PubMed

Nicotine Tob Res. 2024 Jul 19:ntae179. doi: 10.1093/ntr/ntae179. Online ahead of print.ABSTRACTINTRODUCTION: Smoking is one of the most important predisposing factors of intestinal inflammatory diseases. Heated tobacco product (HTP) is a novel tobacco category that is claimed to deliver reduced chemicals to human those reported in combustible cigarette smoke (CS). However, the effect of HTP on intestine is still unknown.METHODS: In the framework of Organization for Economic Co-operation and Development guidelines 413 guidelines, Sprague-Dawley rats were exposed to HTP aerosol and CS for 13 weeks. The atmosphere was characterized and oxidative stress and inflammation of intestine were investigated after exposure. Furthermore, the faeces we performed with 16S sequencing and metabolomics analysis.RESULTS: HTP aerosol and CS led to obvious intestinal damage evidenced by increased intestinal pro-inflammatory cytokines and oxidative stress in male and female rats After HTP and CS exposure, the abundance that obviously changed were Lactobacillus and Turiciacter in male rats and Lactobacillus and Prevotella in female rats. HTP mainly induced the metabolism of amino acids and fatty acyls such as short-chain fatty acids and tryptophan, while CS involved into the main metabolism of bile acids, especially indole and derivatives. Although different metabolic pathways in the gut mediated by HTP and CS, both to inflammation and oxidative stress were ultimately induced.CONCLUSIONS: HTP aerosol and CS induced intestinal damage mediated by different gut microbiota and metabolites, while both lead to inflammation and oxidative stress.IMPLICATIONS: The concentration of various harmful components in heated tobacco product aerosol is reported lower than that of traditional cigarette smoke, however, its health risk impact on consumers remains to be studied. Our research findings indicate that heated tobacco product and cigarette smoke inhalation induced intestinal damage through different metabolic pathways mediated by gut microbiome, indicating the health risk of heated tobacco product in intestine.PMID:39028556 | DOI:10.1093/ntr/ntae179

Mycotoxin Res. 2024 Jul 19. doi: 10.1007/s12550-024-00541-6. Online ahead of print.ABSTRACTEnvironmental factors influence fungal growth and mycotoxin production in stored grains. However, the concentrations of free mycotoxins and their conjugates and how they are impacted by different interacting environment conditions have not been previously examined. The objectives of this study were to examine the impact of storage conditions (0.93-0.98 aw) and temperature (20-25 °C) on (a) the concentrations of deoxynivalenol and zearalenone and their respective glucosides/conjugates and (b) the concentrations of emerging mycotoxins in both naturally contaminated and irradiated wheat grains inoculated with Fusarium graminearum. Contaminated samples were analysed for multiple mycotoxins using Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS). Method validation was performed according to the acceptable performance criteria set and updated by the European Commission regulations No. 2021/808/EC. As an important conjugate of deoxynivalenol, the concentrations of deoxynivalenol-3-glucoside were significantly different from its precursor deoxynivalenol at 0.93 aw (22% moisture content- MC) at 25 °C in the naturally contaminated wheat with a ratio proportion of 56:44% respectively. The high concentrations of deoxynivalenol-3-glucoside could be influenced by the wheat's variety and/or harvested season/fungal strain type/location. Zeralenone-14-sulfate concentrations were surprisingly three times higher than Zearalenone in the naturally contaminated wheat at 0.98 aw (26% MC) at both temperatures. Emerging mycotoxins such as moniliformin increased with temperature rise with the highest concentrations at 0.95 aw and 25 °C. These findings highlight the influence and importance of storage aw x temperature conditions on the relative presence of free vs conjugated mycotoxins which can have implications for food safety.PMID:39028531 | DOI:10.1007/s12550-024-00541-6

