PubMed

PeerJ. 2024 May 20;12:e17414. doi: 10.7717/peerj.17414. eCollection 2024.ABSTRACTBACKGROUND: Sepsis-induced myocardial injury, as one of the important complications of sepsis, can significantly increase the mortality of septic patients. Our previous study found that nucleolin affected mitochondrial function in energy synthesis and had a protective effect on septic cardiomyopathy in mice. During sepsis, glucose metabolism disorders aggravated myocardial injury and had a negative effect on septic patients.OBJECTIVES: We investigated whether nucleolin could regulate glucose metabolism during endotoxemia-induced myocardial injury.METHODS: The study tested whether the nucleolin cardiac-specific knockout in the mice could affect glucose metabolism through untargeted metabolomics, and the results of metabolomics were verified experimentally in H9C2 cells. The ATP content, lactate production, and oxygen consumption rate (OCR) were evaluated.RESULTS: The metabolomics results suggested that glycolytic products were increased in endotoxemia-induced myocardial injury, and that nucleolin myocardial-specific knockout altered oxidative phosphorylation-related pathways. The experiment data showed that TNF-α combined with LPS stimulation could increase the lactate content and the OCR values by about 25%, and decrease the ATP content by about 25%. However, interference with nucleolin expression could further decrease ATP content and OCR values by about 10-20% and partially increase the lactate level in the presence of TNF-α and LPS. However, nucleolin overexpression had the opposite protective effect, which partially reversed the decrease in ATP content and the increase in lactate level.CONCLUSION: Down-regulation of nucleolin can exacerbate glucose metabolism disorders in endotoxemia-induced myocardial injury. Improving glucose metabolism by regulating nucleolin was expected to provide new therapeutic ideas for patients with septic cardiomyopathy.PMID:38784400 | PMC:PMC11114111 | DOI:10.7717/peerj.17414

Front Plant Sci. 2024 May 9;15:1413866. doi: 10.3389/fpls.2024.1413866. eCollection 2024.NO ABSTRACTPMID:38784061 | PMC:PMC11112109 | DOI:10.3389/fpls.2024.1413866

Front Pharmacol. 2024 May 9;15:1372449. doi: 10.3389/fphar.2024.1372449. eCollection 2024.ABSTRACTIschemia/reperfusion (IR) can induce deleterious responses such as apoptosis, inflammation, and oxidative stress; however, there are currently no efficient therapeutics to treat IR brain injury. Dragon's blood (DB) plays a significant role in treating ischemic stroke in China. Borneol (B) is an upper ushering drug that guides drugs to the target organs, including the brain. Therefore, we hypothesized that the combination of DB and B (DB + B) would provide cooperative therapeutic benefits for IR brain injury. To confirm this, we first investigated the protective effect of DB + B in an IR brain injury rat model using the modified neurological severity score (mNSS), infarction size measure, HE staining, and laser speckle contrast imaging. Then, we comprehensively evaluated the mechanism of DB + B in ameliorating IR brain injury based on RNA sequencing, serum untargeted metabolomics, and 16S rRNA sequencing. We have confirmed that DB + B enhanced the efficacy of the ischemic stroke treatment compared to DB or B alone for the first time. Our study provisionally confirms that the mechanism by which DB + B prevents IR brain injury is related to the maintenance of intestinal microecological balance and regulation of metabolic dysfunction, thereby suppressing inflammation and regulating immunity. DB + B may effectively regulate intestinal flora including o_Pseudomonadales, s_Bacteroides_caecimuris, o_unidentified_Bacilli, f-Pseudomonadaceae, and g-Pseudomonas, mainly regulate serum metabolites including improve the protective benefit of IR brain injury lysoPCs and lysoPEs, thus inhibiting TLR4/MyD88/NF-κB and IL-17 signing pathway to reduce inflammatory reactions. hat this mechanism is associated with the maintenance of intestinal flora balance and the regulation of metabolic dysfunction, thereby suppressing inflammation and regulating immunity. This provides scientific support for the clinical translation of DB + B in the prevention and treatment of ischemic stroke and establishes a basis for further investigation of its therapeutic mechanism.PMID:38783945 | PMC:PMC11112420 | DOI:10.3389/fphar.2024.1372449

