PubMed

Chem Sci. 2024 May 7;15(21):8089-8096. doi: 10.1039/d4sc00825a. eCollection 2024 May 29.ABSTRACTMicroorganisms from the order Burkholderiales have been the source of a number of important classes of natural products in recent years. For example, study of the beetle-associated symbiont Burkholderia gladioli led to the discovery of the antifungal polyketide lagriamide; an important molecule from the perspectives of both biotechnology and chemical ecology. As part of a wider project to sequence Burkholderiales genomes from our in-house Burkholderiales library we identified a strain containing a biosynthetic gene cluster (BGC) similar to the original lagriamide BGC. Structure prediction failed to identify any candidate masses for the products of this BGC from untargeted metabolomics mass spectrometry data. However, genome mining from publicly available databases identified fragments of this BGC from a culture collection strain of Paraburkholderia. Whole genome sequencing of this strain revealed the presence of a homologue of this BGC with very high sequence identity. Stable isotope feeding of the two strains in parallel using our newly developed IsoAnalyst platform identified the product of this lagriamide-like BGC directly from the crude fermentation extracts, affording a culturable supply of this interesting compound class. Using a combination of bioinformatic, computational and spectroscopic methods we defined the absolute configurations for all 11 chiral centers in this new metabolite, which we named lagriamide B. Biological testing of lagriamide B against a panel of 21 bacterial and fungal pathogens revealed antifungal activity against the opportunistic human pathogen Aspergillus niger, while image-based Cell Painting analysis indicated that lagriamide B also causes actin filament disruption in U2-OS osteosarcoma cells.PMID:38817573 | PMC:PMC11134395 | DOI:10.1039/d4sc00825a

J Biosci. 2024;49:59.ABSTRACTAdult muscle tissue largely comprised of differentiated myofibers also harbors quiescent muscle-resident stem cells (MuSCs) that are responsible for its maintenance, repair and regeneration. Emerging evidence suggests that quiescent MuSCs exhibit a specific metabolic state, which is regulated during physiological and pathological alterations. However, a detailed understanding of the metabolic state of quiescent MuSCs and its alteration during activation and repair is lacking. Direct profiling of MuSCs in vivo is challenging because the cells are rare and dispersed, while isolation and enrichment leads to their activation and loss of quiescence. In this study, we employed 1H-nuclear magnetic resonance (NMR) spectroscopy to profile metabolites in an established culture model of quiescent MuSC-derived myoblasts and compared with activated, proliferative and differentiated muscle cells to determine the state-specific metabolome. We report that the proliferating and differentiated cells are highly enriched in metabolites involved in energy generation, the quiescent state is enriched in metabolites related to phospholipid catabolism (glycerophosphocholine and choline) and depleted for phosphocholine which is enriched in proliferating cells. We propose that the ratio of these metabolites may be useful as a biomarker of MuSC quiescence.PMID:38817158

Int J Biol Macromol. 2024 May 28:132709. doi: 10.1016/j.ijbiomac.2024.132709. Online ahead of print.ABSTRACTBacterial Metabolite through a fermentation process is a growing trend and a promising alternative for use as functional components. Non-hydrothermal water-soluble (WSPs) and hydrothermally treated water-insoluble (WIPs) Maitake polysaccharides were fermented with Lactobacillus acidophilus (LA) and Lactobacillus plantarum (LP). Chemical composition analysis indicated that Maitake polysaccharides contained 58.22 ± 1.35 % total sugar and 31.46 % β-glucan, essential for metabolites production. 6-glucanase was used to degrade the WIPs, and hydrothermally treated WIP fibers exhibited smooth microstructure. Hence, the LA and LP bacteria investigated the potential fermented metabolic activities and differences between WSPs(Sp1)and WIP(Sp3) Maitake polysaccharides using LC-MS, and 887 metabolites were identified. Using Venn, Partial least squares discriminant analysis (PLS-DA), VIP Metabolites, and other multivariate statistical analysis methods, metabolites were expressed differently in all samples. Due to hydrothermal processing, WIP induced the highest growth of LA and LP, with an abundance of isocitrate metabolites. Furthermore, 50 metabolite correlations were identified, leading to the classification of 6 distinct metabolic groups. Thus, the study offers the initial comprehensive analysis of metabolites in Lactobacillus-fermented Maitake polysaccharides, aiding in understanding its metabolic interactions and facilitating progress in food engineering research.PMID:38815943 | DOI:10.1016/j.ijbiomac.2024.132709

