Metabolic picture of microbial interaction: chemical crosstalk during co-cultivation between three dominant genera of bacteria and fungi in medicinal plants rhizosphere.

INTRODUCTION: Microbial communities affect several aspects of the earth's ecosystem through their metabolic interaction. The dynamics of this interaction emerge from complex multilevel networks of crosstalk. Elucidation of this interaction could help us to maintain the balance for a sustainable future. OBJECTIVES: To investigate the chemical language among highly abundant microbial genera in the rhizospheres of medicinal plants based on the metabolomic analysis at the interaction level. METHODS: Coculturing experiments involving three microbial species: Aspergillus (A), Trichoderma (T), and Bacillus (B), representing fungi (A, T) and bacteria (B), respectively. These experiments encompassed various interaction levels, including dual cultures (AB, AT, TB) and triple cultures (ATB). Metabolic profiling by LC-QTOFMS revealed the effect of interaction level on the productivity and diversity of microbial specialized metabolites. RESULTS: The ATB interaction had the richest profile, while the bacterial profile in the monoculture condition had the lowest. Two native compounds of the Aspergillus genus, aspergillic acid and the dipeptide asperopiperazine B, exhibited decreased levels in the presence of the AT interaction and were undetectable in the presence of bacteria during the interaction. Trichodermarin N and Trichodermatide D isolated from Trichoderma species exclusively detected during coexistence with bacteria (TB and ATB). These findings indicate that the presence of Bacillus activates cryptic biosynthetic gene clusters in Trichoderma. The antibacterial activity of mixed culture extracts was stronger than that of the monoculture extracts. The TB extract exhibited strong antifungal activity compared to the monoculture extract and other mixed culture treatments. CONCLUSION: The elucidation of medicinal plant microbiome interaction chemistry and its effect on the environment will also be of great interest in the context of medicinal plant health Additionally, it sheds light on the content of bioactive constituents, and facilitating the discovery of novel antimicrobials.

Metabolomic and lipidomic profiling of the spinal cord in type 2 diabetes mellitus rats with painful neuropathy.

In this paper we investigated lipid and metabolite changes in diabetic neuropathy, using untargeted lipidomics and metabolomics analyses of the spinal cords from streptozotocin-treated diabetic rats.170 metabolites and 45 lipids were dysregulated in the painful diabetic neuropathy (PDN) phase. Pathway enrichment analysis revealed perturbations in starch and sucrose, tryptophan, pyrimidine, cysteine and methionine, thiamine, tyrosine, and nucleotides. The disturbance of tyrosine, tryptophan, methionine, triacylglycerol, and phosphatidylethanolamine metabolism indicated that pathological mechanisms in the PDN involved energy metabolism, oxidative stress, and neural reparative regeneration. These revelations offered potential biomarkers for PDN and enriched the comprehension of the complex molecular mechanisms characterizing PDN, establishing a solid foundation for subsequent inquiries into neural convalescence and recovery after PDN.

Metabolomic changes in children with autism.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication and repetitive behaviors. Metabolomic profiling has emerged as a valuable tool for understanding the underlying metabolic dysregulations associated with ASD. AIM: To comprehensively explore metabolomic changes in children with ASD, integrating findings from various research articles, reviews, systematic reviews, meta-analyses, case reports, editorials, and a book chapter. METHODS: A systematic search was conducted in electronic databases, including PubMed, PubMed Central, Cochrane Library, Embase, Web of Science, CINAHL, Scopus, LISA, and NLM catalog up until January 2024. Inclusion criteria encompassed research articles (83), review articles (145), meta-analyses (6), systematic reviews (6), case reports (2), editorials (2), and a book chapter (1) related to metabolomic changes in children with ASD. Exclusion criteria were applied to ensure the relevance and quality of included studies. RESULTS: The systematic review identified specific metabolites and metabolic pathways showing consistent differences in children with ASD compared to typically developing individuals. These metabolic biomarkers may serve as objective measures to support clinical assessments, improve diagnostic accuracy, and inform personalized treatment approaches. Metabolomic profiling also offers insights into the metabolic alterations associated with comorbid conditions commonly observed in individuals with ASD. CONCLUSION: Integration of metabolomic changes in children with ASD holds promise for enhancing diagnostic accuracy, guiding personalized treatment approaches, monitoring treatment response, and improving outcomes. Further research is needed to validate findings, establish standardized protocols, and overcome technical challenges in metabolomic analysis. By advancing our understanding of metabolic dysregulations in ASD, clinicians can improve the lives of affected individuals and their families.

