PubMed

Phytochem Rev. 2024;23(5):1415-1442. doi: 10.1007/s11101-024-09928-w. Epub 2024 May 6.ABSTRACTThe isolation of pure compounds from extracts represents a key step common to all investigations of natural product (NP) research. Isolation methods have gone through a remarkable evolution. Current approaches combine powerful metabolite profiling methods for compounds annotation with omics mining results and/or bioassay for bioactive NPs/biomarkers priorisation. Targeted isolation of prioritized NPs is performed using high-resolution chromatographic methods that closely match those used for analytical profiling. Considerable progress has been made by the introduction of innovative stationary phases providing remarkable selectivity for efficient NPs isolation. Today, efficient separation conditions determined at the analytical scale using high- or ultra-high-performance liquid chromatography can be optimized via HPLC modelling software and efficiently transferred to the semi-preparative scale by chromatographic calculation. This ensures similar selectivity at both the analytical and preparative scales and provides a precise separation prediction. High-resolution conditions at the preparative scale can notably be granted using optimized sample preparation and dry load sample introduction. Monitoring by ultraviolet, mass spectrometry, and or universal systems such as evaporative light scattering detectors and nuclear magnetic resonance allows to precisely guide the isolation or trigger the collection of specific NPs with different structural scaffolds. Such approaches can be applied at different scales depending on the amounts of NPs to be isolated. This review will showcase recent research to highlight both the potential and constraints of using these cutting-edge technologies for the isolation of plant and microorganism metabolites. Several strategies involving their application will be examined and critically discussed.PMID:39574436 | PMC:PMC11576662 | DOI:10.1007/s11101-024-09928-w

Nucleic Acids Res. 2024 Nov 22:gkae1067. doi: 10.1093/nar/gkae1067. Online ahead of print.ABSTRACTThe Natural Products Magnetic Resonance Database (NP-MRD; https://np-mrd.org) is a comprehensive, freely accessible, web-based resource for the deposition, distribution, extraction, and retrieval of nuclear magnetic resonance (NMR) data on natural products (NPs). The NP-MRD was initially established to support compound de-replication and data dissemination for the NP community. However, that community has now grown to include many users from the metabolomics, microbiomics, foodomics, and nutrition science fields. Indeed, since its launch in 2022, the NP-MRD has expanded enormously in size, scope, and popularity. The current version of NP-MRD now contains nearly 7× more compounds (281 859 versus 40 908) and 7× more NMR spectra (5.5 million versus 817 278) than the first release. More specifically, an additional 4.6 million predicted spectra and another 11 000 spectra simulated from experimental chemical shifts were deposited into the database. Likewise, the number of NMR raw spectral data depositions has grown from 165 spectra per year to >10 000 per year. As a result of this expansion, the number of monthly webpage views has grown from 55 to 20 000 and the number of monthly visitors has increased from 7 to 2500. To address this growth and to better support the expanding needs of its diverse community of users, many additional improvements to the NP-MRD have been made. These include significant enhancements to the data submission process, notable updates to the database's spectral search utilities and useful additions to support better NMR spectral analysis/prediction. Significant efforts have also been undertaken to remediate and update many of NP-MRD's database entries. This manuscript describes these database improvements and expansion efforts, along with how they have been implemented and what future upgrades to the NP-MRD are planned.PMID:39574402 | DOI:10.1093/nar/gkae1067

J Chem Inf Model. 2024 Nov 22. doi: 10.1021/acs.jcim.4c01234. Online ahead of print.ABSTRACTDetecting doping agents in sports poses a significant challenge due to the continuous emergence of new prohibited substances and methods. Traditional detection methods primarily rely on targeted analysis, which is often labor-intensive and is susceptible to errors. In response, machine learning offers a transformative approach to enhancing doping screening and detection. With its powerful data analysis capabilities, machine learning enables the rapid identification of patterns and features in complex compound data, increasing both the efficiency and the accuracy of detection. Moreover, when integrated with nontargeted metabolomics, machine learning can predict unknown metabolites, aiding the discovery of long-lasting biomarkers of doping. It also excels in classifying novel compounds, thereby reducing false-negative rates. As instrumental analysis and machine learning technologies continue to advance, the development of rapid, scalable, and highly efficient doping detection methods becomes increasingly feasible, supporting the pursuit of fairness and integrity in sports competitions.PMID:39574320 | DOI:10.1021/acs.jcim.4c01234

