PubMed

PeerJ. 2024 Nov 19;12:e18496. doi: 10.7717/peerj.18496. eCollection 2024.ABSTRACTRice grown in Yunnan Province is known for its excellent taste and consumer preference. However, the metabolite composition of this unique rice remains unclear. In this study, the metabolic profile of different rice planted in various producing regions was evaluated. A total of 1,005 metabolites were identified, including nucleotides and their derivatives, amino acids and their derivatives, alkaloids, organic acids, phenolic acids, lignans and coumarins, lipids, terpenoids, quinones, flavones, tannins, and others. Procucing region and varieties can be clearly distinguished on the PCA diagram. Differential metabolites accumulated in the MSD502 vs. MSR88 (138)/LHHG (234)/LHR88 (188) comparison groups. The results in this study provide scientific information for the origin tracing and variety differentiation of raw rice materials.PMID:39583111 | PMC:PMC11583909 | DOI:10.7717/peerj.18496

PeerJ. 2024 Nov 19;12:e18534. doi: 10.7717/peerj.18534. eCollection 2024.ABSTRACTBACKGROUND: Research on serum metabolite profiles in thyroid autoimmunity (TAI) patients during early pregnancy is currently limited.AIM & METHODS: The current study aimed to identify differential serum metabolites and assess the relationship between pregnancy outcomes and metabolic abnormalities in individuals with TAI. This research included 26 pregnant women with TAI and 30 healthy controls (HC). We employed a liquid chromatograph mass spectrometer (LC-MS) to analyze changes between the two groups.RESULTS: Newborns in the TAI patients had lower birth weights than those in the control group (P = 0.007). We identified 92 differential metabolites (including 50 upregulated and 42 downregulated) belonging to amino acids, fatty acyls, glycerophosphocholines, steroid and other categories and four significantly enrichment Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways including taurine and hypotaurine metabolism, citrate cycle (TCA cycle), glyoxylate and dicarboxylate metabolism and 2-oxocarboxylic acid metabolism. We further identified 15 characteristic metabolites (6-Methylquinoline, D-erythrose 4-phosphate, 4-Hydroxyisoleucine, phosphatidylcholine (PC)(16:2e/16:0), N3,N4-Dimethyl-L-arginine, N-desmethyltramadol, 3-Methoxybenzaldehyde, sphingomyelin (SM)(d14:3/28:2), gamma-Glutamylleucine, NSI-189, 3-(1-cyano-1,2-dihydroisoquinolin-2-yl)-3-oxopropyl propionate, lysophosphatidylinositol (LPI) 16:0, cis-Aconitic acid, polyamide (PA)(18:1/18:2) and fatty acyl esters of hydroxy fatty acid (FAHFA)(17:0/18:0)) using least absolute shrinkage and selection operator (LASSO) regression. Correlation analyses revealed that 6-Methylquinoline, D-erythrose 4-phosphate, gamma-Glutamylleucine, and LPI 16:0 exhibited a positive correlation with anemia before delivery, while 3-(1-cyano-1,2-dihydroisoquinolin-2-yl)-3-oxopropyl propionate had a negative correlation. LPI 16:0 displayed a positive correlation with uric acid (UA) during both middle and late pregnancy, whereas 3-Methoxybenzaldehyde exhibited a negative correlation with UA in late pregnancy. Cis-Aconitic acid showed a positive correlation with fasting blood glucose (FBG) in middle pregnancy. Conversely, 6-Methylquinoline and 4-Hydroxyisoleucine had a negative correlation with birth weight. Thyroid autoantibodies were found to be associated with 14 metabolites identified using LASSO, with the exception of PA (18:1/18:2).CONCLUSIONS: Our findings provide new evidence supporting the early screening of serum metabolites and their potential for predicting adverse pregnancy outcomes in women with TAI.PMID:39583110 | PMC:PMC11583911 | DOI:10.7717/peerj.18534

