PubMed

Int J Mol Sci. 2024 Sep 24;25(19):10261. doi: 10.3390/ijms251910261.ABSTRACTFlavonoids are pharmacologically active compounds in flowers of Chrysanthemum morifolium 'Boju' (C. morifolium); however, the molecular regulatory network governing flower development remains largely elusive. Flower samples were collected at four stages, namely budding (BD), bud breaking (BB), early blooming (EB), and full blooming (FB), for omics analysis. We revealed distinct transcriptional regulation patterns at these four stages of the flower from the perspective of differentially expressed unigenes (DEGs). There are 152 DEGs shared among the three comparative groups (BD vs. BB, BB vs EB, EB vs FB), wherein the expression of 44 DEGs (including AtADT6, MDL3, and ROMT) continues to be upregulated, and 85 DEGs (including CYP81E, TPS-Cin-1, and TPS-Cin-2) showed persistent downregulation with flower development. Flavonoid-targeted metabolomics identified 118 differentially abundant metabolites (DAMs) in the FB group compared to the BD stage; the top three upregulated and downregulated metabolites are Cyanidin-3-O-(6″-O-malonyl)glucoside-5-O-glucoside, Luteolin-7-O-(6″-caffeoyl)rhamnoside, Kaempferol-3-O-(6″-p-coumaroyl)glucoside and Chrysoeriol-6,8-di-C-glucoside-7-O-glucoside, Kaempferol, Kaempferol-3,7-O-dirhamnoside, respectively. These DAMs were predominantly enriched in "flavonoid biosynthesis", "isoflavonoid biosynthesis", and "flavone and flavonol biosynthesis" pathways. AtADT6, MDL3, ROMT, CYP81E, TPS-Cin-1, and TPS-Cin-2 were correlated with kaempferol. Our findings provide a new idea for interfering with flavonoid production, especially kaempferol, in flowers.PMID:39408589 | DOI:10.3390/ijms251910261

Int J Mol Sci. 2024 Sep 24;25(19):10252. doi: 10.3390/ijms251910252.ABSTRACTThe incorporation of multi-omics data methodologies facilitates the concurrent examination of proteins, metabolites, and genes associated with inflammation, thereby leveraging multi-dimensional biological data to achieve a comprehensive understanding of the complexities involved in the progression of inflammation. Inspired by ensemble learning principles, we implemented ID normalization preprocessing, categorical sampling homogenization, and pathway enrichment across each sample matrix derived from multi-omics datasets available in the literature, directing our focus on inflammation-related targets within lipopolysaccharide (LPS)-stimulated RAW264.7 cells towards β-alanine metabolism. Additionally, through the use of LPS-treated RAW264.7 cells, we tentatively validated the anti-inflammatory properties of the metabolite Ureidopropionic acid, originating from β-alanine metabolism, by evaluating cell viability, nitric oxide production levels, and mRNA expression of inflammatory biomarkers. In conclusion, our research represents the first instance of an integrated analysis of multi-omics datasets pertaining to LPS-stimulated RAW264.7 cells as documented in the literature, underscoring the pivotal role of β-alanine metabolism in cellular inflammation and successfully identifying Ureidopropionic acid as a novel anti-inflammatory compound. Moreover, the findings from database predictions and molecular docking studies indicated that the inflammatory-related pathways and proteins may serve as potential mechanistic targets for Ureidopropionic acid.PMID:39408583 | DOI:10.3390/ijms251910252