J Frailty Aging. 2024;13(4):331-340. doi: 10.14283/jfa.2024.75.ABSTRACTBACKGROUND: The gut microbiome is recognized as a pivotal factor in the pathophysiology of sarcopenia-a condition marked by the accelerated loss of muscle strength, mass and function with ageing. Despite this well-known gut-muscle axis, the potential links between other microbial ecosystems and sarcopenia remain largely unexplored. The oral microbiome has been linked to various age-related health conditions such as rheumatoid arthritis and colorectal cancer. However, its potential association with sarcopenia is unknown. The Saliva and Muscle (SaMu) study seeks to address this knowledge gap.METHODS: The SaMu study comprises three sequential phases. In phase 1, a cross-sectional analysis will be conducted on a cohort of 200 individuals aged 70 years or older to examine the relationship between salivary microbiome and sarcopenia status. Participants will be recruited in the three main places of living: general community, assisted living facilities and nursing homes. The salivary microbiome composition will be evaluated utilizing shotgun metagenomics sequencing, while sarcopenia status will be determined through muscle mass (determined by whole-body bioelectrical impedance analysis and calf circumference), muscle strength (grip strength and the 5-times-sit-to-stand test) and physical performance (usual walking speed). In addition to investigating the microbiome composition, the study aims to elucidate microbiome functions by exploring potential omic associations with sarcopenia. To achieve this, salivary proteomics, metabolomics and quorum sensing peptidomics will be performed. Covariates that will be measured include clinical variables (sociodemographic factors, health status, health-related behaviours, oral health and quality of life) as well as blood variables (immune profiling, hormones, kidney and liver function, electrolytes and haematocrit). In phase 2, an in-depth mechanistic analysis will be performed on an envisaged subcohort of 50 participants. This analysis will explore pathways in muscle tissue using histology, genomics and transcriptomics, focusing on (maximal) 25 healthy older adults and (maximal) 25 with severe sarcopenia. Phase 3 involves a two-year clinical follow-up of the initial participants from the cross-sectional analysis, along with a resampling of blood and saliva. Additionally, secondary outcomes like falls, hospitalization and mortality will be examined.DISCUSSION: Using a salivary multi-omics approach, SaMu primarily aims to clarify the associations between the oral microbiome and sarcopenia. SaMu is expected to contribute to the discovery of predictive biomarkers of sarcopenia as well as to the identification of potential novel targets to prevent/tackle sarcopenia. This study-protocol is submitted for registration at the ISRCTN registry.PMID:39574252 | DOI:10.14283/jfa.2024.75

Cell Commun Signal. 2024 Nov 21;22(1):558. doi: 10.1186/s12964-024-01922-1.ABSTRACTSarcopenia is a prevalent condition in patients with chronic kidney disease (CKD), intricately linked to adverse prognoses, heightened cardiovascular risks, and increased mortality rates. Extensive studies have found a close and complex association between gut microbiota, kidney and muscle. On one front, patients with CKD manifest disturbances in gut microbiota and alterations in serum metabolites. These abnormal microbiota composition and metabolites in turn participate in the development of CKD. On another front, altered gut microbiota and its metabolites may lead to significant changes in metabolic homeostasis and inflammation, ultimately contributing to the onset of sarcopenia. The disturbance of gut microbial homeostasis, coupled with the accumulation of toxic metabolites, exerts deleterious effects on skeletal muscles in CKD patients with sarcopenia. This review meticulously describes the alterations observed in gut microbiota and its serum metabolites in CKD and sarcopenia patients, providing a comprehensive overview of pertinent studies. By delving into the intricate interplay of gut microbiota and serum metabolites in CKD-associated sarcopenia, we aim to unveil novel treatment strategies for ameliorating their symptoms and prognosis.PMID:39574190 | DOI:10.1186/s12964-024-01922-1

