PubMed

Eur J Endocrinol. 2023 Nov 30:lvad160. doi: 10.1093/ejendo/lvad160. Online ahead of print.ABSTRACTOBJECTIVE: Metabolic profiling is a valuable tool to characterize tumor biology but remains largely unexplored in neuroendocrine tumors (NETs). Our aim was to comprehensively assess the metabolomic profile of NETs and identify novel prognostic biomarkers and dysregulated molecular pathways.DESIGN AND METHODS: Multiplatform untargeted metabolomic profiling (GC-MS, CE-MS and LC-MS) was performed in plasma from 77 patients with G1-2 extra-pancreatic NETs enrolled in the AXINET trial (NCT01744249) (study cohort) and from 68 non-cancer individuals (control). The prognostic value of each differential metabolite (N=155) in NET patients (p<0.05) was analyzed by univariate and multivariate analysis adjusted for multiple testing and other confounding factors. Related pathways were explored by Metabolite Set Enrichment Analysis (MSEA) and Metabolite Pathway Analysis (MPA).RESULTS: 34 metabolites were significantly associated with progression-free survival (PFS) (N=16) and/or overall survival (OS) (N=27).13 metabolites remained significant independent prognostic factors in multivariate analysis, 3 of them with a significant impact on both PFS and OS. Unsupervised clustering of these 3 metabolites stratified patients in 3 distinct prognostic groups (1-year PFS of 71.1%, 47.7% and 15.4% (p=0.012); 5-year OS of 69.7%, 32.5% and 27.7% (p=0.003), respectively). MSEA and MPA of the 13-metablolite signature identified methionine, porphyrin and tryptophan metabolism as the three most relevant dysregulated pathways associated with the prognosis of NETs.CONCLUSIONS: We identified a metabolomic signature that improves prognostic stratification of NET patients beyond classical prognostic factors for clinical decisions. The enriched metabolic pathways identified reveal novel tumor vulnerabilities that may foster the development of new therapeutic strategies for these patients.PMID:38033321 | DOI:10.1093/ejendo/lvad160

Langmuir. 2023 Nov 30. doi: 10.1021/acs.langmuir.3c01818. Online ahead of print.ABSTRACTTo understand the antimicrobial effect of surfaces fabricated with dead probiotics, we prepared surfaces decorated with dead probiotics Lactobacillus rhamnosus GG (LGG) with varied inactivation methods and explored their inhibitory interactions with Pseudomonas aeruginosa (PAO1). By combining several techniques, i.e., digital holographic microscopy (DHM), atomic force microscopy (AFM), RNA sequencing, and metabolomic analysis, we studied the three-dimensional (3D) swimming behaviors, surface adhesion, biofilm formation, and adaptive responses of PAO1 near such surfaces. The results show that planktonic PAO1 decreases their flick and reverse motions by downregulating the chemotaxis pathway and accelerates with less accumulation near dead LGG surfaces by upregulating the flagellar assembly pathway and decreasing cyclic adenosine monophosphate. Distinct from live siblings, the surfaces decorated with dead LGG show a significant reduction in adhesion strength with PAO1 and inhibit biofilm formation with more downregulated genes in the Pseudomonas quinolone signal and biofilm formation pathway. We demonstrate that the antibacterial ability of such surfaces stems from the gradually released lysate from the dead LGG that is unfavorable to PAO1 in close proximity. The releasing rate and order depend on the cell membrane integrity, which closely relates to the inactivation methods.PMID:38033279 | DOI:10.1021/acs.langmuir.3c01818