[Analysis of Reproductive Tract Microecological Changes During the Frozen-Thawed Embryo Transfer Cycle and Clinical Pregnancy Outcomes]. / æ¿€ç´ æ›¿ä»£å†»èƒšç§»æ¤å‘¨æœŸç”Ÿæ®–é“å¾®ç”Ÿæ€å˜åŒ–ä¸Žå¦Šå¨ ç»“å±€åˆ†æž.

Objective: This study aims to analyze the relationship between reproductive tract microecological changes, metabolic differences, and pregnancy outcomes at different time points in the frozen-thawed embryo transfer cycle while patients are undergoing hormone replacement therapy, which will be a breakthrough point for improving outcomes. Methods: A total of 20 women undergoing frozen-thawed single blastocyst transfer for the first time at the Reproductive Medicine Center of Fujian Maternal and Child Health Hospital between July 2022 and January 2023 were recruited for this study. Their vaginal and cervical secretions were collected for 16S rRNA sequencing and non-targeted metabolomics analysis on days 2-5 of menstruation, day 7 after estrogen replacement therapy started, the day when progesterone was added, and the day of transplantation. The subjects were divided into different groups according to their clinical pregnancy status and the sequencing results were analyzed using bioinformatics methods. Results: 1) The alpha-diversity index of the vaginal and cervical microbiota was higher on days 2-5 of menstruation (P<0.01), but did not differ significantly on day 7 after oral estrogen replacement therapy started, the day of progesterone administration, and the day of transplantation (P≥0.1). 2) Both the pregnant group and the non-pregnant group showed a variety of microorganisms and metabolites with significant differences in the lower reproductive tract at different time points. 3) Microbial analysis at different time points showed that there were significant differences in vaginal flora, including Peptoniphilus, Enterocloster, Finegoldia, Klebsiella, Anaerobutyricum, Agathobaculum, Sporanaerobacter, Bilophila, Prevotella, and Anaerococcus in the pregnant group (P<0.05). 4) Metabolite analysis at different time points showed that there were significant differences in 3-hydroxybenzoic acid, linatine, (R)-amphetamine, hydroxychloroquine, and L-altarate in the vaginal secretions of the pregnant group (P<0.05), and that there were significant differences in isocitric acid, quassin, citrinin, and 12(R)-HETE in the cervical secretions (P<0.05). 5) Metabolite analysis at different time points showed that, in the non-pregnant group, there were significant differences in linatine, decanoyl-L-carnitine, aspartame, sphingosine, and hydroxychloroquine in the vaginal secretions (P<0.05), and the isocitric acid, quassin, ctrinin, and 12(R)-HETE in the cervical secretions (P<0.05). 6) Combined microbiome and metabolomics analysis showed that certain metabolites were significantly associated with microbial communities, especially Klebsiella. Conclusions: Significant differences in the microbiota genera and metabolites at different time points were found during the frozen-embryo transfer cycle of hormone replacement therapy, which may be used as potential biomarkers to predict pregnancy outcomes of embryo transfer.

Metabolomic profiling of upper GI malignancies in blood and tissue: a systematic review and meta-analysis.

OBJECTIVE: To conduct a systematic review and meta-analysis of case-control and cohort human studies evaluating metabolite markers identified using high-throughput metabolomics techniques on esophageal cancer (EC), cancer of the gastroesophageal junction (GEJ), and gastric cancer (GC) in blood and tissue. BACKGROUND: Upper gastrointestinal cancers (UGC), predominantly EC, GEJ, and GC, are malignant tumour types with high morbidity and mortality rates. Numerous studies have focused on metabolomic profiling of UGC in recent years. In this systematic review and meta-analysis, we have provided a collective summary of previous findings on metabolites and metabolomic profiling associated with EC, GEJ and GC. METHODS: Following the PRISMA procedure, a systematic search of four databases (Embase, PubMed, MEDLINE, and Web of Science) for molecular epidemiologic studies on the metabolomic profiles of EC, GEJ and GC was conducted and registered at PROSPERO (CRD42023486631). The Newcastle-Ottawa Scale (NOS) was used to benchmark the risk of bias for case-controlled and cohort studies. QUADOMICS, an adaptation of the QUADAS-2 (Quality Assessment of Diagnostic Accuracy) tool, was used to rate diagnostic accuracy studies. Original articles comparing metabolite patterns between patients with and without UGC were included. Two investigators independently completed title and abstract screening, data extraction, and quality evaluation. Meta-analysis was conducted whenever possible. We used a random effects model to investigate the association between metabolite levels and UGC. RESULTS: A total of 66 original studies involving 7267 patients that met the required criteria were included for review. 169 metabolites were differentially distributed in patients with UGC compared to healthy patients among 44 GC, 9 GEJ, and 25 EC studies including metabolites involved in glycolysis, anaerobic respiration, tricarboxylic acid cycle, and lipid metabolism. Phosphatidylcholines, eicosanoids, and adenosine triphosphate were among the most frequently reported lipids and metabolites of cellular respiration, while BCAA, lysine, and asparagine were among the most commonly reported amino acids. Previously identified lipid metabolites included saturated and unsaturated free fatty acids and ketones. However, the key findings across studies have been inconsistent, possibly due to limited sample sizes and the majority being hospital-based case-control analyses lacking an independent replication group. CONCLUSION: Thus far, metabolomic studies have provided new opportunities for screening, etiological factors, and biomarkers for UGC, supporting the potential of applying metabolomic profiling in early cancer diagnosis. According to the results of our meta-analysis especially BCAA and TMAO as well as certain phosphatidylcholines should be implicated into the diagnostic procedure of patients with UGC. We envision that metabolomics will significantly enhance our understanding of the carcinogenesis and progression process of UGC and may eventually facilitate precise oncological and patient-tailored management of UGC.