Cell Biochem Biophys. 2024 Jul 19. doi: 10.1007/s12013-024-01408-4. Online ahead of print.ABSTRACTCratoxylum formosum ssp. pruniflorum (CF), a traditional medicinal plant in Southern China, is widely recognized as a popular medicinal and tea plant traditionally utilized by diverse linguistic groups in the region for the treatment of gastrointestinal ailments. The objective of this study was to explore the active components and mechanisms of CF against gastric cancer (GC). The chemical ingredients of CF were obtained by using UPLC-MS/MS-based metabolomics. MGC-803 and HGC-27 cells were employed to investigate the direct anti-GC effect. The potential targets and signaling pathway of CF were identified through network pharmacology and proteomics, followed by subsequent experimental validation. Through UPLC-MS/MS metabolomics analysis, a total of 197 chemical ingredients were identified in CF leaves. Network pharmacology and proteomics techniques revealed 25 potential targets for GC, with a protein-protein interaction (PPI) network highlighting 12 cores targets, including CTNNB1, CDK2, et al. Furthermore, seven key CF ingredients - vismione B, feruloylcholine, α-amyrin, vanillic acid, galangin, cinnamic acid, and caffeic acid - were found to mediate anti-GC effects through pathways such as reactive oxygen species (ROS) and cell cycle signaling pathway. In vitro experiments demonstrated that CF significantly inhibited the proliferation and migration of GC cells, increased intracellular reactive oxygen species (ROS), malondialdehyde (MDA) and lactate dehydrogenase (LDH) levels, arrested the cell cycle at the S-phase, induced apoptosis and pyroptosis, and upregulated expression of apoptosis proteins (Bax, Bax/Bcl-2, cleaved-Caspase-3/Caspase-3), and pyroptosis proteins (GSDMD-N/GSDMD and GSDME-N/GSDME), while downregulating expression of cell cycle proteins (CDK2 and cyclin A1) as well as necroptosis proteins (RIP1 and MLKL). Collectively, these findings reveal CF's therapeutic potential against GC by the augmentation of ROS production, cell cycle arrest, promotion of apoptosis, and pyroptosis, offering valuable evidence for the development and utilization of CF in clinical settings.PMID:39028496 | DOI:10.1007/s12013-024-01408-4

Anal Methods. 2024 Jul 19. doi: 10.1039/d4ay01225a. Online ahead of print.ABSTRACTThis study investigates the potential and complementarity of high-throughput multipulse and multidimensional NMR methods for metabolomics. Through a chemical ecology case study, three methods are investigated, offering a continuum of methods with complementary features in terms of resolution, sensitivity and experiment time. Ultrafast 2D COSY, adiabatic INEPT and SYMAPS HSQC are shown to provide a very good classification ability, comparable to the reference 1D 1H NMR method. Moreover, a detailed analysis of discriminant buckets upon supervised statistical analysis shows that all methods are highly complementary, since they are able to highlight discriminant signals that could not be detected by 1D 1H NMR. In particular, fast 2D methods appear very efficient to discriminate signals located in highly crowded regions of the 1H spectrum. Overall, the combination of these recent methods within a single NMR metabolomics workflow allows to maximize the accessible metabolic information, and also raises exciting challenges in terms of NMR data analysis for chemical ecology.PMID:39028155 | DOI:10.1039/d4ay01225a

Bioinform Adv. 2024 Apr 24;4(1):vbae060. doi: 10.1093/bioadv/vbae060. eCollection 2024.ABSTRACTMOTIVATION: Many diseases are complex heterogeneous conditions that affect multiple organs in the body and depend on the interplay between several factors that include molecular and environmental factors, requiring a holistic approach to better understand disease pathobiology. Most existing methods for integrating data from multiple sources and classifying individuals into one of multiple classes or disease groups have mainly focused on linear relationships despite the complexity of these relationships. On the other hand, methods for nonlinear association and classification studies are limited in their ability to identify variables to aid in our understanding of the complexity of the disease or can be applied to only two data types.RESULTS: We propose Deep Integrative Discriminant Analysis (IDA), a deep learning method to learn complex nonlinear transformations of two or more views such that resulting projections have maximum association and maximum separation. Further, we propose a feature ranking approach based on ensemble learning for interpretable results. We test Deep IDA on both simulated data and two large real-world datasets, including RNA sequencing, metabolomics, and proteomics data pertaining to COVID-19 severity. We identified signatures that better discriminated COVID-19 patient groups, and related to neurological conditions, cancer, and metabolic diseases, corroborating current research findings and heightening the need to study the post sequelae effects of COVID-19 to devise effective treatments and to improve patient care.AVAILABILITY AND IMPLEMENTATION: Our algorithms are implemented in PyTorch and available at: https://github.com/JiuzhouW/DeepIDA.PMID:39027641 | PMC:PMC11256945 | DOI:10.1093/bioadv/vbae060