Environ Sci Pollut Res Int. 2023 Nov 30. doi: 10.1007/s11356-023-30708-0. Online ahead of print.ABSTRACTGas explosions (GE) are a prevalent and widespread cause of traumatic brain injury (TBI) in coal miners. However, the impact and mechanism of curcumin on GE-induced TBI in rats remain unclear. In this study, we simulated GE-induced TBI in rats and administered curcumin orally at a dose of 100 mg/kg every other day for 7 days to modulate the gut microbiota in TBI rats. We employed 16S rRNA sequencing and LC-MS/MS metabolomic analysis to investigate changes in the intestinal flora and its metabolic profile. Additionally, we utilized ELISA, protein assays, and immunohistochemistry to assess neuroinflammatory signaling molecules for validation. In a rat TBI model, GE resulted in weight loss, pathological abnormalities, and cortical hemorrhage. Treatment with curcumin significantly mitigated histological abnormalities and microscopic mitochondrial structural changes in brain tissue. Furthermore, curcumin treatment markedly ameliorated GE-induced brain dysfunction by reducing the levels of several neuroinflammatory signaling molecules, including neuron-specific enolase, interleukin (IL)-1β, IL-6, and cryptothermic protein 3. Notably, curcumin reshaped the gut microbiome by enhancing evenness, richness, and composition. Prevotella_9, Alloprevotella, Bacilli, Lactobacillales, Proteobacteria, and Gammaproteobacteria were identified as prominent members of the gut microbiota, increasing the linear discriminant analysis scores and specifically enhancing the abundance of bacteria involved in the nuclear factor (NF)-κB signaling pathway, such as Lachnospiraceae and Roseburia. Additionally, there were substantial alterations in serum metabolites associated with metabolic NF-κB signaling pathways in the model group. Curcumin administration reduced serum lipopolysaccharide levels and downregulated downstream Toll-like receptor (TLR)4/myeloid differentiation primary response 88 (MyD88)/NF-κB signaling. Furthermore, curcumin alleviated GE-induced TBI in rats by modulating the gut microbiota and its metabolites. Based on these protective effects, curcumin may exert its influence on the gut microbiota and the TLR4/MyD88/NF-κB signaling pathways to ameliorate GE-induced TBI.PMID:38032526 | DOI:10.1007/s11356-023-30708-0

Pediatr Endocrinol Diabetes Metab. 2023;29(3):143-155. doi: 10.5114/pedm.2023.131162.ABSTRACTINTRODUCTION: Atherosclerosis, a precursor to cardiovascular disease (CVD), is deeply intertwined with lipid metabolism. The metabolic process in the Down syndrome (DS) population remain less explored. Aim of the study: This study examines the lipid profiles of DS in comparison to their siblings (CG), aiming to uncover potential atherosclerotic and CVD risks.MATERIAL AND METHODS: The study included 42 people with DS (mean age 14.17 years) and the CG - 20 individuals (mean age 15.92 years). Anthropometric measurements: BMI, BMI SDS, and TMI were calculated. Lipid profile (LP) and metabolomics were determined.RESULTS: LP: DS display significantly reduced HDL (DS vs. CG: 47±10 vs. 59 ±12 mg/dl; p = 0.0001) and elevated LDL (104 ±25 vs. 90 ±22 mg/dl; p = 0.0331). Triglycerides, APO A1, and APO B/APO A1 ratio corroborate with the elevated risk of CVD in DS. Despite no marked differences in: TCH and APO B, the DS group demonstrated a concerning BMI trend. Of 31 identified metabolites, 12 showed statistical significance (acetate, choline, creatinine, formate, glutamine, histidine, lysine, proline, pyroglutamate, threonine, tyrosine, and xanthine). However, only 8 metabolites passed the FDR validation (acetate, creatinine, formate, glutamine, lysine, proline, pyroglutamate, xanthine).CONCLUSIONS: Down syndrome individuals show distinct cardiovascular risks, with decreased HDL and increased LDL levels. Combined with metabolomic disparities and higher BMI and TMI, this suggests an increased atherosclerosis risk compared to controls.PMID:38031830 | DOI:10.5114/pedm.2023.131162

Comb Chem High Throughput Screen. 2023 Nov 28. doi: 10.2174/0113862073265604231106112203. Online ahead of print.ABSTRACTCancer is a broad category of disease that can start in virtually any organ or tissue of the body when aberrant cells assault surrounding organs and proliferate uncontrollably. According to the most recent statistics, cancer will be the cause of 10 million deaths worldwide in 2020, accounting for one death out of every six worldwide. The typical approach used in anti-cancer research is highly time-consuming and expensive, and the outcomes are not particularly encouraging. Computational techniques have been employed in anti-cancer research to advance our understanding. Recent years have seen a significant and exceptional impact on anticancer research due to the rapid development of computational tools for novel drug discovery, drug design, genetic studies, genome characterization, cancer imaging and detection, radiotherapy, cancer metabolomics, and novel therapeutic approaches. In this paper, we examined the various subfields of contemporary computational techniques, including molecular docking, artificial intelligence, bioinformatics, virtual screening, and QSAR, and their applications in the study of cancer.PMID:38031782 | DOI:10.2174/0113862073265604231106112203

