PubMed

Rapid Commun Mass Spectrom. 2024 Sep 30;38(18):e9857. doi: 10.1002/rcm.9857.ABSTRACTRATIONAL: Aconiti Lateralis Radix Praeparata (AC) is a traditional Chinese medicine with a long history of use. However, the current research on the material basis of AC and its processed products is still not comprehensive, especially the changes in lipo-diterpenoid alkaloids (LDAs) that can be hydrolyzed into diester-diterpenoid alkaloids in AC before and after processing. This study aimed to provide material basis guidance for the clinical use of AC and its processed products by comprehensively analyzing the changes in substances between AC and its processed products.METHODS: An ultra-high-performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UHPLC/Q-TOF-MS/MS) approach was optimized to chemical profiling. The MS data were processed using molecular networking combined with the in-house library database to fast characterize the compounds. Multivariate statistical methods were adopted to determine the dissimilarities of components in AC and its processed products.RESULTS: A total of 310 compounds were tentatively identified from AC, including 109 potential new alkaloids, of which 98 were potential novel LPAs. A metabolomics approach was applied to find the characteristic marker components. As a result, 52 potential chemical markers were selected to distinguish the AC samples of different extraction methods and 42 potential chemical markers for differentiating between AC and its processed products were selected.CONCLUSION: The results indicate that UHPLC/Q-TOF-MS/MS and Global Natural Products Social Molecular Networking coupled with multivariate analysis strategies was a powerful tool to rapidly identify and screen the chemical markers of alkaloids between the AC samples and its processed products. These results also indicate that the toxicity of water extracts of AC and its processed products were decreased. This research not only guides the clinical safe use of AC and its processed products, but also extends the application of the molecular networking strategy in traditional herbal medicine.PMID:39022839 | DOI:10.1002/rcm.9857

Front Plant Sci. 2024 Jul 3;15:1408731. doi: 10.3389/fpls.2024.1408731. eCollection 2024.ABSTRACTThe Mediterranean will be one of the focal points of climate change. The predicted dry and hot summers will lead to water scarcity in agriculture, which may limit crop production and growth. The olive tree serves as a model woody plant for studying drought stress and improving water resource management; thus, it is critical to identify genotypes that are more drought tolerant and perform better under low irrigation or even rainfed conditions. In this study, the metabolomic approach was used to highlight variations in metabolites in stems and leaves of three Italian olive cultivars (previously characterized physiologically) under two and four weeks of drought stress. Phenolic and lipophilic profiles were obtained by gas chromatography-mass spectrometry and ultra-high performance liquid chromatography-mass spectrometry, respectively. The findings identified the leaf as the primary organ in which phenolic variations occurred. The Maurino cultivar exhibited a strong stress response in the form of phenolic compound accumulation, most likely to counteract oxidative stress. The phenolic compound content of 'Giarraffa' and 'Leccino' plants remained relatively stable whether they were exposed to drought or not. Variations in the lipid profile occurred in leaves and stems of all the cultivars. A high accumulation of compounds related to epicuticular wax components was observed in the leaf of 'Giarraffa', while a strong reduction of lipids and long-chain alkanes occurred in 'Maurino' when exposed to drought stress conditions.PMID:39022609 | PMC:PMC11251969 | DOI:10.3389/fpls.2024.1408731

Front Plant Sci. 2024 Jul 3;15:1392460. doi: 10.3389/fpls.2024.1392460. eCollection 2024.ABSTRACTEchinochloa glabrescens Munro ex Hook. f. is a weed of the genus Echinocloa (Echinocloa spp.) that occurs frequently in paddy fields, causing serious harm to rice production. Florpyrauxifen-benzyl (FPB) is a foliar-applied herbicide used to control Echinocloa spp. in paddy fields. However, in recent years, with the widespread use of FPB in rice production, FPB-resistant barnyard grasses have been reported. Here, we identified an FPB-resistant E. glabrescens population with a resistance index (RI) of 10.65 and conducted a comparative analysis using untargeted metabolomics and transcriptomics to investigate the differences between an FPB-resistant E. glabrescens population and a susceptible E. glabrescens population after treatment with the recommended field dose of FPB. Our results showed that the FPB-resistant E. glabrescens had 115 differentially accumulated metabolites (DAMs; 65 up-regulated and 50 down-regulated) and 6397 differentially expressed genes (DEGs; 65 up-regulated and 50 down-regulated) compared to the susceptible E. glabrescens. The analysis of DAMs and DEGs revealed that DAMs were significantly enriched in Glutathione metabolism, Arginine and proline metabolism, and Zeatin biosynthesis pathways, while DEGs were mainly enriched in carbon fixation in photosynthetic organisms, photosynthesis, cyanoamino acid metabolism and glutathione metabolism, etc. The glutathione metabolism pathway was found to be significantly enriched for both DEGs and DAMs. Within this pathway, the metabolites (spermine) and genes (GSTU8, GSTU18, GSTF1) may play a pivotal role in the resistance mechanism of FPB-resistant E. glabrescens. Furthermore, we demonstrated the presence of GST-mediated metabolic resistance in an FPB-resistant E. glabrescens population by using NBD-Cl. Overall, our study provides new insights into the underlying mechanisms of E. glabrescens resistance to FPB through a comparative analysis of untargeted metabolomics and transcriptomics. Additionally, we identified the GST-mediated metabolic resistance in an FPB-resistant E. glabrescens population, and screened for three candidate genes (GSTU8, GSTU18, GSTF1), which has significant implications for improving the weed management efficacy of FPB in rice production and guiding judicious herbicide usage.PMID:39022606 | PMC:PMC11253777 | DOI:10.3389/fpls.2024.1392460

