PubMed

Molecules. 2023 Nov 7;28(22):7471. doi: 10.3390/molecules28227471.ABSTRACTType 2 diabetes mellitus (T2DM) is an increasingly prevalent and serious health problem. Its onset is typically associated with metabolic disorders and disturbances in the gut microbiota. Previous studies have reported the anti-T2DM effects of Pueraria thomsonii Radix as a functional food. However, the mechanism of action is still unknown. In this study, rich polyphenols and polysaccharides from Pueraria Thomsonii Radix water extract (PTR) were quantitatively determined, and then the effects of PTR on db/db mice were evaluated by pharmacology, metabolomics, and 16S rRNA gene sequencing. The results showed that PTR could alleviate pancreatic tissue damage, significantly decrease fasting blood glucose (FBG), fasting serum insulin (FINS), homeostasis model assessment insulin resistance (HOMA-IR), urinary glucose (UGLU), and urinary albumin/creatinine ratio (UACR). Metabolomics showed that the Diabetes Control (DM) group produced 109 differential metabolites, of which 74 could be regulated by PTR. In addition, 16S rRNA sequencing was performed in fecal samples and results showed that PTR could reduce the Firmicutes/Bacteroidetes(F/B) ratio and regulate three beneficial bacteria and one harmful bacterium. In conclusion, the results showed that PTR could ameliorate the T2DM symptoms, metabolic disorder, and gut microbiota imbalance of db/db mice, and it was superior to metformin in some aspects. We suggested for the first time that γ-aminobutyric acid (GABA) may be involved in the regulation of the microbiota-gut-brain axis (MGB) and thus affects the metabolic disorders associated with T2DM. This study will provide a scientific basis for the development of functional food with PTR.PMID:38005193 | DOI:10.3390/molecules28227471

Microorganisms. 2023 Nov 17;11(11):2798. doi: 10.3390/microorganisms11112798.ABSTRACTTrichosporon asahii is a basidiomycete yeast that is pathogenic to humans and animals, and fluconazole-resistant strains have recently increased. Farnesol secreted by fungi is a factor that causes variations in fluconazole resistance; however, few studies have explored the underlying mechanisms. Therefore, this study aims to delineate the fluconazole resistance mechanisms of T. asahii and explore farnesol's effects on these processes. A comparative metabolome-transcriptome analysis of untreated fluconazole-sensitive (YAN), fluconazole-resistant (PB) T. asahii strains, and 25 μM farnesol-treated strains (YAN-25 and PB-25, respectively) was performed. The membrane lipid-related genes and metabolites were upregulated in the PB vs. YAN and PB-25 vs. PB comparisons. Farnesol demonstrated strain-dependent mechanisms underlying fluconazole tolerance between the YAN and PB strains, and upregulated and downregulated efflux pumps in PB-25 and YAN-25 strains, respectively. Membrane lipid-related metabolites were highly correlated with transporter-coding genes. Fluconazole resistance in T. asahii was induced by membrane lipid bio-synthesis activation. Farnesol inhibited fluconazole resistance in the sensitive strain, but enhanced resistance in the resistant strain by upregulating efflux pump genes and membrane lipids. This study offers valuable insights into the mechanisms underlying fungal drug resistance and provides guidance for future research aimed at developing more potent antifungal drugs for clinical use.PMID:38004810 | DOI:10.3390/microorganisms11112798

