PubMed

Aquat Toxicol. 2023 Oct 28;264:106736. doi: 10.1016/j.aquatox.2023.106736. Online ahead of print.ABSTRACTPlastic is undoubtedly the most useful and versatile polymeric material that man has developed in the last two centuries Despite the societal benefits, plastic is now a serious global issue because it is persistent and may bioaccumulate into aquatic biota as microplastics (MPs). This study was designed to evaluate the daily uptake and cellular effects due to a short-term (up to 72 h) exposure to 3 μm red polystyrene MPs (50 beads/mL) in the gills of the Mediterranean mussel Mytilus galloprovincialis, chosen as model species for its ecological and commercial relevance. After measuring the daily uptake of MPs and detecting their presence within the branchial epithelium at all the exposure time-points (T24, T48, T72), some cleaning mechanisms were observed by neutral and acid mucous secretions at mussel gills. The protonic Nuclear Magnetic Resonance (1H NMR)-based metabolomics, combined with chemometrics, allowed to comprehensively explore the time-dependent metabolic disorders triggered by MPs in mussel gills over the short-term trial. Specifically, the clear clustering between MP-treated mussel gills and those from control, together with the grouping for experimental time-points as depicted by the Principal Component Analysis (PCA), were due to changes in the amino acids and energy metabolism, disturbances in the osmoregulatory processes, as well as in the cholinergic neurotransmission. Moreover, as evidenced by enzymatic assays, even the oxidative defense systems and lipid metabolism were hampered by MP exposure. Overall, these findings provides the first insights into the early time-dependent mechanisms of toxicity of polystyrene MPs in marine mussels, and underline the potential environment and human health risk posed by MPs contamination.PMID:37913686 | DOI:10.1016/j.aquatox.2023.106736

Atherosclerosis. 2023 Oct 11;385:117340. doi: 10.1016/j.atherosclerosis.2023.117340. Online ahead of print.ABSTRACTBACKGROUND AND AIMS: Lipids play an important role in atherosclerotic plaque development and are interesting candidate predictive biomarkers. However, the link between circulating lipids, accumulating lipids in the vessel wall, and plaque destabilization processes in humans remains largely unknown. This study aims to provide new insights into the role of lipids in atherosclerosis using lipidomics and mass spectrometry imaging to investigate lipid signatures in advanced human carotid plaque and plasma samples.METHODS: We used lipidomics and desorption electrospray ionization mass spectrometry imaging (DESI-MSI) to investigate lipid signatures of advanced human carotid plaque and plasma obtained from patients who underwent carotid endarterectomy (n = 14 out of 17 whose plaque samples were analyzed by DESI-MSI). Multivariate data analysis and unsupervised clustering were applied to identify lipids that were the most discriminative species between different patterns in plaque and plasma. These patterns were interpreted by quantitative comparison with conventional histology.RESULTS: Lipidomics detected more than 300 lipid species in plasma and plaque, with markedly different relative abundances. DESI-MSI visualized the spatial distribution of 611 lipid-related m/z features in plaques, of which 330 m/z features could be assigned based on exact mass, comparison to the lipidomic data, and high mass resolution MSI. Matching spatial lipid patterns to histological areas of interest revealed several molecular species that were colocalized with pertinent disease processes in plaque including specific sphingomyelin and ceramide species with calcification, phospholipids and free fatty acids with inflammation, and triacylglycerols and phosphatidylinositols with fibrin-rich areas.CONCLUSIONS: By comparing lipid species in plaque and plasma, we identified those circulating species that were also prominently present in plaque. Quantitative comparison of lipid spectral patterns with histology revealed the presence of specific lipid species in destabilized plaque areas, corroborating previous in vitro and animal studies.PMID:37913561 | DOI:10.1016/j.atherosclerosis.2023.117340

Sci Transl Med. 2023 Nov;15(720):eadg3049. doi: 10.1126/scitranslmed.adg3049. Epub 2023 Nov 1.ABSTRACTLipid peroxidation-dependent ferroptosis has become an emerging strategy for tumor therapy. However, current strategies not only selectively induce ferroptosis in malignant cells but also trigger ferroptosis in immune cells simultaneously, which can compromise anti-tumor immunity. Here, we used In-Cell Western assays combined with an unbiased drug screening to identify the compound N6F11 as a ferroptosis inducer that triggered the degradation of glutathione peroxidase 4 (GPX4), a key ferroptosis repressor, specifically in cancer cells. N6F11 did not cause the degradation of GPX4 in immune cells, including dendritic, T, natural killer, and neutrophil cells. Mechanistically, N6F11 bound to the RING domain of E3 ubiquitin ligase tripartite motif containing 25 (TRIM25) in cancer cells to trigger TRIM25-mediated K48-linked ubiquitination of GPX4, resulting in its proteasomal degradation. Functionally, N6F11 treatment caused ferroptotic cancer cell death that initiated HMGB1-dependent antitumor immunity mediated by CD8+ T cells. N6F11 also sensitized immune checkpoint blockade that targeted CD274/PD-L1 in advanced cancer models, including genetically engineered mouse models of pancreatic cancer driven by KRAS and TP53 mutations. These findings may establish a safe and efficient strategy to boost ferroptosis-driven antitumor immunity.PMID:37910602 | DOI:10.1126/scitranslmed.adg3049

