PubMed

Front Cardiovasc Med. 2024 Feb 1;11:1247472. doi: 10.3389/fcvm.2024.1247472. eCollection 2024.ABSTRACTOBJECTIVE: Cold-inducible RNA binding Protein (CIRBP) has been shown to be a potent inflammatory mediator and could serve as a novel biomarker for inflammation. Systemic inflammatory response syndrome (SIRS) and capillary leak syndrome (CLS) are frequent complications after pediatric cardiac surgery increasing morbidity, therefore early diagnosis and therapy is crucial. As CIRBP serum levels have not been analyzed in a pediatric population, we conducted a clinical feasibility establishing a customized magnetic bead panel analyzing CIRBP in pediatric patients undergoing cardiac surgery.METHODS: A prospective hypothesis generating observational clinical study was conducted at the German Heart Center Berlin during a period of 9 months starting in May 2020 (DRKS00020885, https://drks.de/search/de/trial/DRKS00020885). Serum samples were obtained before the cardiac operation, upon arrival at the pediatric intensive care unit, 6 and 24 h after the operation in patients up to 18 years of age with congenital heart disease (CHD). Customized multiplex magnetic bead-based immunoassay panels were developed to analyze CIRBP, Interleukin-1β (IL-1β), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Interleukin-10 (IL-10), Monocyte chemotactic protein 1 (MCP-1), Syndecan-1 (SDC-1), Thrombomodulin (TM), Vascular endothelial growth factor (VEGF-A), Angiopoietin-2 (Ang-2), and Fibroblast growth factor 23 (FGF-23) in 25 µl serum using the Luminex MagPix® system.RESULTS: 19 patients representing a broad range of CHD (10 male patients, median age 2 years, 9 female patients, median age 3 years) were included in the feasibility study. CIRBP was detectable in the whole patient cohort. Relative to individual baseline values, CIRBP concentrations increased 6 h after operation and returned to baseline levels over time. IL-6, IL-8, IL-10, and MCP-1 concentrations were significantly increased after operation and except for MCP-1 concentrations stayed upregulated over time. SDC-1, TM, Ang-2, as well as FGF-23 concentrations were also significantly increased, whereas VEGF-A concentration was significantly decreased after surgery.DISCUSSION: Using customized magnetic bead panels, we were able to detect CIRBP in a minimal serum volume (25 µl) in all enrolled patients. To our knowledge this is the first clinical study to assess CIRBP serum concentrations in a pediatric population.PMID:38361581 | PMC:PMC10867162 | DOI:10.3389/fcvm.2024.1247472

Br J Nutr. 2024 Feb 16:1-31. doi: 10.1017/S0007114524000473. Online ahead of print.ABSTRACTElevated plasma concentrations of several one-carbon metabolites are associated with increased CVD risk. Both diet-induced regulation and dietary content of one-carbon metabolites can influence circulating concentrations of these markers. We cross-sectionally analyzed 1928 patients with suspected stable angina pectoris (geometric mean age 61), representing elevated CVD risk, to assess associations between dietary macronutrient composition (food frequency questionnaire) and plasma one-carbon metabolites and related B-vitamin status markers (GC-MS/MS, LC-MS/MS, or microbiological assay). Diet-metabolite associations were modelled on the continuous scale, adjusted for age, sex, BMI, smoking, alcohol, and total energy intake. Average (geometric mean [95% prediction interval]) intake was 49 (38, 63) energy percent (E%) from carbohydrate, 31 (22, 45) E% from fat, and 17 (12, 22) E% from protein. The strongest associations were seen for higher protein intake, i.e., with higher plasma pyridoxal 5'-phosphate (PLP) (% change [95% confidence interval] 3.1 [2.1, 4.1]), cobalamin (2.9 [2.1, 3.7]), riboflavin (2.4 [1.1, 3.7]), and folate (2.1 [1.2, 3.1]), and lower total homocysteine (tHcy) (-1.4 [-1.9, -0.9]) and methylmalonic acid (MMA) (-1.4 [-2.0, -0.8]). Substitution analyses replacing mono- or polyunsaturated with saturated fatty acids demonstrated higher plasma concentrations of riboflavin (5.0 [0.9, 9.3] and 3.3 [1.1, 5.6]), tHcy (2.3 [0.7, 3.8] and 1.3 [0.5, 2.2]), and MMA (2.0 [0.2, 3.9] and 1.7 [0.7, 2.7]), and lower PLP (-2.5 [-5.3, 0.3] and -2.7 [-4.2, -1.2]). In conclusion, a higher protein intake, and replacing saturated with mono- and polyunsaturated fatty acids, was associated with a more favourable metabolic phenotype regarding metabolites associated with CVD risk.PMID:38361451 | DOI:10.1017/S0007114524000473