Clin Proteomics. 2024 Nov 21;21(1):62. doi: 10.1186/s12014-024-09513-5.ABSTRACTBACKGROUND: Mucosal healing is the therapeutic target for ulcerative colitis (UC). While amino acids (AAs) and the gut microbiota are known to be involved in the pathogenesis of UC, their specific roles in mucosal healing have not been fully defined.OBJECTIVES: To longitudinally assess the changes in AA concentrations and the gut microbiota composition in the context of mucosal healing in UC patients, with the aim of identifying new biomarkers with predictive value for mucosal healing in UC patients and providing a new theoretical basis for dietary therapy.METHODS: A total of 15 UC patients with infliximab-induced mucosal healing were enrolled. Serum and fecal AA concentrations before and after mucosal healing were determined via targeted metabolomics. A receiver operating characteristic (ROC) curve was plotted to evaluate the value of different AAs in predicting mucosal healing in UC patients. The changes in the composition of the fecal gut microbiota were analyzed via metagenomics, and bioinformatics was used to analyze the functional genes and metabolic pathways associated with different bacterial species. Spearman correlation analyses of fecal AAs with significantly different concentrations and the differentially abundant bacterial species before and after mucosal healing were performed.RESULTS: 1. The fecal concentrations of alanine, aspartic acid, glutamic acid, glutamine, glycine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine were significantly decreased after mucosal healing. The serum concentrations of alanine, cysteine and valine significantly increased, whereas that of aspartic acid significantly decreased. Glutamic acid, leucine, lysine, methionine and threonine could accurately predict mucosal healing in UC patients, and the area under the curve (AUC) was > 0.9. After combining the 5 amino acids, the AUC reached 0.96. 2. There were significant differences in the gut microbiota composition before and after mucosal healing in UC, characterized by an increase in the abundance of beneficial microbiota (Faecalibacterium prausnitzii and Bacteroides fragilis) and a decrease in the abundance of harmful microbiota (Enterococcus faecalis). LEfSe analysis identified 57 species that could predict mucosal healing, and the AUC was 0.7846. 3. Amino acid metabolic pathways were enriched in samples after mucosal healing, was associated with the abundance of multiple species, such as Faecalibacterium prausnitzi, Bacteroides fragilis, Bacteroides vulgatus and Alistipes putredinis. 4. The fecal concentrations of several AAs were negatively correlated with the abundance of a variety of beneficial strains, such as Bacteroides fragilis, uncultured Clostridium sp., Firmicutes bacterium CAG:103, Adlercreutzia equolifaciens, Coprococcus comes and positively correlated with the abundance of several harmful strains, such as Citrobacter freundii, Enterococcus faecalis, Klebsiella aerogenes, Salmonella enterica.CONCLUSION: Altered concentrations of amino acids and their associations with the gut microbiota are implicated in the mucosal healing of UC patients and can serve as noninvasive diagnostic biomarkers.PMID:39574001 | DOI:10.1186/s12014-024-09513-5