Elife. 2023 Nov 1;12:e84235. doi: 10.7554/eLife.84235.ABSTRACTCardiac muscle has the highest mitochondrial density of any human tissue, but mitochondrial dysfunction is not a recognized cause of isolated cardiomyopathy. Here, we determined that the rare mitofusin (MFN) 2 R400Q mutation is 15-20× over-represented in clinical cardiomyopathy, whereas this specific mutation is not reported as a cause of MFN2 mutant-induced peripheral neuropathy, Charcot-Marie-Tooth disease type 2A (CMT2A). Accordingly, we interrogated the enzymatic, biophysical, and functional characteristics of MFN2 Q400 versus wild-type and CMT2A-causing MFN2 mutants. All MFN2 mutants had impaired mitochondrial fusion, the canonical MFN2 function. Compared to MFN2 T105M that lacked catalytic GTPase activity and exhibited normal activation-induced changes in conformation, MFN2 R400Q and M376A had normal GTPase activity with impaired conformational shifting. MFN2 R400Q did not suppress mitochondrial motility, provoke mitochondrial depolarization, or dominantly suppress mitochondrial respiration like MFN2 T105M. By contrast to MFN2 T105M and M376A, MFN2 R400Q was uniquely defective in recruiting Parkin to mitochondria. CRISPR editing of the R400Q mutation into the mouse Mfn2 gene induced perinatal cardiomyopathy with no other organ involvement; knock-in of Mfn2 T105M or M376V did not affect the heart. RNA sequencing and metabolomics of cardiomyopathic Mfn2 Q/Q400 hearts revealed signature abnormalities recapitulating experimental mitophagic cardiomyopathy. Indeed, cultured cardiomyoblasts and in vivo cardiomyocytes expressing MFN2 Q400 had mitophagy defects with increased sensitivity to doxorubicin. MFN2 R400Q is the first known natural mitophagy-defective MFN2 mutant. Its unique profile of dysfunction evokes mitophagic cardiomyopathy, suggesting a mechanism for enrichment in clinical cardiomyopathy.PMID:37910431 | DOI:10.7554/eLife.84235

Obes Surg. 2023 Nov 1. doi: 10.1007/s11695-023-06905-8. Online ahead of print.ABSTRACTPURPOSE: Remission of type 2 diabetes (T2D) can be achieved by many, but not all, people following bariatric/metabolic surgery. The mechanisms underlying T2D remission remain incompletely understood. This observational study aimed to identify novel weight-loss independent clinical, metabolic and genetic factors that associate with T2D remission using comprehensive phenotyping.MATERIALS AND METHODS: Ten patients without T2D remission (non-remitters) were matched to 10 patients with T2D remission (remitters) for age, sex, type of surgery, body weight, BMI, post-operative weight loss, duration from surgery and duration of T2D. Detailed body composition assessed using magnetic resonance imaging, gut hormones, serum metabolomics, insulin sensitivity, and genetic risk scores for T2D and anthropometric traits were assessed.RESULTS: Remitters had significantly greater β-cell function and circulating acyl ghrelin levels, but lower visceral adipose tissue (VAT): subcutaneous adipose tissue (SAT) ratio than non-remitters. Branched-chain amino acids (BCAAs) and VLDL particle size were the most discriminant metabolites between groups. A significant positive correlation between, VAT area, VAT:SAT ratio and circulating levels of BCAAs was observed, whereas a significant negative correlation between BCAAs and β-cell function was revealed.CONCLUSION: We highlight a potentially novel relationship between VAT and BCAAs, which may play a role in glucoregulatory control. Improvement in β-cell function, and the role ghrelin plays in its recovery, is likely another key factor influencing T2D remission post-surgery. These findings suggest that adjunctive approaches that target VAT loss and restoration of BCAA metabolism might achieve higher rates of long-term T2D remission post-surgery.PMID:37910328 | DOI:10.1007/s11695-023-06905-8