Nutrients. 2024 Sep 26;16(19):3250. doi: 10.3390/nu16193250.ABSTRACTOBJECTIVES: This study examined the effect of a 4-week unsweetened cranberry beverage (CRAN) (317 mg polyphenols) versus placebo beverage (PLAC) ingestion (240 mL/day) on moderating exercise-induced changes in innate immunity.METHODS: Participants included 25 male and female non-elite cyclists. A randomized, placebo-controlled, double-blind crossover design was used with two 4-week supplementation periods and a 2-week washout period. Supplementation periods were followed by an intensive 2.25 h cycling bout. Six blood samples were collected before and after supplementation (in an overnight fasted state) and at 0 h, 1.5 h, 3 h, and 24 h post-exercise. Stool and urine samples were collected pre- and post-supplementation. Outcome measures included serum creatine kinase, myoglobin, and cortisol, complete blood counts, plasma untargeted proteomics, plasma-targeted oxylipins, untargeted urine metabolomics, and stool microbiome composition via whole genome shotgun (WGS) sequencing.RESULTS: Urine CRAN-linked metabolites increased significantly after supplementation, but no trial differences in alpha or beta microbiota diversity were found in the stool samples. The 2.25 h cycling bout caused significant increases in plasma arachidonic acid (ARA) and 53 oxylipins (FDR q-value < 0.05). The patterns of increase for ARA, four oxylipins generated from ARA-cytochrome P-450 (CYP) (5,6-, 8,9-, 11,12-, and 14,15-diHETrEs), two oxylipins from linoleic acid (LA) and CYP (9,10-DiHOME, 12,13-DiHOME), and two oxylipins generated from LA and lipoxygenase (LOX) (9-HODE, 13-HODE) were slightly but significantly higher for the CRAN versus PLAC trial (all interaction effects, p < 0.05). The untargeted proteomics analysis showed that two protein clusters differed significantly between the CRAN and PLAC trials, with CRAN-related elevations in proteins related to innate immune activation and reduced levels of proteins related to the regulation of the complement cascade, platelet activation, and binding and uptake of ligands by scavenger receptors. No trial differences were found for cortisol and muscle damage biomarkers.CONCLUSIONS: CRAN versus PLAC juice resulted in a significant increase in CRAN-related metabolites but no differences in the gut microbiome. CRAN supplementation was associated with a transient and modest but significant post-exercise elevation in selected oxylipins and proteins associated with the innate immune system.PMID:39408218 | DOI:10.3390/nu16193250

J Clin Med. 2024 Oct 8;13(19):5983. doi: 10.3390/jcm13195983.ABSTRACTBackground: kidney transplant recipients are exposed to multiple pathogenic pathways that may alter short and long-term allograft survival. Metabolomic profiling is useful for detecting potential biomarkers of kidney disease with a predictive capacity. This field is still under development in kidney transplantation and metabolome analysis is faced with analytical challenges. We performed a cross-sectional study including stable kidney transplant patients and aimed to search for relevant associations between baseline plasmatic and urinary metabolites and relevant outcomes over a follow-up period of 3 years. Methods: we performed a cross-sectional study including 72 stable kidney transplant patients with stored plasmatic and urinary samples at the baseline evaluation which were there analyzed by nuclear magnetic resonance in order to quantify and describe metabolites. We performed a 3-year follow-up and searched for relevant associations between renal failure outcomes and baseline metabolites. Between-group comparisons were made after classification by observed estimated glomerular filtration rate slope during the follow-up: positive slope and negative slope. Results: The mean estimated GFR (glomerular filtration rate) was higher at baseline in the patients who exhibited a negative slope during the follow-up (63.4 mL/min/1.73 m2 vs. 55.8 mL/min/1.73 m2, p = 0,019). After log transformation and division by urinary creatinine, urinary dimethylamine (3.63 vs. 3.16, p = 0.027), hippuric acid (7.33 vs. 6.29, p = 0.041), and acetone (1.88 vs. 1, p = 0.023) exhibited higher concentrations in patients with a negative GFR slope when compared to patients with a positive GFR slope. By computing a linear regression, a significant low-strength regression equation between the log 2 transformed plasmatic level of glycine and the estimated glomerular filtration rate was found (F (1,70) = 5.15, p = 0.026), with an R2 of 0.069. Several metabolites were correlated positively with hand grip strength (plasmatic tyrosine with r = 0.336 and p = 0.005 and plasmatic leucine with r = 0.371 and p = 0.002). Other urinary metabolites were found to be correlated negatively with hand grip strength (dimethylamine with r = -0.250 and p = 0.04, citric acid with r = -0.296 and p = 0.014, formic acid with r = -0.349 and p = 0.004, and glycine with r = -0.306 and p = 0.01). Conclusions: some metabolites had different concentrations compared to kidney transplant patients with negative and positive slopes, and significant correlations were found between hand grip strength and urinary and plasmatic metabolites.PMID:39408043 | DOI:10.3390/jcm13195983

