PubMed

PeerJ. 2024 Apr 19;12:e17275. doi: 10.7717/peerj.17275. eCollection 2024.ABSTRACTBACKGROUND: Sect. Chrysantha Chang, belonging to the Camellia genus, is one of the rare and precious ornamental plants distinguished by a distinctive array of yellow-toned petals. However, the variation mechanisms of petal color in Sect. Chrysantha Chang remains largely unclear.METHODS: We conducted an integrated analysis of metabolome and transcriptome to reveal petal coloration mechanism in three species, which have different yellow tones petals, including C. chuongtsoensis (CZ, golden yellow), C. achrysantha (ZD, light yellow), and C. parvipetala (XB, milk white).RESULTS: A total of 356 flavonoid metabolites were detected, and 295 differential metabolites were screened. The contents of 74 differential metabolites showed an upward trend and 19 metabolites showed a downward trend, among which 11 metabolites were annotated to the KEGG pathway database. We speculated that 10 metabolites were closely related to the deepening of the yellowness. Transcriptome analysis indicated that there were 2,948, 14,018 and 13,366 differentially expressed genes (DEGs) between CZ vs. ZD, CZ vs. XB and ZD vs. XB, respectively. Six key structural genes (CcCHI, CcFLS, CcDFR1, CcDFR2, CcDFR3, and CcCYP75B1) and five candidate transcription factors (MYB22, MYB28, MYB17, EREBP9, and EREBP13) were involved in the regulation of flavonoid metabolites. The findings indicate that flavonoid compounds influence the color intensity of yellow-toned petals in Sect. Chrysantha Chang. Our results provide a new perspective on the molecular mechanisms underlying flower color variation and present potential candidate genes for Camellia breeding.PMID:38650646 | PMC:PMC11034495 | DOI:10.7717/peerj.17275

Front Mol Biosci. 2024 Apr 8;11:1353387. doi: 10.3389/fmolb.2024.1353387. eCollection 2024.ABSTRACTIntroduction: Horses are susceptible to oxidative stress during strenuous endurance exercise, leading to muscle fatigue and damage. Mulberry leaf flavonoids (MLFs) possess significant antioxidant properties. However, the antioxidant efficacy of MLFs can be influenced by the extraction process, and their impact on H2O2-induced oxidative stress in equine skeletal muscle satellite cells (ESMCs) remains unexplored. Methods: Our study employed three extraction methods to obtain MLFs: ultrasound-assisted extraction (CEP), purification with AB-8 macroporous resin (RP), and n-butanol extraction (NB-EP). We assessed the protective effects of these MLFs on H2O2-induced oxidative stress in ESMCs and analyzed the MLF components using metabolomics. Results: The results revealed that pre-treatment with MLFs dose-dependently protected ESMCs against H2O2-induced oxidative stress. The most effective concentrations were 0.8 mg/mL of CEP, 0.6 mg/mL of RP, and 0.6 mg/mL of NB-EP, significantly enhancing EMSC viability (p < 0.05). These optimized MLF concentrations promoted the GSH-Px, SOD and T-AOC activities (p < 0.05), while reducing MDA production (p < 0.05) in H2O2-induced ESMCs. Furthermore, these MLFs enhanced the gene expression, including Nrf2 and its downstream regulatory genes (TrxR1, GPX1, GPX3, SOD1, and SOD2) (p < 0.05). In terms of mitochondrial function, ESMCs pre-treated with MLFs exhibited higher basal respiration, spare respiratory capacity, maximal respiration, ATP-linked respiration compared to H2O2-induced ESMCs (p < 0.05). Additionally, MLFs enhanced cellular basal glycolysis, glycolytic reserve, and maximal glycolytic capacity (p < 0.05). Metabolomics analysis results revealed significant differences in mulberrin, kaempferol 3-O-glucoside [X-Mal], neohesperidin, dihydrokaempferol, and isobavachalcone among the three extraction processes (p < 0.05). Discussion: Our study revealed that MLFs enhance antioxidant enzyme activity, alleviate oxidative damage in ESMCs through the activation of the Nrf2 pathway, and improve mitochondrial respiration and cell energy metabolism. Additionally, we identified five potential antioxidant flavonoid compounds, suggesting their potential incorporation into the equine diet as a strategy to alleviate exercise-induced oxidative stress.PMID:38650596 | PMC:PMC11033687 | DOI:10.3389/fmolb.2024.1353387