Anal Chem. 2024 May 24. doi: 10.1021/acs.analchem.4c00630. Online ahead of print.ABSTRACTThe application of machine learning (ML) to -omics research is growing at an exponential rate owing to the increasing availability of large amounts of data for model training. Specifically, in metabolomics, ML has enabled the prediction of tandem mass spectrometry and retention time data. More recently, due to the advent of ion mobility, new ML models have been introduced for collision cross-section (CCS) prediction, but those have been trained with different and relatively small data sets covering a few thousands of small molecules, which hampers their systematic comparison. Here, we compared four existing ML-based CCS prediction models and their capacity to predict CCS values using the recently introduced METLIN-CCS data set. We also compared them with simple linear models and with ML models that used fingerprints as regressors. We analyzed the role of structural diversity of the data on which the ML models are trained with and explored the practical application of these models for metabolite annotation using CCS values. Results showed a limited capability of the existing models to achieve the necessary accuracy to be adopted for routine metabolomics analysis. We showed that for a particular molecule, this accuracy could only be improved when models were trained with a large number of structurally similar counterparts. Therefore, we suggest that current annotation capabilities will only be significantly altered with models trained with heterogeneous data sets composed of large homogeneous hubs of structurally similar molecules to those being predicted.PMID:38783786 | DOI:10.1021/acs.analchem.4c00630

J Microbiol Biotechnol. 2024 Apr 29;34(6):1-8. doi: 10.4014/jmb.2402.02021. Online ahead of print.ABSTRACTThe accumulating evidence substantiates the indispensable role of gut microbiota in modulating the pathogenesis of type 2 diabetes. Uncovering the intricacies of the mechanism is imperative in aiding disease control efforts. Revealing key bacterial species, their metabolites and/or metabolic pathways from the vast array of gut microorganisms can significantly contribute to precise treatment of the disease. With a high prevalence of type 2 diabetes in Inner Mongolia, China, we recruited volunteers from among the Mongolian population to investigate the relationship between gut microbiota and the disease. Fecal samples were collected from the Volunteers of Mongolia with Type 2 Diabetes group and a Control group, and detected by metagenomic analysis and untargeted metabolomics analysis. The findings suggest that Firmicutes and Bacteroidetes phyla are the predominant gut microorganisms that exert significant influence on the pathogenesis of type 2 diabetes in the Mongolian population. In the disease group, despite an increase in the quantity of most gut microbial metabolic enzymes, there was a concomitant weakening of gut metabolic function, suggesting that the gut microbiota may be in a compensatory state during the disease stage. β-Tocotrienol may serve as a pivotal gut metabolite produced by gut microorganisms and a potential biomarker for type 2 diabetes. The metabolic biosynthesis pathways of ubiquinone and other terpenoid quinones could be the crucial mechanism through which the gut microbiota regulates type 2 diabetes. Additionally, certain Clostridium gut species may play a pivotal role in the progression of the disease.PMID:38783719 | DOI:10.4014/jmb.2402.02021

Clin Transl Sci. 2024 May;17(5):e13828. doi: 10.1111/cts.13828.ABSTRACTAs a treatment for relapsed or refractory multiple myeloma (MM), carfilzomib has been associated with a significant risk of cardiovascular adverse events (CVAE). The goals of our study were to evaluate the metabolomic profile of MM patients to identify those at high risk prior to carfilzomib treatment and to explore the mechanisms of carfilzomib-CVAE to inform potential strategies to protect patients from this cardiotoxicity. Global metabolomic profiling was performed on the baseline and post-baseline plasma samples of 60 MM patients treated with carfilzomib-based therapy, including 31 who experienced CVAE, in a prospective cohort study. Baseline metabolites and post-baseline/baseline metabolite ratios that differ between the CVAE and no-CVAE patients were identified using unadjusted and adjusted methods. A baseline metabolomic risk score was created to stratify patients. We observed a lower abundance of tauroursodeoxycholic acid (T-UDCA) in CVAE patients at baseline (odds ratio [OR] = 0.47, 95% confidence interval [CI] = 0.21-0.94, p = 0.044) compared with the no-CVAE patients. A metabolite risk score was able to stratify patients into three risk groups. The area under the receiver-operating curve of the model with clinical predictors and metabolite risk score was 0.93. Glycochenodeoxycholic acid (OR = 0.56, 95% CI = 0.31-0.87, p = 0.023) was significantly lower in post-baseline/baseline ratios of CVAE patients compared with no-CVAE patients. Following metabolomic analysis, we created a baseline metabolite risk score that can stratify MM patients into different risk groups. The result also provided intriguing clues about the mechanism of carfilzomib-CVAE and potential cardioprotective strategies.PMID:38783568 | DOI:10.1111/cts.13828