J Clin Med. 2024 Sep 25;13(19):5697. doi: 10.3390/jcm13195697.ABSTRACTBackground: Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by distinctive physical, cognitive, and behavioral manifestations, coupled with profound alterations in appetite regulation, leading to severe obesity and metabolic dysregulation. These clinical features arise from disruptions in neurodevelopment and neuroendocrine regulation, yet the molecular intricacies of PWS remain incompletely understood. Methods: This study aimed to comprehensively profile circulating neuromodulatory factors in the serum of 53 subjects with PWS and 34 patients with non-syndromic obesity, utilizing a proximity extension assay with the Olink Target 96 neuro-exploratory and neurology panels. The ANOVA p-values were adjusted for multiple testing using the Benjamani-Hochberg method. Protein-protein interaction networks were generated in STRING V.12. Corrplots were calculated with R4.2.2 by using the Hmisc, Performance Analytics, and Corrplot packages Results: Our investigation explored the potential genetic underpinnings of the circulating protein signature observed in PWS, revealing intricate connections between genes in the PWS critical region and the identified circulating proteins associated with impaired oxytocin, NAD metabolism, and sex-related neuromuscular impairment involving, CD38, KYNU, NPM1, NMNAT1, WFIKKN1, and GDF-8/MSTN. The downregulation of CD38 in individuals with PWS (p < 0.01) indicates dysregulation of oxytocin release, implicating pathways associated with NAD metabolism in which KYNU and NMNAT1 are involved and significantly downregulated in PWS (p < 0.01 and p < 0.05, respectively). Sex-related differences in the circulatory levels of WFIKKN1 and GDF-8/MSTN (p < 0.05) were also observed. Conclusions: This study highlights potential circulating protein biomarkers associated with impaired oxytocin, NAD metabolism, and sex-related neuromuscular impairment in PWS individuals with potential clinical implications.PMID:39407757 | DOI:10.3390/jcm13195697

Molecules. 2024 Oct 8;29(19):4754. doi: 10.3390/molecules29194754.ABSTRACTCamellia luteoflora is a rare and endangered plant endemic to China. It has high ornamental and potential economic and medicinal value, and is an important germplasm resource of Camellia. To understand the distributions and differences in metabolites from different parts of C. luteoflora, in this study, we used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to examine the types and contents of chemical constituents in five organs of C. luteoflora: roots, stems, leaves, flowers, and fruits. The results showed that a total of 815 metabolites were identified in the five organs and were classified into 18 main categories, including terpenoids (17.1%), amino acids (10.4%), flavonoids (10.3%), sugars and alcohols (9.8%), organic acids (9.0%), lipids (7.1%), polyphenols (4.8%), alkaloids (4.8%), etc. A total of 684 differentially expressed metabolites (DEMs) in five organs were obtained and annotated into 217 KEGG metabolic pathways, among which metabolic pathways, ABC transporters, the biosynthesis of cofactors, and the biosynthesis of amino acids were significantly enriched. In DEMs, flowers are rich in flavonoids, polyphenols, organic acids, and steroids; fruits are rich in amino acids, alkaloids, vitamins, and xanthones; stems are rich in lignans; and leaves have the highest relative content of phenylpropanoids, ketoaldehydic acids, quinones, sugars and alcohols, terpenoids, coumarins, lipids, and others; meanwhile, the metabolite content is lower in roots. Among the dominant DEMs, 58 were in roots, including arachidonic acid, lucidone, isoliquiritigenin, etc.; 75 were in flowers, including mannose, shikimic acid, d-gluconic acid, kaempferol, etc.; 45 were in the fruit, including pterostilbene, l-ascorbic acid, riboflavin, etc.; 27 were in the stems, including salicylic acid, d-(-)-quinic acid, mannitol, (-)-catechin gallate, etc.; there was a maximum number of 119 dominant metabolites in the leaves, including oleanolic acid, l-glucose, d-arabitol, eugenol, etc. In sum, the rich chemical composition of C. luteoflora and the significant differences in the relative contents of metabolites in different organs will provide theoretical references for the study of tea, flower tea, edible oil, nutraceuticals, and the medicinal components of C. luteoflora.PMID:39407682 | DOI:10.3390/molecules29194754

J Occup Med Toxicol. 2024 Oct 15;19(1):38. doi: 10.1186/s12995-024-00436-3.ABSTRACTBACKGROUND: Occupational biomonitoring is essential for assessing health risks linked to workplace exposures. The use of 'omics' technologies, such as metabolomics and proteomics, has become crucial in detecting subtle biological alterations induced by occupational hazards, thereby opening novel avenues for biomarker discovery.AIMS: This systematic review aims to evaluate the application of metabolomics and proteomics in occupational health.METHODS: Following the PRISMA guidelines, we conducted a comprehensive search on PubMed, Scopus, and Web of Science for original human studies that use metabolomics or proteomics to assess occupational exposure biomarkers. The risk of bias was assessed by adapting the Cochrane Collaboration tool and the Newcastle-Ottawa Quality Assessment Scale.RESULTS: Of 2311 initially identified articles, 85 met the eligibility criteria. These studies were mainly conducted in China, Europe, and the United States of America, covering a wide range of occupational exposures. The findings revealed that metabolomics and proteomics approaches effectively identified biomarkers related to chemical, physical, biomechanical, and psychosocial hazards. Analytical methods varied, with mass spectrometry-based techniques emerging as the most prevalent. The risk of bias was generally low to moderate, with specific concerns about exposure measurement and confounding factors.CONCLUSIONS: Integrating metabolomics and proteomics in occupational health biomonitoring significantly advances our understanding of exposure effects and facilitates the development of personalized preventive interventions. However, challenges remain regarding the complexity of data analysis, biomarker specificity, and the translation of findings into preventive measures. Future research should focus on longitudinal studies and biomarker validation across diverse populations to improve the reliability and applicability of occupational health interventions.PMID:39407251 | DOI:10.1186/s12995-024-00436-3