Bioresour Bioprocess. 2021 Dec 2;8(1):120. doi: 10.1186/s40643-021-00472-5.ABSTRACTPenicillium digitatum is the primary spoilage fungus that causes green mold during postharvest in citrus. To reduce economic losses, developing more efficient and less toxic natural antimicrobial agents is urgently required. We previously found that the X33 antimicrobial oligopeptide (X33 AMOP), produced by Streptomyces lavendulae X33, exhibited a sterilization effect on P. digitatum. In this study, the effects, and physiological mechanisms of X33 AMOP as an inhibitor of P. digitatum were investigated. The transcriptional and metabolome profiling of P. digitatum exposed to X33 AMOP revealed 3648 genes and 190 metabolites that were prominently changed. The omics analyses suggested that X33 AMOP mainly inhibited P. digitatum growth by affecting cell integrity, genetic information delivery, oxidative stress tolerance, and energy metabolism. These findings provide helpful information regarding the antimicrobial mechanism of X33 AMOP against P. digitatum at the molecular level and indicate that X33 AMOP is a potential candidate to control P. digitatum.PMID:38650267 | DOI:10.1186/s40643-021-00472-5

Bioresour Bioprocess. 2021 Aug 19;8(1):77. doi: 10.1186/s40643-021-00429-8.ABSTRACTTo develop an economically feasible fermentation process, this study designed a novel bioprocess based on the co-culture of engineered Bacillus subtilis and Escherichia coli for the co-production of extracellular D-psicose and intracellular lipase. After optimizing the co-culture bioprocess, 11.70 g/L of D-psicose along with 16.03 U/mg of lipase was obtained; the glucose and fructose were completely utilized. Hence, the conversion rate of D-psicose reached 69.54%. Compared with mono-culture, lipase activity increased by 58.24%, and D-psicose production increased by 7.08%. In addition, the co-culture bioprocess was explored through metabolomics analysis, which included 168 carboxylic acids and derivatives, 70 organooxygen compounds, 34 diazines, 32 pyridines and derivatives, 30 benzene and substituted derivatives, and other compounds. It also could be found that the relative abundance of differential metabolites in the co-culture system was significantly higher than that in the mono-culture system. Pathway analysis revealed that, tryptophan metabolism and β-alanine metabolism had the highest correlation and played an important role in the co-culture system; among them, tryptophan metabolism regulates protein synthesis and β-alanine metabolism, which is related to the formation of metabolic by-products. These results confirm that the co-cultivation of B. subtilis and E. coli can provide a novel idea for D-psicose and lipase biorefinery, and are beneficial for the discovery of valuable secondary metabolites such as turanose and morusin.PMID:38650263 | DOI:10.1186/s40643-021-00429-8

Anim Microbiome. 2024 Apr 22;6(1):19. doi: 10.1186/s42523-024-00309-4.ABSTRACTBACKGROUND: A mother's milk is considered the gold standard of nutrition in neonates and is a source of cytokines, immunoglobulins, growth factors, and other important components, yet little is known about the components of canine milk, specifically colostrum, and the knowledge related to its microbial and metabolic profiles is particularly underwhelming. In this study, we characterized canine colostrum and milk microbiota and metabolome for several breeds of dogs and examined profile shifts as milk matures in the first 8 days post-whelping.RESULTS: Through untargeted metabolomics, we identified 63 named metabolites that were significantly differentially abundant between days 1 and 8 of lactation. Surprisingly, the microbial compositions of the colostrum and milk, characterized using 16S rRNA gene sequencing, were largely similar, with only two differentiating genera. The shifts observed, mainly increases in several sugars and amino sugars over time and shifts in amino acid metabolites, align with shifts observed in human milk samples and track with puppy development.CONCLUSION: Like human milk, canine milk composition is dynamic, and shifts are well correlated with developing puppies' needs. Such a study of the metabolic profile of canine milk, and its relation to the microbial community, provides insights into the changing needs of the neonate, as well as the ideal nutrition profile for optimal functionality. This information will add to the existing knowledge base of canine milk composition with the prospect of creating a quality, tailored milk substitute or supplement for puppies.PMID:38650014 | DOI:10.1186/s42523-024-00309-4