BMC Plant Biol. 2024 Nov 22;24(1):1109. doi: 10.1186/s12870-024-05758-2.ABSTRACTThe absorption of the essential element nitrogen by plants affects various aspects of plant physiological activity, including gene expression, metabolite content and growth. However, the molecular mechanism underlying the potato tuberization response to nitrogen remains unclear. Potato plants were subjected to pot experiments under nitrogen deficiency, normal nitrogen levels and nitrogen sufficiency. A comprehensive analysis of the physiological responses, transcriptomic profiles, and metabolic pathways of potato stolons subjected to nitrogen stress was conducted. Transcriptomic analysis revealed 2756 differentially expressed genes (DEGs) associated with nitrogen stress. Metabolomic analysis identified a total of 600 differentially accumulated metabolites (DAMs). Further correlation analysis of the major DEGs and DAMs revealed that 9 key DEGs were associated with alpha-linolenic acid metabolism, 16 key DEGs with starch and sucrose metabolism, 7 key DEGs with nitrogen metabolism, and 16 key DEGs with ABC transporters. Nitrogen deficiency significantly increased the sucrose, GDP-glucose and L-glutamic acid levels and promoted stolon growth by increasing the expression of AMY (alpha-amylase), BE (1,4-alpha-glucan branching enzyme), SS (starch synthase), SPS (sucrose‒phosphate synthase) and AGPS (glucose‒1-phosphate adenylyltransferase). However, high nitrogen levels had the opposite effect. In addition, high nitrogen levels upregulated EG (endoglucanase), SUS (sucrose synthase) and GDH (glutamate dehydrogenase) and led to significant accumulation of 9-Hydroperoxy-10,12,15-octadecatrienoate (9(S)-HpOTrE), (13 S)-Hydroperoxyoctadeca-9,11,15-trienoate (13 (S)-HpOTrE) and L-glutamine, ultimately affecting the balance between plant growth and defense. Overall, our comprehensive study revealed the co-expressed genes and potential pathways related to potato tuber formation under different nitrogen conditions. These data provide a better understanding needed for improving potato tuber traits at the molecular and metabolic levels.PMID:39573986 | DOI:10.1186/s12870-024-05758-2

Oncoimmunology. 2024 Dec 31;13(1):2432059. doi: 10.1080/2162402X.2024.2432059. Epub 2024 Nov 21.ABSTRACTFew clinical studies investigated the putative link between the activation of immunogenic cell death (ICD) and the oncological outcome. Recent data, published in a Phase 1b trial, demonstrated that an ICD-associated surge in the plasma concentration of high-mobility group box 1 (HMGB1) indicates favorable prognosis in patients with advanced leiomyosarcomas treated with the combination of doxorubicin, dacarbazine and nivolumab.PMID:39572927 | DOI:10.1080/2162402X.2024.2432059

NPJ Biofilms Microbiomes. 2024 Nov 21;10(1):133. doi: 10.1038/s41522-024-00609-2.ABSTRACTAn intensive feeding system might improve the production cycle of yaks. However, how intensive feeding system contributes to yak growth is unclear. Here, multi-omics, including rumen metagenomics, rumen and plasma metabolomics, were performed to classify the regulatory mechanisms of intensive feeding system on yaks. Increased growth performance were observed. Rumen metagenomics revealed that Clostridium, Methanobrevibacter, Piromyces and Anaeromyces increased in the intensively fed yaks, contributing to amino acid and carbohydrate metabolism. The grazing yaks had more cellulolytic microbes. These microbiomes were correlated with the pathways of "Alanine aspartate and glutamate metabolism" and "Pyruvate metabolism". Intensive feeding increased methane degradation functions, while grazing yaks had higher methyl metabolites associated with methane production. These rumen microbiomes and their metabolites resulted in changes in plasma metabolome, finally influencing yaks' growth. Thus, an intensive feeding system altered the rumen microbiome and metabolism as well as host metabolism, resulting in improvements of yak growth.PMID:39572587 | DOI:10.1038/s41522-024-00609-2