ACS Pharmacol Transl Sci. 2024 Jul 1;7(7):2185-2195. doi: 10.1021/acsptsci.4c00238. eCollection 2024 Jul 12.ABSTRACTHigh-grade serous ovarian cancer is the most common and lethal gynecologic malignancy, which is often attributed to the lack of available screenings, allowing the disease to progress unnoticed until it is diagnosed at more aggressive stages. As such, identifying signals in the tumor microenvironment involved in the primary metastasis of tumorigenic fallopian tube epithelial (FTE) cells to the ovary could provide new avenues for prevention, diagnostics, or therapeutic intervention. Since our previous work identified that the interaction of tumorigenic FTE and the ovary causes the release of norepinephrine (NE) from the ovary, we intended to determine the effects of ovarian NE on signaling and invasion of tumorigenic FTE models and high-grade serous ovarian cancer cell lines. We demonstrate that NE does not universally enhance migration, invasion, or adhesion by using multiple cell types but does alter specific oncogenic protein expression in certain models. In vivo, we found that blocking NE signaling via slow-release propranolol pellets significantly increased survival time in mice injected intraperitoneally with murine FTE cells engineered to stably express shRNA for PTEN and an activated KRAS expression construct. Finally, we identified that the metabolome released from the ovary is variable depending upon which cell type it is cocultured with, suggesting that distinct driver mutations in fallopian tube epithelial tumor models and early lesions can alter specific metabolomes within the surrounding ovarian microenvironment. These metabolomes provide the next frontier for evaluating local signals of the tumor microenvironment that facilitate ovarian spread of FTE lesions.PMID:39022349 | PMC:PMC11249642 | DOI:10.1021/acsptsci.4c00238

Euroasian J Hepatogastroenterol. 2024 Jan-Jun;14(1):30-34. doi: 10.5005/jp-journals-10018-1416.ABSTRACTBACKGROUND: Cystic echinococcosis (CE) is a parasitic zoonosis caused by the tapeworm Echinococcus granulosus. Over the past few years, a lot of research has been done on liver illnesses using metabolomics techniques to identify biomarkers which could identify the diseases in its early stages. The present study was done to explore biomarkers in serum, urine, and cystic fluid which would help in differentiating, staging, and assessing fertility of intra-abdominal hydatid cyst by using proton nuclear magnetic resonance (1H NMR) metabolomics.MATERIALS AND METHODS: In the study, 28 subjects (16 cases and 12 controls) were enrolled. Staging of hydatid cysts was performed using ultrasonography. In patients complying with case and control definition, blood, urine, and cystic fluid were collected for complete blood count, urine culture, Echinococcus IgG enzyme-linked immunosorbent assay (ELISA), and metabolomic analysis. The 17, 15, and 11 metabolites in serum, urine, and cystic fluid samples were quantified, respectively, to differentiate between case and control group.RESULTS: In this study, we observed that there was a significant downregulation of succinate metabolite in urine samples of cases, down-regulation of five metabolites (isoleucine, valine, histidine, tyrosine and formate) and upregulation of alanine in cystic fluid of cases.CONCLUSION: Current study demonstrates that metabolomics can be used non-invasively for rapid diagnosis of CE. This is one of the very few studies, which used 1H NMR spectroscopy, to analyze the profile of metabolites in serum, urine, and cystic fluid in cases of CE and controls.HOW TO CITE THIS ARTICLE: Raj N, Pandey A, Roy R, et al. Proton Nuclear Magnetic Resonance (1H NMR) Metabolomics Study in Serum, Urine, and Cystic Fluid for Differentiating Fertility and Staging of Intra-abdominal Hydatid Cyst in Adults. Euroasian J Hepato-Gastroenterol 2024;14(1):30-34.PMID:39022208 | PMC:PMC11249894 | DOI:10.5005/jp-journals-10018-1416

