PubMed

Elife. 2024 Nov 7;13:e100068. doi: 10.7554/eLife.100068.ABSTRACTThe gut microbiota is implicated in the pathogenesis of hyperuricemia (HUA) and gout. However, it remains unclear whether probiotics residing in the host gut, such as Lactobacillus, can prevent HUA development. Herein, we isolated Lactobacillus plantarum SQ001 from the cecum of HUA geese and conducted in vitro assays on uric acid (UA) and nucleoside co-culture. Metabolomics and genome-wide analyses, revealed that this strain may promote nucleoside uptake and hydrolysis through its nucleoside hydrolase gene. The functional role of iunH gene was confirmed via heterologous expression and gene knockout studies. Oral administration of L. plantarum SQ001 resulted in increased abundance of Lactobacillus species and reduced serum UA levels. Furthermore, it downregulated hepatic xanthine oxidase, a key enzyme involved in UA synthesis, as well as renal reabsorption protein GLUT9, while enhancing the expression of renal excretion protein ABCG2. Our findings suggest that L. plantarum has potential to ameliorate gut microbial dysbiosis with HUA, thereby offering insights into its potential application as a probiotic therapy for individuals with HUA or gout.PMID:39508089 | DOI:10.7554/eLife.100068

Sichuan Da Xue Xue Bao Yi Xue Ban. 2024 Sep 20;55(5):1195-1201. doi: 10.12182/20240960403.ABSTRACTOBJECTIVE: Radioactive intestinal injury is a common complication during radiotherapy of tumors. The aim of this study is to observe the effect of ionizing radiation on short-term changes in intestinal bile acids and to investigate the radioprotective effect of bile acids on intestinal cells.METHODS: A rat model of small intestinal injury was constructed by exposing the abdomen of the rats to daily irradiation at 2 Gy for 4 d in succession. The bile acids were quantified using metabolomics analysis. IEC-6 cells, a small intestinal epithelial cell line, were divided into a dimethyl sulfoxide (DMSO) control group receiving DMSO and 0 Gy irradiation, a glycoursodeoxycholic acid (GUDCA) experimental group receiving GUDCA and 0 Gy irradiation, a DMSO irradiation group receiving DMSO and 10 Gy irradiation, and a GUDCA irradiation group receiving GUDCA and 10 Gy irradiation. Cell viability and cytotoxicity was assessed by CCK-8 assay test. The apoptosis rate of cells was determined by flow cytometry. The colony formation rate and the radiosensitivity of the cells were determined by colony formation assay on solid media. The expression levels of proteins associated with cell death were determined using Western blot.RESULTS: After exposure to irradiation, the small intestine tissues of the rats showed typical radioactive intestinal injury. In addition, various bile acids showed fluctuation before and after irradiation. Among the bile acids, GUDCA increased significantly at 3 d after irradiation, but returned to the pre-irradiation level at 7 d after irradiation. Compared with the control group, after GUDCA treatment at 20 μmol/L for 24 h, the cell viability rate after irradiation was significantly higher than that of the DMSO group (P<0.05); the expression levels of the proteins, including PARP, caspase-3, RIP, and GSDMD, were significantly lower than those in the control group (P<0.05). After GUDCA treatment at 20 μmol/L for 24 h and 48 h, the cell apoptosis rate of the cells after irradiation was lower than that of the DMSO group (P<0.05). Compared with the DMSO control group, the colony formation ability of the GUDCA experimental group was stronger than that of the DMSO group after irradiation at 0, 2, 4, and 6 Gy (P<0.05). D0, or the mean lethal dose, of the GUDCA group was 6.374, while that of the DMSO group was 4.572. Compared with the DMSO control group, the D0 value of the GUDCA treatment group increased, and the sensitization enhancement ratio (SER) was 0.717.CONCLUSION: After exposing the abdomen of rats to irradiation, the intestinal bile acid metabolism of the rats will change significantly, and GUDCA can produce radioprotective effects on intestinal cells to a certain extent.PMID:39507959 | PMC:PMC11536250 | DOI:10.12182/20240960403