Pharmacol Res. 2024 May 28:107231. doi: 10.1016/j.phrs.2024.107231. Online ahead of print.ABSTRACTWe previously demonstrated that mice carrying natural mtDNA variants of the FVB/NJ strain (m.7778G>T in the mt-Atp8 gene in mitochondrial complex V), namely C57BL/6J-mtFVB/NJ (B6-mtFVB), exhibited (i) partial protection from experimental skin inflammatory diseases in an anti-murine type VII collagen antibody-induced skin inflammation model and psoriasiform dermatitis model; (ii) significantly altered metabolites, including short-chain fatty acids, according to targeted metabolomics of liver, skin and lymph node samples; and (iii) a differential composition of the gut microbiota according to bacterial 16S rRNA gene sequencing of stool samples compared to wild-type C57BL/6J (B6) mice. To further dissect these disease-contributing factors, we induced an experimental antibody-induced skin inflammatory disease in gnotobiotic mice. We performed shotgun metagenomic sequencing of caecum contents and untargeted metabolomics of liver, CD4+ T cell, and caecum content samples from conventional B6-mtFVB and B6 mice. We identified D-glucosamine as a candidate mediator that ameliorated disease severity in experimental antibody-induced skin inflammation by modulating immune cell function in T cells, neutrophils and macrophages. Because mice carrying mtDNA variants of the FVB/NJ strain show differential disease susceptibility to a wide range of experimental diseases, including diet-induced atherosclerosis in low-density lipoprotein receptor knockout mice and collagen antibody-induced arthritis in DBA/1J mice, this experimental approach is valuable for identifying novel therapeutic options for skin inflammatory conditions and other chronic inflammatory diseases to which mice carrying specific mtDNA variants show differential susceptibility.PMID:38815878 | DOI:10.1016/j.phrs.2024.107231

J Ethnopharmacol. 2024 May 28:118401. doi: 10.1016/j.jep.2024.118401. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Compound Zaoren Granules (CZG), an optimized herbal formulation based on the traditional Chinese medicine prescription Suanzaoren decoction, are designed specifically for insomnia treatment. However, the mechanisms underlying its efficacy in treating insomnia are not yet fully understood.AIM OF THE STUDY: The research investigated the mechanisms of CZG's improvement in insomnia by regulating cAMP/CREB signaling pathway and metabolic profiles.METHODS: The main components of CZG were characterized by liquid chromatography-mass spectrometry (LC-MS). Subsequently, these validated components were applied to network pharmacological analysis to predict signaling pathways associated with insomnia. We evaluated the effect of CZG on BV-2 cells in vitro. We also evaluated the behavioral indexes of CUMS combined with PCPA induced insomnia in rats. HE staining and Nissl staining were used to observe the pathological damage of hippocampus. ELISA was used to detect the levels of various neurotransmitters, orexins, HPA axis, and inflammatory factors in insomnia rats. Then we detected the expression of cAMP/CREB signaling pathway through ELISA, WB, and IHC. Finally, the metabolomics was further analyzed by using UHPLC-QTOF-MS/MS to investigate the changes in the hippocampus of insomnia rats and the possible metabolic pathways were also speculated.RESULTS: The results of CZG in vitro experiments showed that CZG has protective and anti-inflammatory effects on LPS induced BV-2 cells. A total of 161 chemical components were identified in CZG. After conducting network pharmacology analysis through these confirmed components, we select the cAMP/CREB signaling pathway for further investigate. The behavioral research results on insomnia rats showed that CZG significantly prolonged sleep time, mitigated brain tissue pathological damage, and exhibited liver protective properties. CZG treats insomnia by regulating the content of various neurotransmitters, reducing levels of orexin, HPA axis, and inflammatory factors. It can also treat insomnia by upregulating the expression of the cAMP/CREB signaling pathway. Hippocampus metabolomics analysis identified 69 differential metabolites associated with insomnia. The metabolic pathways related to these differential metabolites have also been predicted.CONCLUSION: These results indicate that CZG can significantly prolong sleep time. CZG is used to treat insomnia by regulating various neurotransmitters, HPA axis, inflammatory factors, cAMP/CREB signaling pathways, and metabolic disorders.PMID:38815875 | DOI:10.1016/j.jep.2024.118401