Nat Genet. 2024 Feb 15. doi: 10.1038/s41588-024-01662-5. Online ahead of print.ABSTRACTClear cell renal cell carcinoma (ccRCC) is a complex disease with remarkable immune and metabolic heterogeneity. Here we perform genomic, transcriptomic, proteomic, metabolomic and spatial transcriptomic and metabolomic analyses on 100 patients with ccRCC from the Tongji Hospital RCC (TJ-RCC) cohort. Our analysis identifies four ccRCC subtypes including De-clear cell differentiated (DCCD)-ccRCC, a subtype with distinctive metabolic features. DCCD cancer cells are characterized by fewer lipid droplets, reduced metabolic activity, enhanced nutrient uptake capability and a high proliferation rate, leading to poor prognosis. Using single-cell and spatial trajectory analysis, we demonstrate that DCCD is a common mode of ccRCC progression. Even among stage I patients, DCCD is associated with worse outcomes and higher recurrence rate, suggesting that it cannot be cured by nephrectomy alone. Our study also suggests a treatment strategy based on subtype-specific immune cell infiltration that could guide the clinical management of ccRCC.PMID:38361033 | DOI:10.1038/s41588-024-01662-5

Iran J Med Sci. 2024 Feb 1;49(2):121-129. doi: 10.30476/IJMS.2023.96413.2795. eCollection 2024 Feb.ABSTRACTBACKGROUND: Stem cell-derived secretome (SE) released into the extracellular space contributes to tissue repair. The present study aimed to investigate the impact of isolated secretome (SE) from adipose-derived mesenchymal stem cells (ASCs) on Leishmania major (L. major) lesions in BALB/c mice.METHODS: This experimental study was conducted at Ahvaz University of Medical Sciences (Ahvaz, Iran) in 2021. Forty female BALB/c mice were infected with stationary phase promastigotes through intradermal injection in the bottom of their tail and randomly divided into four groups (n=10 per group). The mice were given SE (20 mg/mL), either alone or in combination with Glucantime (GC, 20 mg/mL/Kg), meglumine antimoniate (20 mg/mL/Kg) for the GC group, and phosphate-buffered saline (PBS) for the control group. After eight weeks, the lesion size, histopathology, the levels of Interleukin 10 (IL-10), and Interleukin 12 (IL-12) were assessed. For the comparison of values between groups, the parametric one-way ANOVA was used to assess statistical significance.RESULTS: At the end of the experiment, the mice that received SE had smaller lesions (4.56±0.83 mm versus 3.62±0.59 mm, P=0.092), lower levels of IL-10 (66.5±9.7 pg/mL versus 285.4±25.2 pg/mL, P<0.001), and higher levels of IL-12 (152.2±14.2 pg/mL versus 24.2±4.4 pg/mL, P<0.001) than the control. Histopathology findings revealed that mice treated with SE had a lower parasite burden in lesions and spleen than the control group.CONCLUSION: The current study demonstrated that ADSC-derived SE could protect mice infected with L. major against leishmaniasis.PMID:38356483 | PMC:PMC10862109 | DOI:10.30476/IJMS.2023.96413.2795