Microorganisms. 2023 Oct 30;11(11):2666. doi: 10.3390/microorganisms11112666.ABSTRACTCeratocystis fimbriata (C. fimbriata) is a notorious pathogenic fungus that causes sweet potato black rot disease. The APSES transcription factor Swi6 in fungi is located downstream of the cell wall integrity (CWI)-mitogen-activated protein kinase (MAPK) signaling pathway and has been identified to be involved in cell wall integrity and virulence in several filamentous pathogenic fungi. However, the specific mechanisms by which Swi6 regulates the growth and pathogenicity of plant pathogenic fungi remain elusive. In this study, the SWI6 deletion mutants and complemented strains of C. fimbriata were generated. Deletion of Swi6 in C. fimbriata resulted in aberrant growth patterns. Pathogenicity assays on sweet potato storage roots revealed a significant decrease in virulence in the mutant. Non-targeted metabolomic analysis using LC-MS identified a total of 692 potential differentially accumulated metabolites (PDAMs) in the ∆Cfswi6 mutant compared to the wild type, and the results of KEGG enrichment analysis demonstrated significant enrichment of PDAMs within various metabolic pathways, including amino acid metabolism, lipid metabolism, nucleotide metabolism, GPI-anchored protein synthesis, and ABC transporter metabolism. These metabolic pathways were believed to play a crucial role in mediating the growth and pathogenicity of C. fimbriata through the regulation of CWI. Firstly, the deletion of the SWI6 gene led to abnormal amino acid and lipid metabolism, potentially exacerbating energy storage imbalance. Secondly, significant enrichment of metabolites related to GPI-anchored protein biosynthesis implied compromised cell wall integrity. Lastly, disruption of ABC transport protein metabolism may hinder intracellular transmembrane transport. Importantly, this study represents the first investigation into the potential regulatory mechanisms of SWI6 in plant filamentous pathogenic fungi from a metabolic perspective. The findings provide novel insights into the role of SWI6 in the growth and virulence of C. fimbriata, highlighting its potential as a target for controlling this pathogen.PMID:38004677 | DOI:10.3390/microorganisms11112666

Microorganisms. 2023 Oct 28;11(11):2655. doi: 10.3390/microorganisms11112655.ABSTRACTResidents of the Qinghai-Tibet Plateau might experience shifts in their gut microbiota composition as a result of the plateau environment. For example, high altitudes can increase the abundance of obligate anaerobic bacteria, decrease the number of aerobic bacteria and facultative anaerobic bacteria, increase probiotics, and decrease pathogenic bacteria. This study aimed to determine the structure and metabolic differences in intestinal microbial communities among the Tibetan and Han populations on the Qinghai-Xizang Plateau and shed light on the factors that influence the abundance of the microbial communities in the gut. The structural characteristics of intestinal microorganisms were detected from blood and fecal samples using 16S rRNA sequencing. Metabolic characteristics were detected using gas chromatography-time-of-flight mass spectrometry (GC-TOFMS). The influencing factors were analyzed using Spearman's correlation analysis. Bacteroides and Bifidobacterium were dominant in the intestinal tract of the Han population, while Bacteroides and Prevotella were dominant in that of the Tibetan population, with marked differences in Pseudomonas, Prevotella, and other genera. Ferulic acid and 4-methylcatechol were the main differential metabolites between the Tibetan and Han ethnic groups. This may be the reason for the different adaptability of Tibetan and Han nationalities to the plateau. Alanine aminotransferase and uric acid also have a high correlation with different bacteria and metabolites, which may play a role. These results reveal notable disparities in the compositions and metabolic characteristics of gut microbial communities in the Tibetan and Han people residing on the Qinghai-Tibet Plateau and may provide insights regarding the mechanism of plateau adaptability.PMID:38004668 | DOI:10.3390/microorganisms11112655