Genes Dis. 2023 Nov 7;11(5):101161. doi: 10.1016/j.gendis.2023.101161. eCollection 2024 Sep.ABSTRACTAging is a contributor to liver disease. Hence, the concept of liver aging has become prominent and has attracted considerable interest, but its underlying mechanism remains poorly understood. In our study, the internal mechanism of liver aging was explored via multi-omics analysis and molecular experiments to support future targeted therapy. An aged rat liver model was established with d-galactose, and two other senescent hepatocyte models were established by treating HepG2 cells with d-galactose and H2O2. We then performed transcriptomic and metabolomic assays of the aged liver model and transcriptome analyses of the senescent hepatocyte models. In livers, genes related to peroxisomes, fatty acid elongation, and fatty acid degradation exhibited down-regulated expression with aging, and the hepatokine Fgf21 expression was positively correlated with the down-regulation of these genes. In senescent hepatocytes, similar to the results found in aged livers, FGF21 expression was also decreased. Moreover, the expressions of cell cycle-related genes were significantly down-regulated, and the down-regulated gene E2F8 was the key cell cycle-regulating transcription factor. We then validated that FGF21 overexpression can protect against liver aging and that FGF21 can attenuate the declines in the antioxidant and regenerative capacities in the aging liver. We successfully validated the results from cellular and animal experiments using human liver and blood samples. Our study indicated that FGF21 is an important target for inhibiting liver aging and suggested that pharmacological prevention of the reduction in FGF21 expression due to aging may be used to treat liver aging-related diseases.PMID:39022127 | PMC:PMC11252782 | DOI:10.1016/j.gendis.2023.101161

R Soc Open Sci. 2024 Jul 17;11(7):240890. doi: 10.1098/rsos.240890. eCollection 2024 Jul.ABSTRACTPlant metabolism is a key feature of biodiversity that remains underexploited in functional frameworks used in agroecology. Here, we study how phytochemical diversity considered at three organizational levels can promote pest control. In a factorial field experiment, we manipulated plant diversity in three monocultures and three mixed crops of oilseed rape to explore how intra- and interspecific phytochemical diversity affects pest infestation. We combined recent progress in metabolomics with classic metrics used in ecology to test a box of hypotheses grounded in plant defence theory. According to the hypothesis of 'phytochemically mediated coevolution', our study stresses the relationships between herbivore infestation and particular classes of specialized metabolites like glucosinolates. Among 178 significant relationships between metabolites and herbivory rates, only 20% were negative. At the plant level, phytochemical abundance and richness had poor predictive power on pest regulation. This challenges the hypothesis of 'synergistic effects'. At the crop cover level, in line with the hypothesis of 'associational resistance', the phytochemical dissimilarity between neighbouring plants limited pest infestation. We discuss the intricate links between associational resistance and bottom-up pest control. Bridging different levels of organization in agroecosystems helps to dissect the multi-scale relationships between phytochemistry and insect herbivory.PMID:39021775 | PMC:PMC11251780 | DOI:10.1098/rsos.240890

Front Nutr. 2024 Jul 3;11:1390223. doi: 10.3389/fnut.2024.1390223. eCollection 2024.ABSTRACTIn recent years there has been increased interest in identifying biological signatures of food consumption for use as biomarkers. Traditional metabolomics-based biomarker discovery approaches rely on multivariate statistics which cannot differentiate between host- and food-derived compounds, thus novel approaches to biomarker discovery are required to advance the field. To this aim, we have developed a new method that combines global untargeted stable isotope traced metabolomics and a machine learning approach to identify biological signatures of cruciferous vegetable consumption. Participants consumed a single serving of broccoli (n = 16), alfalfa sprouts (n = 16) or collard greens (n = 26) which contained either control unlabeled metabolites, or that were grown in the presence of deuterium-labeled water to intrinsically label metabolites. Mass spectrometry analysis indicated 133 metabolites in broccoli sprouts and 139 metabolites in the alfalfa sprouts were labeled with deuterium isotopes. Urine and plasma were collected and analyzed using untargeted metabolomics on an AB SCIEX TripleTOF 5,600 mass spectrometer. Global untargeted stable isotope tracing was completed using openly available software and a novel random forest machine learning based classifier. Among participants who consumed labeled broccoli sprouts or collard greens, 13 deuterium-incorporated metabolomic features were detected in urine representing 8 urine metabolites. Plasma was analyzed among collard green consumers and 11 labeled features were detected representing 5 plasma metabolites. These deuterium-labeled metabolites represent potential biological signatures of cruciferous vegetables consumption. Isoleucine, indole-3-acetic acid-N-O-glucuronide, dihydrosinapic acid were annotated as labeled compounds but other labeled metabolites could not be annotated. This work presents a novel framework for identifying biological signatures of food consumption for biomarker discovery. Additionally, this work presents novel applications of metabolomics and machine learning in the life sciences.PMID:39021604 | PMC:PMC11253721 | DOI:10.3389/fnut.2024.1390223