BMC Pregnancy Childbirth. 2024 Apr 22;24(1):297. doi: 10.1186/s12884-024-06507-x.ABSTRACTBACKGROUND: Maternal overweight/obesity and excessive gestational weight gain (GWG) are frequently reported to be risk factors for obesity and other metabolic disorders in offspring. Cord blood metabolites provide information on fetal nutritional and metabolic health and could provide an early window of detection of potential health issues among newborns. The aim of the study was to explore the impact of maternal prepregnancy overweight/obesity and excessive GWG on cord blood metabolic profiles.METHODS: A case control study including 33 pairs of mothers with prepregnancy overweight/obesity and their neonates, 30 pairs of mothers with excessive GWG and their neonates, and 32 control mother-neonate pairs. Untargeted metabolomic profiling of umbilical cord blood samples were performed using UHPLC‒MS/MS.RESULTS: Forty-six metabolites exhibited a significant increase and 60 metabolites exhibited a significant reduction in umbilical cord blood from overweight and obese mothers compared with mothers with normal body weight. Steroid hormone biosynthesis and neuroactive ligand‒receptor interactions were the two top-ranking pathways enriched with these metabolites (P = 0.01 and 0.03, respectively). Compared with mothers with normal GWG, in mothers with excessive GWG, the levels of 63 metabolites were increased and those of 46 metabolites were decreased in umbilical cord blood. Biosynthesis of unsaturated fatty acids was the most altered pathway enriched with these metabolites (P < 0.01).CONCLUSIONS: Prepregnancy overweight and obesity affected the fetal steroid hormone biosynthesis pathway, while excessive GWG affected fetal fatty acid metabolism. This emphasizes the importance of preconception weight loss and maintaining an appropriate GWG, which are beneficial for the long-term metabolic health of offspring.PMID:38649888 | DOI:10.1186/s12884-024-06507-x

BMC Genomics. 2024 Apr 22;25(1):394. doi: 10.1186/s12864-024-10242-0.ABSTRACTBACKGROUND: Untargeted metabolomics and proteomics were employed to investigate the intracellular response of yak rumen epithelial cells (YRECs) to conditions mimicking subacute rumen acidosis (SARA) etiology, including exposure to short-chain fatty acids (SCFA), low pH5.5 (Acid), and lipopolysaccharide (LPS) exposure for 24 h.RESULTS: These treatments significantly altered the cellular morphology of YRECs. Metabolomic analysis identified significant perturbations with SCFA, Acid and LPS treatment affecting 259, 245 and 196 metabolites (VIP > 1, P < 0.05, and fold change (FC) ≥ 1.5 or FC ≤ 0.667). Proteomic analysis revealed that treatment with SCFA, Acid, and LPS resulted in differential expression of 1251, 1396, and 242 proteins, respectively (FC ≥ 1.2 or ≤ 0.83, P < 0.05, FDR < 1%). Treatment with SCFA induced elevated levels of metabolites involved in purine metabolism, glutathione metabolism, and arginine biosynthesis, and dysregulated proteins associated with actin cytoskeleton organization and ribosome pathways. Furthermore, SCFA reduced the number, morphology, and functionality of mitochondria, leading to oxidative damage and inhibition of cell survival. Gene expression analysis revealed a decrease the genes expression of the cytoskeleton and cell cycle, while the genes expression associated with inflammation and autophagy increased (P < 0.05). Acid exposure altered metabolites related to purine metabolism, and affected proteins associated with complement and coagulation cascades and RNA degradation. Acid also leads to mitochondrial dysfunction, alterations in mitochondrial integrity, and reduced ATP generation. It also causes actin filaments to change from filamentous to punctate, affecting cellular cytoskeletal function, and increases inflammation-related molecules, indicating the promotion of inflammatory responses and cellular damage (P < 0.05). LPS treatment induced differential expression of proteins involved in the TNF signaling pathway and cytokine-cytokine receptor interaction, accompanied by alterations in metabolites associated with arachidonic acid metabolism and MAPK signaling (P < 0.05). The inflammatory response and activation of signaling pathways induced by LPS treatment were also confirmed through protein interaction network analysis. The integrated analysis reveals co-enrichment of proteins and metabolites in cellular signaling and metabolic pathways.CONCLUSIONS: In summary, this study contributes to a comprehensive understanding of the detrimental effects of SARA-associated factors on YRECs, elucidating their molecular mechanisms and providing potential therapeutic targets for mitigating SARA.PMID:38649832 | DOI:10.1186/s12864-024-10242-0