J Allergy Clin Immunol Glob. 2024 Oct 18;4(1):100353. doi: 10.1016/j.jacig.2024.100353. eCollection 2025 Feb.ABSTRACTBACKGROUND: Hereditary angioedema (HAE) is a rare inherited disorder that predisposes an individual to develop vasogenic edema. Bradykinin release, which increases vascular permeability, results in angioedema. C1 esterase inhibitor (C1-INH) is a major regulator of critical enzymes involved in bradykinin generation and mutations in genes that encode the C1 inhibitor of complement factor 1, which prevent its synthesis (type I HAE), form a dysfunctional protein (type II HAE), or have normal functioning C1-INH (type III HAE, aka HAE-III).OBJECTIVES: The goals of this study were to use a systems biology analysis to identify novel biomarkers to aid in the diagnosis of HAE-III and to elucidate its underlying pathogenic mechanisms.METHODS: Blood samples were obtained from HAE-III subjects and age- and sex-matched healthy controls. DNA, RNA, and protein purified from the samples were subjected to multiomics analysis using a 1-shot liquid chromatography-mass spectrometry-based multiomics platform (Omni-MS, Dalton Bioanalytics) to profile proteins, lipids, electrolytes, and metabolites enabling concurrent analysis of diverse analyte classes.RESULTS: A total of 1647 novel identifications that included genes, proteins, and metabolites were made when comparing HAE-III samples to control samples. Our identification library included MSFragger for protein identification, LipiDex for lipid identification, and Compound Discoverer for metabolite identification, enabling differential expression analysis. Key findings included a significant increase in the expression levels of galectin-3, lysosomal α-glucosidase, platelet factor 4, and platelet-derived growth factor subunit A in HAE-III subjects compared to controls, all of which generate an immunomodulatory response.CONCLUSION: Galectin-3 plays a critical role in eosinophil recruitment and airway allergic inflammation. It may contribute to chronic inflammation and fibrosis resulting in leaky vasculature, and it could be a potential therapeutic target in HAE-III.PMID:39583036 | PMC:PMC11583700 | DOI:10.1016/j.jacig.2024.100353

Front Vet Sci. 2024 Nov 8;11:1456790. doi: 10.3389/fvets.2024.1456790. eCollection 2024.ABSTRACTThe rearing system of livestock plays a vital role in animal production, meat quality, and overall welfare. This study aimed to assess the influence of cage-rearing system and forest-rearing system on the ileum microbiota, metabolome, and ileal mucosa transcriptome in meat rabbits. Moreover, 16S rDNA sequencing revealed significant differences in the ileal microbiome composition: caged rabbits exhibited a higher abundance of the genera uncultured Erysipelotrichaceae and Delftia, whereas the levels of Muribaculaceae, unclassified Burkholderiales, and uncultured Eubacteriaceae were lower compared to rabbits reared in the forest. Metabolome analysis identified 372 differentially accumulated metabolites in the ileum content, which were predominantly mapped to amino acid metabolism, nucleotide metabolism, and energy metabolism pathways. The cage-rearing system was found to positively correlate with the efficient utilization of nutrient sources. Additionally, transcriptome analysis of the ileal mucosa revealed 984 differentially expressed genes, predominantly involved in metabolic pathways, signal transduction pathways, and immune response processes. Through Pearson correlation analysis, we were able to elucidate the metabolic pathway, immune responses, and disease resistance mechanisms were affected by the rearing system. Overall, the findings suggested that metabolic adaptation, nutrient utilization, and immune response play crucial roles in how rabbits adjust to different rearing systems. While the cage system may enhance nutrient efficiency, it appears to suppress immune function and disease resistance.PMID:39582888 | PMC:PMC11582050 | DOI:10.3389/fvets.2024.1456790