Microorganisms. 2023 Oct 25;11(11):2628. doi: 10.3390/microorganisms11112628.ABSTRACTEpilepsy (EP) is a complex brain disorder showing a lot of unknows reasons. Recent studies showed that gut microbiota can influence epilepsy via the brain-gut axis. Nevertheless, the mechanism by which gut microbiota affects adult epilepsy still remains unclear. In this study, fecal and serum samples were obtained from patients with epilepsy and normal controls. Using an integrated analysis, sequencing was performed by macrogenomics and high-throughput targeted metabolomics with various bioinformatics approaches. The macrogenomic sequencing revealed significant changes in microbial structure in patients suffering from epilepsy. For example, at the phylum level, the relative abundance of Actinobacteria, Bacteroidetes and Proteobacteria showed an increase in the patients with epilepsy, whereas that of Firmicutes decreased. In addition, the patients with epilepsy had significantly differential metabolite profiles compared to normal controls, and five clusters with 21 metabolites, mainly containing the upregulation of some fatty acids and downregulation of some amino acids. Tryptophan (AUC = 91.81, p < 0.0001), kynurenine (AUC = 79.09, p < 0.01) and 7Z,10Z,13Z,16Z-Docosatetraenoic acid (AUC = 80.95, p < 0.01) may be used as potential diagnostic markers for epilepsy. Differential serum metabolites have effects on tryptophan metabolism, iron death and other pathways. Furthermore, a multiomic joint analysis observed a statistically significant correlation between the differential flora and the differential serum metabolites. In our findings, a macrogenomic analysis revealed the presence of dysregulated intestinal flora species and function in adult epileptic patients. Deeper metabolomic analyses revealed differences in serum metabolites between patients with epilepsy and healthy populations. Meanwhile, the multiomic combination showed connection between the gut microbes and circulating metabolites in the EP patients, which may be potential therapeutic targets.PMID:38004640 | DOI:10.3390/microorganisms11112628

Pharmaceuticals (Basel). 2023 Nov 14;16(11):1607. doi: 10.3390/ph16111607.ABSTRACTDepression can trigger an inflammatory response that affects the immune system, leading to the development of other diseases related to inflammation. Xiao-Yao-San (XYS) is a commonly used formula in clinical practice for treating depression. However, it remains unclear whether XYS has a modulating effect on the inflammatory response associated with depression. The objective of this study was to examine the role and mechanism of XYS in regulating the anti-inflammatory response in depression. A chronic unpredictable mild stress (CUMS) mouse model was established to evaluate the antidepressant inflammatory effects of XYS. Metabolomic assays and network pharmacology were utilized to analyze the pathways and targets associated with XYS in its antidepressant inflammatory effects. In addition, molecular docking, immunohistochemistry, Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR), and Western Blot were performed to verify the expression of relevant core targets. The results showed that XYS significantly improved depressive behavior and attenuated the inflammatory response in CUMS mice. Metabolomic analysis revealed the reversible modulation of 21 differential metabolites by XYS in treating depression-related inflammation. Through the combination of liquid chromatography and network pharmacology, we identified seven active ingredients and seven key genes. Furthermore, integrating the predictions from network pharmacology and the findings from metabolomic analysis, Vascular Endothelial Growth Factor A (VEGFA) and Peroxisome Proliferator-Activated Receptor-γ (PPARG) were identified as the core targets. Molecular docking and related molecular experiments confirmed these results. The present study employed metabolomics and network pharmacology analyses to provide evidence that XYS has the ability to alleviate the inflammatory response in depression through the modulation of multiple metabolic pathways and targets.PMID:38004472 | DOI:10.3390/ph16111607

Pharmaceuticals (Basel). 2023 Nov 7;16(11):1568. doi: 10.3390/ph16111568.ABSTRACTIndiscriminate drug administration may lead to drug therapy results with varying effects on patients, and the proposal of personalized medication can help patients to receive effective drug therapy. Conventional ways of personalized medication, such as pharmacogenomics and therapeutic drug monitoring (TDM), can only be implemented from a single perspective. The development of pharmacometabolomics provides a research method for the realization of precise drug administration, which integrates the environmental and genetic factors, and applies metabolomics technology to study how to predict different drug therapeutic responses of organisms based on baseline metabolic levels. The published research on pharmacometabolomics has achieved satisfactory results in predicting the pharmacokinetics, pharmacodynamics, and the discovery of biomarkers of drugs. Among them, the pharmacokinetics related to pharmacometabolomics are used to explore individual variability in drug metabolism from the level of metabolism of the drugs in vivo and the level of endogenous metabolite changes. By searching for relevant literature with the keyword "pharmacometabolomics" on the two major literature retrieval websites, PubMed and Web of Science, from 2006 to 2023, we reviewed articles in the field of pharmacometabolomics that incorporated pharmacokinetics into their research. This review explains the therapeutic effects of drugs on the body from the perspective of endogenous metabolites and pharmacokinetic principles, and reports the latest advances in pharmacometabolomics related to pharmacokinetics to provide research ideas and methods for advancing the implementation of personalized medication.PMID:38004434 | DOI:10.3390/ph16111568