Nat Prod Res. 2023 Nov 30:1-7. doi: 10.1080/14786419.2023.2288934. Online ahead of print.ABSTRACTPleurotus tuber-regium was isolated from a dead trunk of Raphia farinifera (Arecaceae) in a lowland moist forest in Antsohihy, Madagascar, and the species was confirmed by molecular analysis and morphological observations. The main bioactive metabolites of the mycelium extracts were identified by mass spectrometry techniques. Five structural diverse metabolites, tryptophol, pyroglutamic acid, prolyldiketopiperazine B, sporol and RKS-1778, were characterised by LC-MS qTOF analysis of the hydro-alcoholic extract. GC-MS analysis of both chloroform and ethyl acetate extracts revealed the presence of several saturated and -unsaturated fatty acids and their esters derivatives.PMID:38031740 | DOI:10.1080/14786419.2023.2288934

J Asian Nat Prod Res. 2023 Nov 30:1-10. doi: 10.1080/10286020.2023.2287665. Online ahead of print.ABSTRACTA total of 65 phenolic acid compounds were annotated or identified by UHPLC-MS/MS method, among them, 17 p-HAP (p-hydroxyacetophenone) glycosides were firstly targeted profiled based on molecular networking. Their characteristic product ions of MS/MS spectra were found and examined on the guideline of targeted isolation. As a result, a new p-HAP glycoside was thus obtained and determined as 2'-O-caffeoyl-p-HAP-4-O-β-D-glucopyranoside (33) based on 1D and 2D NMR data. Besides, multicomponents quantitative analysis indicated the distinct regional variability in chemicals distribution of A. japonica, and meanwhile, the contents of p-HAP glycosides from A. japonica were higher than those in A. capillaris as a whole, which further suggested the potential medicinal value of A. japonica.PMID:38031435 | DOI:10.1080/10286020.2023.2287665

J Mass Spectrom. 2023 Dec;58(12):e4982. doi: 10.1002/jms.4982.ABSTRACTAcetylation of amino acids is important in the molecular biology and biochemistry because they are part of several metabolic pathways. N-acetyl amino acids can form through degradation of N-acetyl proteins or direct acetylation of amino acids by specific enzymes. Acetylation of α-amino acids can be either on the alpha -NH2 or on the side-chain functional group, where both the acetyl products are isomeric and can show different biological roles. Theoretically, all proteinogenic α-amino acids are expected to undergo acetylation and they can be a part of metabolome. Thus, it is essential to detect and identify all the possible acetylated products of α-amino acids for untargeted metabolomics studies. In this study, it is aimed to synthesize and characterize all acetylated products of natural α-amino acids. A total of 20 Nα -acetyl amino acids (1-20), six side-chain acetyl amino acids (21-26), and six diacetyl amino acids (27-32) were synthesized and characterized by liquid chromatography-electrospray ionizationtandem mass spectrometry (LC-ESI-MS/MS). The [M + H]+ ions of all the acetyl amino acids were subjected to MS/MS experiments to obtain their structural information. Apart from the expected loss of (H2 O + CO) (immonium ions), most of the acetyl amino acids specifically showed loss of H2 O and loss of a ketene (C2 H2 O) from [M+H]+ ions. The side-chain acetyl amino acids showed a clear-cut structure specific fragment ions that enabled easy differentiation from their isomeric Nα -acetyl amino acids. The other isomeric/isobaric acetyl amino acids could also be easily distinguished by their MS/MS spectra. The MS/MS of immonium ions of the acetyl amino acids were also studied, and they included characteristic products reflecting the structures of parent Nα -acetyl and side-chain acetyl amino acids.PMID:38031236 | DOI:10.1002/jms.4982