Heliyon. 2024 Jun 23;10(13):e33370. doi: 10.1016/j.heliyon.2024.e33370. eCollection 2024 Jul 15.ABSTRACTBACKGROUND: Dihydroartemisinin (DHA), a derivative of Artemisia annua, has been shown to possess anti-inflammatory properties. Besides, Yes-associated protein 1 (YAP1) plays a crucial role in maintaining liver homeostasis.METHODS: This study used Yap1 Flox/Flox, Albumin-Cre mice with hepatocyte-specific Yap1 knockout (referred to as Yap1 LKO) and their control mice (Yap1 Flox/Flox, referred to as Yap1 Flox). The effect of Yap1 on lipid metabolism homeostasis was investigated through non-targeted metabolomic analysis of mouse liver. Subsequently, DHA was administered to Yap1 LKO mice to assess its potential as a treatment. Liver pathology was evaluated via H&E staining, and the levels of AST, ALT, and TG were quantified using biochemical assays. The contents of arachidonic acid (AA), prostaglandin E1 (PGE1), and leukotrienes (LT) in the liver were measured using ELISA, while the protein expressions of PLIN2, 5-lipoxygenase (5-LOX), and cyclooxygenase-2 (COX-2) were analyzed through IHC staining.RESULTS: Hepatocyte-specific Yap1 knockout activated the AA metabolic pathway, resulting in increased elevated levels of AA, PGE1, and LT levels, along with inflammatory cytokine infiltration. DHA mitigated the elevation of metabolites such as PGE1 and LT caused by the AA metabolic pathway activation by down-regulating the levels of COX-2 and 5-LOX in the liver of Yap1 LKO mice. Moreover, it alleviated the accumulation of lipid vacuoles and reduced triglyceride (TG) and perilipin-2 (PLIN2) levels in the liver of Yap1 LKO mice.CONCLUSIONS: Excessively low YAP1 expression induces liver inflammation and disturbances in lipid metabolism, whereas DHA modulated AA metabolism and mitigated liver inflammation by inhibiting the activation of 5-LOX and COX-2.PMID:39027511 | PMC:PMC11255665 | DOI:10.1016/j.heliyon.2024.e33370

Front Endocrinol (Lausanne). 2024 Jul 4;15:1406690. doi: 10.3389/fendo.2024.1406690. eCollection 2024.ABSTRACTINTRODUCTION: Secondary hyperparathyroidism (SHPT) is a common and serious complication of chronic kidney disease (CKD). Elucidating the metabolic characteristics of SHPT may provide a new theoretical basis for its prevention and treatment. This study aimed to perform a metabolomic analysis of SHPT in patients with CKD stages 3-5 not receiving dialysis.METHODS: A total of 76 patients with CKD, 85 patients with CKD-SHPT, and 67 healthy controls were enrolled in this study. CKD was diagnosed according to the criteria specified in the Kidney Disease Improving Global Outcomes 2012 guidelines. SHPT was diagnosed by experienced clinicians according to the Renal Disease Outcomes Quality Initiative Clinical Practice Guidelines. Serum renal function markers and the lipid profile were analyzed. Untargeted ultra performance liquid chromatography-tandem mass spectrometry was used to analyze the serum metabolites of patients with CKD and SHPT. Multivariate analysis of the data was performed using principal component analysis and partial least square discriminant analysis. Serum differential metabolites were identified and further characterized using databases. Pathway enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes database. Correlations between differential metabolites and clinical parameters were determined using the Spearman correlation.RESULTS: The serum metabolomic profiles of patients with CKD with and without SHPT differed significantly. Differential metabolites were mainly enriched in the top four Kyoto Encyclopedia of Genes and Genomes pathways: phenylalanine, tyrosine, and tryptophan biosynthesis; sphingolipid metabolism; glycerophospholipid metabolism; and phenylalanine metabolism. In total, 31 differential metabolites were identified; of these, L-tryptophan and (R)-(+)-1-phenylethylamine were decreased, while other amino acids and their derivatives, uremia toxins, carnitine, and lipids, were increased significantly in patients with SHPT compared to those without. The 14 lipid metabolites were positively correlated with levels of Urea, serum creatinine, cystatin C, and triglycerides and negatively correlated with the estimated glomerular filtration rate and levels of total and high- and low-density lipoprotein cholesterol.DISCUSSION: Disturbed amino acid and lipid metabolism were more apparent in patients with SHPT than in those without. This metabolomic profile of SHPT may provide a therapeutic foundation for its future clinical management.PMID:39027473 | PMC:PMC11254665 | DOI:10.3389/fendo.2024.1406690