Biotechnol Biofuels Bioprod. 2024 Oct 15;17(1):128. doi: 10.1186/s13068-024-02572-8.ABSTRACTBACKGROUND: Lignin is an aromatic polymer deposited in secondary cell walls of higher plants to provide strength, rigidity, and hydrophobicity to vascular tissues. Due to its interconnections with cell wall polysaccharides, lignin plays important roles during plant growth and defense, but also has a negative impact on industrial processes aimed at obtaining monosaccharides from plant biomass. Engineering lignin offers a solution to this issue. For example, previous work showed that heterologous expression of a coliphage S-adenosylmethionine hydrolase (AdoMetase) was an effective approach to reduce lignin in the model plant Arabidopsis. The efficacy of this engineering strategy remains to be evaluated in bioenergy crops.RESULTS: We studied the impact of expressing AdoMetase on lignin synthesis in sorghum (Sorghum bicolor L. Moench). Lignin content, monomer composition, and size, as well as biomass saccharification efficiency were determined in transgenic sorghum lines. The transcriptome and metabolome were analyzed in stems at three developmental stages. Plant growth and biomass composition was further evaluated under field conditions. Results evidenced that lignin was reduced by 18% in the best transgenic line, presumably due to reduced activity of the S-adenosylmethionine-dependent O-methyltransferases involved in lignin synthesis. The modified sorghum features altered lignin monomer composition and increased lignin molecular weights. The degree of methylation of glucuronic acid on xylan was reduced. These changes enabled a ~20% increase in glucose yield after biomass pretreatment and saccharification compared to wild type. RNA-seq and untargeted metabolomic analyses evidenced some pleiotropic effects associated with AdoMetase expression. The transgenic sorghum showed developmental delay and reduced biomass yields at harvest, especially under field growing conditions.CONCLUSIONS: The expression of AdoMetase represents an effective lignin engineering approach in sorghum. However, considering that this strategy potentially impacts multiple S-adenosylmethionine-dependent methyltransferases, adequate promoters for fine-tuning AdoMetase expression will be needed to mitigate yield penalty.PMID:39407217 | DOI:10.1186/s13068-024-02572-8

BMC Nephrol. 2024 Oct 15;25(1):352. doi: 10.1186/s12882-024-03819-0.ABSTRACTBACKGROUND: There is a need to develop accurate and reliable non-invasive methods to evaluate chronic kidney disease (CKD) status and assess disease progression. Given it is recognized that dysregulation in metabolic pathways occur from early CKD, there is a basis in utilizing metabolomic biomarkers to monitor CKD progression. Volatile Organic Compounds (VOCs), a form of metabolomic biomarker, are gaseous products of metabolic processes in organisms which are typically released with greater abundance in disease conditions when there is dysregulation in metabolism. How urinary VOCs reflect the abnormal metabolic profile of patients with CKD status is unknown. Our study aimed to explore this.METHODS: Individuals aged 18-75 years undergoing kidney biopsy were included. Pre-biopsy urine samples were collected. All biopsy samples had an interstitial fibrosis and tubular atrophy (IFTA) grade scored by standardized assessment. Urine supernatant was extracted from residue and sampled for stir bar sorptive extraction followed by Gas chromatography-mass spectrometry (GC-MS) analysis. Post-processing of GC-MS data separated complex mixtures of VOCs based on their volatility and polarity. Mass-to-charge ratios and fragment patterns were measured for individual VOCs identification and quantification. Linear discriminant analysis (LDA) was performed to assess the ability of urinary VOCs in discriminating between IFTA 0 ('no or minimal IFTA' i.e. <10%, IFTA), IFTA 1 ('mild IFTA' i.e. 10-25% IFTA) and IFTA ≥ 2 ('moderate or severe IFTA' i.e. >25% IFTA). Linear regression analysis adjusting for age, sex, estimated glomerular filtration rate, diabetes mellitus (DM) status, and albuminuria was conducted to determine significantly regulated urinary VOCs amongst the groups.RESULTS: 64 study participants (22 individuals IFTA 0, 15 individuals IFTA 1, 27 individuals IFTA ≥ 2) were included. There were 34 VOCs identified from GC-MS which were statistically associated with correct classification between the IFTA groups, and LDA demonstrated individuals with IFTA 0, IFTA 1 and IFTA ≥ 2 could be significantly separated by their urinary VOCs profile (p < 0.001). Multivariate linear regression analysis reported 4 VOCs significantly upregulated in the IFTA 1 compared to the IFTA 0 group, and 2 VOCs significantly upregulated in the IFTA ≥ 2 compared to the IFTA 1 group (p < 0.05). Significantly upregulated urinary VOCs belonged to one of four functional groups - aldehydes, ketones, hydrocarbons, or alcohols.CONCLUSIONS: We report novel links between urinary VOCs and tubulointerstitial histopathology. Our findings suggest the application of urinary VOCs as a metabolomic biomarker may have a useful clinical role to non-invasively assess CKD status during disease progression.PMID:39407183 | DOI:10.1186/s12882-024-03819-0