Oncogene. 2023 Nov 29. doi: 10.1038/s41388-023-02887-0. Online ahead of print.ABSTRACTPRAME is a CUL2 ubiquitin ligase subunit that is normally expressed in the testis but becomes aberrantly overexpressed in many cancer types in association with aneuploidy and metastasis. Here, we show that PRAME is expressed predominantly in spermatogonia around the time of meiotic crossing-over in coordination with genes mediating DNA double strand break repair. Expression of PRAME in somatic cells upregulates pathways involved in meiosis, chromosome segregation and DNA repair, and it leads to increased DNA double strand breaks, telomere dysfunction and aneuploidy in neoplastic and non-neoplastic cells. This effect is mediated at least in part by ubiquitination of SMC1A and altered cohesin function. PRAME expression renders cells susceptible to inhibition of PARP1/2, suggesting increased dependence on alternative base excision repair pathways. These findings reveal a distinct oncogenic function of PRAME that can be targeted therapeutically in cancer.PMID:38030788 | DOI:10.1038/s41388-023-02887-0

Sci Rep. 2023 Nov 29;13(1):21023. doi: 10.1038/s41598-023-48269-0.ABSTRACTTomato (Solanum lycopersicum) is among the most important commercial horticultural crops worldwide. The crop quality and production is largely hampered due to the fungal pathogen Alternaria solani causing necrotrophic foliage early blight disease. Crop plants usually respond to the biotic challenges with altered metabolic composition and physiological perturbations. We have deciphered altered metabolite composition, modulated metabolic pathways and identified metabolite biomarkers in A. solani-challenged susceptible tomato variety Kashi Aman using Liquid Chromatography-Mass Spectrometry (LC-MS) based metabolomics. Alteration in the metabolite feature composition of pathogen-challenged (m/z 9405) and non-challenged (m/z 9667) plant leaves including 8487 infection-exclusive and 8742 non-infection exclusive features was observed. Functional annotation revealed putatively annotated metabolites and pathway mapping indicated their enrichment in metabolic pathways, biosynthesis of secondary metabolites, ubiquinone and terpenoid-quinones, brassinosteroids, steroids, terpenoids, phenylpropanoids, carotenoids, oxy/sphingolipids and metabolism of biotin and porphyrin. PCA, multivariate PLS-DA and OPLS-DA analysis showed sample discrimination. Significantly up regulated 481 and down regulated 548 metabolite features were identified based on the fold change (threshold ≥ 2.0). OPLS-DA model based on variable importance in projection (VIP scores) and FC threshold (> 2.0) revealed 41 up regulated discriminant metabolite features annotated as sphingosine, fecosterol, melatonin, serotonin, glucose 6-phosphate, zeatin, dihydrozeatin and zeatin-β-D-glucoside. Similarly, 23 down regulated discriminant metabolites included histidinol, 4-aminobutyraldehyde, propanoate, tyramine and linalool. Melatonin and serotonin in the leaves were the two indoleamines being reported for the first time in tomato in response to the early blight pathogen. Receiver operating characteristic (ROC)-based biomarker analysis identified apigenin-7-glucoside, uridine, adenosyl-homocysteine, cGMP, tyrosine, pantothenic acid, riboflavin (as up regulated) and adenosine, homocyctine and azmaline (as down regulated) biomarkers. These results could aid in the development of metabolite-quantitative trait loci (mQTL). Furthermore, stress-induced biosynthetic pathways may be the potential targets for modifications through breeding programs or genetic engineering for improving crop performance in the fields.PMID:38030710 | DOI:10.1038/s41598-023-48269-0