Reprod Sci. 2024 Apr 22. doi: 10.1007/s43032-024-01536-5. Online ahead of print.ABSTRACTEndometriosis diagnosis is usually delayed. The gold standard for diagnosing endometriosis is laparoscopy, which is invasive and accompanied by several risks. Currently, there are no effective non-invasive biomarkers for diagnosing endometriosis. Here, we investigated whether metabolites whose levels are altered in patients with endometriosis hold potential as diagnostic biomarkers for the disease. This case-control study involved 32 patients with endometriosis and 29 patients with other benign gynecological disease. The diagnosis of all patients was confirmed through postoperative histopathological examination, and the patients were divided into two groups: an endometriosis group (EM) and a control group. Fasting blood was collected and used for non-targeted metabolomic-based detection. The data were processed through principal component analysis, orthogonal partial least squares discriminant analysis, and significance analysis of microarrays. A univariate receiver operating characteristic curve was used to evaluate the diagnostic value of the metabolites. The metabolite profiles of patients with endometriosis were markedly different compared with those of the controls. In addition, several metabolic pathways, including biosynthesis of unsaturated fatty acids, arginine biosynthesis, and glutathione metabolism, were altered. Ornithine and medorinone showed better potential as biomarkers for endometriosis diagnosis than CA125. We analyzed the altered metabolic profiles in patients with endometriosis and found ornithine and medorinone as potential non-invasive biomarkers for endometriosis diagnosis, whereas the combined ornithine-medorinone diagnosis is more valuable. These findings may help advance research on non-invasive diagnostic biomarkers for endometriosis. Further research with an improved study design and a larger cohort should be performed to confirm the diagnostic potential and clinical application of these biomarkers.PMID:38649667 | DOI:10.1007/s43032-024-01536-5

Sci Data. 2024 Apr 22;11(1):415. doi: 10.1038/s41597-024-03094-6.ABSTRACTNatural products exhibit interesting structural features and significant biological activities. The discovery of new bioactive molecules is a complex process that requires high-quality metabolite profiling data to properly target the isolation of compounds of interest and enable their complete structural characterization. The same metabolite profiling data can also be used to better understand chemotaxonomic links between species. This Data Descriptor details a dataset resulting from the untargeted liquid chromatography-mass spectrometry metabolite profiling of 76 natural extracts of the Celastraceae family. The spectral annotation results and related chemical and taxonomic metadata are shared, along with proposed examples of data reuse. This data can be further studied by researchers exploring the chemical diversity of natural products. This can serve as a reference sample set for deep metabolome investigation of this chemically rich plant family.PMID:38649352 | DOI:10.1038/s41597-024-03094-6