BMC Plant Biol. 2024 Oct 16;24(1):969. doi: 10.1186/s12870-024-05654-9.ABSTRACTBACKGROUND: Lilium lancifolium is a special wild triploid species native to China and can produce abundant bulbils on its stem under natural conditions, which is very valuable to study bulbil organogenesis in plants. Although similar to the lateral and tillering principles, the molecular mechanism underlying bulbil formation has remained incompletely understood.RESULTS: The metabolome and transcriptome of L. lancifolium bulbils across four development stages were analyzed. The pairwise comparison of metabolomes across the four stages identified 17 differential hormones, predominantly auxin (IAA), cytokinin (CK), and jasmonic acid (JA). Short Time-series Expression Miner (STEM) trend analysis of differential genes revealed four significant trends across these stages. The KEGG enrichment analysis of the four clusters highlighted pathways, such as plant hormone signal transduction, which were speculated to play a crucial role in development stages. these pathways were speculated to play a crucial role in development stages. To explore the key differential expressed genes and transcription factors associated with bulbil occurrence, two periods were focused on: Ll_UN and Ll_DN, which represented the stages with and without bulbils, respectively. Through correlation analysis and qRT-PCR analysis, 11 candidate differentially expressed genes and 27 candidate transcription factors were selected. By spraying exogenous hormones to validate these candidates, LlbHLH128, LlTIFY10A, LlbHLH93, and LlMYB108, were identified as the key genes for L. lancifolium bulbils.CONCLUSION: A regulatory network of L. lancifolium bulbil development was predicted. LlTIFY10A and LlbHLH93 might be involved in the JA and auxin signal transduction pathways, which jointly formed a regulatory network to affect the occurrence of L. lancifolium bulbil. This study not only provided more information about the differentially expressed genes and metabolites through transcriptome and metabolomics analyses, but also provided a clearer understanding of the effect of hormones on bulbil formation in lily.PMID:39407139 | DOI:10.1186/s12870-024-05654-9

Plant Cell Rep. 2024 Oct 15;43(11):262. doi: 10.1007/s00299-024-03357-x.ABSTRACTAbnormal expression of genes regulating anther and pollen development and insufficient accumulation of male sterility (MS)- related metabolites lead to MS in cybrid pummelo Male sterility (MS) is a major cause of seedlessness in citrus, which is an important trait for fresh fruit. Understanding the mechanism of MS is important for breeding seedless citrus cultivars. In this study, we dissected the transcriptional, metabolic and physiological mechanisms of MS in somatic cybrid of pummelo (G1 + HBP). G1 + HBP exhibited severe male sterility, manifesting as retarded anther differentiation, abnormal anther wall development (especially tapetum and endothecium), and deficient pollen wall formation. In the anthers of G1 + HBP, the expression of genes regulating anther differentiation and tapetum development was abnormal, and the expression of genes regulating endothecium secondary lignification thickening and pollen wall formation was down-regulated. The transcription of genes involved in MS-related biological processes, such as jasmonic acid (JA) signaling pathway, primary metabolism, flavonoid metabolism, and programmed cell death, was altered in G1 + HBP anthers, and the accumulation of MS-associated metabolites, including fatty acids, amino acids, sugars, ATP, flavonols and reactive oxygen species (ROS), was down-regulated in G1 + HBP anthers. In summary, abnormal expression of key genes regulating anther and pollen development, altered transcription of key genes involved in MS-related metabolic pathways, and insufficient accumulation of MS-related metabolites together lead to MS in G1 + HBP. The critical genes and the metabolism pathways identified herein provide new insights into the formation mechanism of MS in citrus and candidate genes for breeding seedless citrus.PMID:39407042 | DOI:10.1007/s00299-024-03357-x