Nat Commun. 2023 Nov 29;14(1):7759. doi: 10.1038/s41467-023-43519-1.ABSTRACTMelanomas can adopt multiple transcriptional states. Little is known about the epigenetic drivers of these cell states, limiting our ability to regulate melanoma heterogeneity. Here, we identify stress-induced HDAC8 activity as driving melanoma brain metastasis development. Exposure of melanocytes and melanoma cells to multiple stresses increases HDAC8 activation leading to a neural crest-stem cell transcriptional state and an amoeboid, invasive phenotype that increases seeding to the brain. Using ATAC-Seq and ChIP-Seq we show that increased HDAC8 activity alters chromatin structure by increasing H3K27ac and enhancing accessibility at c-Jun binding sites. Functionally, HDAC8 deacetylates the histone acetyltransferase EP300, causing its enzymatic inactivation. This, in turn, increases binding of EP300 to Jun-transcriptional sites and decreases binding to MITF-transcriptional sites. Inhibition of EP300 increases melanoma cell invasion, resistance to stress and increases melanoma brain metastasis development. HDAC8 is identified as a mediator of transcriptional co-factor inactivation and chromatin accessibility that drives brain metastasis.PMID:38030596 | DOI:10.1038/s41467-023-43519-1

Int J Epidemiol. 2023 Nov 29:dyad162. doi: 10.1093/ije/dyad162. Online ahead of print.ABSTRACTBACKGROUND: Urinary metabolomics has demonstrated considerable potential to assess kidney function and its metabolic corollaries in health and disease. However, applications in epidemiology remain sparse due to technical challenges.METHODS: We added 17 metabolites to an open-access urinary nuclear magnetic resonance metabolomics platform, extending the panel to 61 metabolites (n = 994). We also introduced automated quantification for 11 metabolites, extending the panel to 12 metabolites (+creatinine). Epidemiological associations between these 12 metabolites and 49 clinical measures were studied in three independent cohorts (up to 5989 participants). Detailed regression analyses with various confounding factors are presented for body mass index (BMI) and smoking.RESULTS: Sex-specific population reference concentrations and distributions are provided for 61 urinary metabolites (419 men and 575 women), together with methodological intra-assay metabolite variations as well as the biological intra-individual and epidemiological population variations. For the 12 metabolites, 362 associations were found. These are mostly novel and reflect potential molecular proxies to estimate kidney function, as the associations cannot be simply explained by estimated glomerular filtration rate. Unspecific renal excretion results in leakage of amino acids (and glucose) to urine in all individuals. Seven urinary metabolites associated with smoking, providing questionnaire-independent proxy measures of smoking status in epidemiological studies. Common confounders did not affect metabolite associations with smoking, but insulin had a clear effect on most associations with BMI, including strong effects on 2-hydroxyisobutyrate, valine, alanine, trigonelline and hippurate.CONCLUSIONS: Urinary metabolomics provides new insight on kidney function and related biomarkers on the renal-cardiometabolic system, supporting large-scale applications in epidemiology.PMID:38030573 | DOI:10.1093/ije/dyad162

Endocr J. 2023 Nov 28. doi: 10.1507/endocrj.EJ23-0506. Online ahead of print.ABSTRACTVisceral fat accumulation is a major determinant of type 2 diabetes mellitus and cardiovascular diseases. Recent studies have reported that glutamate is the most elevated amino acid in the plasma amino acid profile in patients with obesity and/or visceral fat accumulation. Here, we show the relationship between plasma glutamate and the clinical features of patients with type 2 diabetes. The study subjects were 62 (28 men and 34 women) Japanese patients with type 2 diabetes. Blood profiles, including glutamate and adiponectin (APN) levels and estimated visceral fat area (eVFA), were measured. We also evaluated the plasma amino acid levels in mice with or without obesity by GC/MS analysis. In patients with type 2 diabetes, plasma glutamate was positively correlated with BMI, eVFA, and fasting insulin but negatively correlated with APN and duration of diabetes. Additionally, multiple regression analysis revealed that plasma glutamate was a significant determinant of APN. The plasma glutamate level was most significantly increased in obese mice compared to control mice, and it was negatively correlated with APN. These results suggest that the level of plasma glutamate could be a strong indicator of adipocyte dysfunction in patients with type 2 diabetes.PMID:38030259 | DOI:10.1507/endocrj.EJ23-0506