Food Chem X. 2024 Oct 16;24:101899. doi: 10.1016/j.fochx.2024.101899. eCollection 2024 Dec 30.ABSTRACTBlack tea's quality and flavor are largely influenced by its processing stages, which affect its volatile and non-volatile phytochemicals. This study aimed to optimized black tea manufacturing by investigating withering time, fermentation time, and temperature's impact on sensory quality. Using a U*15 (157) uniform design, optimal conditions were determined: 14 h of withering, 5.6 h of fermentation, and a 34 °C temperature. A verification experiment analyzed the volatile and non-volatile profiles. HPLC, GC-MS, and LC-MS revealed dynamic changes in phytochemicals. Among 157 VOCs and 2642 metabolites, 19 VOCs (VIP > 1.5) were crucial for aroma, while 50 (VIP > 1.5, p < 0.01) characteristic metabolites were identified. During processing, fragrant volatile compounds like linalool oxides, geraniol, benzeneacetaldehyde, benzaldehyde, methyl salicylate, and linalyl acetate increased, contributing to rose and honey like aromas. These changes were crucial in developing the characteristic flavor and color of black tea. Twenty-four new compounds formed, while 80 grassy odor volatiles decreased. Non-volatile metabolites changed notably, with decreased catechins and increased gallic acid. Theaflavin compounds rose initially but declined later. This study outlines metabolite changes in Yunkang 10 black tea, crucial for flavor enhancement and quality control.PMID:39507928 | PMC:PMC11539724 | DOI:10.1016/j.fochx.2024.101899

Front Toxicol. 2024 Oct 23;6:1465728. doi: 10.3389/ftox.2024.1465728. eCollection 2024.ABSTRACTCannabinoid hyperemesis syndrome presents as a complex of symptoms and signs encompassing nausea, vomiting, abdominal pain, and hot water bathing behavior, most typically in a heavy cannabis user. Its presentation is frequently associated with hypothalamic-pituitary-adrenal axis activation with stress and weight loss. Recent investigation has identified five statistically significant mutations in patients distinct from those of frequent cannabis users who lack the symptoms, affecting the TRPV1 receptor, two dopamine genes, the cytochrome P450 2C9 enzyme that metabolizes tetrahydrocannabinol, and the adenosine triphosphate-binding cassette transporter. The syndrome is associated with escalating intake of high potency cannabis, or alternatively, other agonists of the cannabinoid-1 receptor including synthetic cannabinoids. Some patients develop environmental triggers in scents or foods that suggest classical conditioned responses. Various alternative "causes" are addressed and refuted in the text, including exposure to pesticides, neem oil or azadirachtin. Nosological confusion of cannabinoid hyperemesis syndrome has arisen with cyclic vomiting syndrome, whose presentation and pathophysiology are clearly distinct. The possible utilization of non-intoxicating antiemetic cannabis components in cannabis for treatment of cannabinoid hyperemesis syndrome is addressed, along with future research suggestions in relation to its genetic foundation and possible metabolomic signatures.PMID:39507417 | PMC:PMC11537899 | DOI:10.3389/ftox.2024.1465728

J Inflamm Res. 2024 Nov 2;17:8027-8045. doi: 10.2147/JIR.S480307. eCollection 2024.ABSTRACTOBJECTIVE: This study aimed to establish a model for identifying chronic gastritis with the traditional Chinese medicine damp phlegm pattern by examining metabolite changes in the tongue coating of patients. It also explored the role of metabolic pathways in the pathogenesis of this condition.METHODS: This cross-sectional study involved 300 patients diagnosed with chronic gastritis. Of these, 200 patients exhibited the damp phlegm pattern, while 100 did not. Metabolomic methods employing GC-TOF-MS and UHPLC-QE-MS were utilized to identify various metabolites in the tongue coating of patients. An identification model for chronic gastritis with the damp phlegm pattern was created based on ROC curves derived from differential biomarkers. Additionally, 50 samples not included in model construction were collected for external validation.RESULTS: Comparison of the damp phlegm pattern group with the non-damp phlegm pattern group revealed a total of 116 differential metabolites. Among these, lipids and lipid-like compounds were most abundant, comprising 27 types, which included four lipid metabolites related to sphingomyelin metabolism. The ROC model, which included phenol, 2.6-diaminoheptanedioic acid, and N-hexadecanoyl pyrrolidine, demonstrated the highest accuracy, with accuracy, sensitivity, and specificity metrics of 94.0%, 91.0%, and 87.0%, respectively. Furthermore, external validation using tongue coating metabolites from 50 patients revealed accuracy, sensitivity, and specificity in the validation set of 93.9%, 90.6%, and 83.3%, respectively.CONCLUSION: Differential metabolites between patients with the damp phlegm pattern and those without are primarily lipids and lipid-like compounds. N-hexadecanoyl pyrrolidine, phenol, and 2.6-diaminoheptanedioic acid may serve as potential biomarkers for chronic gastritis characterized by the damp phlegm pattern.PMID:39507266 | PMC:PMC11539634 | DOI:10.2147/JIR.S480307