Comput Struct Biotechnol J. 2024 Jun 20;23:2623-2636. doi: 10.1016/j.csbj.2024.06.026. eCollection 2024 Dec.ABSTRACTThe rapid advancement of sequencing technologies has enabled the generation of vast datasets, allowing for the in-depth analysis of sequencing data. This analysis has facilitated the validation of novel pathogenesis hypotheses for understanding and treating diseases through ex vivo and in vivo experiments. Androgenetic alopecia (AGA), a common hair loss disorder, has been a key focus of investigators attempting to uncover its underlying mechanisms. Abnormal changes in mRNA, proteins, and metabolites have been identified in individuals with AGA, and future developments in sequencing technologies may reveal new biomarkers for AGA. By integrating multiple omics analysis datasets such as genomics, transcriptomics, proteomics, and metabolomics-along with clinical phenotype data-we can achieve a comprehensive understanding of the molecular underpinnings of AGA. This review summarizes the data-mining studies conducted on various omics analysis datasets as related to AGA that have been adopted to interpret the biological data obtained from different omics layers. We herein discuss the challenges of integrative omics analyses, and suggest that collaborative multi-omics studies can enhance the understanding of the complete pathomechanism(s) of AGA by focusing on the interaction networks comprising DNA, RNA, proteins, and metabolites.PMID:39021583 | PMC:PMC11253216 | DOI:10.1016/j.csbj.2024.06.026

Front Vet Sci. 2024 Jul 3;11:1396053. doi: 10.3389/fvets.2024.1396053. eCollection 2024.ABSTRACTThe nutritional benefits of mare milk are attracting increasing consumer interest. Limited availability due to low yield poses a challenge for widespread adoption. Although lysine and threonine are often used to enhance protein synthesis and muscle mass in horses, their impact on mare milk yield and nutrient composition remains underexplored. This study investigated the effects of lysine and threonine supplementation on 24 healthy Yili mares, mares at day 30 of lactation, over a 120-day period. The mares were divided into control and three experimental groups (six mares each) under pure grazing conditions. The control group received no amino acid supplementation, while experimental groups received varying daily doses of lysine and threonine: Group I (40 g lysine + 20 g threonine), Group II (60 g lysine + 40 g threonine), and Group III (80 g lysine + 60 g threonine). Supplementation in Group II notably increased milk yield, while Groups I and II showed higher milk fat percentages, and all experimental groups exhibited improved milk protein percentages. Additionally, blood levels of total protein, albumin, triglycerides, and glucose were reduced. Detailed analyses from Group II at peak lactation (day 60) included targeted metabolomics and microbial sequencing of milk, blood, and fecal samples. Amino acid metabolomics assessed amino acid content in mare milk and serum, while 16S rRNA gene sequencing evaluated rectal microbial composition. The results indicated that lysine and threonine supplementation significantly increased levels of threonine and creatine in the blood, and lysine, threonine, glutamine, and alanine in mare milk. Microbial analysis revealed a higher prevalence of certain bacterial families and genera, including Prevotellaceae, p_251_o5, and Rikenellaceae at the family level, and unclassified_p_251_o5, Prevotellaceae_UCG_001, and Rikenellaceae_RC9_gut_group at the genus level. Multi-omics analysis showed positive correlations between specific fecal genera and amino acids in mare milk. For instance, Prevotellaceae_UCG_003, unclassified Bacteroidetes_BS11_gut_group, and Corynebacterium were positively correlated with lysine, while unclassified Prevotellaceae was positively correlated with alanine and threonine, and Unclassified_Bacteroidales_BS11_gut_group was positively correlated with glutamine. In summary, lysine and threonine supplementation in grazing lactating mares enhanced milk production and improved milk protein and fat quality. It is recommended that herders, veterinarians, and technicians consider amino acid content in the diet of lactating mares. The optimal supplementation levels under grazing conditions for Yili horses were determined to be 60 g lysine and 40 g threonine per day. Future research should explore the molecular mechanisms by which these amino acids influence milk protein and lipid synthesis in mare mammary epithelial cells.PMID:39021407 | PMC:PMC11251924 | DOI:10.3389/fvets.2024.1396053