NPJ Sci Food. 2024 Nov 22;8(1):99. doi: 10.1038/s41538-024-00343-1.ABSTRACTThe typical edible medicinal plants of Viola inconspicua were compared with leaf-green, biomass, metabolomes, and bacterial communities, after leaf-spraying water (A), brown sugar water (B), brown sugar, urea, and KH2PO4 water (C), or KH2PO4 and urea water (D). The plants sprayed with C solution presented relatively normal leaf-green and the highest biomass. In contrast of A group, B, C, and D groups were found with 72, 94, and 104 leaf differently accumulated metabolites (DAMs) and 105, 88, and 92 root DAMs, respectively. Typically, relative abundances of amino acids were elevated in C and D groups, while those of leaf flavonoids were increased in B group. Noticeably, leaf DAMs of C group versus A group had strong correlations with one to more phylum- or/and genus-dominant bacteria of C group. Taken together, leaf-spraying brown sugar, urea, and KH2PO4 water are ideal for holding leaf-green and biomass in V. inconspicua plants.PMID:39572563 | DOI:10.1038/s41538-024-00343-1

Nat Commun. 2024 Nov 21;15(1):10076. doi: 10.1038/s41467-024-54373-0.ABSTRACTHigh-risk human papillomaviruses (HPVs) cause various cancers. While type-specific prophylactic vaccines are available, additional anti-viral strategies are highly desirable. Initial HPV cell entry involves receptor-switching induced by structural capsid modifications. These modifications are initiated by interactions with cellular heparan sulphates (HS), however, their molecular nature and functional consequences remain elusive. Combining virological assays with hydrogen/deuterium exchange mass spectrometry, and atomic force microscopy, we investigate the effect of capsid-HS binding and structural activation. We show how HS-induced structural activation requires a minimal HS-chain length and simultaneous engagement of several binding sites by a single HS molecule. This engagement introduces a pincer-like force that stabilizes the capsid in a conformation with extended capsomer linkers. It results in capsid enlargement and softening, thereby likely facilitating L1 proteolytic cleavage and subsequent L2-externalization, as needed for cell entry. Our data supports the further devising of prophylactic strategies against HPV infections.PMID:39572555 | DOI:10.1038/s41467-024-54373-0

Nat Commun. 2024 Nov 21;15(1):10092. doi: 10.1038/s41467-024-54357-0.ABSTRACTIdentifying individuals at high risk of chronic diseases via easily measured biomarkers could enhance efforts to prevent avoidable illness and death. Using 'omic data can stratify risk for many diseases simultaneously from a single measurement that captures multiple molecular predictors of risk. Here we present nuclear magnetic resonance metabolomics in blood samples from 700,217 participants in three national biobanks. We built metabolomic scores that identify high-risk groups for diseases that cause the most morbidity in high-income countries and show consistent cross-biobank replication of the relative risk of disease for these groups. We show that these metabolomic scores are more strongly associated with disease onset than polygenic scores for most of these diseases. In a subset of 18,709 individuals with metabolomic biomarkers measured at two time points we show that people whose scores change have different risk of disease, suggesting that repeat measurements capture changes both to health status and disease risk possibly due to treatment, lifestyle changes or other factors. Lastly, we assessed the incremental predictive value of metabolomic scores over existing clinical risk scores for multiple diseases and found modest improvements in discrimination for several diseases whose clinical utility, while promising, remains to be determined.PMID:39572536 | DOI:10.1038/s41467-024-54357-0

Nat Commun. 2024 Nov 21;15(1):10089. doi: 10.1038/s41467-024-54138-9.ABSTRACTGenomic profiling often fails to predict therapeutic outcomes in cancer. This failure is, in part, due to a myriad of genetic alterations and the plasticity of cancer signaling networks. Functional profiling, which ascertains signaling dynamics, is an alternative method to anticipate drug responses. It is unclear whether integrating genomic and functional features of solid tumours can provide unique insight into therapeutic vulnerabilities. We perform combined molecular and functional characterization, via BH3 profiling of the intrinsic apoptotic machinery, in glioma patient samples and derivative models. We identify that standard-of-care therapy rapidly rewires apoptotic signaling in a genotype-specific manner, revealing targetable apoptotic vulnerabilities in gliomas containing specific molecular features (e.g., TP53 WT). However, integration of BH3 profiling reveals high mitochondrial priming is also required to induce glioma apoptosis. Accordingly, a machine-learning approach identifies a composite molecular and functional signature that best predicts responses of diverse intracranial glioma models to standard-of-care therapies combined with ABBV-155, a clinical drug targeting intrinsic apoptosis. This work demonstrates how complementary functional and molecular data can robustly predict therapy-induced cell death.PMID:39572533 | DOI:10.1038/s41467-024-54138-9