Unique urine and serum metabolomic signature in patients with excessive alcohol use: An exploratory study.

BACKGROUND: Excessive alcohol consumption has a multifaceted impact on the body's metabolic pathways and organ systems. The objectives of this study were to characterize global metabolomic changes and identify specific pathways that are altered in individuals with excessive alcohol use. METHODS: This exploratory study included 22 healthy controls with no known history of excessive alcohol use and 38 patients identified as using alcohol excessively. A Fibrosis-4 score was used to determine the risk of underlying alcohol-associated liver disease among the excessive drinkers. RESULTS: We found significantly altered urinary and serum metabolites among excessive drinkers, affecting various metabolic pathways including the metabolism of lipids, amino acids and peptides, cofactors and vitamins, carbohydrates, and nucleotides. Levels of two steroid hormones-5alpha-androstan-3beta,17beta-diol disulfate and androstenediol (3beta,17beta) disulfate-were significantly higher in both the serum and urine samples of excessive drinkers. These elevated levels may be associated with a higher risk of liver fibrosis in individuals with excessive alcohol use. CONCLUSION: Alcohol consumption leads to marked alterations in multiple metabolic pathways, highlighting the systemic impact of alcohol on various tissues and organ systems. These findings provide a foundation for future mechanistic studies aimed at elucidating alcohol-induced changes in these metabolic pathways and their implications.

CircABHD2 Inhibits Malignant Progression of Endometrial Cancer by Regulating NAD+/NAMPT Metabolism Axis.

Circular RNAs (circRNAs) perform important functions in the regulation of diverse physiological and pathological processes. CircABHD2 exhibits down-regulation in both endometrial cancer (EC) cells and tissues, but the biological roles and mechanisms of action in EC are still unclear. This study aims to provide a theoretical basis for the role of circABHD2 in EC and potential targets for individualized precision therapy. Dysregulated circRNAs were identified using RNA sequencing (RNA-Seq) from EC tissues and validated using RT-qPCR. CCK-8, colony formation assay, wound healing assay, transwell assay, cell cycle, and apoptosis assay were used to evaluate the effects of circABHD2 on EC cells. Metabolomics assay and western blot analyses were used to investigate the potential mechanisms of circABHD2. From sequencing of RNA (RNA-Seq) analysis of EC tissues, we obtained 19 dysregulated circRNAs, including 8 upregulated ones and 11 downregulated ones. Using RT-qPCR on 32 EC tissues and 19 normal endometrial tissues, we confirmed that circABHD2 was downregulated in EC tissues. The expression levels of circABHD2 were closely relevant to the International Federation of Gynecology and Obstetrics (FIGO) stage and differentiation degree of EC. Functional experiments demonstrated that overexpression of circABHD2 decreased proliferation, migration, invasion, and promoted cell apoptosis. Un-targeted metabolomic assay revealed 31 differential metabolites in EC cells overexpressing circABHD2. KEGG analysis of differential metabolites indicated that NAD+ is the core metabolite regulated by circABHD2. NAMPT is one key enzyme involved in the synthetic pathway responsible for NAD+. Subsequent experiments confirmed that by inhibiting NAMPT protein expression in EC cells, cirABHD2 can inhibit NAD+ level, suggesting that circABHD2 may inhibit EC by regulating the metabolic axis of NAD+/NAMPT. CircABHD2, a downregulated circRNA in EC cells and tissues, inhibits the malignant progression of EC via the NAD+/NAMPT metabolic axis. This discovery presents a promising diagnostic biomarker and potential therapeutic target for EC.