J Cheminform. 2024 May 23;16(1):58. doi: 10.1186/s13321-024-00851-y.ABSTRACTEffective visualization of small molecules is paramount in conveying concepts and results in cheminformatics. Scalable vector graphics (SVG) are preferred for creating such visualizations, as SVGs can be easily altered in post-production and exported to other formats. A wide spectrum of software applications already exist that can visualize molecules, and customize these visualizations, in many ways. However, software packages that can output projected 3D models onto a 2D canvas directly as SVG, while being programmatically accessible from Python, are lacking. Here, we introduce CineMol, which can draw vectorized approximations of three-dimensional small molecule models in seconds, without triangulation or ray tracing, resulting in files of around 50-300 kilobytes per molecule model for compounds with up to 45 heavy atoms. The SVGs outputted by CineMol can be readily modified in popular vector graphics editing software applications. CineMol is written in Python and can be incorporated into any existing Python cheminformatics workflow, as it only depends on native Python libraries. CineMol also provides programmatic access to all its internal states, allowing for per-atom and per-bond-based customization. CineMol's capacity to programmatically create molecular visualizations suitable for post-production offers researchers and scientists a powerful tool for enhancing the clarity and visual impact of their scientific presentations and publications in cheminformatics, metabolomics, and related scientific disciplines.Scientific contributionWe introduce CineMol, a Python-based tool that provides a valuable solution for cheminformatics researchers by enabling the direct generation of high-quality approximations of two-dimensional SVG visualizations from three-dimensional small molecule models, all within a programmable Python framework. CineMol offers a unique combination of speed, efficiency, and accessibility, making it an indispensable tool for researchers in cheminformatics, especially when working with SVG visualizations.PMID:38783386 | DOI:10.1186/s13321-024-00851-y

Anal Chem. 2024 May 23. doi: 10.1021/acs.analchem.3c04436. Online ahead of print.ABSTRACTMetabolites from feces provide important insights into the functionality of the gut microbiome. As immediate freezing is not always feasible in gut microbiome studies, there is a need for sampling protocols that provide the stability of the fecal metabolome and microbiome at room temperature (RT). Here, we investigated the stability of various metabolites and the microbiome (16S rRNA) in feces collected in 95% ethanol (EtOH) and commercially available sample collection kits with specific preservatives OMNImet•GUT/OMNIgene•GUT. To simulate field-collection scenarios, the samples were stored at different temperatures at varying durations (24 h + 4 °C, 24 h RT, 36 h RT, 48 h RT, and 7 days RT) and compared to aliquots immediately frozen at -80 °C. We applied several targeted and untargeted metabolomics platforms to measure lipids, polar metabolites, endocannabinoids, short-chain fatty acids (SCFAs), and bile acids (BAs). We found that SCFAs in the nonstabilized samples increased over time, while a stable profile was recorded in sample aliquots stored in 95% EtOH and OMNImet•GUT. When comparing the metabolite levels between aliquots stored at room temperature and at +4 °C, we detected several changes in microbial metabolites, including multiple BAs and SCFAs. Taken together, we found that storing samples at RT and stabilizing them in 95% EtOH yielded metabolomic results comparable to those from flash freezing. We also found that the overall composition of the microbiome did not vary significantly between different storage types. However, notable differences were observed in the α diversity. Altogether, the stability of the metabolome and microbiome in 95% EtOH provided results similar to those of the validated commercial collection kits OMNImet•GUT and OMNIgene•GUT, respectively.PMID:38782403 | DOI:10.1021/acs.analchem.3c04436

J Proteome Res. 2024 May 23. doi: 10.1021/acs.jproteome.4c00049. Online ahead of print.ABSTRACTExtracellular chemical cues constitute much of the language of life among marine organisms, from microbes to mammals. Changes in this chemical pool serve as invisible signals of overall ecosystem health and disruption to this finely tuned equilibrium. In coral reefs, the scope and magnitude of the chemicals involved in maintaining reef equilibria are largely unknown. Processes involving small, polar molecules, which form the majority components of labile dissolved organic carbon, are often poorly captured using traditional techniques. We employed chemical derivatization with mass spectrometry-based targeted exometabolomics to quantify polar dissolved phase metabolites on five coral reefs in the U.S. Virgin Islands. We quantified 45 polar exometabolites, demonstrated their spatial variability, and contextualized these findings in terms of geographic and benthic cover differences. By comparing our results to previously published coral reef exometabolomes, we show the novel quantification of 23 metabolites, including central carbon metabolism compounds (e.g., glutamate) and novel metabolites such as homoserine betaine. We highlight the immense potential of chemical derivatization-based exometabolomics for quantifying labile chemical cues on coral reefs and measuring molecular level responses to environmental stressors. Overall, improving our understanding of the composition and dynamics of reef exometabolites is vital for effective ecosystem monitoring and management strategies.PMID:38782401 | DOI:10.1021/acs.jproteome.4c00049