Trends Parasitol. 2024 Nov 20:S1471-4922(24)00309-X. doi: 10.1016/j.pt.2024.10.020. Online ahead of print.ABSTRACTAnthelmintic resistance (AR) in parasitic nematodes poses a global health problem in livestock and domestic animals and is an emerging problem in humans. Consequently, we must understand the mechanisms of AR, including target-site resistance (TSR), in which mutations affect drug binding, and non-target site resistance (NTSR), which involves alterations in drug metabolism and detoxification processes. Because much of the focus has been on TSR, NTSR has received less attention. Here, we describe how metabolomics approaches using Caenorhabditis elegans offer the ability to disentangle nematode drug metabolism, identify metabolic changes associated with resistance, uncover novel biomarkers, and enhance diagnostic methods.PMID:39572328 | DOI:10.1016/j.pt.2024.10.020

CNS Neurosci Ther. 2024 Nov;30(11):e70060. doi: 10.1111/cns.70060.ABSTRACTDiagnosis and prediction of Alzheimer's disease (AD) are increasingly pressing in the early stage of the disease because the biomarker-targeted therapies may be most effective. Diagnosis of AD largely depends on the clinical symptoms of AD. Currently, cerebrospinal fluid biomarkers and neuroimaging techniques are considered for clinical detection and diagnosis. However, these clinical diagnosis results could provide indications of the middle and/or late stages of AD rather than the early stage, and another limitation is the complexity attached to limited access, cost, and perceived invasiveness. Therefore, the prediction of AD still poses immense challenges, and the development of novel biomarkers is needed for early diagnosis and urgent intervention before the onset of obvious phenotypes of AD. Blood-based biomarkers may enable earlier diagnose and aid detection and prognosis for AD because various substances in the blood are vulnerable to AD pathophysiology. The application of a systematic biological paradigm based on high-throughput techniques has demonstrated accurate alterations of molecular levels during AD onset processes, such as protein levels and metabolite levels, which may facilitate the identification of AD at an early stage. Notably, proteomics and metabolomics have been used to identify candidate biomarkers in blood for AD diagnosis. This review summarizes data on potential blood-based biomarkers identified by proteomics and metabolomics that are closest to clinical implementation and discusses the current challenges and the future work of blood-based candidates to achieve the aim of early screening for AD. We also provide an overview of early diagnosis, drug target discovery and even promising therapeutic approaches for AD.PMID:39572036 | DOI:10.1111/cns.70060