Pharmaceuticals (Basel). 2023 Nov 2;16(11):1556. doi: 10.3390/ph16111556.ABSTRACTDemonstrating biosimilarity entails comprehensive analytical assessment, clinical pharmacology profiling, and efficacy testing in patients for at least one medical indication, as required by the U.S. Biologics Price Competition and Innovation Act (BPCIA). The efficacy testing can be waived if the drug has known pharmacodynamic (PD) markers, leaving most therapeutic proteins out of this concession. To overcome this, the FDA suggests that biosimilar developers discover PD biomarkers using omics technologies such as proteomics, glycomics, transcriptomics, genomics, epigenomics, and metabolomics. This approach is redundant since the mode-action-action biomarkers of approved therapeutic proteins are already available, as compiled in this paper for the first time. Other potential biomarkers are receptor binding and pharmacokinetic profiling, which can be made more relevant to ensure biosimilarity without requiring biosimilar developers to conduct extensive research, for which they are rarely qualified.PMID:38004421 | DOI:10.3390/ph16111556

Life (Basel). 2023 Oct 31;13(11):2149. doi: 10.3390/life13112149.ABSTRACTMud loach (Misgurnus mizolepis) has long been consumed in Korea. Recently, Chinese mud loaches were replaced with expensive Korean mud loaches, owing to taste and preference. Such issues occur in aquatic food distribution processes, leading to inferior food delivery. Previously, a study was conducted to confirm the origin of mud loaches using genetic analysis. However, untargeted metabolites profiling of mud loaches has not been reported. Untargeted metabolomics provides information on the overall metabolic profiling of a sample, allowing the identification of new metabolites. Here, we analyzed the metabolites of mud loaches of different geographical origins using liquid chromatography (LC)-quadrupole-time-of-flight mass spectrometry (MS). Orthogonal partial least squares discriminant analysis from LC/MS datasets showed a clear distinction between Korean and Chinese mud loaches, and univariate statistical analysis showed significantly different metabolites between them. N-acetylhistidine and anserine were selected as biomarkers for geographical origin discrimination using the receiver operating characteristic curve. N-acetylhistidine and anserine levels were significantly higher in Chinese than in Korean mud loaches. These results indicate that metabolic analysis can be used to discriminate between the geographical origins of mud loaches, curtailing the inadvertent substitution of mud loaches from different regions.PMID:38004289 | DOI:10.3390/life13112149

Nutrients. 2023 Nov 20;15(22):4849. doi: 10.3390/nu15224849.ABSTRACTBACKGROUND: Feeding intolerance (FI) is a significant concern in the care of preterm infants, impacting their growth and development. We previously reported that FI is linked to lower fecal calprotectin (FC) levels. This study aims to explore the postnatal dynamics and interplay between microbiota, metabolic profiles, and host immunity in preterm infants with and without FI.METHODS: Infants with gestational age <32 weeks or birth weight <1500 g were enrolled at the Children's Hospital of Fudan University between January 2018 and October 2020. Weekly fecal samples were analyzed for bacterial profiling, metabolome, and calprotectin levels, exploring their longitudinal development and interrelationships.RESULTS: Of the 118 very preterm infants studied, 48 showed FI. These infants experienced an interrupted microbial-immune trajectory, particularly at 3-4 weeks of age, marked by a reduced bacterial abundance, alpha diversity, and FC levels. Metabolic changes in FI were pronounced between 3 and 6 weeks. Pantothenic acid and two polyamine metabolites were closely associated with bacterial abundance and FC levels and negatively correlated with the duration to attain full enteral feeding.CONCLUSIONS: FI infants demonstrated compromised microbiome-immune interactions, potentially influenced by specific metabolites. This research underscored the importance of early microbial and metabolic development in the pathogenesis of FI in very preterm infants.PMID:38004243 | DOI:10.3390/nu15224849