Exp Neurol. 2024 May 21:114823. doi: 10.1016/j.expneurol.2024.114823. Online ahead of print.ABSTRACTThe established role of disturbances in the microbiota-gut-brain axis in the development of diabetic cognitive impairment (DCI) has long been recognized. It has shown the potential of Akkermansia muciniphila (A. muciniphila) in improving metabolic disorders and exerting anti-inflammatory effects. However, there remains a lack of comprehensive understanding regarding the specific effects and mechanisms underlying the treatment of DCI with A. muciniphila. This study aimed to evaluate the potential of A. muciniphila in alleviating DCI in db/db mice. Eleven-week-old db/db mice were administered either live or pasteurized A. muciniphila (5 × 109 CFU/200 μL) for a duration of eight weeks. Administering live A. muciniphila significantly ameliorated cognitive impairments, improved the synaptic ultrastructure, and inhibited hippocampal neuron loss in the CA1 and CA3 subregions in db/db mice. Both live and pasteurized A. muciniphila effectively mitigated neuroinflammation. Moreover, live A. muciniphila increased the relative abundance of Lactococcus and Staphylococcus, whereas pasteurized A. muciniphila increased the relative abundance of Lactobacillus, Prevotellaceae_UCG_001, and Alistipes. Supplementation of A. muciniphila also induced alterations in serum and brain metabolites, with a particular enrichment observed in tryptophan metabolism, glyoxylate and dicarboxylate metabolism, nitrogen metabolism, and pentose and glucuronate interconversions. Correlation analysis further demonstrated a direct and substantial correlation between the altered gut microbiota and the metabolites in the serum and brain tissue. In conclusion, the results indicate that live A. muciniphila demonstrated greater efficacy compared to pasteurized A. muciniphila. The observed protective effects of A. muciniphila against DCI are likely mediated through the neuroinflammation and microbiota-metabolites-brain axis.PMID:38782351 | DOI:10.1016/j.expneurol.2024.114823

J Ethnopharmacol. 2024 May 21:118346. doi: 10.1016/j.jep.2024.118346. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Pueraria lobata (Willd.) Ohwi is a typical medicinal and edible plant with a long application history in China and Southeast Asia. As a widely used traditional medicine, P. lobata exhibits the properties of anti-inflammatory, antipyretic, antioxidant, relieving cough and asthma. Particularly, the increasing evidence indicates that the P. lobata has the therapeutic effect on fibrotic-related diseases in terms of metabolic regulation. However, the mechanisms of P. lobata on pulmonary fibrosis (PF) has not been thoroughly explored.AIM OF THE STUDY: This study aimed to explore the effect of arginine metabolites of P. lobata againist PF model by integrating metabolomics and network pharmacology analysis. It might provide a new idea for the target finding of P. lobata anti-pulmonary fibrosis.MATERIALS AND METHODS: In this study, the Sprague Dawley (SD) rats were randomly divided into five experimental groups: saline-treated control group, bleomycin-induced fibrosis group, prednisolone acetate group, P. lobata 3.2 g/kg group and P. lobata 6.4 g/kg group. The therapeutic effect of P. lobata on bleomycin-induced PF in rats was evaluated by clinical symptoms such as lung function, body weight, hematoxylin eosin staining (HE), Masson staining and hydroxyproline assay. Next, the plasma metabolomics analysis was carried out by LC-MS to explore the pathological differences between the group of control, PF and P. lobata-treated rats. Then, the network pharmacology study coupled with experimental validation was conducted to analysis the results of metabolic research. We constructed the "component-target-disease" network of P. lobata in the treatment of PF. In addition, the molecular docking method was used to verify the interaction between potential active ingredients and core targets of P. lobata. Finally, we tested NOS2 and L-OT in arginine-related metabolic pathway in plasma of the rats by enzyme-linked immunosorbent assay (ELISA). Real-time PCR was performed to observe the level of TNF-α mRNA and MMP9 mRNA. And we tested the expression of TNF-α and MMP9 by Western blot analysis.RESULTS: Our findings revealed that P. lobata improved lung function and ameliorated the pathological symptoms, such as pathological damage, collagen deposition, and body weight loss in PF rats. Otherwise, the plasma metabolomics were employed to screen the differential metabolites of amino acids, lipids, flavonoids, arachidonic acid metabolites, glycoside, etc. Finally, we found that the arginine metabolism signaling mainly involved in the regulating of P. lobata on the treatment of PF rats. Furtherly, the network pharmacology predicted that the arginine metabolism pathway was contained in the top 20 pathways. Next, we integrated metabolomics and network pharmacology that identified NOS2, MMP9 and TNF-α as the P. lobata regulated hub genes by molecular docking. Importantly, it indicated a strong affinity between the puerarin and the NOS2. P. lobata attenuated TNF-α, MMP-9 and NOS2 levels, suppressed TNF-α and MMP-9 protein expression, and decreased L-OT and NOS2 content in PF rats. These results indicated that the effects of P. lobata may ameliorated PF via the arginine metabolism pathway in rats. Therefore, P. lobata may be a potential therapeutic agent to ameliorated PF.CONCLUSION: In this work, we used metabolomics and network pharmacology to explore the mechanisms of P. lobata in the treatment of PF. Finally, we confirmed that P. lobata alleviated BLM-induced PF in rats by regulating arginine metabolism pathway based on reducing the L-OT and NOS2-related signal molecular. The search for the biomarkers finding of arginine metabolism pathway revealed a new strategy for P. lobata in the treatment of PF.PMID:38782311 | DOI:10.1016/j.jep.2024.118346