Biomed Chromatogr. 2024 Apr 22:e5882. doi: 10.1002/bmc.5882. Online ahead of print.ABSTRACTThe "schisandra-evodia" herb pair (S-E) is a herbal preparation to treat Alzheimer's disease (AD). This study aims to investigate the therapeutic efficacy and potential mechanism of S-E in AD rats, utilizing pharmacodynamic assessments and serum- and urine-based metabolomic analyses. Pharmacodynamic assessments included Morris water maze test, hematoxylin-eosin staining and immunohistochemistry experiments. The results of the study showed that the AD model was successful; the S-E significantly enhanced long-term memory and spatial learning in AD rats. Meanwhile, S-E notably ameliorated Aβ25-35-induced cognitive impairment, improved hippocampal neuron morphology, decreased Aβ deposition in the hippocampus and mitigated inflammatory damage. We then analyzed serum and urine samples using UPLC-MS/MS to identify potential biomarkers and metabolic pathways. Metabolomic analysis revealed alterations in 40 serum metabolites and 38 urine metabolites following S-E treatment, predominantly affecting pathways related to taurine and hypotaurine metabolism, linoleic acid metabolism, α-linolenic acid metabolism, glycerophospholipid metabolism and arachidonic acid metabolism. This study elucidates the biochemical mechanism underlying AD and the metabolic pathway influenced by S-E, laying the groundwork for future clinical applications.PMID:38649307 | DOI:10.1002/bmc.5882

Fish Shellfish Immunol. 2024 Apr 20:109579. doi: 10.1016/j.fsi.2024.109579. Online ahead of print.ABSTRACTAs a potent antioxidant, the flavonoid compound quercetin (QUE) has been widely used in the farming of aquatic animals. However, there are fewer reports of the beneficial effects, especially in improving immunity of Penaeus vannamei by QUE. The aim of this study was to investigate the effects of dietary QUE on growth, apoptosis, antioxidant and immunity of P. vannamei. It also explored the potential mechanisms of QUE in improving the growth and immunity of P. vannamei. P. vannamei were fed diets with QUE for 60 days. The results revealed that QUE (0.5 or 1.0 g/kg) ameliorated the growth, and the expressions of genes related to apoptosis, antioxidant, and immunity. The differentially expressed genes (DEGs) and differential metabolites (DMs) obtained through transcriptomics and metabolomics, respectively, enriched in pathways related to nutritional metabolism such as lipid metabolism, amino acid metabolism, and carbohydrate metabolism. After QUE addition, especially at 0.5 g/kg, DEGs were enriched into the functions of response to stimulus and antioxidant activity, and the pathways of HIF-1 signaling pathway, C-type lectin receptor signaling pathway, Toll-like receptor signaling pathway, and FoxO signaling pathway. In conclusion, dietary QUE can ameliorate growth, apoptosis, antioxidant and immunity of P. vannamei, the appropriate addition amount was 0.5 g/kg rather than 1.0 g/kg. Regulations of QUE on nutrient metabolism and immune-related pathways, and bioactive metabolites, were important factors for improving the aforementioned abilities in P. vannamei.PMID:38648996 | DOI:10.1016/j.fsi.2024.109579

Clin Immunol. 2024 Apr 20:110224. doi: 10.1016/j.clim.2024.110224. Online ahead of print.ABSTRACTThe pathophysiology of systemic lupus erythematosus (SLE) is multifactorial and involves alterations in metabolic pathways, including glycolysis, lipid metabolism, amino acid metabolism, and mitochondrial dysfunction. Increased glycolysis in SLE T cells, which is associated with elevated glucose transporter 1 expression, suggests targeting glucose transporters and hexokinase as potential treatments. Abnormalities in lipid metabolism, particularly in lipid rafts and enzymes, present new therapeutic targets. This review discusses how changes in glutaminolysis and tryptophan metabolism affect T-cell function, suggesting new therapeutic interventions, as well as mitochondrial dysfunction in SLE, which increases reactive oxygen species. The review also emphasizes that modulating metabolic pathways in immune cells is a promising approach for SLE treatment, and can facilitate personalized therapies based on individual metabolic profiles of patients with SLE. The review provides novel insights into strategies for managing SLE.PMID:38648959 | DOI:10.1016/j.clim.2024.110224