Urine metabolic profile in rats with arterial hypertension of different genesis.

The diversity of pathogenetic mechanisms underlying arterial hypertension leads to the necessity to devise a personalized approach to the diagnosis and treatment of the disease. Metabolomics is one of the promising methods for personalized medicine, as it provides a comprehensive understanding of the physiological processes occurring in the body. The metabolome is a set of low-molecular substances available for detection in a sample and representing intermediate and final products of cell metabolism. Changes in the content and ratio of metabolites in the sample mark the corresponding pathogenetic mechanisms by highlighting them, which is especially important for such a multifactorial disease as arterial hypertension. To identify metabolomic markers for hypertensive conditions of different origins, three forms of arterial hypertension (AH) were studied: rats with hereditary AH (ISIAH rat strain); rats with AH induced by L-NAME administration (a model of endothelial dysfunction with impaired NO production); rats with AH caused by the administration of deoxycorticosterone in combination with salt loading (hormone-dependent form - DOCA-salt AH). WAG rats were used as normotensive controls. 24-hour urine samples were collected from all animals and analyzed by quantitative NMR spectroscopy for metabolic profiling. Then, potential metabolomic markers for the studied forms of hypertensive conditions were identified using multivariate statistics. Analysis of the data obtained showed that hereditary stress-induced arterial hypertension in ISIAH rats was characterized by a decrease in the following urine metabolites: nicotinamide and 1-methylnicotinamide (markers of inflammatory processes), N- acetylglutamate (nitric oxide cycle), isobutyrate and methyl acetoacetate (gut microbiota). Pharmacologically induced forms of hypertension (the L-NAME and DOCA+NaCl groups) do not share metabolomic markers with hereditary AH. They are differentiated by N,N-dimethylglycine (both groups), choline (the L-NAME group) and 1-methylnicotinamide (the group of rats with DOCA-salt hypertension).

Engineering Escherichia coli for efficient glutathione production.

Glutathione is a tripeptide of excellent value in the pharmaceutical, food, and cosmetic industries that is currently produced during yeast fermentation. In this case, glutathione accumulates intracellularly, which hinders high production. Here, we engineered Escherichia coli for the efficient production of glutathione. A total of 4.3 g/L glutathione was produced by overexpressing gshA and gshB, which encode cysteine glutamate ligase and glutathione synthetase, respectively, and most of the glutathione was excreted into the culture medium. Further improvements were achieved by inhibiting degradation (Δggt and ΔpepT); deleting gor (Δgor), which encodes glutathione oxide reductase; attenuating glutathione uptake (ΔyliABCD); and enhancing cysteine production (PompF-cysE). The engineered strain KG06 produced 19.6 g/L glutathione after 48 h of fed-batch fermentation with continuous addition of ammonium sulfate as the sulfur source. We also found that continuous feeding of glycine had a crucial role for effective glutathione production. The results of metabolic flux and metabolomic analyses suggested that the conversion of O-acetylserine to cysteine is the rate-limiting step in glutathione production by KG06. The use of sodium thiosulfate largely overcame this limitation, increasing the glutathione titer to 22.0 g/L, which is, to our knowledge, the highest titer reported to date in the literature. This study is the first report of glutathione fermentation without adding cysteine in E. coli. Our findings provide a great potential of E. coli fermentation process for the industrial production of glutathione.

Effects of dietary selenium deficiency and supplementation on liver in grazing sheep: insights from transcriptomic and metabolomic analysis.