Front Vet Sci. 2024 Oct 23;11:1477575. doi: 10.3389/fvets.2024.1477575. eCollection 2024.ABSTRACTThe aim of this study was to explore whether and how Bacillus subtilis KC1 can enhance the growth performance of Mycoplasma gallisepticum (MG)-infected broilers. Broilers were randomly divided into 4 groups: the control group (basal diet), the MG group (basal diet + MG challenge), the KC group (basal diet + B. subtilis KC1 supplementation), the KC + MG group (basal diet + B. subtilis KC1 supplementation + MG challenge). The results showed that, compared to the control group, MG group exhibited significantly reduced body weight and average daily gain, and increased feed conversion ratio of broilers. However, compared to the MG group, the B. subtilis KC1 + MG group exhibited significantly improved above indicators of growth performance. In addition, compared to the MG group, B. subtilis KC1 + MG group exhibited increased superoxide dismutase levels and reduced levels of malondialdehyde, interleukin-1β, and tumor necrosis factor-α of broilers. Furthermore, metabolomics and transcriptomics analyses indicated that MG infection disrupted amino acid metabolism in broilers, whereas B. subtilis KC1 supplementation alleviated the abnormal amino acid metabolism caused by MG. These results suggested that B. subtilis KC1 may alleviate the poor growth performance caused by MG infection in broilers by improving amino acid metabolism.PMID:39507220 | PMC:PMC11538993 | DOI:10.3389/fvets.2024.1477575

Heliyon. 2024 Oct 10;10(20):e38814. doi: 10.1016/j.heliyon.2024.e38814. eCollection 2024 Oct 30.ABSTRACTBACKGROUND: Renzhu Jianwei Granula (RJG) is a traditional Chinese medicine compound initially formulated to address precancerous lesions for gastric cancer. The aim of this study was to assess RJG's efficacy in treating precancerous lesions of gastric cancer through a comprehensive meta-analysis of randomized clinical trials.METHODS: Two authors separately conducted an exhaustive search across three databases (PubMed, CNKI and Wanfang) without imposing any restrictions on publication year or language. Eligible studies, spanning from the inception of databases to July 18th, 2024, were included. Valid data were summarized and those with a group size of 3 or more were preserved. R software and Cochrane collaboration tools were employed for sensitivity analysis and assessing the quality of the included studies. The data from selected studies were transformed into risk ratios (RRs) and subjected to meta-analysis. This study was prospectively registered in PROSPERO.RESULTS: Data from 9 studies encompassing 912 participants revealed that the RJG group exhibited superior clinical efficacy compared to the control group, with an RR of 0.36 (95 % confidence interval (CI): 0.25 to 0.52). RJG demonstrated enhanced efficacy over the control group in both comprehensive efficacy (RR: 0.42, 95 % CI: 0.31 to 0.55) and gastroscopy efficacy (RR: 0.56, 95 % CI: 0.46 to 0.69). Moreover, significant improvements in pathological features such as atrophy (RR: 0.58, 95 % CI: 0.45 to 0.73), dysplasia (RR: 0.41, 95 % CI: 0.27 to 0.61), and intestinal metaplasia (RR: 0.54, 95 % CI: 0.43 to 0.69) in precancerous lesions of gastric cancer were observed following RJG administration.CONCLUSION: This study's synthesized data provide compelling evidence of RJG's substantial therapeutic impact in ameliorating symptoms associated with precancerous lesions of gastric cancer.TRIAL REGISTRATION NUMBER: The study protocol was registered at PROSPERO (CRD42024572606).PMID:39506958 | PMC:PMC11538645 | DOI:10.1016/j.heliyon.2024.e38814