J Natl Cancer Inst. 2024 Apr 22:djae089. doi: 10.1093/jnci/djae089. Online ahead of print.ABSTRACTBACKGROUND: We aimed to identify plasma and urinary metabolites related to colorectal cancer (CRC) risk and elucidate their mediator role in the associations between modifiable risk factors and CRC.METHODS: Metabolite quantitative trait loci were derived from two published metabolomics genome-wide association studies (GWASs), and summary-level data were extracted for 651 plasma metabolites and 208 urinary metabolites. Genetic associations with CRC were obtained from a large-scale GWAS meta-analysis (100,204 cases; 154,587 controls) and the FinnGen cohort (4,957 cases; 304,197 controls). Mendelian randomization (MR) and colocalization analyses were performed to evaluate the causal roles of metabolites in CRC. Druggability evaluation was employed to prioritize potential therapeutic targets. Multivariable MR and mediation estimation were conducted to elucidate the mediating effects of metabolites on the associations between modifiable risk factors and CRC.RESULTS: The study identified 30 plasma metabolites and four urinary metabolites for CRC. Plasma sphingomyelin and urinary lactose, which were positively associated with CRC risk, could be modulated by drug interventions (ie, Olipudase alfa, Tilactase). Thirteen modifiable risk factors were associated with nine metabolites and eight of these modifiable risk factors were associated with CRC risk. These nine metabolites mediated the effect of modifiable risk factors (Actinobacteria, BMI, waist-hip ratio, fasting insulin, smoking initiation) on CRC.CONCLUSION: This study identified key metabolite biomarkers associated with CRC and elucidated their mediator roles in the associations between modifiable risk factors and CRC. These findings provide new insights into the etiology and potential therapeutic targets for CRC and the etiological pathways of modifiable environmental factors with CRC.PMID:38648753 | DOI:10.1093/jnci/djae089

Food Chem. 2024 Apr 19;450:139376. doi: 10.1016/j.foodchem.2024.139376. Online ahead of print.ABSTRACTWuyi Rock Tea (WRT) has different characteristics of "rock flavor" due to different production areas. In this study, we investigated the flavor characteristics and key components of "rock flavor" and the influence of microorganisms on the substances by combining metabolomics and microbiomics with the Rougui WRTs from the Zhengyan, Banyan, and Waishan production areas. The results showed that Rougui has a strong floral and fruity aroma, which is mainly brought by hotrienol, and the sweet, smooth, and fresh taste is composed of epicatechin gallate, epigallocatechin, epigallocatechin gallate, caffeine, theanine, soluble sugar, and sweet and bitter amino acids. Bacteria Chryseobacterium, Pedobacter, Bosea, Agrobacterium, Stenotrophomonas, and Actinoplanes mainly influence the production of hotrienol, epicatechin gallate, and theanine. Fungi Pestalotiopsis, Fusarium, Elsinoe, Teichospora and Tetracladium mainly influence the production of non-volatile compounds. This study provides a reference for the biological formation mechanism of the characteristic aroma of WRT's "rock falvor".PMID:38648695 | DOI:10.1016/j.foodchem.2024.139376