New Phytol. 2024 Jul 17. doi: 10.1111/nph.19973. Online ahead of print.ABSTRACTEven though they share many thematical overlaps, plant metabolomics and stable isotope ecology have been rather separate fields mainly due to different mass spectrometry demands. New high-resolution bioanalytical mass spectrometers are now not only offering high-throughput metabolite identification but are also suitable for compound- and intramolecular position-specific isotope analysis in the natural isotope abundance range. In plant metabolomics, label-free metabolic pathway and metabolic flux analysis might become possible when applying this new technology. This is because changes in the commitment of substrates to particular metabolic pathways and the activation or deactivation of others alter enzyme-specific isotope effects. This leads to differences in intramolecular and compound-specific isotope compositions. In plant isotope ecology, position-specific isotope analysis in plant archives informed by metabolic pathway analysis could be used to reconstruct and separate environmental impacts on complex metabolic processes. A technology-driven linkage between the two disciplines could allow to extract information on environment-metabolism interaction from plant archives such as tree rings but also within ecosystems. This would contribute to a holistic understanding of how plants react to environmental drivers, thus also providing helpful information on the trajectories of the vegetation under the conditions to come.PMID:39021246 | DOI:10.1111/nph.19973

J Agric Food Chem. 2024 Jul 17. doi: 10.1021/acs.jafc.4c04764. Online ahead of print.ABSTRACTFungi produce various bioactive secondary metabolites (SMs) as protective and weaponized tools to enhance survival in shared ecological niches. By mimicking a competitive ecosystem, cocultivation has been proven to be particularly successful in stimulating SM discovery. Here, we reported the identification of four novel metabolites, epiclactones A and B, epioxochromane and aoergostane, from the coculture of two biotechnologically important strains, Aspergillus oryzae and Epicoccum dendrobii. Transcriptome and metabolome analyses revealed widespread silent gene activation during fungal-fungal interaction. The majority of differentially expressed gene clusters were summarized for both strains. Based on these highly activated biosynthetic pathways, we suggested that a bidirectional chemical defense occurred under cocultivation. E. dendrobii enhanced the production of the spore inhibitor, fumigermin. Moreover, A. oryzae highly accumulated the antifungal agent kojic acid with a yield of up to 1.10 g/L. This study provides an excellent example for the discovery of hidden natural products by cocultivation.PMID:39020512 | DOI:10.1021/acs.jafc.4c04764

Drug Discov Ther. 2024 Jul 18. doi: 10.5582/ddt.2024.01035. Online ahead of print.ABSTRACTParkinson's disease (PD) is a complex multisystem neurodegenerative disease, and cognitive impairment is a common symptom in the trajectory of PD. Duzhong Fang (DZF) consists of Eucommia ulmoides, Dendrobium, Rehmanniae Radix, and Dried Ginger. Our previous study showed that DZF improves motor deficits in mice. However, whether DZF can ameliorate cognitive impairment in PD has not been reported. In this study, we established mice models of PD induced by rotenone and examined the effect of DZF on cognitive impairment in Parkinson's disease (PD-CI). The results confirmed that DZF treatment not only significantly improved the motor deficits in PD mice and decreased the loss of dopaminergic neurons, but also had significant effects in improving cognitive impairment. We further integrate serum metabolome and network pharmacology to explore the mechanisms by which DZF improves PD-CI. The results revealed that DZF can treat PD-CI by regulating sphingolipid metabolism to inhibit neuronal apoptotic pathway. In conclusion, preliminary studies confirmed that DZF contributes to the improvement of cognitive ability in PD, and our results provide a potential drug for the clinical treatment of PD and a theoretical foundation for DZF in clinical application.PMID:39019600 | DOI:10.5582/ddt.2024.01035