BMC Vet Res. 2024 Nov 6;20(1):505. doi: 10.1186/s12917-024-04339-7.ABSTRACTBACKGROUND: Studying the effect of dietary Spirulina and lysozyme supplementation on the metabolome and proteome of liver tissue contributes to understanding potential hepatic adaptations of piglets to these novel diets. This study aimed to understand the influence of including 10% Spirulina on the metabolome and proteome of piglet liver tissue. Three groups of 10 post-weaned piglets, housed in pairs, were fed for 28 days with one of three experimental diets: a cereal and soybean meal-based diet (Control), a base diet with 10% Spirulina (SP), and an SP diet supplemented with 0.01% lysozyme (SP + L). At the end of the trial, animals were sacrificed and liver tissue was collected. Metabolomics analysis (n = 10) was performed using NMR data analysed with PCA and PLS-DA. Proteomics analysis (n = 5) was conducted using a filter aided sample preparation (FASP) protocol and Tandem Mass Tag (TMT)-based quantitative approach with an Orbitrap mass spectrometer.RESULTS: Growth performance showed an average daily gain reduction of 9.5% and a feed conversion ratio increase of 10.6% in groups fed Spirulina compared to the control group. Metabolomic analysis revealed no significant differences among the groups and identified 60 metabolites in the liver tissue. Proteomics analysis identified 2,560 proteins, with 132, 11, and 52 differentially expressed in the Control vs. SP, Control vs. SP + L and SP vs. SP + L comparisons, respectively. This study demonstrated that Spirulina enhances liver energy conversion efficiency, detoxification and cellular secretion. It improves hepatic metabolic efficiency through alterations in fatty acid oxidation (e.g., upregulation of enzymes like fatty acid synthase and increased acetyl-CoA levels), carbohydrate catabolism (e.g., increased glucose and glucose-6-phosphate), pyruvate metabolism (e.g., higher levels of pyruvate and phosphoenolpyruvate carboxykinase), and cellular defence mechanisms (e.g., upregulation of glutathione and metallothionein). Lysozyme supplementation mitigates some adverse effects of Spirulina, bringing physiological responses closer to control levels. This includes fewer differentially expressed proteins and improved dry matter, organic matter and energy digestibility. Lysozyme also enhances coenzyme availability, skeletal myofibril assembly, actin-mediated cell contraction, tissue regeneration and development through mesenchymal migration and nucleic acid synthesis pathways.CONCLUSIONS: While Spirulina inclusion had some adverse effects on growth performance, it also enhanced hepatic metabolic efficiency by improving fatty acid oxidation, carbohydrate catabolism and cellular defence mechanisms. The addition of lysozyme further improved these benefits by reducing some of the negative impacts on growth and enhancing nutrient digestibility, tissue regeneration, and overall metabolic balance. Together, Spirulina and lysozyme demonstrate potential as functional dietary components, but further optimization is needed to fully realize their benefits without compromising growth performance.PMID:39506864 | DOI:10.1186/s12917-024-04339-7

Br J Dermatol. 2024 Nov 7:ljae432. doi: 10.1093/bjd/ljae432. Online ahead of print.NO ABSTRACTPMID:39506538 | DOI:10.1093/bjd/ljae432

Bioessays. 2024 Nov 6:e2400154. doi: 10.1002/bies.202400154. Online ahead of print.ABSTRACTHematopoiesis unfolds within the bone marrow niche where hematopoietic stem cells (HSCs) play a central role in continually replenishing blood cells. The hypoxic bone marrow environment imparts peculiar metabolic characteristics to hematopoietic processes. Here, we discuss the internal metabolism of HSCs and describe external influences exerted on HSC metabolism by the bone marrow niche environment. Importantly, we suggest that the metabolic environment and metabolic cues are intertwined with HSC cell fate, and are crucial for hematopoietic processes. Metabolic dysregulation within the bone marrow niche during acute stress, inflammation, and chronic inflammatory conditions can lead to reduced HSC vitality. Additionally, we raise questions regarding metabolic stresses imposed on HSCs during implementation of stem cell protocols such as allo-SCT and gene therapy, and the potential ramifications. Enhancing our comprehension of metabolic influences on HSCs will expand our understanding of pathophysiology in the bone marrow and improve the application of stem cell therapies.PMID:39506498 | DOI:10.1002/bies.202400154