Physiol Plant. 2024 Jan-Feb;176(1):e14220. doi: 10.1111/ppl.14220.ABSTRACTMyrtaceae species are abundant in tropical Atlantic rainforests, but 41% of the 5500 species of this family are of extreme conservation concern. Eugenia astringens and E. uniflora are native Brazilian Myrtaceae species that occur in the same habitats and produce desiccation-sensitive (DS) seeds. We hypothesized that their seed desiccation-sensitivity degree is associated with specific metabolic signatures. To test it, we analyzed the germination and metabolic profiles of fresh and desiccated seeds. The water content (WC) at which at least half of the seeds survived desiccation was lower in E. astringens (0.17 g H2 O g-1 DW) than in E. uniflora (0.41 g H2 O g-1 DW). We identified 103 annotated metabolites from 3261 peaks in both species, which differed in their relative contents between E. astringens and E. uniflora seeds. The main differences in seed metabolic profiles include several protective molecules in the group of carbohydrates and organic acids and amino acid contents. The relative contents of monosaccharides and disaccharides, malic and quinic acids, amino acids and saturated fatty acids may have taken part in the distinct DS behaviour of E. astringens and E. uniflora seeds. Our study provides evidence of the relationship between desiccation sensitivity, seed viability and metabolic profile of tropical seeds by comparing two closely related Eugenia species with different DS degrees.PMID:38356368 | DOI:10.1111/ppl.14220

Leukemia. 2024 Feb 15. doi: 10.1038/s41375-024-02137-6. Online ahead of print.ABSTRACTSubtyping of acute myeloid leukaemia (AML) is predominantly based on recurrent genetic abnormalities, but recent literature indicates that transcriptomic phenotyping holds immense potential to further refine AML classification. Here we integrated five AML transcriptomic datasets with corresponding genetic information to provide an overview (n = 1224) of the transcriptomic AML landscape. Consensus clustering identified 17 robust patient clusters which improved identification of CEBPA-mutated patients with favourable outcomes, and uncovered transcriptomic subtypes for KMT2A rearrangements (2), NPM1 mutations (5), and AML with myelodysplasia-related changes (AML-MRC) (5). Transcriptomic subtypes of KMT2A, NPM1 and AML-MRC showed distinct mutational profiles, cell type differentiation arrests and immune properties, suggesting differences in underlying disease biology. Moreover, our transcriptomic clusters show differences in ex-vivo drug responses, even when corrected for differentiation arrest and superiorly capture differences in drug response compared to genetic classification. In conclusion, our findings underscore the importance of transcriptomics in AML subtyping and offer a basis for future research and personalised treatment strategies. Our transcriptomic compendium is publicly available and we supply an R package to project clusters to new transcriptomic studies.PMID:38360865 | DOI:10.1038/s41375-024-02137-6

Mol Pharmacol. 2024 Feb 15;105(3):118-120. doi: 10.1124/molpharm.124.000866.ABSTRACTLong thought to be structural components of cell membranes, sphingolipids (SLs) have emerged as bioactive molecules whose metabolism is tightly regulated. These bioactive lipids and their metabolic enzymes have been implicated in numerous disease states, including lysosomal storage disorders, multiple sclerosis, inflammation, and cancer as well as metabolic syndrome and obesity. In addition, the indications for many of these lipids to potentially serve as biomarkers for disease continue to emerge with increasing metabolomic and lipidomic studies. The implications of these studies have, in turn, led to the examination of SL enzymes and their bioactive lipids as potential therapeutic targets and as markers for therapeutic efficacy. SIGNIFICANCE STATEMENT: Many sphingolipids (SLs) and their metabolizing enzymes have been implicated in disease. This perspective highlights the potential for SLs to serve as therapeutic targets and diagnostic markers and discusses the implications for the studies and reviews highlighted in this Special Section on Therapeutic Implications for Sphingolipids in Health and Disease.PMID:38360837 | DOI:10.1124/molpharm.124.000866

Sci Rep. 2024 Feb 15;14(1):3841. doi: 10.1038/s41598-024-53305-8.NO ABSTRACTPMID:38360824 | DOI:10.1038/s41598-024-53305-8

Sci Rep. 2024 Feb 15;14(1):3823. doi: 10.1038/s41598-023-45608-z.ABSTRACTZebrafish have been utilized for many years as a model animal for pharmacological studies on diabetes and obesity. High-fat diet (HFD), streptozotocin and alloxan injection, and glucose immersion have all been used to induce diabetes and obesity in zebrafish. Currently, studies commonly used both male and female zebrafish, which may influence the outcomes since male and female zebrafish are biologically different. This study was designed to investigate the difference between the metabolites of male and female diabetic zebrafish, using limonene - a natural product which has shown several promising results in vitro and in vivo in treating diabetes and obesity-and provide new insights into how endogenous metabolites change following limonene treatment. Using HFD-fed male and female zebrafish, we were able to develop an animal model of T2D and identify several endogenous metabolites that might be used as diagnostic biomarkers for diabetes. The endogenous metabolites in males and females were different, even though both genders had high blood glucose levels and a high BMI. Treatment with limonene prevented high blood glucose levels and improved in diabesity zebrafish by limonene, through reversal of the metabolic changes caused by HFD in both genders. In addition, limonene was able to reverse the elevated expression of AKT during HFD.PMID:38360784 | DOI:10.1038/s41598-023-45608-z