Talanta. 2024 Apr 17;275:126109. doi: 10.1016/j.talanta.2024.126109. Online ahead of print.ABSTRACTTo investigate the metabolic alterations in maternal individuals with fetal congenital heart disease (FCHD), establish the FCHD diagnostic models, and assess the performance of these models, we recruited two batches of pregnant women. By metabolomics analysis using Ultra High-performance Liquid Chromatography-Mass/Mass (UPLC-MS/MS), a total of 36 significantly altered metabolites (VIP >1.0) were identified between FCHD and non-FCHD groups. Two logistic regression models and four support vector machine (SVM) models exhibited strong performance and clinical utility in the training set (area under the curve (AUC) = 1.00). The convolutional neural network (CNN) model also demonstrated commendable performance and clinical utility (AUC = 0.89 in the training set). Notably, in the validation set, the performance of the CNN model (AUC = 0.66, precision = 0.714) exhibited better robustness than the six models above (AUC≤0.50). In conclusion, the CNN model based on pseudo-MS images holds promise for real-world and clinical applications due to its better repeatability.PMID:38648686 | DOI:10.1016/j.talanta.2024.126109

J Agric Food Chem. 2024 Apr 22. doi: 10.1021/acs.jafc.3c09531. Online ahead of print.ABSTRACTThis study focuses on countering Fusarium graminearum, a harmful fungal pathogen impacting cereal crops and human health through mycotoxin production. These mycotoxins, categorized as type B trichothecenes, pose significant health risks. Research explores natural alternatives to synthetic fungicides, particularly investigating phenolics in grapevine byproducts. Thirteen eco-extracts from five French grape varieties (Merlot, Cabernet Sauvignon, Sauvignon blanc, Tannat, and Artaban) exhibited substantial antifungal properties, with ten extracts displaying remarkable effects. Extracts from grapevine stems and roots notably reduced fungal growth by over 91% after five days. Through UHPLC-HRMS/MS analysis and metabolomics, the study identified potent antifungal compounds such as ampelopsin A and cyphostemmin B, among other oligomeric stilbenes. Interestingly, this approach showed that flavan-3-ols have been identified as markers for extracts that induce fungal growth. Root extracts from rootstocks, rich in oligostilbenes, demonstrated the highest antifungal activity. This research underscores grapevine byproducts' potential both as a sustainable approach to control F. graminearum and mycotoxin contamination in cereal crops and the presence of different metabolites from the cultivars of grapevine, suggesting different activities.PMID:38648422 | DOI:10.1021/acs.jafc.3c09531

ACS Nano. 2024 Apr 22. doi: 10.1021/acsnano.3c11257. Online ahead of print.ABSTRACTUlcerative colitis is a chronic condition in which a dysregulated immune response contributes to the acute intestinal inflammation of the colon. Current clinical therapies often exhibit limited efficacy and undesirable side effects. Here, programmable nanomicelles were designed for colitis treatment and loaded with RU.521, an inhibitor of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. STING-inhibiting micelles (SIMs) comprise hyaluronic acid-stearic acid conjugates and include a reactive oxygen species (ROS)-responsive thioketal linker. SIMs were designed to selectively accumulate at the site of inflammation and trigger drug release in the presence of ROS. Our in vitro studies in macrophages and in vivo studies in a murine model of colitis demonstrated that SIMs leverage HA-CD44 binding to target sites of inflammation. Oral delivery of SIMs to mice in both preventive and delayed therapeutic models ameliorated colitis's severity by reducing STING expression, suppressing the secretion of proinflammatory cytokines, enabling bodyweight recovery, protecting mice from colon shortening, and restoring colonic epithelium. In vivo end points combined with metabolomics identified key metabolites with a therapeutic role in reducing intestinal and mucosal inflammation. Our findings highlight the significance of programmable delivery platforms that downregulate inflammatory pathways at the intestinal mucosa for managing inflammatory bowel diseases.PMID:38648373 | DOI:10.1021/acsnano.3c11257