Physiol Plant. 2024 Nov-Dec;176(6):e14592. doi: 10.1111/ppl.14592.ABSTRACTSoil salinization, which severely limits crop yield and quality, has become a global environmental and resource issue. Melatonin plays an important role in plant responses to salt stress. Smooth bromegrass is an important forage with excellent feed value and is widely grown in northern and north-west China for pasture and sand binding. However, the physiological and molecular mechanisms underlying exogenous melatonin regulation of salt stress in smooth bromegrass are not clear. This study compared the phenotype, physiological, transcriptome, and metabolome profiles of two varieties with contrasting salt tolerance attributes under salt and melatonin treatment. After melatonin treatment, the catalase (CAT) and ascorbate peroxidase (APX) activity, proline content, actual photochemical efficiency (Y(II)), relative water content, and fresh weight above ground were significantly higher than under salt treatment, while relative conductivity, H2O2 content, and Na+/K+ ratio were significantly lower than salt treatment. The transcriptome and metabolite profiling analysis of smooth bromegrass seedlings treated without melatonin under salt stress identified the presence of 22522 differentially expressed genes (DEGs) and 862 differentially expressed metabolites (DEMs) in SS, 17809 DEGs and 812 DEMs in ST, while treated with melatonin under salt stress identified the presence of 7033 DEGs and 177 DEMs in SS, 2951 DEGs and 545 DEMs in ST. Furthermore, in response to salt stress, melatonin may be involved in regulating the correlation between DEGs and DEMs in flavonoid biosynthesis, proline biosynthesis, and melatonin biosynthesis. Moreover, melatonin participated in mediating melatonin biosynthesis pathways and affected the expression of ASMT in response to salt stress.PMID:39506145 | DOI:10.1111/ppl.14592

Commun Biol. 2024 Nov 6;7(1):1450. doi: 10.1038/s42003-024-07137-x.ABSTRACTThe aim of this study was to explore the intricate relationship between serum metabolomics and lifestyle factors, shedding light on their impact on health in the context of breast cancer risk. Detailed metabolic profiles of 2283 female participants in the Trøndelag Health Study (HUNT study) were obtained through nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS).We show that lifestyle-related variables can explain up to 30% of the variance in individual metabolites. Age and obesity were the primary factors affecting the serum metabolic profile, both associated with increased levels of triglyceride-rich very low-density lipoproteins (VLDL) and intermediate-density lipoproteins (IDL), amino acids and glycolysis-related metabolites, and decreased levels of high-density lipoproteins (HDL). Moreover, factors like hormonal changes associated with menstruation and contraceptive use or education level influence the metabolite levels.Participants were clustered into three distinct clusters based on lifestyle-related factors, revealing metabolic similarities between obese and older individuals, despite diverse lifestyle factors, suggesting accelerated metabolic aging with obesity. Our results show that metabolic associations to cancer risk may partly be explained by modifiable lifestyle factors.PMID:39506131 | DOI:10.1038/s42003-024-07137-x

Acta Pharmacol Sin. 2024 Nov 6. doi: 10.1038/s41401-024-01409-2. Online ahead of print.ABSTRACTRAS is the most frequently mutated oncoprotein for cancer driving. Understanding of RAS biology and discovery of druggable lynchpins in RAS pathway is a prerequisite for targeted therapy of RAS-mutant cancers. The recent identification of KRASG12C inhibitor breaks the "undruggable" curse on RAS and has changed the therapy paradigm of KRAS-mutant cancers. However, KRAS mutations, let alone KRASG12C mutation, account for only part of RAS-mutated cancers. Targeted therapies for cancers harboring other RAS mutations remain the urgent need. In this study we explored the pivotal regulatory molecules that allow for broad inhibition of RAS mutants. By comparing the expression levels of nucleotide pyrophosphatase (NPPS) in a panel of cell lines and the functional consequence of increased NPPS expression in RAS-mutant cells, we demonstrated that cancer cells with various kinds of RAS mutations depended on NPPS for growth and survival, and that this dependence conferred a vulnerability of RAS-mutant cancer to treatment of NPPS inhibition. RAS-mutant cells, compared with RAS-wildtype cells, bored and required an upregulation of NPPS. Transcriptomics and metabolomics analyses revealed a NPPS-dependent hyperglycolysis in RAS-mutant cells. We demonstrated that NPPS promoted glucose-derived glycolytic intermediates in RAS-mutant cells by enhancing its interaction with hexokinase 1 (HK1), the enzyme catalyzing the first committed step of glycolysis. Pharmacological inhibition of NPPS-HK1 axis using NPPS inhibitor Enpp-1-IN-1 or HK1 inhibitor 2-deoxyglucose (2-DG), or genetic interfere with NPPS suppressed RAS-mutant cancers in vitro and in vivo. In conclusion, this study reveals an unrecognized mechanism and druggable lynchpin for modulation of pan-mutant-RAS pathway, proposing a new potential therapeutic approach for treating RAS-mutant cancers.PMID:39506063 | DOI:10.1038/s41401-024-01409-2