Nutrients. 2023 Nov 16;15(22):4804. doi: 10.3390/nu15224804.ABSTRACTThe gut microbiota exert a profound influence on human health and metabolism, with microbial metabolites playing a pivotal role in shaping host physiology. This study investigated the impact of prolonged egg supplementation on insulin-like growth factor 1 (IGF-1) and circulating short-chain fatty acids (SCFAs). In a subset of a cluster-randomized trial, participants aged 8-14 years were randomly assigned into three groups: (1) Whole Egg (WE)-consuming 10 additional eggs per week [n = 24], (2) Protein Substitute (PS)-consuming yolk-free egg substitute equivalent to 10 eggs per week [n = 25], and (3) Control Group (C) [n = 26]. At week 35, IGF-1 levels in WE significantly increased (66.6 ± 27.7 ng/mL, p < 0.05) compared to C, with positive SCFA correlations, except acetate. Acetate was stable in WE, increasing in PS and C. Significant propionate differences occurred between WE and PS (14.8 ± 5.6 μmol/L, p = 0.010). WE exhibited notable changes in the relative abundance of the Bifidobacterium and Prevotella genera. Strong positive SCFA correlations were observed with MAT-CR-H4-C10 and Libanicoccus, while Roseburia, Terrisporobacter, Clostridia_UCG-014, and Coprococcus showed negative correlations. In conclusion, whole egg supplementation improves growth factors that may be related to bone formation and growth; it may also promote benefits to gut microbiota but may not affect SCFAs.PMID:38004198 | DOI:10.3390/nu15224804

Nutrients. 2023 Nov 15;15(22):4791. doi: 10.3390/nu15224791.ABSTRACTProgressive decline in pancreatic beta-cell function is central to the pathogenesis of type 2 diabetes (T2D). Here, we explore the relationship between the beta cell and its nutritional environment, asking how an excess of energy substrate leads to altered energy production and subsequent insulin secretion. Alterations in intracellular metabolic homeostasis are key markers of islets with T2D, but changes in cellular metabolite exchanges with their environment remain unknown. We answered this question using nuclear magnetic resonance-based quantitative metabolomics and evaluated the consumption or secretion of 31 extracellular metabolites from healthy and T2D human islets. Islets were also cultured under high levels of glucose and/or palmitate to induce gluco-, lipo-, and glucolipotoxicity. Biochemical analyses revealed drastic alterations in the pyruvate and citrate pathways, which appear to be associated with mitochondrial oxoglutarate dehydrogenase (OGDH) downregulation. We repeated these manipulations on the rat insulinoma-derived beta-pancreatic cell line (INS-1E). Our results highlight an OGDH downregulation with a clear effect on the pyruvate and citrate pathways. However, citrate is directed to lipogenesis in the INS-1E cells instead of being secreted as in human islets. Our results demonstrate the ability of metabolomic approaches performed on culture media to easily discriminate T2D from healthy and functional islets.PMID:38004183 | DOI:10.3390/nu15224791

Nutrients. 2023 Nov 13;15(22):4768. doi: 10.3390/nu15224768.ABSTRACTThe human gut microbiota is an ecosystem harboring trillions of microorganisms, encompassing bacteria, viruses, archaea, fungi, and protozoa [...].PMID:38004160 | DOI:10.3390/nu15224768