iScience. 2024 Jun 13;27(7):110265. doi: 10.1016/j.isci.2024.110265. eCollection 2024 Jul 19.ABSTRACTPatients with tuberous sclerosis complex (TSC) develop multi-organ disease manifestations, with kidney angiomyolipomas (AML) and cysts being one of the most common and deadly. Early and regular AML/cyst detection and monitoring are vital to lower TSC patient morbidity and mortality. However, the current standard of care involves imaging-based methods that are not designed for rapid screening, posing challenges for early detection. To identify potential diagnostic screening biomarkers of AML/cysts, we performed global untargeted metabolomics in blood samples from 283 kidney AML/cyst-positive or -negative TSC patients using mass spectrometry. We identified 7 highly sensitive chemical features, including octanoic acid, that predict kidney AML/cysts in TSC patients. Patients with elevated octanoic acid have lower levels of very long-chain fatty acids (VLCFAs), suggesting that dysregulated peroxisome activity leads to overproduction of octanoic acid via VLCFA oxidation. These data highlight AML/cysts blood biomarkers for TSC patients and offers valuable metabolic insights into the disease.PMID:39027368 | PMC:PMC11255849 | DOI:10.1016/j.isci.2024.110265

Front Pharmacol. 2024 Jul 4;15:1426944. doi: 10.3389/fphar.2024.1426944. eCollection 2024.ABSTRACTWolfberry, esteemed as a traditional Chinese medicinal material and functional food, is replete with nutrients and boasts a diverse array of health benefits, including hypoglycemic, antitumor, antioxidant, anti-inflammatory, and immune-enhancing properties. Notably, inflammation is a pivotal factor in the onset and progression of numerous diseases. Despite this, there is a paucity of research on the comprehensive evaluation of the components found in different wolfberries, and the exploration of their primary active components is limited. To address this issue, we conducted a comprehensive targeted metabolomics analysis, employing statistical methods such as principal component analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA), KEGG pathway analysis, and volcano plots to delineate the compositional differences among red, black, and yellow wolfberries. Furthermore, we investigated the anti-inflammatory effects of their primary components through in vitro experiments. Our analysis revealed a total of 1,104 chemical compositions in the three wolfberries, with alkaloids, phenolic acids, flavonoids, and lipids being the predominant nutritional components. KEGG enrichment analysis indicated that these compositions were primarily involved in the biosynthesis of secondary metabolites, ABC transport, and galactose metabolism pathway. Moreover, our study demonstrated that quercetin exhibited dose-dependent anti-inflammatory activity in LPS-stimulated HUVECs. It effectively inhibited the production of inflammatory factors such as TNF-α, MCP-1, and IL-1β, while also down-regulating the gene and protein expression levels of ICAM-1 and VCAM-1. In conclusion, our findings indicate that there are variations in compositions among the three wolfberries, with flavonoids being the most abundant, and in vitro studies also confirmed the anti-inflammatory potential of quercetin. It is worth noting that Lycium ruthenicum contains higher levels of antioxidant components and possesses greater nutritional value, providing valuable insights for the future development and utilization of the three wolfberries.PMID:39027334 | PMC:PMC11255399 | DOI:10.3389/fphar.2024.1426944