Sci Rep. 2024 Nov 6;14(1):27010. doi: 10.1038/s41598-024-75773-8.ABSTRACTSpices played crucial and variable roles in traditions, culture, history, religious ceremonials and festivals along with fetching food flavor and microbial protection globally due to presence of structurally unique and multi-natured chemotypes. Their existence in dishes portrayed key roles in improving shelf life by regulating spoilage of cuisine with different synergistic mechanism. Histo-anatomically (A) sowa exhibited distinguished cellular attributes which created remarkable differences with T. ammi. HPTLC chemometrics of both fruits revealed several peaks for active metabolomics with unique isocratic combination of menstruum. GC-MS study of hydro-distillate exhibited presence of monoterpenic cyclic and aromatic hydrocarbons, alcoholic and ketonic groups along with phenolic derivative that covers majorly 90% of total metabolites. Combined essential oils (EOs 1 + 2) of both fruits showed excellent antimicrobial activity against various clinical pathogenic strains such as K. pneumoniae at 10 µL/mL, S. aureus at 2.5 µL/mL, E. coli and E. faecalis at 1.25 µL/mL, and MRSA and Bcereus at 0.625 µL/mL and (C) albicans at 0.312 µL/mL as the MIC. The antioxidant study of (EOs 1 + 2) with maximum inhibition percentage to DPPH assay was 84.02 ± 1.05 at 100 µg/mL, and minimal inhibition was 72.31 ± 0.63 at 5 µg/mL with IC50 value 4.69 ± 0.22 µg/mL, while ABTS assay extreme was 79.15 ± 2.14 µg/mL and minimal was 67 ± 1.34 with the IC50 value of 18.37 ± 0.15 µg/mL, in superoxide assay uppermost inhibition was 81.03 ± 0.27 µg/mL and lowest was at 65.16 ± 3.15 with the IC50 value 16.46 ± 0.54, and H2O2 radical scavenging activity, predominant value was 78.01 ± 0.47 and least was 64.1 ± 2.01 with IC50 15.58 ± 0.34. These comparative key diagnostic features and synergistic effect of multicomponent natural antimicrobials will provide profound intellect of ancient utility and further scientists to explore their multiple mechanistic modality and application in food and beverages industry.PMID:39505931 | DOI:10.1038/s41598-024-75773-8

Sci Rep. 2024 Nov 6;14(1):26875. doi: 10.1038/s41598-024-75300-9.ABSTRACTThe cation-independent mannose 6-phosphate receptor (CI-MPR) is clinically significant in the treatment of patients with lysosomal storage diseases because it functions in the biogenesis of lysosomes by transporting mannose 6-phosphate (M6P)-containing lysosomal enzymes to endosomal compartments. CI-MPR is multifunctional and modulates embryonic growth and fetal size by downregulating circulating levels of the peptide hormone insulin-like growth factor 2 (IGF2). The extracellular region of CI-MPR comprises 15 homologous domains with binding sites for M6P-containing ligands located in domains 3, 5, 9, and 15, whereas IGF2 interacts with residues in domain 11. How a particular ligand affects the receptor's conformation or its ability to bind other ligands remains poorly understood. To address these questions, we purified a soluble form of the receptor from newborn calf serum, carried out glycoproteomics to define the N-glycans at its 19 potential glycosylation sites, probed its ability to bind lysosomal enzymes in the presence and absence of IGF2 using surface plasmon resonance, and assessed its conformation in the presence and absence of IGF2 by negative-staining electron microscopy and hydroxyl radical protein footprinting studies. Together, our findings support the hypothesis that IGF2 acts as an allosteric inhibitor of lysosomal enzyme binding by inducing global conformational changes of CI-MPR.PMID:39505925 | DOI:10.1038/s41598-024-75300-9

