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Plasma lipid levels are commonly measured using traditional methods such as triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and cholesterol (CH). However, the use of newer technologies, such as nuclear magnetic resonance (NMR) with post-analysis platforms, has made it easier to assess lipoprotein profiles in research. In this study involving ApoE-deficient mice that were fed high-fat diets, significant changes were observed in TG, CH, free cholesterol (FC), and phospholipid (PL) levels within the LDL fraction. The varied proportions of TG in wild-type mice and CH, FC, and PL in ApoE-/- mice were strikingly different in very low-density lipoproteins (VLDL), LDL, intermediate-density lipoprotein (IDL), and HDL. This comprehensive analysis expands our understanding of lipoprotein subfractions and the impacts of the APOE protein and high-fat diet in mouse models. The new testing method allows for a complete assessment of plasma lipids and their correlation with genetic background and diet in mice. [ABSTRACT FROM AUTHOR]

Background: There remains an unmet need in objective tests for diagnosing asthma in children. The objective of this study was to investigate the potential of metabolomic profiles of exhaled breath condensate (EBC) to discriminate stable asthma in Asian children in the community. Methods: One hundred and sixty‐five Asian children (92 stable asthma and 73 non‐asthmatic controls) participating in a population‐based cohort were enrolled and divided into training and validation sets. Nuclear magnetic resonance‐based metabolomic profiles of EBC samples were analyzed by using orthogonal partial least squares discriminant analysis. Results: EBC metabolomic signature (lactate, formate, butyrate, and isobutyrate) had an area under the receiver operator characteristic curve (AUC) of 0.826 in discriminating children with and without asthma in the training set, which significantly outperformed FeNO (AUC = 0.574; P <.001) and FEV1/FVC % predicted (AUC = 0.569; P <.001). The AUC for EBC metabolomic signature was 0.745 in the validation set, which was slightly but not significantly lower than in the testing set (P =.282). We further extrapolated two potentially involved metabolic pathways, including pyruvate (P = 1.67 × 10−3; impact: 0.14) and methane (P = 1.89 × 10−3; impact: 0.15), as the most likely divergent metabolisms between children with and without asthma. Conclusion: This study provided evidence supporting the role of EBC metabolomic signature to discriminate stable asthma in Asian children in the community, with a discriminative property outperforming conventional clinical tests such as FeNO or spirometry. [ABSTRACT FROM AUTHOR]

Mutations within the β-amyloid peptide (Aβ) sequence that cause early onset familial Alzheimer's disease (FAD) have been shown to promote Aβ aggregation. How these FAD-related mutants increase the aggregative ability of Aβ is not fully understood. Here, we characterized the effect of the Arctic variant (E22G) on the conformational stability of Aβ using various forms of spectroscopy and kinetic analyses, including nuclear magnetic resonance (NMR), circular dichroism (CD) spectroscopy, Fourier-transform infrared (FT-IR) spectroscopy and transmission electron microscopy (TEM). The E22G mutation in the Arctic variant reduced the α-helical propensity and conformational stability of Aβ on residues 15-25. This mutation also caused an increase in both α-helix-to-β-strand conversion and fibril nucleation rates. Our results suggest that the α-helical propensity of residues 15-25 may play a determinant role in the aggregative ability of Aβ. This may provide a structural basis for understanding the molecular mechanism of Aβ aggregation. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease is the most common form of neurodegenerative disease. Beta-amyloid peptides (Aβ) are responsible for neuronal death both in vitro and in vivo. Previously, L17 and F19 residues were identified as playing key roles in the stabilization of the Aβ40 conformation and in the reduction of its neurotoxicity. In this study, the effects of L17A/F19A mutations on the neurotoxicity of Aβ genetic mutant Arctic-type Aβ40(E22G) were tested. The results showed that compared to Aβ40(E22G), Aβ40(L17A/F19A/E22G) reduced the rate of conformation conversion, aggregation, and cytotoxicity, suggesting that L17 and F19 are critical residues responsible for conformational changes which may trigger the neurotoxic cascade of Aβ. Aβ40(L17A/F19A/E22G) also had decreased damage due to reactive oxygen species. The results are consistent with the discordant helix hypothesis, and confirm that residues 17–25 are in the discordant helix region. Compared to Aβ40(L17A/F19A), reduction in aggregation of Aβ40(L17A/F19A/E22G) was less significantly decreased. This observation provides an explanation based on the discordant helix hypothesis that the mutation of E22 to G22 of Aβ40(E22G) alters the propensity of the discordant helix. Arctic-type Aβ40(E22G) aggregates more severely than wild-type Aβ40, with a consequential increase in toxicity. [ABSTRACT FROM AUTHOR]