Sci Total Environ. 2024 May 28:173384. doi: 10.1016/j.scitotenv.2024.173384. Online ahead of print.ABSTRACTThe interaction between the gut and the liver plays a significant role in individual health and diseases. Mounting evidence supports that bile acids are important metabolites in the bidirectional communication between the gut and the liver. Most of the current studies on the "gut-liver axis" have focused on higher vertebrates, however, few was reported on lower invertebrates such as shrimp with an open circulatory system. Here, microbiomic and metabolomic analyses were conducted to investigate the bacterial composition and bile acid metabolism in intestine, hemolymph and hepatopancreas of Penaeus vannamei fed diets supplemented with octanoic acid and oleic acid. After six days of feeding, the bacterial composition in intestine, hemolymph and hepatopancreas changed at different stages, with significant increases in the relative abundance of several genera such as Pseudomonas and Rheinheimera in intestine and hepatopancreas. Notably, there was a more similar bacterial composition in intestine and hepatopancreas at the genus level, which indicated the close communication between shrimp intestine and hepatopancreas. Meanwhile, higher content of some bile acids such as lithocholic acid (LCA) and α-muricholic acid (α-MCA) in intestine and lower content of some bile acids such as taurohyocholic acids (THCA) and isolithocholic acid (IsoLCA) in hepatopancreas were detected. Furthermore, Spearman correlation analysis revealed a significant correlation between bacterial composition and bile acid metabolism in intestine and hepatopancreas. The microbial source tracking analysis showed that there was a high proportion of intestine and hepatopancreas bacterial community as the source of each other. Collectively, these results showed a strong crosstalk between shrimp intestine and hepatopancreas, which suggests a unique potential "intestine-hepatopancreas axis" in lower invertebrate shrimp with an open circulatory system. Our finding contributed to the understanding of the interplay between shrimp intestine and hepatopancreas in the view of microecology and provided new ideas for shrimp farming and disease control.PMID:38815838 | DOI:10.1016/j.scitotenv.2024.173384

Am J Kidney Dis. 2024 May 28:S0272-6386(24)00787-X. doi: 10.1053/j.ajkd.2024.03.028. Online ahead of print.ABSTRACTRATIONALE & OBJECTIVE: Biomarkers that enable better identification of persons with chronic kidney disease (CKD) who are at higher risk for disease progression and adverse events are needed. This study sought to identify urine and plasma metabolites associated with progression of kidney disease.STUDY DESIGN: Prospective metabolome-wide association study.SETTING & PARTICIPANTS: Persons with CKD enrolled in the German CKD Study (GCKD) with metabolite measurements; with external validation within the Atherosclerosis Risk in Communities Study.EXPOSURES: 1,513 urine and 1,416 plasma metabolites (Metabolon, Inc.) measured at study entry using untargeted mass spectrometry.OUTCOMES: Main endpoints were kidney failure (KF), and a composite endpoint of KF, eGFR <15 mL/min/1.73m2, or 40% decline in eGFR (CKE). Death from any cause was a secondary endpoint. After a median of 6.5 years follow-up, 500 persons experienced KF, 1,083 experienced CKE and 680 died.ANALYTICAL APPROACH: Time-to-event analyses using multivariable proportional hazard regression models in a discovery-replication design, with external validation.RESULTS: 5,088 GCKD participants were included in analyses of urine metabolites and 5,144 in analyses of plasma metabolites. Among 182 unique metabolites, 30 were significantly associated with KF, 49 with CKE, and 163 with death. The strongest association with KF was observed for plasma hydroxyasparagine (hazard ratio: 1.95, 95% confidence interval: 1.68-2.25). An unnamed metabolite measured in plasma and urine was significantly associated with KF, CKE, and death. External validation of the identified associations of metabolites with KF or CKE revealed direction-consistency for 88% of observed associations. Selected associations of 18 metabolites with study outcomes have not been previously reported.LIMITATIONS: Use of observational data and semi-quantitative metabolite measurements at a single time point.CONCLUSIONS: The observed associations between metabolites and KF, CKE or death in persons with CKD confirmed previously reported findings and also revealed several associations not previously described. These findings warrant confirmatory research in other study cohorts.PMID:38815646 | DOI:10.1053/j.ajkd.2024.03.028