Commun Biol. 2024 Oct 15;7(1):1329. doi: 10.1038/s42003-024-07033-4.ABSTRACTThere is need for advancing minimally invasive diagnostic techniques for sex differentiation at early life-stage classes in sea turtles. The objectives of this study were to determine whether there are sex-specific effects on the metabolome of the loggerhead sea turtle (Caretta caretta) and to identify potential biomarkers for sex classification at early life-stage classes (50 post-hatchling and 50 juvenile). Comprehensive analyses including plasma chemistry (n = 100) and untargeted (n = 48) metabolomic analyses were performed. Unlike with plasma chemistry analytes, there were significant differences in the metabolomic profiles between sexes. Nine metabolites differed significantly between sexes, with several metabolites deserving greater attention as potential biomarkers: C22H32O6 and pantothenic acid was higher in females than in males, and carboxylic acid ester (C10H16O5), 1-methylhistidine and C7H14N2O7 was higher in males than females. These differences remained constant both across and within the same life-stage class. This work identified a discernible effect on the metabolic profile based on sex of loggerhead sea turtles and it suggests that these metabolites and/or their ratios could serve as potential biomarker candidates for sex classification in this species.PMID:39406821 | DOI:10.1038/s42003-024-07033-4

Sci Rep. 2024 Oct 15;14(1):24123. doi: 10.1038/s41598-024-74861-z.ABSTRACTInhibition of glycogen phosphorylase (Pyg) - a regulatory enzyme of glycogen phosphorolysis - influences memory formation in rodents. We have previously shown that 2-week intraperitoneal administration of a Pyg inhibitor BAY U6751 stimulated the "rejuvenation" of the hippocampal proteome and dendritic spines morphology and improved cognitive skills of old mice. Given the tedious nature of daily intraperitoneal drug administration, in this study we investigated whether a single dose of BAY U6751 could induce enduring behavioral effects. Obtained results support the efficacy of such treatment in significantly improving the cognitive performance of 20-22-month-old mice. Metabolomic analysis of alterations observed in the hippocampus, cerebellum, and cortex reveal that the inhibition of glycogen phosphorolysis impacts not only glucose metabolism but also various other metabolic processes.PMID:39406810 | DOI:10.1038/s41598-024-74861-z

Nat Commun. 2024 Oct 15;15(1):8898. doi: 10.1038/s41467-024-53156-x.ABSTRACTPromiscuous enzymes often serve as the starting point for the evolution of novel functions. Yet, the extent to which the promiscuity of an individual enzyme can be harnessed several times independently for different purposes during evolution is poorly reported. Here, we present a case study illustrating how NAD(P)+-dependent succinate semialdehyde dehydrogenase of Escherichia coli (Sad) is independently recruited through various evolutionary mechanisms for distinct metabolic demands, in particular vitamin biosynthesis and central carbon metabolism. Using adaptive laboratory evolution (ALE), we show that Sad can substitute for the roles of erythrose 4-phosphate dehydrogenase in pyridoxal 5'-phosphate (PLP) biosynthesis and glyceraldehyde 3-phosphate dehydrogenase in glycolysis. To recruit Sad for PLP biosynthesis and glycolysis, ALE employs various mechanisms, including active site mutation, copy number amplification, and (de)regulation of gene expression. Our study traces down these different evolutionary trajectories, reports on the surprising active site plasticity of Sad, identifies regulatory links in amino acid metabolism, and highlights the potential of an ordinary enzyme as innovation reservoir for evolution.PMID:39406738 | DOI:10.1038/s41467-024-53156-x

Sci Data. 2024 Oct 15;11(1):1129. doi: 10.1038/s41597-024-03947-0.ABSTRACTStudying the regulatory mechanisms in different tissues of pepper is crucial for understanding organ formation, growth, and development. However, relevant studies are far from sufficient. In the current study, the stipe, calyx, pericarp, placenta, and seed of ripe pepper were sampled, and metabolites were determined by the untargeted metabolomics method. Transcriptome sequencing was performed by Illumina NovaSeq 6000, and then a high-throughput data set was built. The results showed that a total of 4879 annotated metabolites were detected in 15 samples of the five tissues under positive and negative ion mode. A total of 110.66 Gb of clean data was obtained by transcriptome sequencing, the clean data of each sample reached 6.21 Gb, and a total of 35 336 annotated expression genes were obtained. Furthermore, validate the accuracy of the data by combining principal component analysis and other methods. In summary, this study provides valuable information for the genetic improvement and breeding of peppers, and it holds potential application value, particularly in enhancing the quality and nutritional value of pepper fruits.PMID:39406716 | DOI:10.1038/s41597-024-03947-0