Mol Nutr Food Res. 2023 Nov 1:e2200525. doi: 10.1002/mnfr.202200525. Online ahead of print.ABSTRACTSCOPE: Aged laying hen is recently suggested as a more attractive animal model than rodent for studying nonalcoholic fatty liver disease (NAFLD) of humans. This study aims to reveal effects and metabolic regulation mechanisms of taurine alleviating NAFLD by using the aged laying hen model.METHODS AND RESULTS: Liver histomorphology and biochemical indices showe 0.02% taurine effectively alleviates fat deposition and liver damage. Comparative liver lipidomics and gene expressions analyses reveal taurine promoted lipolysis, fatty acids oxidation, lipids transport, and reduced oxidative stress in liver. Furthermore, comparative serum metabolomics screen six core metabolites negatively correlated with NAFLD, including linoleic acid, gamma-linolenic acid, pantothenate, L-methionine, 2-methylbutyroylcarnitine, L-carnitine; and two core metabolites positively correlated with NAFLD, including lysophosphatidylcholine (14:0/0:0) and lysophosphatidylcholine (16:0/0:0). Metabolic pathway analysis reveals taurine mainly regulated linoleic acid metabolism, cysteine and methionine metabolism, carnitine metabolism, pantothenic acid and coenzyme A biosynthesis metabolism, and glycerophospholipid metabolism to up-adjust levels of six negatively correlated metabolites and down-adjust two positively correlated metabolites for alleviating NAFLD of aged hens.CONCLUSION: This study firstly reveals underlying metabolic mechanisms of taurine alleviating NAFLD using the aged hen model, thereby laying the foundation for taurine's application in the prevention of NAFLD in both human and poultry.PMID:37909476 | DOI:10.1002/mnfr.202200525

Food Funct. 2023 Nov 1. doi: 10.1039/d3fo03031h. Online ahead of print.ABSTRACTSea cucumber peptides (SCPs) have been proven to have many active functions; however, their impact on testosterone synthesis and the corresponding mechanism are not yet clear. This study attempts to explore the effects of SCPs on sex hormone regulation in acute exhaustive swimming (AES) male mice and the possible mechanisms. In the present study, SCP intervention significantly prolonged exhaustive swimming time and reduced exercise metabolite accumulation. The reproductive ability-related parameters including penile index, mating ability, testicular morphology, and sperm storage were dramatically improved by SCP intervention. Notably, SCPs markedly reversed the AES-induced decrease in serum testosterone (T), estradiol (E2), and follicle-stimulating hormone (FSH) levels. Moreover, treatment with a high dose of SCP (0.6 mg per g bw) significantly enhanced the expression of testosterone synthesis-related proteins in testis, meanwhile markedly increasing the gene expression of StAR, Hsd17b3, Hsd17b2, Ldlr, and Cyp19a1. Serum metabolomics results indicated that SCP intervention notably upregulated the expression of 1-stearoyl-2-arachidonoyl-sn-glycerol but downregulated the concentrations of succinate and DL-lactate. Furthermore, serum metabolomics combined with testicular transcriptome, western blot, and correlation analyses demonstrated that SCPs may regulate testosterone synthesis via the Ca2+/PKA signaling pathway. This study indicated that the SCP could be a potential dietary supplement to improve the symptoms of decreased sex hormones related to exercise fatigue.PMID:37909356 | DOI:10.1039/d3fo03031h

Immunity. 2023 Oct 26:S1074-7613(23)00418-1. doi: 10.1016/j.immuni.2023.09.013. Online ahead of print.ABSTRACTDimeric IgA (dIgA) can move through cells via the IgA/IgM polymeric immunoglobulin receptor (PIGR), which is expressed mainly on mucosal epithelia. Here, we studied the ability of dIgA to target commonly mutated cytoplasmic oncodrivers. Mutation-specific dIgA, but not IgG, neutralized KRASG12D within ovarian carcinoma cells and expelled this oncodriver from tumor cells. dIgA binding changed endosomal trafficking of KRASG12D from accumulation in recycling endosomes to aggregation in the early/late endosomes through which dIgA transcytoses. dIgA targeting of KRASG12D abrogated tumor cell proliferation in cell culture assays. In vivo, KRASG12D-specific dIgA1 limited the growth of KRASG12D-mutated ovarian and lung carcinomas in a manner dependent on CD8+ T cells. dIgA specific for IDH1R132H reduced colon cancer growth, demonstrating effective targeting of a cytoplasmic oncodriver not associated with surface receptors. dIgA targeting of KRASG12D restricted tumor growth more effectively than small-molecule KRASG12D inhibitors, supporting the potential of this approach for the treatment of human cancers.PMID:37909039 | DOI:10.1016/j.immuni.2023.09.013