Environ Int. 2024 May 26;188:108778. doi: 10.1016/j.envint.2024.108778. Online ahead of print.ABSTRACTWith the discovery of evidence that many endocrine-disrupting chemicals (EDCs) in the environment influence human health, their toxic effects and mechanisms have become a hot topic of research. However, investigations into their endocrine-disrupting toxicity under combined binary exposure, especially the molecular mechanism of combined effects, have rarely been documented. In this study, two typical EDCs, perfluorooctanoic acid (PFOA) and 4-hydroxybenzophenone (4-HBP), were selected to examine their combined effects and molecular mechanism on MCF-7 cell proliferation at environmentally relevant exposure concentrations. We have successfully established a model to evaluate the binary combined toxic effects of endocrine disruptors, presenting combined effects in a simple and direct way. Results indicated that the combined effect changed from additive to synergistic from 1.25 × 10-8 M to 4 × 10-7 M. Metabolomics analyses suggested that exposure to PFOA and 4-HBP caused significant alterations in purine metabolism, arginine, and proline metabolism and had superimposed influences on metabolism. Enhanced combined effects were observed in glycine, serine, and threonine metabolic pathways compared to exposure to PFOS and 4-HBP alone. Additionally, the differentially expressed genes (DEGs) are primarily involved in Biological Processes, especially protein targeting the endoplasmic reticulum, and significantly impact the oxidative phosphorylation and thermogenesis-related KEGG pathway. By integrating metabolome and transcriptome analyses, PFOA and 4-HBP regulate purine metabolism, the TCA cycle, and endoplasmic reticulum protein synthesis in MCF-7 cells via mTORC1, which provides genetic material, protein, and energy for cell proliferation. Furthermore, molecular docking confirmed the ability of PFOA and 4-HBP to stably bind the estrogen receptor, indicating that they have different binding pockets. Collectively, these findings will offer new insights into understanding the mechanisms by which EDCs produce combined toxicity.PMID:38815467 | DOI:10.1016/j.envint.2024.108778

Leg Med (Tokyo). 2024 May 16;70:102461. doi: 10.1016/j.legalmed.2024.102461. Online ahead of print.ABSTRACTSARS-CoV-2 virus has become a worldwide pandemic causing millions of death. This severe disaster lead to a immense panic and stress all over the world. Several studies were dedicated to understand its mechanism, pathogenesis and spreading characteristics. By this way, scientists try to develop different therapy and diagnose strategies. For these reasons, several metabolomics, proteomics and genomics studies were also carried out to improve knowledge in this newly identified virus. In this study, we are aimed to explain the pathogenesis of SARS-CoV-2 exposure on postmortem COVID (+) patients via untargeted metabolomics analysis. To carry out this study, a Data Independent Acquisition SWATH method is optimized and performed. Vitreous samples were analyzed in both MS1 and MS2 ESI(+) mode. An orthogonal Partial Least Square Discriminant Analysis were performed for classification. It was observed that lipid metabolism, several amino acids and oxidative stress biomarkers were strongly affected due to high inflammation and possible cytokine storm.PMID:38815416 | DOI:10.1016/j.legalmed.2024.102461

Phytomedicine. 2024 May 23;130:155768. doi: 10.1016/j.phymed.2024.155768. Online ahead of print.ABSTRACTBACKGROUND: Polymyxin E is widely recognized as a last resort for treating multidrug-resistant gram-negative bacteria. Unfortunately, the effectiveness of polymyxin E is significantly reduced when treating life-threatening bacterial infections due to plasmid-mediated polymyxin E resistance. The synergistic effect of applying a polymyxin E adjuvant is a promising strategy for overcoming the growing threat of antibiotic-resistant pathogens.PURPOSE: To evaluate the synergistic effect of fisetin and polymyxin E on S. typhimurium infections in vivo and further elucidate the underlying mechanism of this effect.METHODS: The effect of combining fisetin and polymyxin E to treat mobilized colistin resistance-1-positive (MCR-1-positive) gram-negative bacteria in vitro was examined using various methods, such as checkerboard assays, growth curves and time‒kill curves. To elucidate the mechanism by which fisetin affects MCR-1, we employed ultraviolet (UV) absorption spectroscopy, thin layer chromatography (TLC), and western blot analysis to investigate its effect at the protein level. Subsequently, molecular dynamics simulations (MDS) and metabolomics analysis were utilized to determine the site of interaction between fisetin and MCR-1 as well as the potential pathways and mechanisms involved. A new nanoemulsion of fisetin was produced using high-pressure homogenization, and its stability was tested. Finally, two animal models of S. typhimurium HYM2 infection were established to evaluate the synergistic effect of polymyxin E and fisetin in vivo.RESULTS: Our study revealed that fisetin exhibited a synergistic effect when combined with polymyxin E against MCR-1-positive S. typhimurium. The TLC results demonstrated that fisetin could inhibit the phosphoethanolamine (PEA) transfer of the MCR-1 protein, thereby restoring the activity of polymyxin E in strains against MCR-1. The MDS analysis indicated robust and immediate binding between fisetin and the MCR-1 protein, with both hydrophobic and polar effects playing significant roles in determining the binding energy of the former. Metabolomic studies demonstrated that the addition of fisetin significantly modulated bacterial metabolites. Moreover, it effectively inhibited the activity of ABC transporters in bacteria, thereby mitigating bacterial drug resistance and enhancing the therapeutic efficacy of polymyxin E. Furthermore, in mouse and chick models of infection, intragastric administration of the fisetin nanoemulsion together with polymyxin E resulted in significant therapeutic benefits, including increased survival rates, reduced bacterial colonization, and decreased levels of inflammatory factors.CONCLUSION: Fisetin, an MCR-1 inhibitor and a promising synergistic partner of polymyxin E, has significant potential for clinical application in the treatment of S. typhimurium infections, particularly those resulting extensively from drug-resistant MCR-1-positive strains.PMID:38815408 | DOI:10.1016/j.phymed.2024.155768