J Ethnopharmacol. 2024 May 21:118376. doi: 10.1016/j.jep.2024.118376. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Zingiberis rhizoma recens-/wine-/euodiae fructus-processed Coptidis Rhizoma (CR, zCR/wCR/eCR) are the commonly used processed products of CR in clinic. After being processed with different excipients, the efficacy of CR will change accordingly. I.e., wCR could resolve excessive heat of the upper energizer, zCR could eliminate gastric heat and harmonize the stomach, eCR could smooth the liver and harmonize the stomach. However, the underlying mechanisms were still unclear.AIM OF THE STUDY: To further verify the differential efficacy of the three processed CR products and compare the mechanisms on gastric ulcer.MATERIAL AND METHODS: First, a GU model, whose onset is closely related to the heat in stomach and the disharmony between liver and stomach, was established, and the therapeutic effects of zCR/wCR/eCR/CR were evaluated by pathologic observation and measurement of cytokine levels. Second, metabolomics analysis and network pharmacology were conducted to reveal the differential intervening mechanism of zCR/eCR on GU. Third, the predicted mechanisms from metabolomics analysis and network pharmacology were validated using western blotting, flow cytometry and immunofluorescence.RESULTS: zCR/wCR/eCR/CR could alleviate the pathologic damage to varying degrees. In metabolomics research, fewer metabolic pathways were enriched in serum samples, and most of them were also present in the results of gastric tissue samples. The gastroprotective, anti-inflammatory, antioxidant, and anti-apoptotic effects of zCR/wCR/eCR/CR might be due to their interference on histidine, arachidonic acid, and glycerophospholipids metabolism. Quantitative results indicated that zCR/eCR had a better therapeutic effect than wCR/CR in treating GU. A comprehensive analysis of metabolomics and network pharmacology revealed that zCR and eCR exerted anti-GU effects via intervening in five core targets, including AKT, TNF-α, IL6, IL1B and PPARG. In the validation experiment, zCR/eCR could significantly reverse the abnormal expression of proteins related to apoptosis, inflammation, oxidative stress, gastric function, as well as the PI3K/AKT signaling pathways.CONCLUSION: zCR and eCR could offer gastroprotective benefits by resisting inflammation and apoptosis, inhibiting gastric-acid secretion, as well as strengthening gastric mucosal defense and antioxidant capacity. Integrating network pharmacology and metabolomics analysis could reveal the acting mechanism of drugs and promote the development of medications to counteract GU.PMID:38782310 | DOI:10.1016/j.jep.2024.118376