Background: Mineral elements play a crucial role in supporting the life activities and physiological functions of animals. However, numerous studies have revealed that in some geographical areas and certain grazing situations, grazing livestock frequently suffers from mineral element deficiencies due to the loss of mineral elements from grassland forages, such as selenium (Se). To shed fresh light on this issue, this study aims to investigate the impact of dietary Se deficiency and supplementation on the liver of grazing sheep in these challenging conditions. Method: This study involved 28 grazing Mongolian Wu Ranke sheep with an average body weight of about 32.20 ± 0.37 kg, which were divided into the Se treatment group and the control group. The Se treatment group was fed with the low-Se diet for 60 days and then continued to be fed with the high-Se diet for 41 days. The liver concentration of minerals, transcriptomic analysis, and untargeted metabolomic analysis were conducted to assess the impact of Se deficiency and supplementation on the liver of grazing sheep. Results: Dietary Se deficiency and supplementation significantly reduced and elevated liver concentration of Se, respectively (p < 0.05). Gene functional enrichment analysis suggested that dietary Se deficiency might impair protein synthesis efficiency, while Se supplementation was found to enhance liver protein synthesis in grazing sheep. AGAP1, ERN1, MAL2, NFIC, and RERG were identified as critical genes through the weighted gene correlation network analysis, the quantitative real-time polymerase chain reaction, and the receiver operating characteristic curve validation that could potentially serve as biomarkers. Metabolomics analysis revealed that dietary Se deficiency significantly reduced the abundance of metabolites such as 5-hydroxytryptamine, while dietary Se supplementation significantly elevated the abundance of metabolites such as 5-hydroxytryptophan (p < 0.05). Conclusion: Integrative analysis of the transcriptome and metabolome revealed that dietary Se deficiency led to reduced hepatic antioxidant and anti-inflammatory capacity, whereas Se supplementation increased the hepatic antioxidant and anti-inflammatory capacity in grazing Wu Ranke sheep. These findings provide new insights into the effects of dietary Se deficiency and supplementation on the liver of grazing sheep, potentially leading to improved overall health and well-being of grazing livestock.

Multiomics to Characterize the Molecular Events Underlying Impaired Glucose Tolerance in FXR-Knockout Mice.

The prevalence of different metabolic syndromes has grown globally, and the farnesoid X receptor (FXR), a metabolic homeostat for glucose, lipid, and bile acid metabolisms, may serve an important role in the progression of metabolic disorders. Glucose intolerance by FXR deficiency was previously reported and observed in our study, but the underlying biology remained unclear. To investigate the ambiguity, we collected the nontargeted profiles of the fecal metaproteome, serum metabolome, and liver proteome in Fxr-null (Fxr-/-) and wild-type (WT) mice with LC-HRMS. FXR deficiency showed a global impact on the different molecular levels we monitored, suggesting its serious disruption in the gut microbiota, hepatic metabolism, and circulating biomolecules. The network and enrichment analyses of the dysregulated metabolites and proteins suggested the perturbation of carbohydrate and lipid metabolism by FXR deficiency. Fxr-/- mice presented lower levels of hepatic proteins involved in glycogenesis. The impairment of glycogenesis by an FXR deficiency may leave glucose to accumulate in the circulation, which may deteriorate glucose tolerance. Lipid metabolism was dysregulated by FXR deficiency in a structural-dependent manner. Fatty acid ß-oxidations were alleviated, but cholesterol metabolism was promoted by an FXR deficiency. Together, we explored the molecular events associated with glucose intolerance by impaired FXR with integrated novel multiomic data.

Anti-inflammation mechanisms of a homogeneous polysaccharide from Phyllanthus emblica L. on DSS induced colitis mice via the gut microbiota and metabolites alteration.

Phyllanthus emblica L. offers promising therapeutic potential for inflammatory diseases. This study revealed the molecular structure of a homogeneous polysaccharide purified from Phyllanthus emblica L. (PEP-1) and evaluated its anti-inflammatory effects on ulcerative colitis (UC) in mice. In the in vivo experiment, administered in varying dosages to dextran sulfate sodium (DSS)-induced UC models, PEP-1 significantly alleviated colonic symptoms, histological damages and reshaped the gut microbiota. Notably, it adjusted the Firmicutes/Bacteroidetes ratio and reduced pro-inflammatory species, closely aligning with shifts in the fecal metabolites and metabolic pathways such as the metabolism of pyrimidine, beta-alanine, and purine. These findings underscore the potential of PEP-1 as a therapeutic agent for UC, providing insights into the mechanisms through gut microbiota and metabolic modulation.

Identifying ligands directly interacting with target protein in medicinal herbs by metabolomic analysis of T2-filtered HSQC spectra.