Sci Total Environ. 2024 Feb 13:170975. doi: 10.1016/j.scitotenv.2024.170975. Online ahead of print.ABSTRACTStudies on the dose effects of kidney impairment and metabolomes in co-exposure to polycyclic aromatic hydrocarbons (PAHs) and metals are limited. We aimed to identify overall associations and metabolic perturbations in 130 participants (53 petrochemical workers and 77 controls) exposed to a PAHs-metals mixture in Southern China. Studies on dose effects on kidney impairment and metabolomes of co-exposure to polycyclic aromatic hydrocarbons (PAHs) and metals are limited. We aim to identify overall associations and metabolic perturbations in 130 participants (53 petrochemical workers vs. 77 controls) exposed to the PAHs-metals mixture in Southern China. The urinary 7 hydroxylated PAHs and 15 metals were determined, and serum creatinine, beta-2 microglobulin, and estimated glomerular filtration rate were health outcomes. The liquid chromatography-mass spectrometry-based method was applied to serum metabolomics. Generalized weighted quantile sum (gWQS) regressions were used to estimate the overall dose-response relationships, and pathway analysis, "meet-in-the-middle" approach, and mediation effect analyses were conducted to identify potential metabolites and biological mechanisms linking exposure with nephrotoxic effects. Our results indicated that renal function reduction was associated with a PAHs-metals mixture in a dose-dependent manner, and 1-hydroxynaphthalene and copper were the most predominant contributors to two families of pollutants. Furthermore, the metabolic disruptions associated with the early onset of kidney impairment induced by the combination of PAHs and metals encompassed pathways such as phenylalanine-tyrosine-tryptophan biosynthesis, phenylalanine metabolism, and alpha-linolenic acid metabolism. In addition, the specifically identified metabolites demonstrated excellent potential as bridging biomarkers connecting the reduction in renal function with the mixture of PAHs and metals. These findings shed light on understanding the overall associations and metabolic mechanism of nephrotoxic effects of co-exposure to PAHs and metals.PMID:38360308 | DOI:10.1016/j.scitotenv.2024.170975

Sci Total Environ. 2024 Feb 13:170946. doi: 10.1016/j.scitotenv.2024.170946. Online ahead of print.ABSTRACTFuran represents one of the dietary-sourced persistent organic pollutants and thermal processing contaminants. Given its widespread occurrence in food and various toxicological effects, accurately assessing furan exposure is essential for informing public health risks. Furan is metabolized to a reactive primary product, cis-2-butene-1,4-dial (BDA) upon absorption. Some of the resulting BDA-derived metabolites have been proposed as potential exposure biomarkers of furan. However, the lack of quantification for recognized and feasible furan biomarkers has hampered the development of internal exposure risk assessment of furan. In this study, we employed reliable non-targeted metabolomics techniques to uncover urinary furan metabolites and elucidate their chemical structures. We characterized 8 reported and 11 new furan metabolites derived from the binding of BDA with glutathione (GSH), biogenic amines, and/or amino acids in the urine of male rats subjected to varying doses of furan. Notably, a mono-GSH-BDA adduct named cyclic GSH-BDA emerged as a highly prospective specific biomarker of furan exposure, as determined by an ultrahigh-performance liquid chromatography-tandem mass spectrometry method. Cyclic GSH-BDA demonstrated a robust mass spectrometry ion response intensity and exhibited evident time- and dose response. Additionally, we conducted a comprehensive profiling of the kinetics of potential furan biomarkers over time to capture the metabolic dynamics of furan in vivo. Most urinary furan metabolites reached peak concentrations at either the first (3 h) or second (6 h) sampling time point and were largely eliminated within 36 h following furan treatment. The present study provides novel insights into furan metabolism and sheds light on the biomonitoring of furan exposure.PMID:38360302 | DOI:10.1016/j.scitotenv.2024.170946