Clin Chim Acta. 2024 Jul 15:119873. doi: 10.1016/j.cca.2024.119873. Online ahead of print.ABSTRACTOBJECTIVE: Serum metabolites from 19 myasthenia gravis (MG) patients and 15 normal controls were analyzed via untargeted metabolomics, including 6 pre/post-treatment paired MG patients, to assess the value of serum metabolites as biomarkers in monitoring MG.METHOD: Differential metabolites between MG patients and normal controls were identified through liquid and gas chromatography-mass spectrometry simultaneously. Principal component analysis and orthogonal partial least squares-discriminant analysis were conducted to identify the differential metabolites. Candidate metabolites and pathways associated with MG were selected through a random forest machine learning model.RESULT: A total of 310 differential metabolites were identified with a threshold of variable projected importance > 1 and P value < 0.05. Among these, 158 metabolites were upregulated and 152 were downregulated. The random forest machine learning model selected 5 metabolites as potential biomarkers associated with MG: lignoceric acid (AUC=0.944), uridine diphosphate-N-acetylglucosamine (AUC=0.951), arachidonic acid (AUC=0.951), beta-glycerophosphoric acid (AUC=0.933), and L-Asparagine (AUC=0.877). Further analysis using 6 paired MG patients pre- and post-immunosuppression treatment revealed 25 upregulated and 6 downregulated metabolites in post-treatment serum, which might be relevant to disease intervention. The significance remains elusive due to the limited number of patients.CONCLUSION: A subset of differential metabolites was identified in the serum of MG patients, some of which changed with immunosuppressive therapy. Small molecule metabolites may serve as valuable biomarkers for disease monitoring in MG.PMID:39019424 | DOI:10.1016/j.cca.2024.119873

J Ethnopharmacol. 2024 Jul 15:118584. doi: 10.1016/j.jep.2024.118584. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Fuzheng-Qushi decoction (FZQS) is a practical Chinese herbal formula for relieving cough and fever. Therefore, the action and specific molecular mechanism of FZQS in the treatment of lung injury with cough and fever as the main symptoms need to be further investigated.AIMS OF THE STUDY: To elucidate the protective effects of FZQS against lung injury in mice and reveal its potential targets and key biological pathways for the treatment of lung injury based on transcriptomics, microbiomics, and untargeted metabolomics analyses.MATERIALS AND METHODS: Lipopolysaccharide (LPS) was used to induce a mouse model of lung injury, followed by the administration of FZQS. ELISA was used to detect IL-1β, IL-6, IL-17A, IL-4, IL-10, and TNF-α, in mouse lung tissues. Macrophage polarization and neutrophil activation were measured by flow cytometry. RNA sequencing (RNA-seq) was applied to screen for differentially expressed genes (DEGs) in lung tissues. RT-qPCR and Western blot assays were utilized to validate key DEGs and target proteins in lung tissues. 16S rRNA sequencing was employed to characterize the gut microbiota of mice. Metabolites in the gut were analyzed using untargeted metabolomics.RESULTS: FZQS treatment significantly ameliorated lung histopathological damage, decreased pro-inflammatory cytokine levels, and increased anti-inflammatory cytokine levels. M1 macrophage levels in the peripheral blood decreased, M2 macrophage levels increased, and activated neutrophils were inhibited in mice with LPS-induced lung injury. Importantly, transcriptomic analysis showed that FZQS downregulated macrophage and neutrophil activation and migration and adhesion pathways by reversing 51 DEGs, which was further confirmed by RT-qPCR and Western blot analysis. In addition, FZQS modulated the dysbiosis of the gut microbiota by reversing the abundance of Corynebacterium, Facklamia, Staphylococcus, Paenalcaligenes, Lachnoclostridium, norank_f_Muribaculaceae, and unclassified_f_Lachnospiraceae. Meanwhile, metabolomics analysis revealed that FZQS significantly regulated tryptophan metabolism by reducing the levels of 3-Indoleacetonitrile and 5-Hydroxykynurenine.CONCLUSION: FZQS effectively ameliorated LPS-induced lung injury by inhibiting the activation, migration, and adhesion of macrophages and neutrophils and modulating gut microbiota and its metabolites.PMID:39019418 | DOI:10.1016/j.jep.2024.118584