J Adv Res. 2024 Nov 19:S2090-1232(24)00543-5. doi: 10.1016/j.jare.2024.11.024. Online ahead of print.ABSTRACTINTRODUCTION: The intricate interplay of interleukin-10 (IL-10) and gut microbiota influences tumor development and progression, yet the impacts on colorectal cancer (CRC) metastasis remain incompletely understood.METHODS: The impact of Il10 deficiency on CRC metastasis was first evaluated in CRC metastasis tumor samples and mouse model. Antibiotic sterilization and fecal microbiota transplantation (FMT) experiment were used to assess the role of gut microbiota in IL-10 mediated CRC metastasis, and full-length 16S rDNA sequencing analysis further identified the potential target bacteria influencing CRC metastasis. The inhibitory effect of Parabacteroides distasonis (P. distasonis) on CRC metastasis was evaluated by oral administration in mice. Key metabolites involved in P. distasonis inhibition of CRC metastasis was identified by widely-targeted metabolome analysis and validated both in vivo and in vitro. The underlying mechanisms of P-hydroxyphenyl acetic acid (4-HPAA) inhibiting CRC metastasis was investigated via RNA-sequencing and validated in cellular experiments.RESULTS: We revealed that serum IL-10 levels were markedly elevated in metastatic CRC patients compared to non-metastatic cases. In parallel, Il10-deficiency (Il10-/) in mice resulted in decreased CRC metastasis in a gut microbiota-dependent manner. Mechanistically, Il10-/- mice reshaped gut microbiota composition, notably enriching P. distasonis. The enriched P. distasonis produced 4-HPAA, which activated the aryl hydrocarbon receptor (AHR) and subsequently inhibited the expression of VEGFA, a typical oncogene, thereby sequentially suppressing CRC metastasis. Importantly, engineered bacteria capable of producing 4-HPAA effectively hindered CRC metastasis. Furthermore, AHR depletion significantly disrupted the 4-HPAA-induced reduction in CRC cell migration and the inhibition of metastasis in both in vitro and in vivo lung metastasis mouse models.CONCLUSIONS: These findings demonstrate the significance of IL-10 deficiency in suppressing CRC metastasis through the 4-HPPA-AHR-VEGFA axis mediated by gut P. distasonis, suggesting that P. distasonis or 4-HPAA supplementation could offer a promising therapeutic strategy for CRC metastasis prevention.PMID:39571733 | DOI:10.1016/j.jare.2024.11.024

J Ethnopharmacol. 2024 Nov 19:119129. doi: 10.1016/j.jep.2024.119129. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Type 2 diabetes mellitus (T2DM) poses significant threats to public health. In Traditional Chinese Medicine (TCM), the Phellodendri Chinensis Cortex-Anemarrhenae Rhizoma (PCC/AR) herb pair has long been used for T2DM treatment, although its specific anti-diabetic mechanisms remain unclear.AIM OF THE STUDY: This study aimed to elucidate the relationship between metabolomics of T2DM patients and the anti-diabetic effects of PCC/AR herb pair in mice through clinical metabolomics and both in vitro and in vivo experiments.MATERIALS AND METHODS: In this study, a T2DM mouse model was established via high-fat feeding (HFD) and streptozotocin (STZ) injection. The effects of PCC/AR on blood glucose, lipid metabolism, and inflammatory markers were evaluated. High-performance liquid chromatography-mass spectrometry (HPLC-MS) was performed for metabolomics analysis of T2DM patients.RESULTS: Serum metabolomics analysis identified significant alterations in metabolites linked to the biosynthesis of unsaturated fatty acids and purine metabolism in T2DM patients, with elevated 2-hydroxyvaleric acid (2HB) levels. In T2DM mice, PCC/AR intervention normalized FBG, GHbA1c, TC, TG, LDL-C, HDL-C, TNF-α and IL-1β levels, while improving insulin sensitivity and pancreatic β-cell function in T2DM mice. Notably, PCC/AR reduced key enzymes in gluconeogenesis and fatty acid synthesis, PEPCK and ACC1.CONCLUSION: PCC/AR herb pair exerts an anti-diabetes effect in T2DM mice by regulating 2HB through ACC1 inhibition, thereby reducing FFA and TG synthesis. Additionally, PCC/AR may also exert its effects by modulating glucose and lipid metabolism and reducing inflammation. These results support further investigation into the PCC/AR herb pair as a complementary therapy for T2DM.PMID:39571697 | DOI:10.1016/j.jep.2024.119129