Front Immunol. 2024 Nov 8;15:1469163. doi: 10.3389/fimmu.2024.1469163. eCollection 2024.ABSTRACTINTRODUCTION: During an immune response, macrophages undergo systematic metabolic rewiring tailored to support their functions. Branched-chain amino acid (BCAA) metabolism has been reported to modulate macrophage function; however, its role in macrophage alternative activation remain unclear. We aimed to investigate the role of BCAA metabolism in macrophage alternative activation.METHOD: The metabolomics of BMDM-derived M0 and M2 macrophages were analyzed using LC-MS. BCAAs were supplemented and genes involved in BCAA catabolism were inhibited during M2 macrophage polarization. The expression of M2 marker genes was assessed through RT-qPCR, immunofluorescence, and flow cytometry.RESULTS AND DISCUSSION: Metabolomic analysis identified increased BCAA metabolism as one of the most significantly rewired pathways upon alternative activation. M2 macrophages had significantly lower BCAA levels compared to controls. BCAA supplementation promoted M2 macrophage polarization both in vitro and in vivo and increased oxidative phosphorylation in M2 macrophages. Blocking BCAA entry into mitochondria by knockdown of SLC25A44 inhibited M2 macrophage polarization. Furthermore, M2 macrophages polarization was suppressed by knockdown of Branched-chain amino-acid transaminase 2 (BCAT2) and branched chain keto acid dehydrogenase E1 subunit alpha (BCKDHA), both of which are key enzymes involved in BCAA oxidation. Overall, our findings suggest that BCAA catabolism plays an important role in polarization toward M2 macrophages.PMID:39582859 | PMC:PMC11582057 | DOI:10.3389/fimmu.2024.1469163

Food Chem (Oxf). 2024 Nov 6;9:100228. doi: 10.1016/j.fochms.2024.100228. eCollection 2024 Dec 30.ABSTRACTThe flavor of guava, an important tropical fruit, is influenced by secondary metabolites. However, the mechanisms and processes underlying flavor formation in guava remain unclear. In this study, dynamic changes in volatile organic compounds (VOCs), sugars, and organic acids in guava peel and flesh across different developmental stages were investigated using headspace solid-phase microextraction (HS-SPME) combined with gas chromatography-mass spectrometry (GC-MS) and high-performance liquid chromatography (HPLC). Here, we identified 90 VOCs, three sugars and eight organic acids. The dynamics of VOCs differ between the flesh and peel. The early developmental stages are more critical in influencing the variation of VOCs in the flesh, while VOC changes in peel occur more progressively across the developmental stages. By integrating transcriptomic and metabolomic analyses, we identified several key genes involved in VOC, sugar, and acid metabolism. This is the first study to describe the expression patterns of these genes throughout guava development, providing new insights into guava flavor development.PMID:39582733 | PMC:PMC11583725 | DOI:10.1016/j.fochms.2024.100228

Food Chem X. 2024 Nov 5;24:101971. doi: 10.1016/j.fochx.2024.101971. eCollection 2024 Dec 30.ABSTRACTAvocado is widely grown in tropical and subtropical regions of China. Diverse germplasms have been generated through natural hybridization and selective breeding. Here, to screen high-quality avocado germplasms, we characterized the nutritional quality of 95 avocado germplasms grown in China based on metabolomics. The oil content of the 95 avocado germplasms was 2.18 %-16.60 % and followed a normal distribution. We further profiled nine fatty acids, 16 hydrolyzed amino acids, and eight mineral elements in avocado fruit, which varied widely among different germplasms. Correlation analysis revealed significant positive correlations between fatty acid components, as well as between amino acid components and between mineral elements. Clustering analysis and evaluation of the 95 avocado germplasms identified 14 germplasms with high nutritional quality. These findings provide a basis for evaluation of avocado fruit quality and utilization of high-quality avocado germplasms, as well as important implications for the breeding of avocado.PMID:39582637 | PMC:PMC11585822 | DOI:10.1016/j.fochx.2024.101971