J Ethnopharmacol. 2024 Jul 15:118577. doi: 10.1016/j.jep.2024.118577. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Gynostemma pentaphyllum (Thunb.) Makino (G. pentaphyllum) is an oriental herb documented to treat many diseases, including obesity, hyperlipidemia, metabolic syndromes and aging. However, the anti-obesity mechanism of G. pentaphyllum remains poorly understood.AIM OF THE STUDY: To reveal the anti-obesity mechanism of G. pentaphyllum Extract (GPE) in High-Fat Diet (HFD)-induced obese mice through untargeted metabolomics, Real-Time Quantitative PCR (RT-qPCR), and immunohistochemical experiments. Additionally, to tentatively identify the active constituents through LC-MS/MS and molecular docking approaches.MATERIALS AND METHODS: GPE was prepared using ethanol reflux and purified by HP-20 macroporous resins. The components of GPE were identified by Liquid Chromatography- Mass Spectrometry (LC-MS) system. Forty-two C57BL/6J mice were randomly and evenly divided into six groups, with seven mice in each group: the control group, obese model group, Beinaglutide group (positive control), and GPE low, medium, and high-dose groups (50 mg/kg, 100 mg/kg, and 200 mg/kg of 80% ethanol extract). Body weight, liver weight, blood glucose, blood lipids, and liver histopathological changes were assessed. Untargeted metabolomics was employed to characterize metabolic changes in obese mice after GPE treatment. The expression of genes related to differential metabolites was verified using Real-Time Quantitative PCR (RT-qPCR) and immunohistochemical experiments. The constituents with anti-obesity effects from GPE were tentatively identified through molecular docking approaches.RESULTS: A total of 17 compounds were identified in GPE. GPE significantly lowered body weight, total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) in obese mice and reduced liver weight and hepatic steatosis. Serum metabolomics identified 33 potential biomarkers associated with GPE treatment in obese mice, primarily related to tryptophan metabolism. GPE treatment downregulated the expression of Slc6a19 and Tph1 and upregulated Ucp1 expression. Molecular docking illustrated that compounds such as 20(R)-ginsenoside Rg3, Araliasaponin I, Damulin B, Gypenoside L, Oleifolioside B, and Tricin7-neohesperidoside identified in GPE exhibited favorable interaction with Tph1.CONCLUSION: The extract of G. pentaphyllum can inhibit the absorption of tryptophan and its conversion to 5-HT through the Slc6a19/Tph1 pathway, upregulating the expression of Ucp1, thereby promoting thermogenesis in brown adipose tissue, facilitating weight loss, and mitigating symptoms of fatty liver. Triterpenoids such as Araliasaponin I, identified in GPE, could be the potential inhibitor of Tph1 and responsible for the anti-obesity activities.PMID:39019414 | DOI:10.1016/j.jep.2024.118577

J Proteomics. 2024 Jul 15:105259. doi: 10.1016/j.jprot.2024.105259. Online ahead of print.ABSTRACTThe present study investigated the urinary metabolic profiles of early pregnant and non-pregnant Mithun to identify potential pregnancy detection biomarkers. Urine samples were collected on days 0, 10, 18, 35 and 45 of gestation from pregnant (n = 6) and on days 0, 10 and 18 from non-pregnant (n = 6) Mithun. Urinary metabolites were assessed using proton nuclear magnetic resonance (1H NMR) spectroscopy and identified 270 metabolites. Statistical analyses demonstrated pronounced distinctions in metabolite profiles between pregnant and non-pregnant samples. Twenty-five metabolites that could discriminate between pregnant and non-pregnant Mithun based on Variable Importance in Projection (VIP) scores >1 were identified. Upon further examination of six metabolites (kynurenine, kynurenate, 3-hydroxykynurenine, quinolinate, tyrosine and leucine) identified with high VIP scores, ROC curve analyses demonstrated their significant predictive potential, with AUC values ranging between 0.50 and 0.85. Additionally, a combined panel of top 25 metabolites yielded an AUC value of 0.85. Pathway analysis identified seven potential metabolic pathway modulations during early gestation, with particular emphasis on phenylalanine, tyrosine and tryptophan biosynthesis, tryptophan pathway and pathways involved in the metabolism of various amino acids. In conclusion, kynurenine, kynurenate, 3-hydroxykynurenine, quinolinate, tyrosine, and leucine show promise as non-invasive urinary biomarkers for early pregnancy detection in Mithun. SIGNIFICANCE: This study presents the first report on the metabolic profile of urine from early pregnant and non-pregnant Mithun (Bos frontalis). The metabolites like kynurenine and its derivatives (kynurenate, 3-hydroxykynurenine and quinolinate), tyrosine and leucine were documented signature urinary metabolites associated with early pregnancy in Mithun. The identified combination of metabolites holds promise as predictive biomarkers for non-invasive urinary-based early pregnancy diagnostics in Mithun. In addition, this study identified changes in metabolic pathways that involve phenylalanine, tyrosine, tryptophan and related amino acids and biomarkers identified were either precursors or products within these metabolic pathways.PMID:39019397 | DOI:10.1016/j.jprot.2024.105259