Toxicol Appl Pharmacol. 2024 Nov 19:117161. doi: 10.1016/j.taap.2024.117161. Online ahead of print.ABSTRACTBrain injury following acute diquat poisoning has become increasingly common in moderate to severe cases, with unclear pathogenesis and high mortality. To investigate this, we conducted metabolomics on brain tissue from poisoned rats, combined with clinical biochemical and pathological analyses. In the high-dose group, 24 metabolites showed significant differences compared to the control group: 18 were upregulated, including cytosine, sedoheptulose-7-phosphate, indole, 3-dehydroshikimate, etc.; 6 were downregulated, including 6-phosphogluconic acid, 3-hydroxybenzoic acid, dAMP, etc. In the low-dose group, 10 metabolites showed significant differences: 4 were upregulated, including pentamidine, γ-tocotrienol, benzoylecgonine, etc.; and 6 were downregulated, including dAMP, glutathione, 3-hydroxybenzoic acid, etc. Enrichment analysis identified two key pathways-phenylalanine, tyrosine, and tryptophan biosynthesis, and the pentose phosphate pathway-as involved in brain injury. ROC analysis of six differential metabolites showed that sedoheptulose-7-phosphate, (2R)-2-hydroxy-3-(phosphonatooxy)propanoate, and 3-hydroxybenzoic acid had AUC values above 0.8. These findings suggest that these three metabolites demonstrate strong diagnostic potential for brain injury induced by diquat poisoning. Correlation analysis linked these biomarkers to clinical indicators such as neutrophil count and the eutrophil to lymphocyte ratio, supporting their relevance. This study provides insights into the mechanisms and biomarkers of diquat-induced brain injury, offering a foundation for future treatment and rapid detection.PMID:39571689 | DOI:10.1016/j.taap.2024.117161

Immunity. 2024 Nov 15:S1074-7613(24)00492-8. doi: 10.1016/j.immuni.2024.10.012. Online ahead of print.ABSTRACTHow mitochondria reconcile roles in functionally divergent cell death pathways of apoptosis and NLRP3 inflammasome-mediated pyroptosis remains elusive, as is their precise role in NLRP3 activation and the evolutionarily conserved physiological function of NLRP3. Here, we have shown that when cells were challenged simultaneously, apoptosis was inhibited and NLRP3 activation prevailed. Apoptosis inhibition by structurally diverse NLRP3 activators, including nigericin, imiquimod, extracellular ATP, particles, and viruses, was not a consequence of inflammasome activation but rather of their effects on mitochondria. NLRP3 activators turned out as oxidative phosphorylation (OXPHOS) inhibitors, which we found to disrupt mitochondrial cristae architecture, leading to trapping of cytochrome c. Although this effect was alone not sufficient for NLRP3 activation, OXPHOS inhibitors became triggers of NLRP3 when combined with resiquimod or Yoda-1, suggesting that NLRP3 activation requires two simultaneous cellular signals, one of mitochondrial origin. Therefore, OXPHOS and apoptosis inhibition by NLRP3 activators provide stringency in cell death decisions.PMID:39571574 | DOI:10.1016/j.immuni.2024.10.012

Food Chem. 2024 Nov 16;465(Pt 2):142089. doi: 10.1016/j.foodchem.2024.142089. Online ahead of print.ABSTRACTAll-aqueous (water-in-water) emulsions are increasingly used as droplets reactors. The present communication reports that precursors of a reaction segregated by partitioning between emulsion phases can undergo reaction at the interface, i.e., on droplet surface, while the interface remains liquid. Na2SO4-in-polyethylene glycol (PEG) emulsions were prepared, and precursors (glucose, asparagine, and tryptophan) of the Maillard reaction were partitioned either inside the droplets (co-encapsulation) or segregated between the emulsion interior and exterior phases. It was found that following the interfacial (i.e., on-droplet) reaction of the segregated precursors, ∼99 % of the Amadori product N-(1-deoxy-D-fructos-1-yl)-L-tryptophan (Fru-Trp) partitioned into the PEG phase. Also, hydrophobic advanced reaction products including β-carboline derivatives and Strecker aldehyde, alongside melanoidins, showed a clear affinity towards the PEG phase. Once the precursors were co-encapsulated within Na2SO4 droplets, following their generation succinimide and pyridine derivatives remained partitioned within the droplets, whereas N-hydroxysuccinimide, pyrrole derivatives, and melanoidins predominantly partitioned into the PEG phase.PMID:39571442 | DOI:10.1016/j.foodchem.2024.142089