Curr Res Food Sci. 2024 Nov 7;9:100919. doi: 10.1016/j.crfs.2024.100919. eCollection 2024.ABSTRACTThis work was aimed to explore the antioxidative properties, bioavailability and the safety of bioactive peptides obtained by the enzymatic hydrolysis of ultrasound-treated (UO) and untreated (nUO) soybean okara proteins. Particularly, the peptidomic profiles of both hydrolysates were examined using an untargeted metabolomics technique for suspect screening that was specifically designed for the profiling of short-chain peptides and relied on ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) and bioinformatics. Next, both UO and nUO hydrolysates reduce Dipeptidyl peptidase-IV (DPP-IV) enzyme activity until 39.54 ± 0.26 % and 43.29 ± 0.36 % respectively and inhibit angiotensin converting enzyme (ACE) activities by 30.54 ± 0.42 % and 30.76 ± 0.02 %, respectively. Moreover, they demonstrate to exerted antioxidant properties. Particularly, they show a comparable in vitro antioxidant activity but when the oxidative stress is induced by H2O2 in Caco-2 cells, UO hydrolysate is more active in lowering the levels of reactive oxygen species (ROS) and of lipid peroxidation induced of 48% and 20% respectively. In addition, UO- and nUO-derived peptides trans-epithelial transported by human differentiated intestinal cell monolayer, were identified. Lastly, the possible hepatotoxicity of UO and nUO hydrolysates in HepG2 cells has not been observed by measuring alanine transferase (ALT) and aspartate transferase (AST) levels and cytotoxic effects.PMID:39582575 | PMC:PMC11582538 | DOI:10.1016/j.crfs.2024.100919

J Pediatr Gastroenterol Nutr. 2024 Nov 25. doi: 10.1002/jpn3.12420. Online ahead of print.ABSTRACTOBJECTIVES: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common pediatric liver disease and can progress to liver fibrosis. Latino adolescents have increased MASLD and fibrosis risk. While fibrosis is diagnosed by biopsy or imaging, more accessible, noninvasive, and economical screening methods are needed. We aimed to use plasma metabolomics/lipidomics to identify potential fibrosis biomarkers in Latino adolescents with obesity.METHODS: Liver stiffness (LS) was measured in 93 Latino adolescents with obesity using magnetic resonance elastography. Metabolites and lipids were extracted from plasma and identified on Compound Discoverer. Associations between metabolites/lipids and fibrosis (LS > 2.73 kPa) were determined using linear regression models after covariate adjustment. False discovery rate (FDR) adjusted Pearson's correlations were performed. Analytes yielding significant FDR-adjusted correlations were examined further by receiver operator curve analysis.RESULTS: Mean (±standard deviation) alanine transaminase (ALT) was 45.7(±65.2) IU/L, hepatic fat fraction was 12.7(±9.1)%, and LS was 2.4(±0.3) kPa. We identified 795 metabolites and 413 lipids in plasma, but only one single metabolite, dihydroxyacetone phosphate (DHAP), a marker of triglyceride synthesis, was significantly associated with fibrosis after FDR adjustment (p < 0.05). In terms of predicting fibrosis, ALT had an area under the curve (AUC) of 0.79, and DHAP had an AUC of 0.79. When combined, ALT + DHAP had an AUC of 0.89.CONCLUSIONS: The combination of ALT + DHAP may have the potential as an accurate, noninvasive test for liver fibrosis. Our data is limited to Latino children with obesity, and a larger cohort should be examined to further validate this novel biomarker.PMID:39582475 | DOI:10.1002/jpn3.12420

Microb Biotechnol. 2024 Nov;17(11):e70011. doi: 10.1111/1751-7915.70011.ABSTRACTMicrobial biosurfactants have garnered significant interest from industry due to their lower toxicity, biodegradability, activity at lower concentrations and higher resistance compared to synthetic surfactants. The deep-sea Rhodococcus sp. I2R has been identified as a producer of glycolipid biosurfactants, specifically succinoyl trehalolipids, which exhibit antiviral activity. However, genome mining of this bacterium has revealed a still unexplored repertoire of biosurfactants. The microbial genome was found to host five non-ribosomal peptide synthetase (NRPS) gene clusters containing starter condensation domains that direct lipopeptide biosynthesis. Genomics and mass spectrometry (MS)-based metabolomics enabled the linking of two NRPS gene clusters to the corresponding lipopeptide families, leading to the identification of 20 new cyclolipopeptides, designated as rhodoheptins, and 33 new glycolipopeptides, designated as rhodamides. An integrated in silico gene cluster and high-resolution MS/MS data analysis allowed us to elucidate the planar structure, inference of stereochemistry and reconstruction of the biosynthesis of rhodoheptins and rhodamides. Rhodoheptins are cyclic heptapeptides where the N-terminus is bonded to a β-hydroxy fatty acid forming a macrolactone ring with the C-terminal amino acid residue. Rhodamides are linear 14-mer glycolipopeptides with a serine- and alanine-rich peptide backbone, featuring a distinctive pattern of acetylation, glycosylation and succinylation. These molecules exhibited biosurfactant activity in the oil-spreading assay and showed moderate antiproliferative effects against human A375 melanoma cells.PMID:39582288 | DOI:10.1111/1751-7915.70011