Front Plant Sci. 2023 Oct 16;14:1236145. doi: 10.3389/fpls.2023.1236145. eCollection 2023.ABSTRACTEphedra is an important plant in Chinese medicine; however, there are few reports on two species of Ephedra which are distributed at high altitudes from 3000 to 5200 meters. We collected a total of 84 individuals representing five Ephedra gerardiana and nine Ephedra saxatilis populations respectively located from 3158 to 5200 meters altitude, and determined the relative content of 213 metabolites using UHPLC-MS/MS (Ultra-High-Performance Liquid Chromatography-tandem mass spectrometry). 37 Chemical compositions were annotated using the KEGG (Kyoto Encyclopaedia of Genes and Genomes) database. From the top five significant enrichments in metabolic KEGG pathway analysis, we found a total of 166 compounds belonging to phenylpropanoids, 123 flavonoids, 67 metabolites carried by ABC transporters, and 61 in purine metabolism. We identified the top 8 altitude-related compounds in two species. Ephedrine and pseudoephedrine were found to be associated with altitude in both E. saxatilis and E. gerardiana. To verify which environmental factors influenced the metabolic content, the soil moisture and temperature of each population site were collected, and quantitative analysis of ephedrine and pseudoephedrine was performed using UHPLC-MS (Ultra-High-Performance liquid chromatography-tandem mass spectrometry). After detection, soil moisture ranged from 0.074 to 0.177 mm3/mm3, and temperature ranged from 9.7°C to 23.9°C. The content of ephedrine ranged from (0.84 ± 0.49)% to (2.01 ± 0.41)% in E. saxatilis, which was positively correlated with soil moisture; the content of pseudoephedrine ranged from (0.72 ± 0.45)% to (1.11 ± 0.57)% and was negatively correlated with soil moisture. In contrast to these results, in E. gerardiana, the content of ephedrine and pseudoephedrine was negatively correlated with soil moisture. Furthermore, the trends of alkaloid contents in two kinds of Ephedra were similar when the temperature was lower than 17°C even if the sum was various. With the increase in soil moisture and temperature, the total alkaloid content of E. saxatilis was higher than that of E. gerardiana. When the soil moisture was lower, the alkaloid content of the two Ephedra species was higher. These results provide useful data for the future separation of new compounds, and for seed homogeneous growth to determine artificial breeding of Ephedra located at high altitudes.PMID:37908827 | PMC:PMC10613977 | DOI:10.3389/fpls.2023.1236145

Front Endocrinol (Lausanne). 2023 Oct 16;14:1248575. doi: 10.3389/fendo.2023.1248575. eCollection 2023.ABSTRACTINTRODUCTION: Reprogramming of cellular metabolism is now a hallmark of tumorigenesis. In recent years, research on pancreatic neuroendocrine tumors (pNETs) has focused on genetic and epigenetic modifications and related signaling pathways, but few studies have been devoted to characterizing the metabolic profile of these tumors. In this review, we thoroughly investigate the metabolic pathways in pNETs by analyzing the transcriptomic and metabolomic data available in the literature.METHODOLOGY: We retrieved and downloaded gene expression profiles from all publicly available gene set enrichments (GSE43797, GSE73338, and GSE117851) to compare the differences in expressed genes based on both the stage and MEN1 mutational status. In addition, we conducted a systematic review of metabolomic data in NETs.RESULTS: By combining transcriptomic and metabolomic approaches, we have identified a distinctive metabolism in pNETs compared with controls without pNETs. Our analysis showed dysregulations in the one-carbon, glutathione, and polyamine metabolisms, fatty acid biosynthesis, and branched-chain amino acid catabolism, which supply the tricarboxylic acid cycle. These targets are implicated in pNET cell proliferation and metastasis and could also have a prognostic impact. When analyzing the profiles of patients with or without metastasis, or with or without MEN1 mutation, we observed only a few differences due to the scarcity of published clinical data in the existing research. Consequently, further studies are now necessary to validate our data and investigate these potential targets as biomarkers or therapeutic solutions, with a specific focus on pNETs.PMID:37908747 | PMC:PMC10613989 | DOI:10.3389/fendo.2023.1248575