J Ethnopharmacol. 2024 May 21:118377. doi: 10.1016/j.jep.2024.118377. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: The Tibetan medicine Ganlu Formula, as a classic prescription, is widely used across the Qinghai-Tibet Plateau area of China, which has a significant effect on relieving the course of rheumatoid arthritis (RA). However, the active compounds and underlying mechanisms of Ganlu Formula in RA treatment remain largely unexplored.AIM OF THE STUDY: This study aimed to elucidate the active substances and potential mechanisms of the ethyl acetate extract of Ganlu Formula ethyl acetate extract (GLEE) in the treatment of RA.MATERIALS AND METHODS: Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) was utilized to analyze and identify the chemical constituents within GLEE. Discovery Studio molecular virtual docking technology was utilized to dock the interaction of GLEE with inflammation-related pathway proteins. The GLEE gene library was obtained by transcriptome sequencing. Collagen-induced arthritic（CIA) rats were utilized to assess the antiarthritic efficacy of GLEE. Micro-CT imaging was employed to visualize the rat paw, and ultrasound imaging revealed knee joint effusion. Evaluation of synovial tissue pathological changes was conducted through hematoxylin-eosin staining and saffranine solid green staining, while immunohistochemical staining was employed to assess NLRP3 expression along with inflammatory markers. Immunofluorescence staining was utilized to identify M1 macrophages.RESULTS: Metabolomic analysis via UPLC-Q-TOF-MS identified 28 potentially bioactive compounds in GLEE, which interacted with the active sites of key proteins such as NLRP3, NF-κB, and STAT3 through hydrogen bonds, C-H bonds, and electrostatic attractions. In vitro analyses demonstrated that GLEE significantly attenuated NLRP3 inflammasome activation and inhibited the polarization of bone marrow-derived macrophages (BMDMs) towards the M1 phenotype. In vivo, GLEE not only prevented bone mineral density (BMD) loss but also reduced ankle swelling in CIA rats. Furthermore, it decreased the expression of the NLRP3 inflammasome and curtailed the release of inflammatory mediators within the knee joint.CONCLUSION: GLEE effectively mitigated inflammatory responses in both blood and knee synovial membranes of CIA rats, potentially through the down-regulation of the NLRP3/Caspase-1/IL-1β signaling pathway and reduction in M1 macrophage polarization.PMID:38782307 | DOI:10.1016/j.jep.2024.118377

Clin Chim Acta. 2024 May 21:119717. doi: 10.1016/j.cca.2024.119717. Online ahead of print.ABSTRACTBACKGROUND: Preeclampsia (PE) is a leading cause of maternal and fetal morbidity and mortality, with limited effective clinical treatment options. Active metabolomics offers a promising approach to uncover metabolic changes in PE and identify potential biomarkers or therapeutic targets. This study performed untargeted metabolomics using LC-MS to compare serum samples from preeclampsia and normal pregnancies.METHODS: We performed untargeted metabolomics using liquid chromatography-mass spectrometry (LC-MS) to compare serum samples from PE patients and normal pregnancies. We analyzed the alterations in metabolites and conducted functional experiments to assess the effects of LysoPE(16:0) on trophoblast cell invasion and migration. Mechanistic studies were performed to explore the potential targeting of GSK-3β by LysoPE(16:0).RESULTS: Our metabolomics analysis revealed significant alterations in several metabolites, including lysophosphatidylcholines and organic acids. Notably, LysoPE(16:0) was found to be downregulated in the serum of PE patients. Functional experiments demonstrated that LysoPE(16:0) could promote trophoblast cell invasion and migration. Mechanistic studies suggest that the protective effect of LysoPE(16:0) against PE might be mediated through the modulation of the GSK-3β/β-Catenin pathway, with LysoPE(16:0) potentially targeting the GSK-3β protein.CONCLUSIONS: Our findings highlight the potential role of LysoPE(16:0) in the pathophysiology of PE and its ability to modulate the GSK-3β/β-Catenin pathway. These results provide new insights into the metabolic changes associated with PE and suggest that LysoPE(16:0) could serve as a promising biomarker or therapeutic target for the prevention and treatment of PE.PMID:38782157 | DOI:10.1016/j.cca.2024.119717