Acta Pharm Sin B. 2024 Jul;14(7):3068-3085. doi: 10.1016/j.apsb.2024.03.025. Epub 2024 Mar 22.ABSTRACTSepsis progression is significantly associated with the disruption of gut eubiosis. However, the modulatory mechanisms of gut microbiota operating during sepsis are still unclear. Herein, we investigated how gut commensals impact sepsis development in a pre-clinical model. Cecal ligation and puncture (CLP) surgery was used to establish polymicrobial sepsis in mice. Mice depleted of gut microbiota by an antibiotic cocktail (ABX) exhibited a significantly higher level of mortality than controls. As determined by metabolomics analysis, ABX treatment has depleted many metabolites, and subsequent supplementation with l-rhamnose (rhamnose, Rha), a bacterial carbohydrate metabolite, exerted profound immunomodulatory properties with a significant enhancement in macrophage phagocytosis, which in turn improved organ damage and mortality. Mechanistically, rhamnose binds directly to and activates the solute carrier family 12 (potassium-chloride symporter), member 4 (SLC12A4) in macrophages and promotes phagocytosis by activating the small G-proteins, Ras-related C3 botulinum toxin substrate1 (Rac1) and cell division control protein 42 homolog (Cdc42). Interestingly, rhamnose has enhanced the phagocytosis capacity of macrophages from sepsis patients. In conclusion, by identifying SLC12A4 as the host interacting protein, we disclosed that the gut commensal metabolite rhamnose is a functional molecular that could promote the phagocytosis capacity of macrophages and protect the host against sepsis.PMID:39027244 | PMC:PMC11252530 | DOI:10.1016/j.apsb.2024.03.025

Front Microbiol. 2024 Jul 3;15:1435503. doi: 10.3389/fmicb.2024.1435503. eCollection 2024.ABSTRACTINTRODUCTION: Streptococcus mutans was the primary pathogenic organism responsible for dental caries. Lonicera japonica flos (LJF) is a traditional herb in Asia and Europe and consumed as a tea beverage for thousands of years.METHODS: The inhibitory effect and mechanism of LJF on biofilm formation by S. mutans was investigated. The active extracts of LJF were validated for their inhibitory activity by examining changes in surface properties such as adherence, hydrophobicity, auto-aggregation abilities, and exopolysaccharides (EPS) production, including water-soluble glucan and water-insoluble glucan.RESULTS AND DISCUSSION: LJF primarily inhibited biofilm formation through the reduction of EPS production, resulting in alterations in cell surface characteristics and growth retardation in biofilm formation cycles. Integrated transcriptomic and untargeted metabolomics analyses revealed that EPS production was modulated through two-component systems (TCS), quorum sensing (QS), and phosphotransferase system (PTS) pathways under LJF stress conditions. The sensing histidine kinase VicK was identified as an important target protein, as LJF caused its dysregulated expression and blocked the sensing of autoinducer II (AI-2). This led to the inhibition of response regulator transcriptional factors, down-regulated glycosyltransferase (Gtf) activity, and decreased production of water-insoluble glucans (WIG) and water-soluble glucans (WSG). This is the first exploration of the inhibitory effect and mechanism of LJF on S. mutans, providing a theoretical basis for the application of LJF in functional food, oral health care, and related areas.PMID:39027105 | PMC:PMC11256199 | DOI:10.3389/fmicb.2024.1435503

bioRxiv [Preprint]. 2024 Jul 13:2024.07.10.601875. doi: 10.1101/2024.07.10.601875.ABSTRACTAnnotating compounds with high confidence is a critical element in metabolomics. 13 C-detection NMR experiment INADEQUATE (incredible natural abundance double-quantum transfer experiment) stands out as a powerful tool for structural elucidation, whereas this valuable experiment is not often included in metabolomics studies. This is partly due to the lack of community platform that provides structural information based INADEQUATE. Also, it is often the case that a single study uses various NMR experiments synergistically to improve the quality of information or balance total NMR experiment time, but there is no public platform that can integrate the outputs of INADEQUATE and other NMR experiments either. Here, we introduce PyINETA, Python-based INADEQUATE network analysis. PyINETA is an open-source platform that provides structural information of molecules using INADEQUATE, conducts database search, and integrates information of INADEQUATE and a complementary NMR experiment 13 C J -resolved experiment ( 13 C-JRES). Those steps are carried out automatically, and PyINETA keeps track of all the pipeline parameters and outputs, ensuring the transparency of annotation in metabolomics. Our evaluation of PyINETA using a model mouse study showed that our pipeline successfully integrated INADEQUATE and 13 C-JRES. The results showed that 13 C-labeled amino acids that were fed to mice were transferred to different tissues, and, also, they were transformed to other metabolites. The distribution of those compounds was tissue-specific, showing enrichment of particular metabolites in liver, spleen, pancreas, muscle, or lung. The value of PyINETA was not limited to those known compounds; PyINETA also provided fragment information for unknown compounds. PyINETA is available on NMRbox.PMID:39026850 | PMC:PMC11257532 | DOI:10.1101/2024.07.10.601875