Liver transplantation has become the ultimate treatment for patients with end stage liver disease. However, early allograft dysfunction (EAD) has been associated with allograft loss or mortality after transplantation. We aim to utilize a metabolomic platform to identify novel biomarkers for more accurate correlation with EAD using blood samples collected from 51 recipients undergoing living donor liver transplantation (LDLT) by 1H-nuclear magnetic resonance spectroscopy (NMR) and liquid chromatography coupled with mass spectrometry (LC-MS). Principal component analysis (PCA) and orthogonal projection to latent structures-discriminant analysis (OPLS-DA) were used to search for a relationship between the metabolomic profiles and the presence of EAD.Cholesteryl esters (CEs), triacylglycerols (TGs), phosphatidylcholines (PCs) and lysophosphatidylcholine (lysoPC) were identified in association with EAD and a combination of cholesterol oleate, PC (16:0/16:0), and lysoPC (16:0) gave an optimal area under the curve (AUC) of 0.9487 and 0.7884 in the prediction of EAD and in-hospital mortality, respectively after LDLT. Such biomarkers may add as a potential clinical panel for the prediction of graft function and mortality after LDLT. [ABSTRACT FROM AUTHOR]

Aging is a complex progression of biological processes and is the causal contributor to the development of diabetes mellitus (DM). DM is the most common degenerative disease and is the fifth leading cause of death in Taiwan, where the trend of DM mortality has been steadily increasing. Metabolomics, important branch of systems biology, has been mainly utilized to understand endogenous metabolites in biological systems and their dynamic changes as they relate to endogenous and exogenous factors. The purpose of this study was to elucidate the metabolomic profiles in elderly people and its relation to lipid disorder (LD). We collected 486 elderly individuals aged ≥65 years and performed untargeted and targeted metabolite analysis using nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography—mass spectrometry (LC/MS). Several metabolites, including branched-chain amino acids, alanine, glutamate and alpha-aminoadipic acid were elevated in LD compared to the control group. Based on multivariate analysis, four metabolites were selected in the best model to predict DM progression: phosphatidylcholine acyl-alkyl (PC ae) C34:3, PC ae C44:3, SM C24:1 and PCae C36:3. The combined area under the curve (AUC) of those metabolites (0.82) was better for DM classification than individual values. This study found that targeted metabolic signatures not only distinguish the LD within the control group but also differentiated DM from LD in elderly Taiwanese. These metabolites could indicate the nutritional status and act as potential metabolic biomarkers for the elderly in Taiwan. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor about the resonance assignments of calmodulin complexed with the calmodulin-binding domain of calcineurin.

Alzheimer’s disease is the most common form of neurodegenerative disease. Beta-amyloid peptides (Aβ) are responsible for neuronal death both in vitro and in vivo. Previously, L17 and F19 residues were identified as playing key roles in the stabilization of the Aβ40 conformation and in the reduction of its neurotoxicity. In this study, the effects of L17A/F19A mutations on the neurotoxicity of Aβ genetic mutant Arctic-type Aβ40(E22G) were tested. The results showed that compared to Aβ40(E22G), Aβ40(L17A/F19A/E22G) reduced the rate of conformation conversion, aggregation, and cytotoxicity, suggesting that L17 and F19 are critical residues responsible for conformational changes which may trigger the neurotoxic cascade of Aβ. Aβ40(L17A/F19A/E22G) also had decreased damage due to reactive oxygen species. The results are consistent with the discordant helix hypothesis, and confirm that residues 17–25 are in the discordant helix region. Compared to Aβ40(L17A/F19A), reduction in aggregation of Aβ40(L17A/F19A/E22G) was less significantly decreased. This observation provides an explanation based on the discordant helix hypothesis that the mutation of E22 to G22 of Aβ40(E22G) alters the propensity of the discordant helix. Arctic-type Aβ40(E22G) aggregates more severely than wild-type Aβ40, with a consequential increase in toxicity. [ABSTRACT FROM AUTHOR]