Nutrients. 2023 Nov 13;15(22):4767. doi: 10.3390/nu15224767.ABSTRACTIt has been found that Streptococcus thermophilus (S. thermophilus) influenced the gut microbiota and host metabolism with strain specificity in C57BL/6J mice in the previous study, though it remains unclear whether lactose as a dietary factor associated with dairy consumption is involved as the mediator in the interaction. In the present study, integrated analysis of 16S rRNA gene sequencing and untargeted metabolomics by liquid chromatography-mass spectrometry of fecal samples in C57BL/6J mice was applied to evaluate the effect of lactose on the regulation of gut microbiota by two S. thermophilus strains (4M6 and DYNDL13-4). The results showed that the influence of lactose supplementation on gut microbiota induced by S. thermophilus ingestion was strain-specific. Although two S. thermophilus strains ingestion introduced similar perturbations in the fecal microbiota and gut microbial metabolism, the regulation of DYNDL13-4 on the gut microbiota and metabolism was more affected by lactose than 4M6. More specifically, lactose and 4M6 supplementation mainly enriched pathways of d-glutamine and d-glutamate metabolism, alanine, aspartate, and glutamate metabolism, and tryptophan and phenylalanine metabolism in the gut, whereas 4M6 only enriched tryptophan and phenylalanine metabolism. DYNDL13-4-L (DYNDL13-4 with lactose) had significant effects on sulfur, taurine, and hypotaurine metabolism in the gut and on phenylalanine, tyrosine, tryptophan biosynthesis, and linoleic acid metabolism in serum relative to the DYNDL13-4. Our study demonstrated the strain-specific effect of lactose and S. thermophilus supplementation on gut microbiota and host metabolism. However, considering the complexity of the gut microbiota, further research is necessary to provide insights to facilitate the design of personalized fermented milk products as a dietary therapeutic strategy for improving host health.PMID:38004159 | DOI:10.3390/nu15224767

J Pers Med. 2023 Nov 10;13(11):1590. doi: 10.3390/jpm13111590.ABSTRACTCancer is the second major cause of disease-related death worldwide, and its accurate early diagnosis and therapeutic intervention are fundamental for saving the patient's life. Cancer, as a complex and heterogeneous disorder, results from the disruption and alteration of a wide variety of biological entities, including genes, proteins, mRNAs, miRNAs, and metabolites, that eventually emerge as clinical symptoms. Traditionally, diagnosis is based on clinical examination, blood tests for biomarkers, the histopathology of a biopsy, and imaging (MRI, CT, PET, and US). Additionally, omics biotechnologies help to further characterize the genome, metabolome, microbiome traits of the patient that could have an impact on the prognosis and patient's response to the therapy. The integration of all these data relies on gathering of several experts and may require considerable time, and, unfortunately, it is not without the risk of error in the interpretation and therefore in the decision. Systems biology algorithms exploit Artificial Intelligence (AI) combined with omics technologies to perform a rapid and accurate analysis and integration of patient's big data, and support the physician in making diagnosis and tailoring the most appropriate therapeutic intervention. However, AI is not free from possible diagnostic and prognostic errors in the interpretation of images or biochemical-clinical data. Here, we first describe the methods used by systems biology for combining AI with omics and then discuss the potential, challenges, limitations, and critical issues in using AI in cancer research.PMID:38003905 | DOI:10.3390/jpm13111590