J Adv Res. 2023 Nov 27:S2090-1232(23)00365-X. doi: 10.1016/j.jare.2023.11.026. Online ahead of print.ABSTRACTINTRODUCTION: Type 2 diabetes (T2D) is a heterogeneous metabolic disease with large variations in the relative contributions of insulin resistance and β-cell dysfunction across different glucose tolerance subgroups and ethnicities. A more precise yet feasible approach to categorize risk preceding T2D onset is urgently needed. This study aimed to identify potential metabolic biomarkers that could contribute to the development of T2D and investigate whether their impact on T2D is mediated through insulin resistance and β-cell dysfunction.METHODS: A non-targeted metabolomic analysis was performed in plasma samples of 196 incident T2D cases and 196 age- and sex-matched non-T2D controls recruited from a long-term prospective Chinese community-based cohort with a follow-up period of ∼16 years.RESULTS: Metabolic profiles revealed profound perturbation of metabolomes before T2D onset. Overall metabolic shifts were strongly associated with insulin resistance rather than β-cell dysfunction. In addition, 188 out of the 578 annotated metabolites were associated with insulin resistance. Bi-directional mediation analysis revealed putative causal relationships among the metabolites, insulin resistance and T2D risk. We built a machine-learning based prediction model, integrating the conventional clinical risk factors (age, BMI, TyG index and 2hG) and 10 metabolites (acetyl-tryptophan, kynurenine, γ-glutamyl-phenylalanine, DG(18:2/22:6), DG(38:7), LPI(18:2), LPC(P-16:0), LPC(P-18:1), LPC(P-20:0) and LPE(P-20:0)) (AUROC = 0.894, 5.6% improvement comparing to the conventional clinical risk model), that successfully predicts the development of T2D.CONCLUSIONS: Our findings support the notion that the metabolic changes resulting from insulin resistance, rather than β-cell dysfunction, are the primary drivers of T2D in Chinese adults. Metabolomes as a valuable phenotype hold potential clinical utility in the prediction of T2D.PMID:38030128 | DOI:10.1016/j.jare.2023.11.026

J Ethnopharmacol. 2023 Nov 27:117487. doi: 10.1016/j.jep.2023.117487. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Acute lung injury (ALI) is a life-threatening condition with high morbidity and mortality, underscoring the urgent need for novel treatments. Monochasma savatieri Franch. (LRC) is commonly used clinically to treat wind-heat cold, bronchitis, acute pneumonia and acute gastroenteritis. However, its role in the treatment of ALI and its mechanism of action are still unclear.AIM OF THE STUDY: This study aimed to demonstrate the pharmacological effects and underlying mechanisms of LRC extract, and provide important therapeutic strategies and theoretical basis for ALI.MATERIALS AND METHODS: In this study, a research paradigm of integrated pharmacology combining histopathological analysis, network pharmacology, metabolomics, and biochemical assays was used to elucidate the mechanisms underlaying the effects of LRC extract on LPS-induced ALI in BALB/c mice.RESULTS: The research findings demonstrated that LRC extract significantly alleviated pathological damage in lung tissues and inhibited apoptosis in alveolar epithelial cells, and the main active components were luteolin, isoacteoside, and aucubin. Lung tissue metabolomic and immunohistochemical methods confirmed that LRC extract could restore metabolic disorders in ALI mice by correcting energy metabolism imbalance, activating cholinergic anti-inflammatory pathway (CAP), and inhibiting TLR4/NF-κB signaling pathway.CONCLUSIONS: This study showed that LRC extract inhibited the occurrence and development of ALI inflammation by promoting the synthesis of antioxidant metabolites, balancing energy metabolism, activating CAP and suppressing the α7nAChR-TLR4/NF-κB p65 signaling pathway. In addition, our study provided an innovative research model for exploring the effective ingredients and mechanisms of traditional Chinese medicine. To the best of our knowledge, this is the first report describing the protective effects of LRC extract in LPS-induced ALI mice.PMID:38030024 | DOI:10.1016/j.jep.2023.117487