Heliyon. 2023 Oct 19;9(11):e21108. doi: 10.1016/j.heliyon.2023.e21108. eCollection 2023 Nov.ABSTRACTINTRODUCTION: Researchers have investigated the causal effect between serum uric acid (SUA) concentrations and kidney function for decades, but studies produced inconsistent results. This study aimed to clarify the bidirectional causal effects between SUA concentrations and kidney function and to explore the potential ethnic disparities by conducting a trans-ethnic Mendelian randomization study in European, African, and Asian ancestries.MATERIALS AND METHODS: The summary-level data for this study were obtained from the Global Urate Genetics Consortium, CKDGen Consortium, UK Biobank, and Japan Biobank for different outcomes and exposures, respectively. The traits of kidney function were estimated glomerular filtration rate from serum creatinine (eGFRcr), estimated glomerular filtration rate from cystatin C (eGFRcys), and blood urea nitrogen (BUN). Using the multiplicative random-effects inverse variance weighting mode, our primary analysis produced robust results despite heterogeneity. Additionally, we performed the Mendelian randomization pleiotropy residual sum and outlier test to eliminate the horizontal pleiotropy and obtain accurate results.RESULTS: Our findings revealed that elevated SUA concentrations had causal effects on declined eGFRcys, BUN, and a diagnosis of chronic kidney disease in European ancestries and eGFRcr in Asian ancestries. Additionally, the causal effects of declined eGFRcr and elevated BUN concentrations on elevated SUA concentrations were observed in both European and Asian ancestries. However, no bidirectional causal effect was found between SUA concentrations and eGFRcr among African ancestries.CONCLUSIONS: This trans-ethnic Mendelian randomization study confirmed the bidirectional causal effects between SUA concentrations and kidney function and highlighted the importance of considering ethnic disparities in clinical treatments.PMID:37908715 | PMC:PMC10613891 | DOI:10.1016/j.heliyon.2023.e21108

Front Toxicol. 2023 Oct 16;5:1216802. doi: 10.3389/ftox.2023.1216802. eCollection 2023.ABSTRACTIntroduction: The positive identification of xenobiotics and their metabolites in human biosamples is an integral aspect of exposomics research, yet challenges in compound annotation and identification continue to limit the feasibility of comprehensive identification of total chemical exposure. Nonetheless, the adoption of in silico tools such as metabolite prediction software, QSAR-ready structural conversion workflows, and molecular standards databases can aid in identifying novel compounds in untargeted mass spectral investigations, permitting the assessment of a more expansive pool of compounds for human health hazard. This strategy is particularly applicable when it comes to flame retardant chemicals. The population is ubiquitously exposed to flame retardants, and evidence implicates some of these compounds as developmental neurotoxicants, endocrine disruptors, reproductive toxicants, immunotoxicants, and carcinogens. However, many flame retardants are poorly characterized, have not been linked to a definitive mode of toxic action, and are known to share metabolic breakdown products which may themselves harbor toxicity. As U.S. regulatory bodies begin to pursue a subclass- based risk assessment of organohalogen flame retardants, little consideration has been paid to the role of potentially toxic metabolites, or to expanding the identification of parent flame retardants and their metabolic breakdown products in human biosamples to better inform the human health hazards imposed by these compounds. Methods: The purpose of this study is to utilize publicly available in silico tools to 1) characterize the structural and metabolic fates of proposed flame retardant classes, 2) predict first pass metabolites, 3) ascertain whether metabolic products segregate among parent flame retardant classification patterns, and 4) assess the existing coverage in of these compounds in mass spectral database. Results: We found that flame retardant classes as currently defined by the National Academies of Science, Engineering and Medicine (NASEM) are structurally diverse, with highly variable predicted pharmacokinetic properties and metabolic fates among member compounds. The vast majority of flame retardants (96%) and their predicted metabolites (99%) are not present in spectral databases, posing a challenge for identifying these compounds in human biosamples. However, we also demonstrate the utility of publicly available in silico methods in generating a fit for purpose synthetic spectral library for flame retardants and their metabolites that have yet to be identified in human biosamples. Discussion: In conclusion, exposomics studies making use of fit-for-purpose synthetic spectral databases will better resolve internal exposure and windows of vulnerability associated with complex exposures to flame retardant chemicals and perturbed neurodevelopmental, reproductive, and other associated apical human health impacts.PMID:37908592 | PMC:PMC10613991 | DOI:10.3389/ftox.2023.1216802