Abstract: Aggregated β-amyloid peptides (Aβ) are neurotoxic and responsible for neuronal death both in vitro and in vivo. From the structural point of view, Aβ self-aggregation involves a conformational change in the peptide. Here, we investigated the relationship between conformational changes and amino acid residues of Aβ40. Urea unfolding in combination with NMR spectroscopy was applied to probe the stabilization of Aβ40 conformation. L17 and F19 residues were found more sensitive to environmental changes than the other residues. Replacement of these two residues with alanine could stabilize the conformation of Aβ40. Further analysis indicated that the Aβ40(L17A/F19A) mutant could diminish the aggregation and reduce the neurotoxicity. These results suggest that L17 and F19 are the critical residues responsible for conformational changes which may trigger neurotoxic cascade of Aβ40. [Copyright &y& Elsevier]

Introduction: The influence of deranged body composition on stage I/II HCC after surgery remains undetermined. The current study aimed to investigate the impact of low skeletal muscle bulk and disturbed body fat mass on the recurrence outcome of stage I/II HCC patients undergoing liver resection. The associated metabolomic alterations were also assessed., Methods: From 2012 to 2021, stage I and II HCC patients who underwent liver resection at our institute were retrospectively reviewed. Their preoperative body composition including skeletal muscle mass and body fat volume was measured by computed tomography (CT). The recurrence outcome was recorded and analyzed. The preoperative serum was collected and subjected to metabolomic analysis., Results: A total of 450 stage I and II HCC patients were included in the current study. Among them, 76% were male and around 60% had HBV infection. After stratified by normal cutoff values obtained from a healthy cohort, 6.4% of stage I/II HCC patients were found to have a low psoas muscle index (PMI), 17.8% a high subcutaneous adipose tissue (SAT) index, and 27.8% a high visceral adipose tissue (VAT) index. Cox regression multivariate analysis further demonstrated that low PMI and high SAT index were independent prognostic factors for time-to-recurrence (TTR) after surgery. Metabolomic analysis discovered that free fatty acid β-oxidation was enhanced in with low PMI or high SAT index., Conclusion: The current study demonstrated that reduced psoas muscle mass may impair while elevated SAT may prolong the TTR of stage I/II HCC patients undergoing liver resections. VAT, on the other hand, was not associated with recurrence outcome after surgery. Further studies are warranted to validate our findings., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Helicobacter pylori , a dominant member of the gastric microbiota was associated with various gastrointestinal diseases and presents a significant challenge due to increasing antibiotic resistance. This study identifies H. pylori 's phospholipase A (PldA) as a critical factor in modulating host macrophage responses, facilitating H. pylori 's evasion of the immune system and persistence. PldA alters membrane lipids through reversible acylation and deacylation, affecting their structure and function. We found that PldA incorporates lysophosphatidylethanolamine into macrophage membranes, disrupting their bilayer structure and impairing TNFR1-mediated p38-MK2 signaling. This disruption results in reduced macrophage autophagy and elevated RIP1-dependent apoptosis, thereby enhancing H. pylori survival, a mechanism also observed in multidrug-resistant strains. Pharmacological inhibition of PldA significantly decreases H. pylori viability and increases macrophage survival. In vivo studies corroborate PldA's essential role in H. pylori persistence and immune cell recruitment. Our findings position PldA as a pivotal element in H. pylori pathogenesis through TNFR1-mediated membrane modulation, offering a promising therapeutic target to counteract bacterial resistance.