A protocol for efficiently identifying ligands directly interacting with a target protein in complex extracts of medicinal herbs was proposed by combining an adapted 2D perfect-echo Carr-Purcell-Meiboom-Gill heteronuclear single quantum correlation (PE-CPMG HSQC) spectrum with metabolomic analysis. PE-CPMG HSQC can suppress the signal interference from the target protein, allowing more accurate peak quantification than conventional HSQC. Inspired from untargeted metabolomics, regions of interest (ROIs) are constructed and quantified for the mixture or complex extract samples with and without a target protein, and then a binding index (BI) of each ROI is determined. ROIs or corresponding peaks significantly perturbed by the presence of the target protein (BI ≥1.5) are detected as differential features, and potential binding ligands identified from the differential features can be equated with bioactive markers associated with the 'treatment' of the target protein. Quantifying ROI can inclusively report the ligand bindings to a target protein in fast, intermediate and slow exchange regimes on nuclear magnetic resonance (NMR) time scale. The approach was successfully implemented and identified Angoroside C, Cinnamic acid and Harpagoside from the extract of Scrophularia ningpoensis Hemsl. as ligands binding to peroxisome proliferator-activated receptor γ. The proposed 2D NMR-based approach saves excess steps for sample processing and has a higher chance of detecting the weaker ligands in the complex extracts of medicinal herbs. We expect that this approach can be applied as an alternative to mining the potential ligands binding to a variety of target proteins from traditional Chinese medicines and herbal extracts.

Identification of metabolites associated with preserved muscle volume after aneurysmal subarachnoid hemorrhage due to high protein supplementation and neuromuscular electrical stimulation.

The INSPIRE randomized clinical trial demonstrated that a high protein diet (HPRO) combined with neuromuscular electrical stimulation (NMES) attenuates muscle atrophy and may improve outcomes after aneurysmal subarachnoid hemorrhage We sought to identify specific metabolites mediating these effects. Blood samples were collected from subjects on admission prior to randomization to either standard of care (SOC; N = 12) or HPRO + NMES (N = 12) and at 7 days. Untargeted metabolomics were performed for each plasma sample. Sparse partial least squared discriminant analysis identified metabolites differentiating each group. Correlation coefficients were calculated between each metabolite and total protein per day and muscle volume. Multivariable models determined associations between metabolites and muscle volume. Unique metabolites (18) were identified differentiating SOC from HPRO + NMES. Of these, 9 had significant positive correlations with protein intake. In multivariable models, N-acetylleucine was significantly associated with preserved temporalis [OR 1.08 (95% CI 1.01, 1.16)] and quadricep [OR 1.08 (95% CI 1.02, 1.15)] muscle volume. Quinolinate was also significantly associated with preserved temporalis [OR 1.05 (95% CI 1.01, 1.09)] and quadricep [OR 1.04 (95% CI 1.00, 1.07)] muscle volume. N-acetylserine and ß-hydroxyisovaleroylcarnitine were associated with preserved temporalis or quadricep volume. Metabolites defining HPRO + NMES had strong correlations with protein intake and were associated with preserved muscle volume.

Multi-omics analysis of renal vein serum with Ischemia-Reperfusion injury.

BACKGROUND: Acute kidney injury (AKI) is frequently caused by renal ischemia-reperfusion injury (IRI). Identifying potential renal IRI disease biomarkers would be useful for evaluating AKI severity. OBJECTIVE: We used proteomics and metabolomics to investigate the differences in renal venous blood between ischemic and healthy kidneys in an animal model by identifying differentially expressed proteins (DEPs) and differentially expressed protein metabolites (DEMs). METHODS: Nine pairs of renal venous blood samples were collected before and at 20, 40, and 60 min post ischemia. The ischemia time of Group A, B and C was 20,40 and 60 min. The proteome and metabolome of renal venous blood were evaluated to establish the differences between renal venous blood before and after ischemia. RESULTS: We identified 79 common DEPs in all samples of Group A, 80 in Group B, and 131 in Group C. Further common DEPs among all three groups were Tyrosineprotein kinase, GPR15LG, KAZALD1, ADH1B. We also identified 81, 64, and 83 common DEMs in each group respectively, in which 30 DEMs were further common to all groups. Bioinformatic analysis of the DEPs and DEMs was conducted. CONCLUSION: This study demonstrated that different pathological processes occur during short- and long-term renal IRI. Tyrosine protein kinase, GPR15LG, Kazal-type serine peptidase inhibitor domain 1, and all-trans-retinol dehydrogenase are potential biomarkers of renal IRI.

Metabolome-wide association identifies altered metabolites and metabolic pathways in the serum of patients with cholangiocarcinoma.