NPJ Biofilms Microbiomes. 2024 Nov 24;10(1):135. doi: 10.1038/s41522-024-00612-7.ABSTRACTThe rapid development of high-throughput sequencing techniques provides an unprecedented opportunity to generate biological insights into microbiome-related diseases. However, the relationships among microbes, metabolites and human microenvironment are extremely complex, making data analysis challenging. Here, we present NMFGOT, which is a versatile toolkit for the integrative analysis of microbiome and metabolome data from the same samples. NMFGOT is an unsupervised learning framework based on nonnegative matrix factorization with graph regularized optimal transport, where it utilizes the optimal transport plan to measure the probability distance between microbiome samples, which better dealt with the nonlinear high-order interactions among microbial taxa and metabolites. Moreover, it also includes a spatial regularization term to preserve the spatial consistency of samples in the embedding space across different data modalities. We implemented NMFGOT in several multi-omics microbiome datasets from multiple cohorts. The experimental results showed that NMFGOT consistently performed well compared with several recently published multi-omics integrating methods. Moreover, NMFGOT also facilitates downstream biological analysis, including pathway enrichment analysis and disease-specific metabolite-microbe association analysis. Using NMFGOT, we identified the significantly and stable metabolite-microbe associations in GC and ESRD diseases, which improves our understanding for the mechanisms of human complex diseases.PMID:39582023 | DOI:10.1038/s41522-024-00612-7

Am J Chin Med. 2024 Nov 25:1-33. doi: 10.1142/S0192415X24500745. Online ahead of print.ABSTRACTAcupuncture and moxibustion are widely acknowledged as effective complementary therapies for managing inflammatory bowel disease (IBD) in traditional Chinese medicine. However, the regulatory mechanisms by which these two therapies exert their therapeutic effects in IBD are yet to be fully elucidated. The objective of this study was to investigate the mechanisms of action underlying acupuncture and moxibustion and the regulative differences between them as therapeutic interventions for IBD. Using a dextran sodium sulfate-induced IBD mice model, the effects of the two treatments were evaluated by examination of body weight, stool samples, colon morphology, inflammatory factors, gut microbiota, and metabolites. The results indicated that both acupuncture and moxibustion mitigated body weight reduction; improved the structural characteristics of intestinal tissues; increased levels of anti-inflammatory cytokines including interleukin (IL)-10; and decreased levels of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-[Formula: see text]), nuclear factor kappa B (NF-[Formula: see text]B), IL-6, IL-1[Formula: see text], and IL-17. Acupuncture and moxibustion had distinct effects on the regulation of the intestinal microbiota and metabolic pathways in IBD mice. Moxibustion regulated a greater number of metabolic pathways than acupuncture, the majority of which were associated with amino acid metabolism, brain signal transmission, energy metabolism, and anti-inflammatory pathways. These findings provide a scientific basis for the differential applications of acupuncture and moxibustion in clinical practice.PMID:39581856 | DOI:10.1142/S0192415X24500745