bioRxiv [Preprint]. 2024 Jul 13:2024.07.13.603378. doi: 10.1101/2024.07.13.603378.ABSTRACTPseudomonas aeruginosa (PA), an opportunistic gram-negative pathogen, is the most common pathogen identified in all culture positive cases of infectious keratitis. Extracellular vesicles (EVs) are released by most cells in the body and function in intercellular communication. We have previously reported a change in the proteome of host-derived EVs from corneal epithelial cells during PA infection. In the present study, we investigated changes in the metabolome of host-derived EVs from PA infected (PA-C EVs) and non-infected cells (C EVs). We found that one metabolite, palmitoyl carnitine (PAMC), was significantly upregulated in PA-C EVs. To determine the significance of PAMC release, we investigated the effect of PAMC treatment on corneal epithelial cells and neutrophils. EVs were isolated from culture media using size exclusion chromatography. EVs were then characterized using nanoparticle tracking analysis, transmission electron microscopy, and western blot. Metabolomics was performed using an untargeted approach. We found that palmitoyl carnitine (PAMC) was the most abundant metabolite present in PA-C EVs and was increased more than 3 fold compared to C EVs. Treatment of corneal epithelial cells with increasing levels of PAMC increased nuclear translocation of the NF-κB subunit p65. This was associated with an increase in IL-8 production and neutrophil migration. PAMC also increased levels of mitochondrial calcium. Upon inoculation of corneal epithelial cells with PA, 50 μM PAMC completely eradicated intracellular PA, but stimulated growth of extracellular PA. Taken together, these findings suggest that PA exploits EV release by host cells to deplete PAMC from the intracellular environment.PMID:39026691 | PMC:PMC11257627 | DOI:10.1101/2024.07.13.603378

Front Immunol. 2024 Jul 4;15:1424332. doi: 10.3389/fimmu.2024.1424332. eCollection 2024.ABSTRACTBACKGROUND: The protective role of gut microbiota and its metabolites against intestinal damage in sepsis patients remain unclear.METHODS: Fecal samples were acquired from patients categorized into sepsis and non-sepsis groups for analysis of microbial composition via 16S rRNA sequencing and untargeted metabolomics analysis. We assessed the impact of gut microbiota from sepsis patients on intestinal barriers in antibiotic-treated mice. Furthermore, We conducted spearman's correlation analysis to examine the relationship between metabolites and the severity of sepsis. Additionally, we performed animal experiments to validate the functionality of identified metabolites.RESULTS: The diversity of intestinal flora is decreased in patients with sepsis compared to the control group. Through fecal microbiota transplantation experiments, it was discovered that the gut microbiota derived from sepsis patients could induce intestinal damage in antibiotic-treated mice. Metabolomics analysis of the microbiota revealed a significant enrichment of the Valine, leucine, and isoleucine biosynthesis pathway. Further analysis showed a significant decrease in the abundance of L-valine in sepsis patients, which was negatively correlated with APACHE-II and SOFA scores. In sepsis mouse experiments, it was found that L-valine could alleviate sepsis-induced intestinal damage.CONCLUSION: Alterations in microbial and metabolic features in the gut can affect the severity of sepsis. Furthermore, L-valine can protect against sepsis-induced intestinal injury.PMID:39026673 | PMC:PMC11254637 | DOI:10.3389/fimmu.2024.1424332