Background & Aims: Metabolomic and lipidomic analyses provide an opportunity for novel biological insights. Cholangiocarcinoma (CCA) remains a highly lethal cancer with limited response to systemic, targeted, and immunotherapeutic approaches. Using a global metabolomics and lipidomics platform, this study aimed to discover and characterize metabolomic variations and associated pathway derangements in patients with CCA. Methods: Leveraging a biospecimen collection, including samples from patients with digestive diseases and normal controls, global serum metabolomic and lipidomic profiling was performed on 213 patients with CCA and 98 healthy controls. The CCA cohort of patients included representation of intrahepatic, perihilar, and distal CCA tumours. Metabolome-wide association studies utilizing multivariable linear regression were used to perform case-control comparisons, followed by pathway enrichment analysis, CCA subtype analysis, and disease stage analysis. The impact of biliary obstruction was evaluated by repeating analyses in subsets of patients only with normal bilirubin levels. Results: Of the 420 metabolites that discriminated patients with CCA from controls, decreased abundance of cysteine-glutathione disulfide was most closely associated with CCA. Additional conjugated bile acid species were found in increased abundance even in the absence of clinically relevant biliary obstruction denoted by elevated serum bilirubin levels. Pathway enrichment analysis also revealed alterations in caffeine metabolism and mitochondrial redox-associated pathways in the serum of patients with CCA. Conclusions: The presented metabolomic and lipidomic profiling demonstrated multiple alterations in the serum of patients with CCA. These exploratory data highlight novel metabolic pathways in CCA and support future work in therapeutic targeting of these pathways and the development of a precision biomarker panel for diagnosis. Impact and implications: Cholangiocarcinoma (CCA) is a highly lethal hepatobiliary cancer with limited treatment response, highlighting the need for a better understanding of the disease biology. Using a global metabolomics and lipidomics platform, we characterized distinct changes in the serum of 213 patients with CCA compared with healthy controls. The results of this study elucidate novel metabolic pathways in CCA. These findings benefit stakeholders in both the clinical and research realms by providing a foundation for improved disease diagnostics and identifying novel targets for therapeutic design.

The mechanism by which oriented polypropylene packaging alleviates postharvest 'Black Spot' in radish root (Raphanus sativus).

INTRODUCTION: The postharvest physiological disorder known as 'black spot' in radish roots (Raphanus sativus) poses a significant challenge to quality maintenance during storage, particularly under summer conditions. The cause of this disorder, however, is poorly understood. OBJECTIVES: Characterize the underlying causes of 'black spot' disorder in radish roots and identify strategies to delay its onset. METHODS: Radish roots were placed in either polyvinyl chloride (PVC) or oriented polypropylene (OPP) packaging and stored for 4 days at 30 °C. Appearance and physiological parameters were assessed and transcriptomic and metabolomic analyses were conducted to identify the key molecular and biochemical factors contributing to the disorder and strategies for delaying its onset and development. RESULTS: OPP packaging effectively delayed the onset of 'black spot' in radishes, potentially due to changes in phenolic and lipid metabolism. Regarding phenolic metabolism, POD and PPO activity decreased, RsCCR and RsPOD expression was downregulated, genes involved in phenols and flavonoids synthesis were upregulated and their content increased, preventing the oxidative browning of phenols and generally enhancing stress tolerance. Regarding lipid metabolism, the level of alpha-linolenic acid increased, and genes regulating cutin and wax synthesis were upregulated. Notably, high flavonoid and low ROS levels collectively inhibited RsPLA2G expression, which reduced the production of arachidonic acid, pro-inflammatory compounds (LTA4 and PGG2), and ROS, alleviating the inflammatory response and oxidative stress in radish epidermal tissues. CONCLUSION: PVC packaging enhanced the postharvest onset of 'black spot' in radishes, while OPP packaging delayed both its onset and development. Our study provides insights into the response of radishes to different packaging materials during storage, and the causes and host responses that either enhance or delay 'black spot' disorder onset. Further studies will be conducted to confirm the molecular and biochemical processes responsible for the onset and development of 'black spot' in radishes.

Partial substitution of soybean meal with microalgae meal (Arthrospira spp. - Spirulina) in grower and finisher diets for broiler chickens: implications on performance parameters, footpad dermatitis occurrence, breast meat quality traits, amino acid digestibility and plasma metabolomics profile.