Br J Pharmacol. 2024 Nov 24. doi: 10.1111/bph.17393. Online ahead of print.ABSTRACTBACKGROUND AND PURPOSE: While pain and itch are both commonly associated with chronic dermatitis (CD), the molecular mechanisms underlying these debilitating symptoms is not well understood. This study aims to identify novel, endogenous compounds that mediate CD-associated pain and itch.EXPERIMENTAL APPROACH: Lesional skin of CD model mice was examined using unbiased metabolomic analysis to identify candidate pain or itch inducing compounds in CD. Sphingosine-1-phosphate (S1P) concentration in CD model skin was analysed using UPLC/MS/MS. Behaviour, calcium imaging and immunofluorescence staining were used to determine the pain and itch effects and mechanisms of the identified CD-related compounds.KEY RESULTS: In the lesional skin of CD model mice, 136 compounds were significantly changed. These compounds are predominately associated with the sphingolipids metabolism pathway. S1P is significantly increased in the lesional skin . The TRPV4 channel was critical for S1P induced itch and pain. Sphingosine kinase 2 (SPHK2), the key enzyme controlling S1P synthesis, was significantly increased in lesional skin. ABC294640, a SPHK2 inhibitor, significantly decreased S1P concentration in lesional CD model skin, as well as in model associated epidermal hyperplasia and chronic pain and itch. In CD patients, SPHK2 expression and S1P concentration were significantly elevated compared to healthy control skin.CONCLUSION AND IMPLICATIONS: Our results indicate that, in CD, increased S1P induces chronic pain and itch partly through TRPV4. Inhibition of S1P synthesis or the S1P/S1P receptor-TRPV4 pathway are promising treatment strategies for CD-associated pain and itch.PMID:39581852 | DOI:10.1111/bph.17393

Urol Oncol. 2024 Nov 23:S1078-1439(24)00724-5. doi: 10.1016/j.urolonc.2024.11.008. Online ahead of print.ABSTRACTThis review assesses the current understanding of the relationship between the human microbiome and BCa. Recognizing how the microbiome affects the tumor microenvironment provides valuable insights into cancer biology, potentially uncovering interactions that could be leveraged to develop innovative therapeutic approaches. By clarifying these intricate microbial-tumor dynamics, novel targets for microbiome-based interventions can be identified, ultimately improving treatment effectiveness and patient outcomes. Current literature lacks comprehensive insights into the effects of BCa treatment on the microbiome and the prevalence of immunotherapy-related toxicities. Further research into the microbiome's role in BCa development could bridge the gap between fundamental research and therapeutic applications. Implementing microbiome surveillance, metagenomic sequencing, and metabolomics in clinical trials could deepen our understanding of BCa and its treatment. This review explores the existing understanding of the urine, tissue, and gut microbiomes and their connections to BCa. Enhanced knowledge of these relationships can pave the way for future research to identify reliable disease predictors, prognostic markers, and novel therapeutic targets.PMID:39581825 | DOI:10.1016/j.urolonc.2024.11.008

BMJ Open. 2024 Nov 24;14(11):e087430. doi: 10.1136/bmjopen-2024-087430.ABSTRACTINTRODUCTION: Suspected preterm labour (SPL) is an obstetric complication that occurs in 9% of all pregnancies and is the leading cause of antenatal hospital admissions. More than half of women with SPL deliver a premature baby which is a known risk factor for developing cardiovascular and metabolic disorders in childhood and later in adult life. On the other hand, the other half of these women will deliver at term, labelled as 'false preterm labour'. Although this has been thought to be a benign condition, accumulating evidence reported in recent years showed long-term effects for the foetus, neonate and infant even when birth occurs at term. However, the impact of SPL on cardiovascular and metabolic programming has not been studied yet. The aim of this prospective cohort study is to evaluate the impact of SPL on cardiac remodelling and function and on cardiovascular and metabolic profiles independently of gestational age at birth.METHODS AND ANALYSIS: Prospective cohort study of subjects exposed and not exposed to an episode of SPL. Women with singleton pregnancies who are admitted at a tertiary hospital due to SPL and matched controls will be recruited. Evaluation of cardiovascular remodelling by foetal echocardiography will be performed during admission. Cord blood will be collected at birth in order to analyse different metabolomic footprints and several cardiovascular and metabolic risk biomarkers. Moreover, children will undergo an echocardiography 6 months after birth. The relationship between SPL and cardiovascular and metabolic programming will be modelled considering different covariates such as socioeconomic factors, perinatal characteristics, lifestyle, diet and exercise.ETHICS AND DISSEMINATION: Ethical approval was granted in April 2020 from CEIC Aragón (CEICA) (C.P.-C.I. PI20/136). Study outcomes will be disseminated at international conferences and published in peer-reviewed scientific journals.TRIAL REGISTRATION NUMBER: NCT05670665.PMID:39581725 | DOI:10.1136/bmjopen-2024-087430