RSC Med Chem. 2024 Apr 11;15(7):2286-2299. doi: 10.1039/d4md00057a. eCollection 2024 Jul 17.ABSTRACTSeveral scientific evidences report that a central role in the pathogenesis of Alzheimer's disease is played by the deposition of insoluble aggregates of β-amyloid proteins in the brain. Because Aβ is self-assembling, one possible design strategy is to inhibit the aggregation of Aβ peptides using short peptide fragments homologous to the full-length wild-type Aβ protein. In the past years, several studies have reported on the synthesis of some short synthetic peptides called β-sheet breaker peptides (BSBPs). Herein, we present the synthesis of novel (cell-permeable) N-methyl BSBPs, designed based on literature information on the structural key features of BSBPs. Three-dimensional GRID-based pharmacophore peptide screening combined with PT-WTE metadynamics was performed to support the results of the design and microwave-assisted synthesis of peptides 2 and 3 prepared and analyzed for their fibrillogenesis inhibition activity and cytotoxicity. An HR-MS-based cell metabolomic approach highlighted their cell permeability properties.PMID:39026638 | PMC:PMC11253850 | DOI:10.1039/d4md00057a

Clin Exp Emerg Med. 2024 Jul 19. doi: 10.15441/ceem.24.211. Online ahead of print.ABSTRACTSepsis accounts for high cases of morbidity and mortality in hospitalized patients. It has a very complex pathophysiology and swiftly progresses to a severe form of the disease, such as septic shock leading to organ dysfunction, organ failure, and death. Metabolomics has transformed sepsis's clinical and research topography with its application in prognosis, diagnosis, and risk assessment in patients with sepsis and septic shock. Metabolites in blood and urine are detected and analyzed, which helps in understanding the pathogenesis of the disease and aid in better disease management by identifying biomarkers early on. Metabolomics, sepsis and septic shock were the keywords were searched in PubMed and Scopus, from its inception to Dec 2023. This article provides information regarding metabolic profiling performed in sepsis and septic shock We demonstrated that metabolomics will change the world of sepsis by analyzing and detecting the diagnosis, prognosis, mortality, and treatment response biomarkers.PMID:39026452 | DOI:10.15441/ceem.24.211

J Nutr Biochem. 2024 Jul 16:109703. doi: 10.1016/j.jnutbio.2024.109703. Online ahead of print.ABSTRACTSestrin2 is a highly conserved protein that can be induced under various stress conditions. Researches have revealed that the signaling pathway of the mammalian target of rapamycin (mTOR) is essential in modulating both glucose and lipid metabolism. However, the precise involvement of Sestrin2 in the hypothalamus, particularly in pro-opiomelanocortin (POMC) neurons, in control of energy homeostasis remains uncertain. In this study, we aimed to investigate the functional role of Sestrin2 in hypothalamic POMC neurons in regulation of energy balance, as well as revealing the underlying mechanisms. Therefore, Cre-dependent AAV virus encoding or silencing Sestrin2 was injected into the hypothalamic ARC of Pomc-cre transgenic mice. The results demonstrated that Sestrin2 overexpression in POMC neurons ameliorated high-fat diet (HFD)-induced obesity and increased energy expenditure. Conversely, Sestrin2 deficiency in POMC neurons predisposed mice to HFD induced obesity. Additionally, the thermogenesis of brown adipose tissue and lipolysis of inguinal white adipose tissue were both enhanced by the increased sympathetic nerve innervation in Sestrin2 overexpressed mice. Further exploration revealed that Sestrin2 overexpression inhibited the mTOR signaling pathway in hypothalamic POMC neurons, which may account for the alleviation of systematic metabolic disturbance induced by HFD in these mice. Collectively, our findings demonstrate that Sestrin2 in POMC neurons plays a pivotal role in maintaining energy balance in a context of HFD-induced obesity by inhibiting the mTOR pathway, providing new insights into how hypothalamic neurons respond to nutritional signals to protect against obesity-associated metabolic dysfunction.PMID:39025457 | DOI:10.1016/j.jnutbio.2024.109703