This trial was conducted to evaluate the effects of replacing soybean meal with microalgae meal (MM; Arthrospira spp.) during grower and finisher phases on productive performance, footpad dermatitis (FPD) occurrence, breast meat quality, amino acid digestibility and plasma metabolomics profile of broiler chickens. One thousand day-old Ross 308 male chicks were divided into 5 experimental groups (8 replicates, 25 birds/each): CON, fed a commercial soybean-based diet throughout the trial (0-41 d); F3 and F6, fed the CON diet up to 28 d of age and then a finisher diet (29-41 d) with either 30 or 60 g MM/kg, respectively; and GF3 and GF6, receiving CON diet until 14 d and then diets containing 30 or 60 g MM/kg from 15 to 41 d, respectively. All diets were iso-energetic and with a similar amino acid profile. Growth performances were recorded on a pen basis at the end of each feeding phase and apparent ileal amino acid digestibility was determined at 41 d. Footpad dermatitis occurrence was assessed on all processed birds, while breast and plasma samples were collected for meat quality and metabolomics analysis (proton nuclear magnetic resonance - 1H-NMR). At 41 d, CON group showed higher body weight than F6 and GF6 ones (2,541 vs. 2,412 vs. 2,384 g, respectively; P < 0.05). Overall, GF6 group exhibited the highest feed conversion ratio, while F3 did not present significant differences compared to CON (1.785 vs. 1.810 vs. 1.934 g feed/g gain, respectively for CON, F3 and GF6; P < 0.01). The occurrence and the risk of developing FPD were similar among groups. MM administration increased breast meat yellowness and reduced amino acid digestibility (P < 0.001). The 1H-NMR analysis revealed variations in the levels of some circulating metabolites, including histidine, arginine and creatine, which play important metabolic roles. Overall, these findings can contribute to expand the knowledge about the use of Arthrospira spp. as protein source in broiler diets.

NMN synbiotics intervention modulates gut microbiota and metabolism in APP/PS1 Alzheimer's disease mouse models.

Alzheimer's disease (AD) is a complex neurodegenerative condition with growing evidence implicating the gut microbiota in its pathogenesis. This study aimed to investigate the effects of NMN synbiotics, a combination of ß-nicotinamide mononucleotide (NMN), Lactobacillus plantarum, and lactulose, on the gut microbiota composition and metabolic profiles in APP/PS1 transgenic mice. Results demonstrated that NMN synbiotics led to a notable restructuring of the gut microbiota, with a decreased Firmicutes/Bacteroidetes ratio in the AD mice, suggesting a potential amelioration of gut dysbiosis. Alpha diversity indices indicated a reduction in microbial diversity following NMN synbiotics supplementation, while beta diversity analyses revealed a shift towards a more balanced microbial community structure. Functional predictions based on the 16S rRNA data highlighted alterations in metabolic pathways, particularly those related to amino acid and energy metabolism, which are crucial for neuronal health. The metabolomic analysis uncovered a significant impact of NMN synbiotics on the gut metabolome, with normalization of metabolic composition in AD mice. Differential metabolite functions were enriched in pathways associated with neurotransmitter synthesis and energy metabolism, pointing to the potential therapeutic effects of NMN synbiotics in modulating the gut-brain axis and synaptic function in AD. Immunohistochemical staining observed a significant reduction of amyloid plaques formed by Aß deposition in the brain of AD mice after NMN synbiotics intervention. The findings underscore the potential of using synbiotics to ameliorate the neurodegenerative processes associated with Alzheimer's disease, opening new avenues for therapeutic interventions.

Metabolomic and Physiological Effects of a Cardiorenal Protective Diet Intervention in African American Adults with Chronic Kidney Disease.

Chronic kidney disease (CKD) impacts 14% of adults in the United States, and African American (AA) individuals are disproportionately affected, with more than 3 times higher risk of kidney failure as compared to White individuals. This study evaluated the effects of base-producing fruit and vegetables (FVs) on cardiorenal outcomes in AA persons with CKD and hypertension (HTN) in a low socioeconomic area. The "Cardiorenal Protective Diet" prospective randomized trial evaluated the effects of a 6-week, community-based FV intervention compared to a waitlist control (WL) in 91 AA adults (age = 58.3 ± 10.1 years, 66% female, 48% income ≤ USD 25K). Biometric and metabolomic variables were collected at baseline and 6 weeks post-intervention. The change in health outcomes for both groups was statistically insignificant (p > 0.05), though small reductions in albumin to creatinine ratio, body mass index, total cholesterol, and systolic blood pressure were observed in the FV group. Metabolomic profiling identified key markers (p < 0.05), including C3, C5, 1-Met-His, kynurenine, PC ae 38:5, and choline, indicating kidney function decline in the WL group. Overall, delivering a directed cardiorenal protective diet intervention improved cardiorenal outcomes in AA adults with CKD and HTN. Additionally, metabolomic profiling may serve as a prognostic technique for the early identification of biomarkers as indicators for worsening CKD and increased CVD risk.