Pharmacol Res. 2024 May 21:107229. doi: 10.1016/j.phrs.2024.107229. Online ahead of print.ABSTRACTAfter long-term clinical application, traditional Chinese medicine (TCM) has accumulated rich experience in the stroke treatment. Huang-Qi-Long-Dan Granule (HQLDG) is a TCM formula that was used in clinical for the treatment of acute ischemic stroke. However, its mechanism against ischemic stroke still unknown. This study aimed to identify HQLDG's effect against ischemic stroke and explore its underlying mechanism. 16s rRNA sequencing, metabolomics/tryptophan (Trp)-targeted metabolomics analysis and transcriptomic analysis were used to investigate HQLDG underlying therapeutic mechanism. Our results revealed that HQLDG significantly decreased the infarct volume, improved mouse behavior and brain slices pathological staining. In addition, it could ameliorate intestinal barrier damage and regulate tight junction gene expression. 16s rRNA, metabolomics and transcriptomics analysis revealed that HQLDG treatment significantly improved the composition of gut microbiota and Trp metabolism pathway, and further downregulated Th17/IL-17 signaling pathway. HQLDG treatment could significantly decrease serum inflammatory cytokines, IL-17A and IL-22; down-regulate Trp metabolism receptor gene (Ahr), inflammatory cytokines genes (IL-17a, IL-22), and an important coding gene for maintaining the mature Th17 (rorc) in both brain and intestinal tissues. In the contrary, after gut microbiota removal, this effect of HQLDG was impaired. HQLDG treated mouse fecal microbiota transplantation also had positive effect against tMCAO injury. Moreover, AhR inhibitor could decrease IL-17A immunofluorescence. These results suggested that the gut microbiota regulation might be an important intermediate in HQLDG against tMCAO injury. HQLDG might exerts anti-ischemic stroke effects through the gut microbiota-Trp metabolism-Th17/IL-17 signaling, which provides new insights into HQLDG-mediated prevention in ischemic stroke.PMID:38782148 | DOI:10.1016/j.phrs.2024.107229

Biochem Pharmacol. 2024 May 21:116306. doi: 10.1016/j.bcp.2024.116306. Online ahead of print.ABSTRACTFibroblast growth factor 21 (FGF21) has promise for treating diabetes and its associated comorbidities. It has been found to reduce blood glucose in mice and humans; however, its underlying mechanism is not known. Here, the metabolic function of FGF21 in diabetes was investigated. Diabetic db/db mice received intraperitoneal injections of FGF21 for 28 days, the serum of each mouse was collected, and their metabolites were analyzed by untargeted metabolomics using UHPLC-MS/MS. It was found that FGF21 reduced blood glucose and oral glucose tolerance without causing hypoglycemia. Moreover, administration of FGF21 reduced the levels of TG and LDL levels while increasing those of HDL and adiponectin. Importantly, the levels of 45 metabolites, including amino acids and lipids, were significantly altered, suggesting their potential as biomarkers. We speculated that FGF21 may treat T2DM through the regulation of fatty acid biosynthesis, the TCA cycle, and vitamin digestion and absorption. These findings provide insight into the mechanism of FGF21 in diabetes and suggest its potential for treating diabetes.PMID:38782076 | DOI:10.1016/j.bcp.2024.116306

Dev Cell. 2024 May 20:S1534-5807(24)00298-3. doi: 10.1016/j.devcel.2024.04.022. Online ahead of print.ABSTRACTThe transcription factor EHF is highly expressed in the lactating mammary gland, but its role in mammary development and tumorigenesis is not fully understood. Utilizing a mouse model of Ehf deletion, herein, we demonstrate that loss of Ehf impairs mammary lobuloalveolar differentiation at late pregnancy, indicated by significantly reduced levels of milk genes and milk lipids, fewer differentiated alveolar cells, and an accumulation of alveolar progenitor cells. Further, deletion of Ehf increased proliferative capacity and attenuated prolactin-induced alveolar differentiation in mammary organoids. Ehf deletion also increased tumor incidence in the MMTV-PyMT mammary tumor model and increased the proliferative capacity of mammary tumor organoids, while low EHF expression was associated with higher tumor grade and poorer outcome in luminal A and basal human breast cancers. Collectively, these findings establish EHF as a non-redundant regulator of mammary alveolar differentiation and a putative suppressor of mammary tumorigenesis.PMID:38781975 | DOI:10.1016/j.devcel.2024.04.022