Int J Mol Sci. 2023 Nov 17;24(22):16435. doi: 10.3390/ijms242216435.ABSTRACTImproving nitrogen (N) assimilation efficiency without yield penalties is important to sustainable food security. The chemical regulation approach of N assimilation efficiency is still less explored. We previously found that the co-application of brassinolide (BL) and pyraclostrobin (Pyr) synergistically boosted biomass and yield via regulating photosynthesis in Arabidopsis thaliana. However, the synergistic effect of BL and Pyr on N metabolism remains unclear. In this work, we examined the N and protein contents, key N assimilatory enzyme activities, and transcriptomic and metabolomic changes in the four treatments (untreated, BL, Pyr, and BL + Pyr). Our results showed that BL + Pyr treatment synergistically improved N and protein contents by 56.2% and 58.0%, exceeding the effects of individual BL (no increase) or Pyr treatment (36.4% and 36.1%). Besides synergistically increasing the activity of NR (354%), NiR (42%), GS (62%), and GOGAT (62%), the BL + Pyr treatment uniquely coordinated N metabolism, carbon utilization, and photosynthesis at the transcriptional and metabolic levels, outperforming the effects of individual BL or Pyr treatments. These results revealed that BL + Pyr treatments could synergistically improve N assimilation efficiency through improving N assimilatory enzyme activities and coordinated regulation of N and carbon metabolism. The identified genes and metabolites also informed potential targets and agrochemical combinations to enhance N assimilation efficiency.PMID:38003624 | DOI:10.3390/ijms242216435

Int J Mol Sci. 2023 Nov 16;24(22):16384. doi: 10.3390/ijms242216384.ABSTRACTPineapple color yellowing and quality promotion gradually manifest as pineapple fruit ripening progresses. To understand the molecular mechanism underlying yellowing in pineapples during ripening, coupled with alterations in fruit quality, comprehensive metabolome and transcriptome investigations were carried out. These investigations were conducted using pulp samples collected at three distinct stages of maturity: young fruit (YF), mature fruit (MF), and fully mature fruit (FMF). This study revealed a noteworthy increase in the levels of total phenols and flavones, coupled with a concurrent decline in lignin and total acid contents as the fruit transitioned from YF to FMF. Furthermore, the analysis yielded 167 differentially accumulated metabolites (DAMs) and 2194 differentially expressed genes (DEGs). Integration analysis based on DAMs and DEGs revealed that the biosynthesis of plant secondary metabolites, particularly the flavonol, flavonoid, and phenypropanoid pathways, plays a pivotal role in fruit yellowing. Additionally, RNA-seq analysis showed that structural genes, such as FLS, FNS, F3H, DFR, ANR, and GST, in the flavonoid biosynthetic pathway were upregulated, whereas the COMT, CCR, and CAD genes involved in lignin metabolism were downregulated as fruit ripening progressed. APX as well as PPO, and ACO genes related to the organic acid accumulations were upregulated and downregulated, respectively. Importantly, a comprehensive regulatory network encompassing genes that contribute to the metabolism of flavones, flavonols, lignin, and organic acids was proposed. This network sheds light on the intricate processes that underlie fruit yellowing and quality alterations. These findings enhance our understanding of the regulatory pathways governing pineapple ripening and offer valuable scientific insight into the molecular breeding of pineapples.PMID:38003574 | DOI:10.3390/ijms242216384

Int J Mol Sci. 2023 Nov 15;24(22):16378. doi: 10.3390/ijms242216378.ABSTRACTSaccharomyces cerevisiae is a promising host for the bioproduction of higher alcohols, such as 2,3-butanediol (2,3-BDO). Metabolically engineered S. cerevisiae strains that produce 2,3-BDO via glycolysis have been constructed. However, the specific 2,3-BDO production rates of engineered strains must be improved. To identify approaches to improving the 2,3-BDO production rate, we investigated the factors contributing to higher ethanol production rates in certain industrial strains of S. cerevisiae compared to laboratory strains. Sequence analysis of 11 industrial strains revealed the accumulation of many nonsynonymous substitutions in RIM15, a negative regulator of high fermentation capability. Comparative metabolome analysis suggested a positive correlation between the rate of ethanol production and the activity of the pyruvate-consuming pathway. Based on these findings, RIM15 was deleted, and the pyruvate-consuming pathway was activated in YHI030, a metabolically engineered S. cerevisiae strain that produces 2,3-BDO. The titer, specific production rate, and yield of 2,3-BDO in the test tube-scale culture using the YMS106 strain reached 66.4 ± 4.4 mM, 1.17 ± 0.017 mmol (g dry cell weight h)-1, and 0.70 ± 0.03 mol (mol glucose consumed)-1. These values were 2.14-, 2.92-, and 1.81-fold higher than those of the vector control, respectively. These results suggest that bioalcohol production via glycolysis can be enhanced in a metabolically engineered S. cerevisiae strain by deleting RIM15 and activating the pyruvate-consuming pathway.PMID:38003568 | DOI:10.3390/ijms242216378