Br J Pharmacol. 2024 Oct 15. doi: 10.1111/bph.17346. Online ahead of print.ABSTRACTBACKGROUND AND PURPOSE: Drug repurposing (DR) offers a compelling alternative to traditional drug discovery's lengthy, resource-intensive process. DR is the process of identifying alternative clinical applications for pre-approved drugs as a low-risk and low-cost strategy. Computational approaches are crucial during the early hypothesis-generating stage of DR. However, 'large-scale' data retrieval remains a significant challenge. A computational workflow addressing such limitations might improve hypothesis generation, ultimately benefit patients and advance DR research.EXPERIMENTAL APPROACH: We introduce a novel computational workflow (combining free-accessible computational platforms) to provide 'proof-of-concept' of the pre-approved drug's suitability for repurposing. Three key phases are included: target fishing (via reverse pharmacophore mapping), target identification (via disease- and drug-target pathway identification) and retrospective literature and drug-like analysis (via in silico ADMET properties determination). Istradefylline is a Parkinson's disease-approved drug with literature-attributed antidepressant properties remaining unclear. Practically applied, istradefylline's antidepressant activity was assessed in the context of major depressive disorder (MDD).KEY RESULTS: Data mining aided by target identification resulted in istradefylline potentially representing a novel antidepressant drug class. Retrieved drug targets (KYNU, MAO-B, ALOX12 and PLCB2) associated with selected MDD pathways (tryptophan metabolism and serotonergic synapse) generated a hypothesis that istradefylline increased extracellular 5-HT levels (MAO-B inhibition) and reduced inflammation (KYNU, ALOX12 and PLCB2 inhibition).CONCLUSION AND IMPLICATIONS: The practically applied workflow's generated hypothesis aligns with known experimental data, validating the effectiveness of this novel computational workflow. It is a low-risk and low-cost DR computational tool providing a bird's-eye view for exploring alternative clinical applications of pre-approved drugs.PMID:39406391 | DOI:10.1111/bph.17346

J Agric Food Chem. 2024 Oct 15. doi: 10.1021/acs.jafc.4c02671. Online ahead of print.ABSTRACTAlcoholic liver disease (ALD) is the predominant type of liver disease worldwide, resulting in significant mortality and a high disease burden. ALD damages multiple organs, including the liver, gut, and brain, causing inflammation, oxidative stress, and fat deposition. In this study, we investigated the effects of rice protein peptides (RPP) on ALD in mice with a primary focus on the gut microbiota and liver metabolites. The results showed that administration of RPP significantly alleviated the symptoms of ALD in mice including adiposity, oxidative stress, and inflammation. The KEGG pathway shows that RPP downregulates the liver metabolite of capric acid and the metabolism of fatty acid biosynthesis compared with the MOD group. Mechanistically, RPP downregulated the PPARγ signaling pathway and suppressed the expression of fatty acid biosynthesis genes (FASN, ACC1, ACSL1, and ACSL3). Furthermore, two active peptides (YLPTKQ and PKLPR) with potential therapeutic functions for ALD were screened by Caco-2 cell modeling and molecular docking techniques. In addition, RPP treatment alleviates gut microbiota dysbiosis by reversing the F/B ratio, increasing the relative abundance of Alloprevotella and Alistipes, and upregulating the level of short-chain fatty acids. In conclusion, RPP alleviates ALD steatosis through the PPARγ signaling pathway by YLPTKQ and PKLPR and regulates gut microbiota.PMID:39406388 | DOI:10.1021/acs.jafc.4c02671