PLoS Genet. 2024 Apr 22;20(4):e1011246. doi: 10.1371/journal.pgen.1011246. Online ahead of print.ABSTRACTGenome-wide association studies (GWAS) have identified many genetic loci associated with complex traits and diseases in the past 20 years. Multiple heritable covariates may be added into GWAS regression models to estimate direct effects of genetic variants on a focal trait, or to improve the power by accounting for environmental effects and other sources of trait variations. When one or more covariates are causally affected by both genetic variants and hidden confounders, adjusting for them in GWAS will produce biased estimation of SNP effects, known as collider bias. Several approaches have been developed to correct collider bias through estimating the bias by Mendelian randomization (MR). However, these methods work for only one covariate, some of which utilize MR methods with relatively strong assumptions, both of which may not hold in practice. In this paper, we extend the bias-correction approaches in two aspects: first we derive an analytical expression for the collider bias in the presence of multiple covariates, then we propose estimating the bias using a robust multivariable MR (MVMR) method based on constrained maximum likelihood (called MVMR-cML), allowing the presence of invalid instrumental variables (IVs) and correlated pleiotropy. We also established the estimation consistency and asymptotic normality of the new bias-corrected estimator. We conducted simulations to show that all methods mitigated collider bias under various scenarios. In real data analyses, we applied the methods to two GWAS examples, the first a GWAS of waist-hip ratio with adjustment for only one covariate, body-mass index (BMI), and the second a GWAS of BMI adjusting metabolomic principle components as multiple covariates, illustrating the effectiveness of bias correction.PMID:38648211 | DOI:10.1371/journal.pgen.1011246

J Proteome Res. 2024 Apr 22. doi: 10.1021/acs.jproteome.3c00772. Online ahead of print.ABSTRACTThe expansion of agriculture and the need for sustainable practices drives breeders to develop plant varieties better adapted to abiotic stress such as nutrient deficiency, which negatively impacts yields. Phosphorus (P) is crucial for photosynthesis and plant growth, but its availability in the soil is often limited, hampering crop development. In this study, we examined the response of two popcorn inbred lines, L80 and P7, which have been characterized previously as P-use inefficient and P-use efficient, respectively, under low (stress) and high P (control) availability. Physiological measurements, proteomic analysis, and metabolite assays were performed to unravel the physiological and molecular responses associated with the efficient use of P in popcorn. We observed significant differences in protein abundances in response to the P supply between the two inbred lines. A total of 421 differentially expressed proteins (DEPs) were observed in L80 and 436 DEPs in P7. These proteins were involved in photosynthesis, protein biosynthesis, biosynthesis of secondary metabolites, and energy metabolism. In addition, flavonoids accumulated in higher abundance in P7. Our results help us understand the major components of P utilization in popcorn, providing new insights for popcorn molecular breeding programs.PMID:38648199 | DOI:10.1021/acs.jproteome.3c00772

Bioresour Bioprocess. 2023 Apr 26;10(1):29. doi: 10.1186/s40643-023-00650-7.ABSTRACTAstaxanthin is an important ketocarotenoid widely used in industries. However, its application is limited because of its low yield. Sodium citrate (Na-citrate), one of the major carbon sources for microorganisms, can promote cell growth and product accumulation. The basidiomycetous red yeast Xanthophyllomyces dendrorhous was thus used to study the effect of Na-citrate on cell growth and astaxanthin synthesis. The highest biomass and astaxanthin yield (6.0 g/L and 22.5 mg/L) were obtained in shake-flask when 3 g/L Na-citrate was added at 24 h and were 1.8 and 2.0 times higher than those of the control group, respectively. Furthermore, metabolomics and real-time reverse transcription PCR (qRT-PCR) analysis were conducted to study the metabolic pathways of X. dendrorhous in response to Na-citrate. The qRT-PCR assay revealed that Na-citrate facilitated glucose consumption, promoted the metabolic flux from glycolysis, and regulated the tricarboxylic acid (TCA) cycle, providing more energy and substrates for the synthesis of astaxanthin. The gene analysis revealed that adding Na-citrate significantly upregulated the expression of six key genes (ICL, HMGS, crtE, crtYB, crtI, and crtS) involved in pathways related to astaxanthin biosynthesis. These results suggest that exogenous Na-citrate treatment is a potentially valuable strategy to stimulate astaxanthin production in X. dendrorhous.PMID:38647925 | PMC:PMC10992204 | DOI:10.1186/s40643-023-00650-7