Neuroimage. 2024 Nov 4:120918. doi: 10.1016/j.neuroimage.2024.120918. Online ahead of print.ABSTRACTBACKGROUND: Prior efforts have revealed changes in gut microbiome, circulating metabolome, and multimodal neuroimaging features in cerebral small vessel disease (CSVD). However, there is a paucity of research integrating the multi-omic information to characterize the role of the microbiota-gut-brain axis in CSVD.METHODS: We collected gut microbiome, fecal and blood metabolome, multimodal magnetic resonance imaging data from 37 CSVD patients with white matter hyperintensities and 46 healthy controls. Between-group comparison was performed to identify the differential gut microbial taxa, followed by performance of multi-stage microbiome-metabolome-neuroimaging-neuropsychology correlation analyses in CSVD patients.RESULTS: Our data showed both depleted and enriched gut microbes in CSVD patients. Among the differential microbes, Haemophilus and Akkermansia were associated with a range of metabolites enriched for Aminoacyl-tRNA biosynthesis pathway. Furthermore, the affected metabolites were associated with neuroimaging measures involving gray matter morphology, spontaneous intrinsic brain activity, white matter integrity, and global structural network topology, which were in turn related to cognition and emotion in CSVD patients.CONCLUSION: Our findings provide an integrative framework to understand the pathophysiological mechanisms underlying the interplay between gut microbiota dysbiosis and CSVD, highlighting the potential of targeting the microbiota-gut-brain axis as a therapeutic strategy in CSVD patients.PMID:39505226 | DOI:10.1016/j.neuroimage.2024.120918

Mol Metab. 2024 Nov 4:102052. doi: 10.1016/j.molmet.2024.102052. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Deficiency in the transcription factor (TF) GLI-Similar 3 (GLIS3) in humans and mice leads to the development of polycystic kidney disease (PKD). In this study, we investigate the role of GLIS3 in the regulation of energy metabolism and mitochondrial functions in relation to its role in normal kidney and metabolic reprogramming in PKD pathogenesis.APPROACH AND RESULTS: Transcriptomics, cistromics, and metabolomics were used to obtain insights into the role of GLIS3 in the regulation of energy homeostasis and mitochondrial metabolism in normal kidney and PKD pathogenesis using GLIS3-deficient mice. Transcriptome analysis showed that many genes critical for mitochondrial biogenesis, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and the tricarboxylic acid (TCA) cycle, including Tfam, Tfb1m, Tfb2m, Ppargc1a, Ppargc1b, Atp5j2, Hadha, and Sdha, are significantly suppressed in kidneys from both ubiquitous and tissue-specific Glis3-deficient mice. ChIP-Seq analysis demonstrated that GLIS3 is associated with the regulatory region of many of these genes, indicating that their transcription is directly regulated by GLIS3. Cistrome analyses revealed that GLIS3 binding loci frequently located near those of hepatocyte nuclear factor 1-Beta (HNF1B) and nuclear respiratory factor 1 (NRF1) suggesting GLIS3 regulates transcription of many metabolic and mitochondrial function-related genes in coordination with these TFs. Seahorse analysis and untargeted metabolomics corroborated that mitochondrial OXPHOS utilization is suppressed in GLIS3-deficient kidneys and showed that key metabolites in glycolysis, TCA cycle, and glutamine pathways were altered indicating increased reliance on aerobic glycolysis and glutamine anaplerosis. These features of metabolic reprogramming may contribute to a bioenergetic environment that supports renal cyst formation and progression in Glis3-deficient mice kidneys.CONCLUSIONS: We identify GLIS3 as a novel positive regulator of the transition from aerobic glycolysis to OXPHOS in normal early postnatal kidney development by directly regulating the transcription of mitochondrial metabolic genes. Loss of GLIS3 induces several features of renal cell metabolic reprogramming. Our study identifies GLIS3 as a new participant in an interconnected transcription regulatory network, that includes HNF1B and NRF1, critical in the regulation of mitochondrial-related gene expression and energy metabolism in normal postnatal kidneys and PKD pathogenesis in Glis3-deficient mice.PMID:39505148 | DOI:10.1016/j.molmet.2024.102052