Am J Physiol Gastrointest Liver Physiol. 2024 Oct 15. doi: 10.1152/ajpgi.00146.2024. Online ahead of print.ABSTRACTThe post-weaning period in pigs is a critical window where nutritional interventions are implemented to prevent post-weaning diarrhea (PWD) and antibiotic use. One common strategy is feeding of low protein diets immediately following weaning. This intervention may reduce protein fermentation and pathogen proliferation, therefore decreasing the incidence of post-weaning diarrhea. These effects may also be mitigated by providing dietary fiber. However, studies examining the role of protein and fiber on gastrointestinal microbiota and metabolism are complicated by the presence of other substrates, including polyphenols and antinutritional factors in complex ingredients. In this study, semi-purified diets formulated to meet nutrient requirements were fed to 40 weaned pigs (n = 10/diet) to examine the effects of high protein (HP), high fiber (HF), or both (HFHP) compared to a control (CON) diet with industry standard crude protein and fiber content. Critical alterations in host metabolism and cecal transcriptome were identified in response to the CON diet. Diets with lower protein levels (CON and HF) induced alteration in transcripts from the serine synthesis pathways and integrated stress response in cecal tissue alongside systemic increases in metabolic pathways related to lysine degradation. High protein diets did not induce increases in gastrointestinal pathogen abundance. These results challenge the practice of feeding low protein diets post-weaning, by demonstrating a detrimental effect on intestinal cell function and muscle accretion. This suggests that with careful ingredient selection, increased dietary protein post-weaning could better pig health and growth compared to a standard diet.PMID:39406387 | DOI:10.1152/ajpgi.00146.2024

Reprod Toxicol. 2024 Oct 13:108734. doi: 10.1016/j.reprotox.2024.108734. Online ahead of print.ABSTRACTNotable variations in semen parameters among non-smoking males have been documented post-COVID-19 pandemic. The role of smoking as a significant contributing factor to male infertility has been substantiated. Does the combined effect of smoking and SARS-CoV-2 infection impact male reproductive function? A prospective descriptive cohort study was performed using data from 90 smoking and 90 non-smoking males before and after coronavirus infection in a single center over a period of 3 months. Semen samples were collected before and within 15 days after COVID-19 infection, ensuring no more than three months elapsed between the two collections. The semen parameters evaluated included volume, concentration, progressive motility, normal morphology, and DNA fragmentation rate. Proteomic and metabolomic studies were further used to explore the differences between groups. Both non-smokers and smokers exhibited a marked reduction in sperm concentration, progressive motility, and normal morphology rate. Additionally, an increase in sperm DNA fragmentation index was noted for non-smokers and smokers. In the non-smoking group, dysregulation proteins including SEMG1, SEMG2 and DNAH5, and metabolites including L-glutamine, cis-9-Palmitoleic acid and Linoleamide were observed. In smokers, dysregulation proteins including SMCP, ROPN1B and IZUMO4, alongside metabolites including carnitine, gamma-Glutamylglutamic acid, and hypoxanthine were found. Comparative analysis between smoking and non-smoking patients post-COVID-19 also revealed significant differences in semen concentration, morphology and sperm DNA fragmentation rate. Dysregulated proteins including HSPA5, HSPA2 and PGK2, and metabolites such as acetylcarnitine, oxaloacetate and nicotinate were associated with impaired sperm function. Our study demonstrates that the virus also significantly compromises sperm quality in smoking males, who experience more pronounced declines post-infection compared to their non-smoking counterparts. This research underscores the necessity for comprehensive fertility assessments for smoking males after recovering from COVID-19.PMID:39406274 | DOI:10.1016/j.reprotox.2024.108734

Animal. 2024 Sep 18;18(11):101338. doi: 10.1016/j.animal.2024.101338. Online ahead of print.ABSTRACTThe gastrointestinal nematode infection poses a covert threat to both humans and domestic animals worldwide, eliciting a type 2 immune response within the small intestine. Intestinal tuft cells detect the nematode and activated group 2 innate lymphoid cells. Tuft cell-derived leukotrienes (one of the metabolites of arachidonic acid) were found to drive rapid anti-helminth immunity, but it is still poorly understood whether the tuft cell-mediated type 2 immune circuit and arachidonic acid metabolism modulate anti-parasitic immunity in the gastric epithelium. This study was designed to evaluate the immunological responses of goats inoculated with or without H. contortus. Results showed that H. contortus infection induced a systemic type 2 immune response, characterised by lymphocyte proliferation and greater eosinophils both in peripheral blood and abomasal mucosa, as well as increased type 2 cytokines IL-4, IL-5, and IL-13. Infection of H. contortus altered the transcriptome of the abomasum epithelium, especially tuft cell-mediated circuit-key genes. The infection also influenced the abomasal microbiota, arachidonic acid metabolism and related lipid metabolites, accompanying with great increases in the secretion of leukotrienes and prostaglandins. These findings demonstrate the role of tuft cells mediated circuit in sensing H. contortus infection and immune activation, reveal the candidate function of arachidonic acid involved in anti-helminth immunity, and suggest novel strategies for the control of parasitic diseases in livestock and humans.PMID:39405961 | DOI:10.1016/j.animal.2024.101338