Br J Ophthalmol. 2024 Nov 24:bjo-2024-325846. doi: 10.1136/bjo-2024-325846. Online ahead of print.ABSTRACTBACKGROUND/AIMS: To identify the metabolic underpinnings of retinal aging and examine how it is related to mortality and morbidity of common diseases.METHODS: The retinal age gap has been established as essential aging indicator for mortality and systemic health. We applied neural network to train the retinal age gap among the participants in UK Biobank and used nuclear magnetic resonance (NMR) to profile plasma metabolites. The metabolomic signature of retinal ageing (MSRA) was identified using an elastic network model. Multivariable Cox regressions were used to assess associations between the signature with 12 serious health conditions. The participants in Guangzhou Diabetic Eye Study (GDES) cohort were analyzed for validation.RESULTS: This study included 110 722 participants (mean age 56.5±8.1 years at baseline, 53.8% female), and 28 plasma metabolites associated with retinal ageing were identified. The MSRA revealed significant correlations with each 12 serious health conditions beyond traditional risk factors and genetic predispositions. Each SD increase in MSRA was linked to a 24%-76% higher risk of mortality, cardiovascular diseases, dementia and diabetes mellitus. MSRA showed dose-response relationships with risks of these diseases, with seven showing non-linear and five showing linear increases. Validation in the GDES further established the relation between retinal ageing-related metabolites and increased risks of cardiovascular and chronic kidney diseases (all p<0.05).CONCLUSIONS: The metabolic connections between ocular and systemic health offer a novel tool for identifying individuals at high risk of premature ageing, promoting a more holistic view of human health.PMID:39581638 | DOI:10.1136/bjo-2024-325846

J Food Sci. 2024 Nov 24. doi: 10.1111/1750-3841.17550. Online ahead of print.ABSTRACTLacticaseibacillus rhamnosus grx10 (grx10) has shown promising potential in promoting intestinal health as predicted by genomic and metabolomic analyses. Given the increasing prevalence of ulcerative colitis (UC) and the limitations of existing treatments, exploring alternative therapeutic strategies is essential. This study explored the therapeutic effects and underlying mechanisms of grx10 and its derived postbiotic (P-grx10) in a mouse model of dextran sulfate sodium (DSS)-induced chronic UC. The intervention with grx10 and P-grx10 significantly alleviated clinical symptoms and improved biochemical markers in UC mice. These effects included reducing the disease activity index (DAI), improving colon length and histopathological damage, decreasing the secretion of inflammatory cytokines, and preventing the reduction of antioxidant enzymes. Additionally, grx10 and P-grx10 downregulated key proteins in the Mitogen-Activated Protein Kinase (MAPK)/myosin light chain kinase (MLCK)/myosin light chain (MLC) pathway, prevented the dissociation of tight junction (TJ) proteins and E-cadherin, reduced intestinal permeability, and restored the integrity of the intestinal barrier. Furthermore, both grx10 and P-grx10 modulated the composition and abundance of gut microbiota, helping to maintain intestinal microbiome homeostasis. In conclusion, this study provided evidence regarding the role of grx10 and P-grx10 in alleviating intestinal barrier dysfunction associated with UC and restoring gut microbiota balance. Notably, P-grx10 exhibited higher anti-inflammatory activity and better restoration of intestinal barrier function, whereas the live probiotic grx10 showed a stronger regulatory effect on the gut microbiota. These findings suggest that grx10 and P-grx10 could serve as promising nutritional adjunct therapies for UC, providing novel insights into the distinct roles of probiotic and its derived postbiotic in UC treatment.PMID:39581622 | DOI:10.1111/1750-3841.17550