Front Microbiol. 2023 Oct 16;14:1275649. doi: 10.3389/fmicb.2023.1275649. eCollection 2023.ABSTRACTInfectious hematopoietic necrosis (IHN) is a major disease that limits the culture of rainbow trout. In practical production, it has been found that the temperature of the culture water is a crucial factor affecting its mortality. Currently, little is known about how temperature affects the immune response of rainbow trout gut microbiota and metabolites to IHNV. In this study, our main objective is to analyze the changes in gut microorganisms of rainbow trout (juvenile fish with a consistent genetic background) after 14 days of infection with IHNV (5 × 105 pfu/fish) at 12-13°C (C: injected with saline, A: injected with IHNV) and 16-17°C (D: injected with saline, B: injected with IHNV) using metagenomic and metabolomic analyses, and to screen for probiotics that are effective against IHNV. The results showed that infection with IHNV at 12-13°C caused Eukaryote loss. Compared to Group C, Group A showed a significant increase in harmful pathogens, such as Yersiniaceae, and a significant alteration of 4,087 gut metabolites. Compared to group D, group B showed a significant increase in the abundance of Streptococcaceae and Lactococcus lactis, along with significant changes in 4,259 intestinal metabolites. Compared with their respective groups, the levels of two immune-related metabolites, 1-Octadecanoyl-glycero-3-phosphoethanolamine and L-Glutamate, were significantly upregulated in groups A and B. Compared to group B, Group A showed significantly higher pathogenic bacteria including Aeromonas, Pseudomonas, and Yersiniaceae, while group B showed a significant increase in Streptococcaceae and Lactococcus lactis. Additionally, there were 4,018 significantly different metabolites between the two groups. Interestingly, 1-Octadecanoyl-sn-glycero-3-phosphoethanolamine and L-Glutamate were significantly higher in group A than in group B. Some of the different metabolites in C vs. A are correlated with Fomitopsis pinicola, while in D vs. B they were correlated with Lactococcus raffinolactis, and in A vs. B they were correlated with Hypsizygus marmoreus. This study exposed how rainbow trout gut microbiota and metabolites respond to IHNV at different temperatures, and screens beneficial bacteria with potential resistance to IHN, providing new insights and scientific basis for the prevention and treatment of IHN.PMID:37908544 | PMC:PMC10614001 | DOI:10.3389/fmicb.2023.1275649

ERJ Open Res. 2023 Oct 30;9(5):00180-2023. doi: 10.1183/23120541.00180-2023. eCollection 2023 Sep.ABSTRACTCOPD is a heterogeneous disorder that shows diverse clinical presentations (phenotypes and "treatable traits") and biological mechanisms (endotypes). This heterogeneity implies that to carry out a more personalised clinical management, it is necessary to classify each patient accurately. With this objective, and in addition to clinical features, it would be very useful to have well-defined biological markers. The search for these markers may either be done through more conventional laboratory and hypothesis-driven techniques or relatively blind high-throughput methods, with the omics approaches being suitable for the latter. Metabolomics is the science that studies biological processes through their metabolites, using various techniques such as gas and liquid chromatography, mass spectrometry and nuclear magnetic resonance. The most relevant metabolomics studies carried out in COPD highlight the importance of metabolites involved in pathways directly related to proteins (peptides and amino acids), nucleic acids (nitrogenous bases and nucleosides), and lipids and their derivatives (especially fatty acids, phospholipids, ceramides and eicosanoids). These findings indicate the relevance of inflammatory-immune processes, oxidative stress, increased catabolism and alterations in the energy production. However, some specific findings have also been reported for different COPD phenotypes, demographic characteristics of the patients, disease progression profiles, exacerbations, systemic manifestations and even diverse treatments. Unfortunately, the studies carried out to date have some limitations and shortcomings and there is still a need to define clear metabolomic profiles with clinical utility for the management of COPD and its implicit heterogeneity.PMID:37908399 | PMC:PMC10613990 | DOI:10.1183/23120541.00180-2023

Front Physiol. 2023 Oct 16;14:1258678. doi: 10.3389/fphys.2023.1258678. eCollection 2023.ABSTRACTIntroduction: Novel markers of vitamin D status are currently being investigated, including free 25-(OH)D (25-(OH)DF) and the vitamin D metabolite ratio (24,25-(OH)2D3:25-(OH)D3; VMR). The VMR may provide additional functional information on vitamin D metabolism in athletes. Therefore, the main objective of the current study was to evaluate 25-(OH)DF, bioavailable 25-(OH)D (25-(OH)DB), VMR, and psychophysical stress markers during different training periods over a half-season. The second aim was to assess the association between vitamin D binding protein (VDBP), total and free 25-(OH)D, VMRs, and psychophysical stress markers in professional football players. Moreover, we examined the relationship between 25-(OH)D3 and vitamin D metabolites (24,25-(OH)2D3, 3-epi-25-(OH)D3) to determine if training loads in different training periods influenced the vitamin D metabolome. Methods: Twenty professional football players were tested at six different time points across half a year (V1-June; V2-July; V3-August; V4-October; V5-December; V6-January). Results: Analyses indicated a significant seasonal rhythm for VDBP, and total 25-(OH)D (25-(OH)DT), 25-(OH)DB, 24,25-(OH)2D3, 3-epi-25-(OH)D3, 25-(OH)D3:24,25-(OH)2D3, and 24,25-(OH)2D3:25-(OH)D3 VMRs throughout the training period. No correlation was detected between 25-(OH)DT, 25-(OH)DB, 25-(OH)DF, vitamin D metabolites, VMRs, VDBP, and ferritin, liver enzymes (aspartate transaminase [AST] and alanine transaminase [ALT]), creatine kinase (CK), cortisol, testosterone, and testosterone-to-cortisol ratio (T/C) in each period (V1-V6). However, there was a strong statistically significant correlation between 25-(OH)D3 and 24,25-(OH)D3 in each training period. Conclusion: In conclusion, a seasonal rhythm was present for VDBP, 25-(OH)DT, 25-(OH)DB, vitamin D metabolites (24,25-(OH)2D3, 3-epi-25-(OH)D3), and VMRs (25-(OH)D3:24,25-(OH)2D3, 25-(OH)D3:3-epi-25-(OH)D3). However, no rhythm was detected for 25-(OH)DF and markers of psychophysical stress (ferritin, liver enzymes, CK, testosterone, cortisol, and T/C ratio). Moreover, the relationships between free and total 25-(OH)D with psychophysical stress markers did not demonstrate the superiority of free over total measurements. Furthermore, training loads in different training periods did not affect resting vitamin D metabolite concentrations in football players.PMID:37908338 | PMC:PMC10613696 | DOI:10.3389/fphys.2023.1258678

