ascomycota, and Basidiomycota, were associated with the production of specific secondary metabolites in C. salsa, including the plant-specific compound salsaside.DISCUSSION: Our findings highlight the intricate relationship between C. salsa and its endophytic microbiota, suggesting a potential role of these microorganisms in modulating the biosynthesis of bioactive compounds. The differential preferences of endophytic bacteria and fungi across various microenvironments within the parasitic plant system underscore the complexity of these interactions. Further elucidation of these dynamics could enhance our understanding of C. salsa's medicinal properties and its ecological adaptations as a holoparasitic herb.PMID:39132140 | PMC:PMC11312099 | DOI:10.3389/fmicb.2024.1279536