Pharmacol Biochem Behav. 2024 Nov 22:173913. doi: 10.1016/j.pbb.2024.173913. Online ahead of print.ABSTRACTBACKGROUND: Previous studies have demonstrated that early life stress (ELS) impacts hoarding behavior in adult humans. This study aimed to assess the potential mitigation by environmental enrichment on hoarding behavior in rodents caused by maternal separation, thereby providing insights into therapeutic strategies for hoarding disorder.METHODS: Newborn mice were randomly divided into four groups. The control group was allowed to grow naturally. The maternal separation group underwent two weeks of maternal separation. The short-term environmental enrichment group received two weeks of environmental enrichment intervention after the two weeks of maternal separation. The long-term environmental enrichment group received five weeks of environmental enrichment intervention after the two weeks of maternal separation. Hoarding behavior was assessed during adolescence and adulthood. Hippocampal tissue from adult female mice was analyzed using LC-MS/MS-based metabolomics. Spearman correlation analysis was then performed to assess the relationship between differentially expressed metabolites and hoarding behavior.RESULTS: Environmental enrichment attenuates maternal separation-induced excessive hoarding behavior in adult female mice. The untargeted metabolomics of the hippocampal region in female mice showed that long-term environmental enrichment reversed multiple differential metabolites, including Substance P, which were mainly concentrated in metabolic pathways such as cancer choline metabolism, glycolipid metabolism, and linoleic acid metabolism.CONCLUSIONS: Our findings indicate that ELS and long-term environmental enrichment have sex-dependent effects on adult hoarding behavior, potentially related to altered hippocampal metabolism. This study highlights the importance of environmental enrichment in mitigating the long-term effects of early maternal separation on hoarding behavior.PMID:39581387 | DOI:10.1016/j.pbb.2024.173913

Gene. 2024 Nov 22:149122. doi: 10.1016/j.gene.2024.149122. Online ahead of print.ABSTRACTThe field of gene therapy using Adeno-associated viral (AAV) vector delivery is rapidly advancing in the biotherapeutics industry. Despite its successes, AAV manufacturing remains a challenge due to limited production yields. The triple plasmid transfection of HEK293 cells represents the most extensively utilized system for AAV production. The regulatory factors and mechanisms underlying viral production in HEK293 cells are largely unknown. In this study, we isolated high-titer AAV production clones from a parental HEK293 population using a single limiting dilution step, and subsequently elucidating their underlying molecular mechanisms through whole transcriptome analysis. LncRNA TCONS_00160397 was upregulated in clones and shown to promoted HEK293 cells proliferation and improved the titer of AAV production. Mechanistically, results from proteomics and metabolomics indicated that TCONS_00160397 regulated the ABC transporters pathway. These findings furnish a rich repository of knowledge and actionable targets for the rational optimization of HEK293-based producer lines, thereby paving the way for tangible improvements in AAV vector output and expediting the broad implementation of gene therapies.PMID:39581356 | DOI:10.1016/j.gene.2024.149122

Metab Eng. 2024 Nov 22:S1096-7176(24)00150-2. doi: 10.1016/j.ymben.2024.11.008. Online ahead of print.ABSTRACTPlecomacrolides, such as concanamycin and bafilomycin, are potent and specific inhibitors of vacuolar-type ATPase. Concanamycins are 18-membered macrolides with promising therapeutic potential against multiple diseases, including viral infection, osteoporosis, and cancer. Due to the complexity of their total synthesis, the production of concanamycins is only achieved through microbial fermentation. However, the low titers of concanamycin A and its analogs in the native producing strains are a significant bottleneck for scale-up, robust structure-activity relationship studies, and drug development. To address this challenge, we designed a library of engineered Streptomyces strains for the overproduction of concanamycins by combining the overexpression of target regulatory genes with the optimization of fermentation media. Integration of two endogenous regulators from the concanamycin biosynthetic gene cluster (cms) and one heterologous regulatory gene from the bafilomycin biosynthetic gene cluster into the attB site significantly increased production of concanamycin A and its low abundant analog concanamycin B in Streptomyces eitanensis. The highest titers reported to date were observed in the engineered S. eitanensis DHS10676, which produced over 900 mg/L of concanamycin A and 300 mg/L of concanamycin B. Heterologous overexpression of the identified target regulatory genes across a panel of Streptomyces spp., harboring a putative concanamycin biosynthetic gene cluster confirmed its identity, and significantly improved concanamycin A production in all tested strains. Strain engineering, optimization of fermentation, and extraction purification protocols enabled swift access to these structurally complex plecomacrolides for semi-synthetic medicinal chemistry-based approaches. Together, this work established a platform for robust overproduction of concanamycin analogs across species.PMID:39581342 | DOI:10.1016/j.ymben.2024.11.008