J Biol Chem. 2024 Jul 16:107582. doi: 10.1016/j.jbc.2024.107582. Online ahead of print.ABSTRACTThe Ccr4-Not complex contains the poorly understood Not4 ubiquitin ligase that functions in transcription, mRNA decay, translation, proteostasis, and endolysosomal nutrient signaling. To gain further insight into the in vivo functions of the ligase, we performed quantitative proteomics in Saccharomyces cerevisiae using yeast cells lacking Not4, or cells overexpressing wild-type Not4 or an inactive Not4 mutant. Herein, we provide evidence that balanced Not4 activity maintains ribosomal protein (RP) homeostasis independent of changes to RP mRNA or known Not4 ribosomal substrates. Intriguingly, we also find that Not4 loss activates 40S ribosomal autophagy independently of canonical Atg7-dependent macroautophagy, indicating that microautophagy is responsible. We previously demonstrated that Ccr4-Not stimulates target of rapamycin complex 1 (TORC1) signaling, which activates RP expression and inhibits autophagy, by maintaining vacuole V-ATPase H+ pump activity. Importantly, combining Not4 deficient cells with a mutant that blocks vacuole H+ export fully restores RP expression and increases 40S RP autophagy efficiency. In contrast, restoring TORC1 activity alone fails to rescue either process, indicating that Not4 loss disrupts additional endolysosomal functions that regulate RP expression and 40S autophagy. Analysis of the Not4 regulated proteome reveals increases in endolysosomal and autophagy-related factors that functionally interact with Not4 to control RP expression and affect 40S autophagy. Collectively, our data indicate that balanced Ccr4-Not ubiquitin ligase signaling maintains RP homeostasis and inhibits 40S autophagy via the ligase's emerging role as an endolysosomal regulator.PMID:39025453 | DOI:10.1016/j.jbc.2024.107582

Biochem Pharmacol. 2024 Jul 16:116435. doi: 10.1016/j.bcp.2024.116435. Online ahead of print.ABSTRACTAcute kidney injury (AKI) is one of the most serious complications of cisplatin anticancer therapies. Cilastatin is a highly promising nephroprotective agent to eventually enter clinical use, but its biochemical mechanism is still not fully understood. We have employed an untargeted metabolomics approach based on capillary electrophoresis mass spectrometry (CE-MS) analysis of serum and urine from an in vivo rat model, to explore the metabolic pathways involved in cisplatin-induced AKI and cilastatin nephroprotection. A total of 155 and 76 identified metabolites were found to be significantly altered during cisplatin treatment in urine and serum, respectively. Most of these altered metabolites were either partially or totally recovered by cilastatin and cisplatin co-treatment. The main metabolic pathways disturbed by cisplatin during AKI involved diverse amino acids metabolism and biosynthesis, tricarboxylic acids (TCA) cycle, nicotinate and nicotinamide metabolism, among others. Cilastatin was proved to protect diverse cisplatin-altered pathways involving metabolites related to immunomodulation, inflammation, oxidative stress and amino acid metabolism in proximal tubules. However, cisplatin-altered mitochondrial metabolism (especially, the energy-producing TCA cycle) remained largely unprotected by cilastatin, suggesting an unresolved mitochondrial direct damage. Multivariate analysis allowed effective discrimination of cisplatin-induced AKI and cilastatin renoprotection based on metabolic features. A number of potential serum and urine biomarkers could also be foreseen for cisplatin-induced AKI detection and cilastatin nephroprotection.PMID:39025411 | DOI:10.1016/j.bcp.2024.116435

Gene. 2024 Jul 16:148772. doi: 10.1016/j.gene.2024.148772. Online ahead of print.ABSTRACTCumulus cells play a crucial role in the oocyte growth and maturation processes through providing necessary nutrients and growth signals by gap junction communication. However, a global overview of metabolic events in goat cumulus cells is still lacking. In the present study, we collected cumulus cells from goat cumulus-oocyte complexes (COCs) at different developmental stages. Metabolomics analysis was performed to investigate the global metabolic patterns in cumulus cells during oocyte in vitro maturation. In particular, we revealed the several significantly altered metabolic pathways and metaboliccharacteristics in goat cumulus cells, including the accumulation of fatty acids, steroid hormones metabolism, active catabolism of arginine during meiotic resumption, and a progressive decline in nucleotide metabolism. In conclusion, the dataset generated by our metabolomic profiling will provide valuable information to understand the key metabolic pathways and metabolites involved in COCs development.PMID:39025339 | DOI:10.1016/j.gene.2024.148772