Food Chem. 2024 May 21;454:139732. doi: 10.1016/j.foodchem.2024.139732. Online ahead of print.ABSTRACTThe spine grapes (Vitis davidii Foëx.) are wild grape species that grow in southern China, and can be used for table grapes, juicing and winemaking. To systematically investigate the flavor profiles of spine grapes, flavonoids and volatile compounds were detected in five spine grape varieties (Seputao, Ziqiu, Miputao, Tianputao and Baiputao) using HPLC-QqQ-MS/MS and GC-MS. The content of flavonoids highly depended on the variety, such as the total concentrations of anthocyanins (91.43-328.85 mg/kg FW) and flavonols (33.90 to 83.16 mg/kg FW). The volatile compounds with higher odor active value were selected to describe the aroma of spine grapes. Hexanal, (E)-2-hexenal and (E, Z)-2,6-nonadienal contributed to the higher herbaceous flavor to Baiputao and Ziqiu. β-Damascenone and (E)-2-nonenal gave Baiputao a flavor with more floral, fruity and earthy. Their characteristic flavor compounds were subsequently revealed using multivariate statistical analysis. The results helped producers to further develop and utilize the spine grapes.PMID:38815327 | DOI:10.1016/j.foodchem.2024.139732

Adv Rheumatol. 2024 May 30;64(1):44. doi: 10.1186/s42358-024-00382-y.ABSTRACTOBJECTIVES: Research has demonstrated that obesity may be associated with rheumatoid arthritis (RA). In addition, gut microbiota and its metabolites contribute to the occurrence and development of RA and obesity. However, the mechanism by which obesity affects RA remains unclear. In this study, we aimed to investigate whether gut microbiota and their metabolites alter the effects of high fat diet (HFD) on the severity of collagen-induced arthritis (CIA) in mice.METHODS: Briefly, mice were divided into normal group (N), CIA model group (C), HFD group (T), and HFD CIA group (CT). Hematoxylin and Eosin staining(HE) and Safranin O-fast green staining were conducted, and levels of blood lipid and inflammatory cytokines were measured. 16S rDNA sequencing technique and liquid chromatography-mass spectrometry (LC-MS)-based metabolomics were performed to explore changes in the microbiota structure to further reveal the pathomechanism of HFD on CIA.RESULTS: HFD aggravated the severity of CIA in mice. The CT group had the highest proportion of microbial abundance of Blautia, Oscillibacter, Ruminiclostridium-9, and Lachnospiraceae UCG 006 at the genus level, but had a lower proportion of Alistipes. Additionally, the fecal metabolic phenotype of the combined CT group shows significant changes, with differential metabolites enriched in 9 metabolic pathways, including primary bile acid biosynthesis, arginine biosynthesis, sphingolipid metabolism, purine metabolism, linoleic acid metabolism, oxytocin signaling pathway, aminoacyl-tRNA biosynthesis, the pentose phosphate pathway, and sphingolipid signaling pathway. Correlation analysis revealed that some of the altered gut microbiota genera were strongly correlated with changes in fecal metabolites, total cholesterol (TC), triglyceride (TG), and inflammatory cytokine levels.CONCLUSIONS: This study shows that HFD may aggravate inflammatory reaction in CIA mice by altering the gut microbiota and metabolic pathways.PMID:38816873 | DOI:10.1186/s42358-024-00382-y

Nat Aging. 2024 May 30. doi: 10.1038/s43587-024-00642-y. Online ahead of print.ABSTRACTIt has been reported that accumulation of senescent cells in various tissues contributes to pathological aging and that elimination of senescent cells (senolysis) improves age-associated pathologies. Here, we demonstrate that inhibition of sodium-glucose co-transporter 2 (SGLT2) enhances clearance of senescent cells, thereby ameliorating age-associated phenotypic changes. In a mouse model of dietary obesity, short-term treatment with the SGLT2 inhibitor canagliflozin reduced the senescence load in visceral adipose tissue and improved adipose tissue inflammation and metabolic dysfunction, but normalization of plasma glucose by insulin treatment had no effect on senescent cells. Canagliflozin extended the lifespan of mice with premature aging even when treatment was started in middle age. Metabolomic analyses revealed that short-term treatment with canagliflozin upregulated 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, enhancing immune-mediated clearance of senescent cells by downregulating expression of programmed cell death-ligand 1. These findings suggest that inhibition of SGLT2 has an indirect senolytic effect by enhancing endogenous immunosurveillance of senescent cells.PMID:38816549 | DOI:10.1038/s43587-024-00642-y