Nutr Cancer. 2023 Oct 31:1-11. doi: 10.1080/01635581.2023.2267779. Online ahead of print.ABSTRACTChemotherapy-induced diarrhea (CID) is a common adverse event in cancer patients, which, unless treated, may lead to drug discontinuation and treatment failure. Some probiotics such as Lactobacillus, Bifidobacterium, and Saccharomyces species have been gaining clinical attention in alleviating chemotherapy-induced adverse events including diarrhea. This comprehensive review provides an overview and discusses preventive approaches of probiotics with respect to CID in several types of cancers. The potential mechanisms of probiotics may comprise regulation of intestinal microbiota, modulation of immune functions, or reduction of proinflammatory cytokines. The efficacy and safety precautions of probiotics in immunocompromised cancer patients are discussed. The non-pharmacological strategy using probiotics could reduce the use of anti-diarrheal or antibiotic agents. Some individuals experienced shorter length of hospital stay, better gastrointestinal function, and reduced incidence of chemotherapy dose reduction after probiotic administration. Nonetheless, some studies failed to report the benefits of probiotics in certain patients. This review also highlights preventive protocols and therapeutic implications by considering the potential influencing factors, particularly types of probiotic strains, dosages of probiotics, duration of their administration, patients' tolerability, and variations in probiotic effects over the cancer stages.PMID:37908158 | DOI:10.1080/01635581.2023.2267779

Diabetol Metab Syndr. 2023 Oct 31;15(1):223. doi: 10.1186/s13098-023-01196-6.ABSTRACTBACKGROUND: Sodium-glucose cotransporter (SGLT)2 inhibitors have displayed beneficial effects on the cardiovascular system in diabetes mellitus (DM) patients. As most clinical trials were performed in Type 2 DM, their effects in Type 1 DM have not been established.OBJECTIVE: To evaluate the influence of long-term treatment with SGLT2 inhibitor dapagliflozin on cardiac remodeling, myocardial function, energy metabolism, and metabolomics in rats with Type 1 DM.METHODS: Male Wistar rats were divided into groups: Control (C, n = 15); DM (n = 15); and DM treated with dapagliflozin (DM + DAPA, n = 15) for 30 weeks. DM was induced by streptozotocin. Dapagliflozin 5 mg/kg/day was added to chow.STATISTICAL ANALYSIS: ANOVA and Tukey or Kruskal-Wallis and Dunn.RESULTS: DM + DAPA presented lower glycemia and higher body weight than DM. Echocardiogram showed DM with left atrium dilation and left ventricular (LV) hypertrophy, dilation, and systolic and diastolic dysfunction. In LV isolated papillary muscles, DM had reduced developed tension, +dT/dt and -dT/dt in basal condition and after inotropic stimulation. All functional changes were attenuated by dapagliflozin. Hexokinase (HK), phosphofructokinase (PFK) and pyruvate kinase (PK) activity was lower in DM than C, and PFK and PK activity higher in DM + DAPA than DM. Metabolomics revealed 21 and 5 metabolites positively regulated in DM vs. C and DM + DAPA vs. DM, respectively; 6 and 3 metabolites were negatively regulated in DM vs. C and DM + DAPA vs. DM, respectively. Five metabolites that participate in cell membrane ultrastructure were higher in DM than C. Metabolites levels of N-oleoyl glutamic acid, chlorocresol and N-oleoyl-L-serine were lower and phosphatidylethanolamine and ceramide higher in DM + DAPA than DM.CONCLUSION: Long-term treatment with dapagliflozin attenuates cardiac remodeling, myocardial dysfunction, and contractile reserve impairment in Type 1 diabetic rats. The functional improvement is combined with restored pyruvate kinase and phosphofructokinase activity and attenuated metabolomics changes.PMID:37908006 | DOI:10.1186/s13098-023-01196-6