Food Chem Toxicol. 2023 Nov 27:114197. doi: 10.1016/j.fct.2023.114197. Online ahead of print.ABSTRACTHuman exposure to the hazardous chemical, Bisphenol A (BPA), is almost ubiquitous. Due to the prevalence of hypertension (CVD risk factor) in the aged human population, it is necessary to explore its adverse effect in hypertensive subjects. The current study exposed the Nω-nitro-l-arginine methyl ester (L-NAME) induced hypertensive Wistar rats to human exposure relevant low dose of BPA (50 μg/kg) for 30 days period. The liver biochemical parameters, histopathology, immunohistochemistry, gene expression (RT-qPCR), trace elements (ICP-MS), primary rat hepatocytes cell culture and metabolomic (1H NMR) assessments were performed. Results illustrate that BPA exposure potentiates/aggravates hypertension induced tissue abnormalities (hepatic fibrosis), oxidative stress, ACE activity, malfunction of the antioxidant system, lipid abnormalities and inflammatory factor (TNF-α and IL-6) expression. Also, in cells, BPA increased ROS generation, mitochondrial dysfunction and lipid peroxidation without any impact on cytotoxicity and caspase 3 and 9 activation. Notably, BPA exposure modulate lipid metabolism (cholesterol and fatty acid) in primary hepatocytes. Finally, the influence of ERK1/2, p38MAPK, ER stress and oxidative stress during relatively high dose of BPA elicited cytotoxicity was observed. Therefore, a precise hazardous risk investigation of BPA exposure in hypertensive populations is highly recommended.PMID:38029875 | DOI:10.1016/j.fct.2023.114197

J Thromb Haemost. 2023 Nov 27:S1538-7836(23)00852-8. doi: 10.1016/j.jtha.2023.11.014. Online ahead of print.ABSTRACTBACKGROUD: Platelets play a key role in hemostasis, inflammation and cardiovascular diseases. Platelet reactivity is highly variable between individuals. The drivers of this variability in populations from Sub-Saharan Africa remain largely unknown.AIM: We investigated the non-genetic and genetic determinants of platelet reactivity in healthy adults living in a rapidly urbanizing area in Northern Tanzania.METHODS: Platelet activation and reactivity were measured by platelet P-selectin expression and the binding of fibrinogen in unstimulated blood and after ex-vivo stimulation with adenosine diphosphate and PAR-1 and PAR-4 ligands. We then analysed the associations between platelet parameters with host genetic and non-genetic factors, environmental factors, plasma inflammatory markers, and plasma metabolites.RESULTS: Only a few associations were found between platelet reactivity parameters and plasma inflammatory markers, non-genetic host and environmental factors. In contrast, untargeted plasma metabolomics revealed a large number of associations with food-derived metabolites, including phytochemicals that were previously reported to inhibit platelet reactivity. Genome-wide single-nucleotide polymorphism (SNP) genotyping identified two novel SNPs (rs903650 and rs4789332) that were associated with platelet reactivity at the genome-wide level (P <5x10-8), as well as a number of variants in the PAR4 gene (F2RL3) that were associated with PAR4-induced reactivity.CONCLUSION: Our study uncovered factors that determine variation in platelet reactivity in a population in East Africa that is rapidly transitioning to an urban lifestyle, including the importance of genetic ancestry and the gradual abandoning of the traditional East African diet.PMID:38029856 | DOI:10.1016/j.jtha.2023.11.014

Exp Neurol. 2023 Nov 27:114619. doi: 10.1016/j.expneurol.2023.114619. Online ahead of print.ABSTRACTBone marrow mesenchymal stem cells (BMSCs) have therapeutic potential in the subacute/chronic phase of acute ischemic stroke (AIS), but the underlying mechanisms are not yet fully elucidated. There is a knowledge gap in understanding the metabolic mechanisms of BMSCs in stroke therapy. In this study, we administered BMSCs intravenously 24 h after reperfusion in rats with transient cerebral artery occlusion (MCAO). The treatment with BMSCs for 21 days significantly reduced the modified neurological severity score of MCAO rats (P < 0.01) and increased the number of surviving neurons in both the striatum and hippocampal dentate gyrus region (P < 0.01, respectively). Moreover, BMSCs treatment resulted in significant enhancements in various structural parameters of dendrites in layer V pyramidal neurons in the injured hemispheric motor cortex, including total length (P < 0.05), number of branches (P < 0.05), number of intersections (P < 0.01), and spine density (P < 0.05). Then, we performed plasma untargeted metabolomics analysis to study the metabolic changes of BMSCs on AIS. There were 65 differential metabolites identified in the BMSCs treatment group. Metabolic profiling analysis revealed that BMSCs modulate abnormal sphingolipid metabolism and glycerophospholipid metabolism, particularly affecting core members such as sphingomyelin (SM), ceramide (Cer) and sphingosine-1-phosphate (S1P). The metabolic network analysis and pathway-based compound-reaction-enzyme-gene network analysis showed that BMSCs inhibited the Cer-induced apoptotic pathway and promoted the S1P signaling pathway. These findings suggest that the enhanced effects of BMSCs on neuronal survival and synaptic plasticity after stroke may be mediated through these pathways. In conclusion, our study provides novel insight into the potential mechanisms of BMSCs treatment in stroke and sheds light on the possible clinical translation of BMSCs.PMID:38029808 | DOI:10.1016/j.expneurol.2023.114619