Int J Mol Sci. 2023 Nov 13;24(22):16271. doi: 10.3390/ijms242216271.ABSTRACTMultiple sclerosis (MS) is a demyelinating and neurodegenerative autoimmune disease of the central nervous system (CNS) damaging myelin and axons. Diagnosis is based on the combination of clinical findings, magnetic resonance imaging (MRI) and analysis of cerebrospinal fluid (CSF). Metabolomics is a systematic study that allows us to track amounts of different metabolites in a chosen medium. The aim of this study was to establish metabolomic differences between the cerebrospinal fluid of patients in the early stages of multiple sclerosis and healthy controls, which could potentially serve as markers for predicting disease activity. We collected CSF from 40 patients after the first attack of clinical symptoms who fulfilled revised McDonald criteria of MS, and the CSF of 33 controls. Analyses of CSF samples were performed by using the high-performance liquid chromatography system coupled with a mass spectrometer with a high-resolution detector. Significant changes in concentrations of arginine, histidine, spermidine, glutamate, choline, tyrosine, serine, oleic acid, stearic acid and linoleic acid were observed. More prominently, Expanded Disability Status Scale values significantly correlated with lower concentrations of histidine. We conclude that these metabolites could potentially play a role as a biomarker of disease activity and predict presumable inflammatory changes.PMID:38003464 | DOI:10.3390/ijms242216271

Int J Mol Sci. 2023 Nov 13;24(22):16272. doi: 10.3390/ijms242216272.ABSTRACTInflammation is the host response of immune cells during infection and traumatic tissue injury. An uncontrolled inflammatory response leads to inflammatory cascade, which in turn triggers a variety of diseases threatening human and animal health. The use of existing inflammatory therapeutic drugs is constrained by their high cost and susceptibility to systemic side effects, and therefore new therapeutic candidates for inflammatory diseases need to be urgently developed. Natural products are characterized by wide sources and rich pharmacological activities, which are valuable resources for the development of new drugs. This study aimed to uncover the alleviating effect and potential mechanism of natural product Limonium aureum (LAH) on LPS-induced inflammatory responses in macrophages. The experimental results showed that the optimized conditions for LAH ultrasound-assisted extraction via response surface methodology were an ethanol concentration of 72%, a material-to-solvent ratio of 1:37 g/mL, an extraction temperature of 73 °C, and an extraction power of 70 W, and the average extraction rate of LAH total flavonoids was 0.3776%. Then, data of 1666 components in LAH ethanol extracts were obtained through quasi-targeted metabolomics analysis. The ELISA showed that LAH significantly inhibited the production of pro-inflammatory cytokines while promoting the secretion of anti-inflammatory cytokines. Finally, combined with the results of network pharmacology analysis and protein expression validation of hub genes, it was speculated that LAH may alleviate LPS-induced inflammatory responses of macrophages through the AKT1/RELA/PTGS2 signaling pathway and the MAPK3/JUN signaling pathway. This study preliminarily revealed the anti-inflammatory activity of LAH and the molecular mechanism of its anti-inflammatory action, and provided a theoretical basis for the development of LAH as a new natural anti-inflammatory drug.PMID:38003461 | DOI:10.3390/ijms242216272