Biol Direct. 2023 Nov 1;18(1):71. doi: 10.1186/s13062-023-00430-5.ABSTRACTCancer immunotherapy, alone or in combination with conventional therapies, has revolutionized the landscape of antineoplastic treatments, with dendritic cells (DC) emerging as key orchestrators of anti-tumor immune responses. Among the distinct DC subsets, conventional type 1 dendritic cells (cDC1) have gained prominence due to their unique ability to cross-present antigens and activate cytotoxic T lymphocytes. This review summarizes the distinctive characteristics of cDC1, their pivotal role in anticancer immunity, and the potential applications of cDC1-based strategies in immunotherapy.PMID:37907944 | DOI:10.1186/s13062-023-00430-5

J Transl Med. 2023 Oct 31;21(1):770. doi: 10.1186/s12967-023-04648-9.ABSTRACTBACKGROUND: Lycium barbarum polysaccharide (LBP) is an active ingredient extracted from Lycium barbarum that inhibits neuroinflammation, and Lycium barbarum glycopeptide (LbGp) is a glycoprotein with immunological activity that was purified and isolated from LBP. Previous studies have shown that LbGp can regulate the immune microenvironment, but its specific mechanism of action remains unclear.AIMS: In this study, we aimed to explore the mechanism of action of LbGp in the treatment of spinal cord injury through metabolomics and molecular experiments.METHODS: SD male rats were randomly assigned to three experimental groups, and after establishing the spinal cord hemisection model, LbGp was administered orally. Spinal cord tissue was sampled on the seventh day after surgery for molecular and metabolomic experiments. In vitro, LbGp was administered to mimic the inflammatory microenvironment by activating microglia, and its mechanism of action in suppressing neuroinflammation was further elaborated using metabolomics and molecular biology techniques such as western blotting and q-PCR.RESULTS: In vivo and in vitro experiments found that LbGp can improve the inflammatory microenvironment by inhibiting the NF-kB and pyroptosis pathways. Furthermore, LbGp induced the secretion of docosahexaenoic acid (DHA) by microglia, and DHA inhibited neuroinflammation through the MAPK/NF-κB and pyroptosis pathways.CONCLUSIONS: In summary, we hypothesize that LbGp improves the inflammatory microenvironment by regulating the secretion of DHA by microglia and thereby inhibiting the MAPK/NF-κB and pyroptosis pathways and promoting nerve repair and motor function recovery. This study provides a new direction for the treatment of spinal cord injury and elucidates the potential mechanism of action of LbGp.PMID:37907930 | DOI:10.1186/s12967-023-04648-9

Rice (N Y). 2023 Oct 31;16(1):49. doi: 10.1186/s12284-023-00667-8.ABSTRACTDirect seeding of rice is a lightweight and simple cultivation method, which can effectively promote rice production. Anaerobic germination tolerance is one of the main traits of rice adaptability to direct seeding. The mining of related genetic loci, analysis of anaerobic traits and screening of tolerance genes provided valuable genetic resources for improving the anaerobic germination ability of direct seeding rice. This study conducted a dynamic genome-wide association study (GWAS) based on coleoptile-related traits of 591 rice natural populations, and a total of 317 SNP sites were detected. Integrated dynamic widely targeted metabolomics analysis, we found that xanthine, L-alanine and GABA may be key biomarkers that are sensitive and respond strongly to hypoxic stress perception. By WGCNA analysis of targeted metabolomics and transcriptomics, a total of 3 modules were obtained that were significantly correlated with the above three marker metabolites, namely dark green, dark gray and light green modules, respectively, and several key structural genes of OsAlaAT1, OsGAD4, OsAAH and Os09g0424600 that may affect hypoxic germination were screened from the 3 modules. Among them, OsAlaAT1 (Os10g0390500), located in Chr10-12877840, which is within the GWAS location range of CVAN3d, is considered to be a more reliable candidate gene. Overall, in addition to providing new insight into the metabolic regulation of L-alanine, GABA and xanthine during hypoxic germination of rice. This study also provided a reference for the basic theoretical research and breeding application research on the related traits of anaerobic germination in direct-seeding rice.PMID:37907655 | DOI:10.1186/s12284-023-00667-8