J Pharm Biomed Anal. 2023 Nov 22;239:115864. doi: 10.1016/j.jpba.2023.115864. Online ahead of print.ABSTRACTPURPOSE: Many studies have shown that the imbalance of the intestinal flora and metabolite can lead to the development of ulcerative colitis (UC), but their role in recurrent-UC is still unclear. We studied the intestinal flora and metabolites associated with recurrent-UC to elucidate the mechanism and biomarkers of recurrent-UC.METHODS: Ulcerative colitis (UC) models in active, remission, and recurrence stages were established, and the abundance of intestinal flora was determined by 16 S rRNA sequencing. The changes in the metabolites present in feces and serum were analyzed by UPLC-MS/MS.RESULTS: We identified 24 metabolites in feces and serum, which might be used as diagnostic and predictive biomarkers of recurrent-UC. The dominant flora of recurrent-UC included Romboutsia, UCG-005, etc. The results of a network analysis found that long-chain fatty acids and phenylalanine were strongly correlated with Firmicutes and Proteobacteria, which indicated that the recurrence of UC might be closely related to metabolites and microorganisms.CONCLUSION: The changes in intestinal microbiota and metabolites are closely related to the development of UC. Microbiota is an important inducer of UC, which can regulate metabolites through the 'microorganism-gut-metabolite' axis. It may provide a new method for the prediction and treatment of UC.PMID:38029703 | DOI:10.1016/j.jpba.2023.115864

Theriogenology. 2023 Nov 23;215:113-124. doi: 10.1016/j.theriogenology.2023.11.019. Online ahead of print.ABSTRACTIf a mechanism of more efficient glycolysis depending on pyruvate is present in stallion spermatozoa, detrimental effects of higher glucose concentrations that are common in current commercial extenders could be counteracted. To test this hypothesis, spermatozoa were incubated in a 67 mM Glucose modified Tyrode's media in the presence of 1- or 10-mM pyruvate and in the Tyrode's basal media which contains 5 mM glucose. Spermatozoa incubated for 3 h at 37 °C in 67 mM Tyrode's media with 10 mM pyruvate showed increased motility in comparison with aliquots incubated in Tyrode's 5 mM glucose and Tyrode's 67 mM glucose (57.1 ± 3.5 and 58.1 ± 1.9 to 73.0 ± 1.1 %; P < 0.01). Spermatozoa incubated in Tyrode's with 67 mM glucose 10 mM pyruvate maintained the viability along the incubation (64.03 ± 15.4 vs 61.3 ± 10.2), while spermatozoa incubated in 67 mM Glucose-Tyrode's showed a decrease in viability (38.01 ± 11.2, P < 0.01). 40 mM oxamate, an inhibitor of the lactate dehydrogenase LDH, reduced sperm viability (P < 0.05, from 76 ± 5 in 67 mM Glucose/10 mM pyruvate to 68.0 ± 4.3 %, P < 0.05). Apoptotic markers increased in the presence of oxamate. (P < 0.01). UHPLC/MS/MS showed that 10 mM pyruvate increased pyruvate, lactate, ATP and NAD+ while phosphoenolpyruvate decreased. The mechanisms that explain the improvement of in presence of 10 mM pyruvate involve the conversion of lactate to pyruvate and increased NAD+ enhancing the efficiency of the glycolysis.PMID:38029686 | DOI:10.1016/j.theriogenology.2023.11.019