Transl Psychiatry. 2024 May 30;14(1):229. doi: 10.1038/s41398-024-02948-2.ABSTRACTDepression is a prevalent mental disorder with a complex biological mechanism. Following the rapid development of systems biology technology, a growing number of studies have applied proteomics and metabolomics to explore the molecular profiles of depression. However, a standardized resource facilitating the identification and annotation of the available knowledge from these scattered studies associated with depression is currently lacking. This study presents ProMENDA, an upgraded resource that provides a platform for manual annotation of candidate proteins and metabolites linked to depression. Following the establishment of the protein dataset and the update of the metabolite dataset, the ProMENDA database was developed as a major extension of its initial release. A multi-faceted annotation scheme was employed to provide comprehensive knowledge of the molecules and studies. A new web interface was also developed to improve the user experience. The ProMENDA database now contains 43,366 molecular entries, comprising 20,847 protein entries and 22,519 metabolite entries, which were manually curated from 1370 human, rat, mouse, and non-human primate studies. This represents a significant increase (more than 7-fold) in molecular entries compared to the initial release. To demonstrate the usage of ProMENDA, a case study identifying consistently reported proteins and metabolites in the brains of animal models of depression was presented. Overall, ProMENDA is a comprehensive resource that offers a panoramic view of proteomic and metabolomic knowledge in depression. ProMENDA is freely available at https://menda.cqmu.edu.cn .PMID:38816410 | DOI:10.1038/s41398-024-02948-2

Sci Rep. 2024 May 30;14(1):12431. doi: 10.1038/s41598-024-62163-3.ABSTRACTPulmonary arterial hypertension (PAH) is a fatal disease featured by high morbidity and mortality. Although Cordycepin is known for its anti-inflammatory, antioxidant and immune-enhancing effects, its role in PAH treatment and the underlying mechanisms remain unclear. The therapeutic effects of Cordycepin on rats with PAH were investigated using a monocrotaline (MCT)-induced rat model. The metabolic effects of Cordycepin were assessed based on the plasma metabolome. The potential mechanisms of Cordycepin in PAH treatment were investigated through transcriptome sequencing and validated in pulmonary artery smooth muscle cells (PASMC). Evaluations included hematoxylin and eosin staining for pulmonary vascular remodeling, CCK-8 assay, EDU, and TUNEL kits for cell viability, proliferation, and apoptosis, respectively, and western blot for protein expression. Cordycepin significantly reduced right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI) in PAH rats, and mitigated pulmonary vascular remodeling. Plasma metabolomics showed that Cordycepin could reverse the metabolic disorders in the lungs of MCT-induced PAH rats, particularly impacting linoleic acid and alpha-linolenic acid metabolism pathways. Transcriptomics revealed that the P53 pathway might be the primary pathway involved, and western blot results showed that Cordycepin significantly increased P53 and P21 protein levels in lung tissues. Integrated analysis of transcriptomics and metabolomics suggested that these pathways were mainly enriched in linoleic acid metabolism and alpha-linolenic acid metabolism pathway. In vitro experiments demonstrated that Cordycepin significantly inhibited the PDGFBB (PD)-induced abnormal proliferation and migration of PASMC and promoted PD-induced apoptosis. Meanwhile, Cordycepin enhanced the expression levels of P53 and P21 proteins in PD-insulted PASMC. However, inhibitors of P53 and P21 eliminated these effects of Cordycepin. Cordycepin may activate the P53-P21 pathway to inhibit abnormal proliferation and migration of PASMC and promote apoptosis, offering a potential approach for PAH treatment.PMID:38816406 | DOI:10.1038/s41598-024-62163-3