Metab Eng. 2024 Nov 4:S1096-7176(24)00144-7. doi: 10.1016/j.ymben.2024.11.002. Online ahead of print.ABSTRACTEngineering of a specialized metabolic pathway in plants is a promising approach to produce high-value bioactive compounds to address the challenges of climate change and population growth. Understanding the interaction between the heterologous pathway and the native metabolic network of the host plant is crucial for optimizing the engineered system and maximizing the yield of the target compound. In this study, we performed transcriptomic, metabolomic and metagenomic analysis of tobacco (Nicotiana tabacum) plants engineered to produce betanin, an alkaloid pigment that is found in Caryophyllaceae plants. Our data reveals that, in a dose-dependent manor, the biosynthesis of betanin promotes carbohydrate metabolism and represses nitrogen metabolism in the leaf, but enhances nitrogen assimilation and metabolism in the root. By supplying nitrate or ammonium, the accumulation of betanin increased by 1.5∼3.8-fold in leaves and roots of the transgenic plants, confirming the pivotal role of nitrogen in betanin production. In addition, the rhizosphere microbial community is reshaped to reduce denitrification and increase respiration and oxidation, assistant to suppress nitrogen loss. Our analysis not only provides a framework for evaluating the pleiotropic effects of an engineered metabolic pathway on the host plant, but also facilitates the development of novel strategies to balance the heterologous process and the native metabolic network for the high-yield and nutrient-efficient production of bioactive compounds in plants.PMID:39505140 | DOI:10.1016/j.ymben.2024.11.002

Environ Pollut. 2024 Nov 4:125246. doi: 10.1016/j.envpol.2024.125246. Online ahead of print.ABSTRACTNanoplastics (NPs) can adversely affect living organisms. However, the uptake of NPs by plants and the physiological and molecular mechanisms underlying NP-mediated plant growth remain unclear, particularly in the presence of iron minerals and humic acid (HA). In this study, we investigated NP accumulation in rice (Oryza sativa L.) and the physiological effects of exposure to polystyrene NPs (0, 20, and 100 mg L-1) in the presence of iron plaque (IP) and HA. NPs were absorbed on the root surface and entered cells, and confocal laser scanning microscopy confirmed NP uptake by the roots. NP treatments decreased root superoxide dismutase (SOD) activity (28.9-44.0%) and protein contents (31.2-38.6%). IP and HA (5 and 20 mg L-1) decreased the root protein content (20.44-58.3% and 44.2-45.2%, respectively) and increased the root lignin content (22.3-27.5% and 19.2-29.6%, respectively) under NP stress. IP inhibited the NP-induced decreasing trend of SOD activity (19.2-29.5%), while HA promoted this trend (48.7-50.3%). Transcriptomic and metabolomic analysis (Control, 100NPs, and IP-100NPs-20HA) showed that NPs inhibited arginine biosynthesis, and alanine, aspartate, and glutamate metabolism and activated phenylpropanoid biosynthesis related to lignin. The coexistence of IP and HA had positive effects on the amino acid metabolism and phenylpropanoid biosynthesis induced by NPs. Regulation of genes and metabolites involved in nitrogen metabolism and secondary metabolism significantly altered the levels of protein and lignin in rice roots. These findings provide a scientific basis for understanding the environmental risk of NPs under real environmental conditions.PMID:39505096 | DOI:10.1016/j.envpol.2024.125246

Microb Pathog. 2024 Nov 4:107048. doi: 10.1016/j.micpath.2024.107048. Online ahead of print.ABSTRACTHuman adenovirus type 7 (HAdV-7) is a prominent pathogen that causes severe pneumonia in children in China. However, the interaction between HAdV-7 infection and host metabolism is still poorly understood. To gain a comprehensive understanding of the metabolic interplay between host cells and the virus, we analysed the energy and lipid metabolism profiles of the HAdV-7-infected lung cancer cell line A549 by ultrahigh-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (ESI-QTRAP-MS/MS). Our study revealed significant alterations in various metabolic processes, including the tricarboxylic acid cycle, purine and pyrimidine metabolism, amino acid metabolism, nucleotide metabolism, and lipid metabolism, in A549 cells after HAdV-7 infection. Moreover, HAdV-7 infection stimulated enhanced synthesis of membrane lipids in A549 cells. These findings emphasize the crucial role of metabolism in viral infection and suggest that modulating host cell metabolism could be a promising approach for targeted drug development and infection control.PMID:39505087 | DOI:10.1016/j.micpath.2024.107048