Biomed Pharmacother. 2024 May 22;175:116780. doi: 10.1016/j.biopha.2024.116780. Online ahead of print.ABSTRACTPueraria lobata, commonly known as kudzu, is a medicinal and food plant widely used in the food, health food, and pharmaceutical industries. It has clinical pharmacological effects, including hypoglycemic, antiinflammatory, and antioxidant effects. However, its mechanism of hypoglycemic effect on type 2 diabetes mellitus (T2DM) has not yet been elucidated. In this study, we prepared a Pueraria lobata oral liquid (POL) and conducted a comparative study in a T2DM rat model to evaluate the hypoglycemic effect of different doses of Pueraria lobata oral liquid. Our objective was to investigate the hypoglycemic effect of Puerarin on T2DM rats and understand its mechanism from the perspective of metabolomics. In this study, we assessed the hypoglycemic effect of POL through measurements of FBG, fasting glucose tolerance test, plasma lipids, and liver injury levels. Furthermore, we examined the mechanism of action of POL using hepatic metabolomics. The study's findings demonstrated that POL intervention led to improvements in weight loss, blood glucose, insulin, and lipid levels in T2DM rats, while also providing a protective effect on the liver. Finally, POL significantly affected the types and amounts of hepatic metabolites enriched in metabolic pathways, providing an important basis for revealing the molecular mechanism of Pueraria lobata intervention in T2DM rats. These findings indicate that POL may regulate insulin levels, reduce liver damage, and improve metabolic uptake in the liver. This provides direction for new applications and research on Pueraria lobata to prevent or improve T2DM.PMID:38781864 | DOI:10.1016/j.biopha.2024.116780

Sci Total Environ. 2024 May 21;934:173399. doi: 10.1016/j.scitotenv.2024.173399. Online ahead of print.ABSTRACTPlastic pollution poses a significant threat to terrestrial ecosystems, yet the potential for soil fauna to contribute to plastic biodegradation remains largely unexplored. In this study, we reveal that soil-dwelling grubs, Protaetia brevitarsis larvae, can effectively biodegrade polystyrene (PS) plastics. Over a period of 4 weeks, these grubs achieved a remarkable 61.5 % reduction in PS foam mass. This biodegradation was confirmed by the depolymerization of ingested PS, formation of oxidative functional groups, noticeable chemical modifications, and an increase of δ13C of residual PS in frass. Additionally, antibiotic treatment to suppress gut microbes led to variations in the biodegradation process. PS ingestion induced a significant shift in the gut microbiome, promoting the growth of degradation-related bacteria such as Promicromonosporaceae, Bacillaceae, and Paenibacillaceae. Furthermore, the digestion of plastic triggered extensive metabolomic reprogramming of grubs' intestines, enhancing redox capabilities and facilitating PS biodegradation. These results indicate that responsive adaptation of both the gut microbiome and the host's intestinal metabolism contributes to PS degradation. Collectively, these findings demonstrate P. brevitarsis larvae's capability to alleviate soil plastic pollution, and highlight the potential of researching soil fauna further for sustainable plastic waste management solutions.PMID:38781836 | DOI:10.1016/j.scitotenv.2024.173399

Phytomedicine. 2024 May 22;130:155727. doi: 10.1016/j.phymed.2024.155727. Online ahead of print.ABSTRACTBACKGROUND: It has been clinically confirmed that the Shexiang Baoxin Pill (SBP) dramatically reduces the frequency of angina in patients with stable coronary artery disease (SCAD). However, potential therapeutic mechanism of SBP has not been fully explored.PURPOSE: The study explored the therapeutic mechanism of SBP in the treatment of SCAD patients.METHODS: We examined the serum metabolic profiles of patients with SCAD following SBP treatment. A rat model of acute myocardial infarction (AMI) was established, and the potential therapeutic mechanism of SBP was explored using metabolomics, transcriptomics, and 16S rRNA sequencing.RESULTS: SBP decreased inosine production and improved purine metabolic disorders in patients with SCAD and in animal models of AMI. Inosine was implicated as a potential biomarker for SBP efficacy. Furthermore, SBP inhibited the expression of genes involved in purine metabolism, which are closely associated with thrombosis, inflammation, and platelet function. The regulation of purine metabolism by SBP was associated with the enrichment of Lactobacillus. Finally, the effects of SBP on inosine production and vascular function could be transmitted through the transplantation of fecal microbiota.CONCLUSION: Our study reveals a novel mechanism by which SBP regulates purine metabolism by enriching Lactobacillus to exert cardioprotective effects in patients with SCAD. The data also provide previously undocumented evidence indicating that inosine is a potential biomarker for evaluating the efficacy of SBP in the treatment of SCAD.PMID:38781732 | DOI:10.1016/j.phymed.2024.155727