Phytochem Anal. 2024 May 30. doi: 10.1002/pca.3395. Online ahead of print.ABSTRACTINTRODUCTION: The fruit wastes, in particular agricultural wastes, are considered potential and inexpensive sources of bioactive compounds.OBJECTIVE: The current study was aimed at the preparation of an optimized extract of sugarcane bagasse using microwave-assisted extraction (MAE) technology and comparative evaluation of chemical composition, antioxidant, and antidiabetic activities with extract prepared through maceration technique.METHODOLOGY: Box-Behnken Design (BDD) with response surface methodology was applied to observe interactions of three independent variables (ethanol concentrations [%], microwave power [W], and extraction time [min]) on the dependent variables (total phenolic content [TPC] and antioxidant status via 2,2-diphenyl-1-picrylhydrazyl [DPPH] to establish optimal extraction conditions. The ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) analysis was applied for untargeted metabolite profiling, and in vitro assays were used for evaluation of the antidiabetic and antioxidant potential of the extract. Moreover, an in silico study was used to predict the interaction of five dominant compounds from the UHPLC-Q-TOF-MS profile against the dipeptidyl peptidase-IV (DPP-IV) enzyme.RESULTS: The optimal conditions for the extraction were established at 60% (v/v) ethanol, 500 W microwave power, and 5 min time with TPC 12.83 ± 0.66 mg GAE/g d.w. and DPPH 45.09 ± 0.07%. The UHPLC-Q-TOF-MS analysis revealed the presence of a total of 106 compounds in the extract. Moreover, the extract prepared through MAE technology presented higher TPC and DPPH findings than the extract prepared through maceration. Similarly, the extract was also found with good antidiabetic activity by inhibiting the DPP-IV enzyme which was also rectified theoretically by a molecular docking study.CONCLUSION: The current study presents a sustainable and an optimized approach for the preparation of sugarcane bagasse extract with functional phytoconstituents and higher antidiabetic and antioxidant activities.PMID:38816275 | DOI:10.1002/pca.3395

PLoS One. 2024 May 30;19(5):e0302977. doi: 10.1371/journal.pone.0302977. eCollection 2024.ABSTRACTBACKGROUND: After its emergence in China, the coronavirus SARS-CoV-2 has swept the world, leading to global health crises with millions of deaths. COVID-19 clinical manifestations differ in severity, ranging from mild symptoms to severe disease. Although perturbation of metabolism has been reported as a part of the host response to COVID-19 infection, scarce data exist that describe stage-specific changes in host metabolites during the infection and how this could stratify patients based on severity.METHODS: Given this knowledge gap, we performed targeted metabolomics profiling and then used machine learning models and biostatistics to characterize the alteration patterns of 50 metabolites and 17 blood parameters measured in a cohort of 295 human subjects. They were categorized into healthy controls, non-severe, severe and critical groups with their outcomes. Subject's demographic and clinical data were also used in the analyses to provide more robust predictive models.RESULTS: The non-severe and severe COVID-19 patients experienced the strongest changes in metabolite repertoire, whereas less intense changes occur during the critical phase. Panels of 15, 14, 2 and 2 key metabolites were identified as predictors for non-severe, severe, critical and dead patients, respectively. Specifically, arginine and malonyl methylmalonyl succinylcarnitine were significant biomarkers for the onset of COVID-19 infection and tauroursodeoxycholic acid were potential biomarkers for disease progression. Measuring blood parameters enhanced the predictive power of metabolic signatures during critical illness.CONCLUSIONS: Metabolomic signatures are distinctive for each stage of COVID-19 infection. This has great translation potential as it opens new therapeutic and diagnostic prospective based on key metabolites.PMID:38814977 | DOI:10.1371/journal.pone.0302977

PLoS One. 2024 May 30;19(5):e0303500. doi: 10.1371/journal.pone.0303500. eCollection 2024.ABSTRACTUntargeted metabolomics investigations have characterized metabolic disturbances associated with various diseases in domestic cats. However, the pre-analytic stability of serum metabolites in the species is unknown. Our objective was to compare serum metabolomes from healthy cats stored at -20°C for up to 12 months to samples stored at -80°C. Serum samples from 8 adult, healthy cats were stored at -20°C for 6 months, -20°C for 12 months, or -80°C for 12 months. Untargeted liquid chromatography-mass spectrometry was used to generate serum metabolite profiles containing relative abundances of 733 serum metabolites that were compared among storage conditions. Unsupervised analysis with principal component analysis and hierarchical clustering of Euclidian distances revealed separation of samples from individual cats regardless of storage condition. Linear mixed-effects models identified 75 metabolites that differed significantly among storage conditions. Intraclass correlation analysis (ICC) classified most serum metabolites as having excellent (ICC ≥ 0.9; 33%) or moderate (ICC 0.75-0.89; 33%) stability, whereas 13% had poor stability (ICC < 0.5). Biochemicals that varied significantly among storage conditions and classified with poor stability included glutathione metabolites, amino acids, gamma-glutamyl amino acids, and polyunsaturated fatty acids. The benzoate; glycine, serine and threonine; tryptophan; chemical (xenobiotics); acetylated peptide, and primary bile acid sub pathways were enriched among highly stable metabolites, whereas the monohydroxy fatty acid, polyunsaturated fatty, and monoacylglycerol sub-pathways were enriched among unstable metabolites. Our findings suggest that serum metabolome profiles are representative of the cat of origin, regardless of storage condition. However, changes in specific serum metabolites, especially glutathione, gamma-glutamyl amino acid, and fatty acid metabolites were consistent with increased sample oxidation during storage at -20°C compared with -80°C. By investigating the pre-analytic stability of serum metabolites, this investigation provides valuable insights that could aid other investigators in planning and interpreting studies of serum metabolomes in cats.PMID:38814947 | DOI:10.1371/journal.pone.0303500