Neurobiol Dis. 2024 Jul 15:106606. doi: 10.1016/j.nbd.2024.106606. Online ahead of print.ABSTRACTThe gut microbiota produces metabolites that enrich the host metabolome and play a part in host physiology, including brain functions. Yet the biological mediators of this gut-brain signal transduction remain largely unknown. In this study, the possible role of the gut microbiota metabolite indole, originating from tryptophan, was investigated. Oral administration of indole to simulate microbial overproduction of this compound in the gut consistently led to impaired locomotion and anxiety-like behaviour in both C3H/HeN and C57BL/6 J mice. By employing c-Fos protein expression mapping in mice, we observed a noticeable increase in brain activation within the dorsal motor nucleus of the vagus nerve (DMX) and the locus coeruleus (LC) regions in a dose-dependent manner. Further immune co-labelling experiments elucidated that the primary cells activated within the LC were tyrosine hydroxylase positive. To delve deeper into the mechanistic aspects, we conducted chemogenetic activation experiments on LC norepinephrine neurons with two doses of clozapine N-oxide (CNO). Low dose of CNO at 0.5 mg/kg induced no change in locomotion but anxiety-like behaviour, while high dose of CNO at 2 mg/kg resulted in locomotion impairment and anxiety-like behaviour. These findings support the neuroactive roles of indole in mediating gut-brain communication. It also highlights the LC as a novel hub in the gut-brain axis, encouraging further investigations.PMID:39019292 | DOI:10.1016/j.nbd.2024.106606

J Steroid Biochem Mol Biol. 2024 Jul 15:106585. doi: 10.1016/j.jsbmb.2024.106585. Online ahead of print.ABSTRACTAlzheimer's Disease (AD) is a neurodegenerative disorder characterized by cognitive decline and memory loss. Recent studies have suggested a potential role for steroid synthesis in AD pathology. This study investigated the co-localization of steroidogenic enzymes in neuronal cells, changes in enzyme expression in an AD mouse model, and steroid expressions in human AD samples. Additionally, we conducted a steroidomic metabolomics analysis and evaluated the effects of dehydroepiandrosterone sulfate (DHEAS) treatment in an AD mouse model. Immunofluorescence analysis revealed significant co-localization of cytochrome P450 family 17 subfamily A member 1 (CYP17A1) and steroidogenic acute regulatory protein (StAR) proteins with α-synuclein in presynaptic neurons, suggesting active steroid synthesis in these cells. Conversely, such co-localization was absent in astrocytes. In the AD mouse model, a marked decrease in the expression of steroidogenic enzymes (Cyp11a1, Cyp17a1, Star) was observed, especially in areas with amyloid beta plaque accumulation. Human AD and MS brain tissues showed similar reductions in StAR and CYP17A1 expressions. Steroidomic analysis indicated a downregulation of key steroids in the serum of AD patients. DHEAS treatment in AD mice resulted in improved cognitive function and reduced Aβ accumulation. Our findings indicate a neuron-specific pathway for steroid synthesis, potentially playing a crucial role in AD pathology. The reduction in steroidogenic enzymes and key steroids in AD models and human samples suggests that impaired steroid synthesis is a feature of neurodegenerative diseases. The therapeutic potential of targeting steroid synthesis pathways, as indicated by the positive effects of DHEAS treatment, warrants further investigation.PMID:39019196 | DOI:10.1016/j.jsbmb.2024.106585

Cancer Lett. 2024 Jul 15:217117. doi: 10.1016/j.canlet.2024.217117. Online ahead of print.ABSTRACTCancer cells rewire metabolism to sculpt the immune tumor microenvironment (TME) and propel tumor advancement, which intricately tied to post-translational modifications. Histone lactylation has emerged as a novel player in modulating protein functions, whereas little is known about its pathological role in pancreatic ductal adenocarcinoma (PDAC) progression. Employing a multi-omics approach encompassing bulk and single-cell RNA sequencing, metabolomics, ATAC-seq, and CUT&Tag methodologies, we unveiled the potential of histone lactylation in prognostic prediction, patient stratification and TME characterization. Notably, "LDHA-H4K12la-immuno-genes" axis has introduced a novel node into the regulatory framework of "metabolism-epigenetics-immunity," shedding new light on the landscape of PDAC progression. Furthermore, the heightened interplay between cancer cells and immune counterparts via Nectin-2 in liver metastasis with elevated HLS unraveled a positive feedback loop in driving immune evasion. Simultaneously, immune cells exhibited altered HLS and autonomous functionality across the metastatic cascade. Consequently, the exploration of innovative combination strategies targeting the metabolism-epigenetics-immunity axis holds promise in curbing distant metastasis and improving survival prospects for individuals grappling with challenges of PDAC.PMID:39019144 | DOI:10.1016/j.canlet.2024.217117