PLoS One. 2024 May 30;19(5):e0304574. doi: 10.1371/journal.pone.0304574. eCollection 2024.ABSTRACTBACKGROUND: The prevalence of gastrointestinal tumors continues to be significant. To uncover promising therapeutic targets for these tumors, we rigorously executed a Mendelian randomization (MR) study to comprehensively screen the blood metabolomes for potential causal mediators of five frequently encountered gastrointestinal tumors (Liver Cancer, Colorectal Cancer, Esophageal Cancer, Gastric Cancer and Pancreatic Cancer).METHODS: We selected a comprehensive set of 137 distinct blood metabolites derived from three large-scale genome-wide association studies (GWASs) involving a total of 147827 participants of European ancestry. The gastrointestinal tumors-related data were obtained from a GWAS conducted within the Finnish study. Through meticulous MR analyses, we thoroughly assessed the associations between blood metabolites and gastrointestinal tumors. Additionally, a phenome-wide MR (Phe-MR) analysis was employed to investigate the potential on-target side effects of metabolite interventions.RESULTS: We have identified 1 blood metabolites, namely isovalerylcarnitine (ORlog10: 1.01; 95%CI, 1.01-1.02; P = 1.81×10-7), as the potential causal mediators for liver cancer. However, no potential pathogenic mediators were detected for the other four tumors.CONCLUSIONS: The current systematic MR analysis elucidated the potential role of isovalerylcarnitine as a causal mediator in the development of liver cancer. Leveraging the power of Phe-MR study facilitated the identification of potential adverse effects associated with drug targets for liver cancer prevention. Considering the weighing of pros and cons, isovalerylcarnitine emerges as a promising candidate for targeted drug interventions in the realm of liver cancer prevention.PMID:38814898 | DOI:10.1371/journal.pone.0304574

Mol Microbiol. 2024 May 30. doi: 10.1111/mmi.15279. Online ahead of print.ABSTRACTTrypanosoma cruzi, a flagellated protozoan, is the causative agent of Chagas disease. The parasite has developed various mechanisms to get through its intricate life cycle and adapt to different evolutionary phases. T. cruzi proliferates in the insect vector's digestive tract as an epimastigote form, encountering fluctuating nutrient availability and oxidative stress caused by the digestion of red blood cells from the mammalian host blood meal. To unravel how the parasite's metabolism adapts to these changing conditions, we conducted an analysis of the chemical species present in epimastigote forms. This involved comparing cultured parasites with those subjected to nutritional deficiency or oxidative stress using untargeted metabolomics. We looked at 21 samples: seven biological copies of parasites that were actively growing, seven samples that were put in a medium without nutrients for 3 h, and seven samples that were treated with glucose oxidase for 30 min to make H2O2 continuously. Importantly, in all conditions, parasite viability was maintained when the samples were collected. Upon nutrient removal, we observed a substantial decrease in amino acids and carbohydrate metabolites, accompanied by the accumulation of fatty acids and steroids, with the predominance of inositol and sphingolipid metabolism, along with a simultaneous decrease in the levels of H2O2. In the presence of H2O2, a significant rise in components of the pentose pathway and specific amino acids such as methionine and serine occurred, along with pathways related to an increase in antioxidant species metabolism such as ribulose 5-phosphate and glyceric acid. Conversely, fatty acid and steroid levels decrease. We found no common increase in metabolites or lipids. In contrast, eight species (succinic acid, glutamic acid, valine, 2-hydroxyisocaproic acid, alanine, indolelactic acid, proline, and lanosterol) were consumed under both stresses. These findings underscore the rapid and distinct enrichment responses in amino acids, lipids, and carbohydrates required to cope with each different environmental condition. We concluded that T. cruzi presents a flexible metabolism that rapidly adapts to variable changes in the environment.PMID:38814666 | DOI:10.1111/mmi.15279