Bone. 2024 Feb 13:117042. doi: 10.1016/j.bone.2024.117042. Online ahead of print.ABSTRACTThis study investigated the efficacy of the two FDA-approved bone anabolic ligands of the parathyroid hormone receptor 1 (PTH1R), teriparatide or human parathyroid hormone 1-34 (PTH) and abaloparatide (ABL), to restoring skeletal health using a preclinical murine model of streptozotocin-induced T1-DM. Intermittent daily subcutaneous injections of equal molar doses (12 pmoles/g/day) of PTH (50 ng/g/day), ABL (47.5 ng/g/day), or vehicle, were administered for 28 days to 5-month-old C57Bl/6 J male mice with established T1-DM or control (C) mice. ABL was superior to PTH in increasing or restoring bone mass in control or T1-MD mice, respectively, which was associated with superior stimulation of trabecular and periosteal bone formation, upregulation of osteoclastic/osteoblastic gene expression, and increased circulating bone remodeling markers. Only ABL corrected the reduction in ultimate load, which is a measure of bone strength, induced by T1-DM, and it also increased energy to ultimate load. In addition, bones from T1-DM mice treated with PTH or ABL exhibited increased ultimate stress, a material index, compared to T1-DM mice administered with vehicle. And both PTH and ABL prevented the increased expression of the Wnt antagonist Sost/sclerostin displayed by T1-DM mice. Further, PTH and ABL increased to a similar extent the circulating bone resorption marker CTX and the bone formation marker P1NP in T1-DM after 2 weeks of treatment; however, only ABL sustained these increases after 4 weeks of treatment. We conclude that at equal molar doses, ABL is more effective than PTH in increasing bone mass and restoring the cortical and trabecular bone lost with T1-DM, due to higher and longer-lasting increases in bone remodeling.PMID:38360197 | DOI:10.1016/j.bone.2024.117042

Biofouling. 2024 Feb 15:1-14. doi: 10.1080/08927014.2024.2305381. Online ahead of print.ABSTRACTThe Parsurameswara stone monument, built in the seventh century, is one of the oldest stone monuments in Odisha, India. Metagenomic analysis of the biological crust samples collected from the stone monument revealed 17 phyla in the microbiome, with Proteobacteria being the most dominant phylum, followed by cyanobacteria. Eight cyanobacteria were isolated. Lyngbya corticicola was the dominant cyanobacterium in all crust samples and could tolerate six months of desiccation in vitro. With six months of desiccation, chlorophyll-a decreased; however, carotenoid and cellular carbohydrate contents of this organism increased in the desiccated state. Resistance to desiccation, high carotenoid content, and effective trehalose biosynthesis in this cyanobacterium provide a distinct advantage over other microbiomes. Comparative metabolic profiles of the biological crust and L. corticicola show strongly corrosive organic acids such as dichloroacetic acid, which might be responsible for the biocorrosion of stone monuments.PMID:38359904 | DOI:10.1080/08927014.2024.2305381

Anal Chem. 2024 Feb 15. doi: 10.1021/acs.analchem.3c04501. Online ahead of print.ABSTRACTMetabolomics is a powerful tool for uncovering biochemical diversity in a wide range of organisms. Metabolic network modeling is commonly used to frame metabolomics data in the context of a broader biological system. However, network modeling of poorly characterized nonmodel organisms remains challenging due to gene homology mismatches which lead to network architecture errors. To address this, we developed the Metabolic Interactive Nodular Network for Omics (MINNO), a web-based mapping tool that uses empirical metabolomics data to refine metabolic networks. MINNO allows users to create, modify, and interact with metabolic pathway visualizations for thousands of organisms, in both individual and multispecies contexts. Herein, we illustrate the use of MINNO in elucidating the metabolic networks of understudied species, such as those of the Borrelia genus, which cause Lyme and relapsing fever diseases. Using a hybrid genomics-metabolomics modeling approach, we constructed species-specific metabolic networks for threeBorrelia species. Using these empirically refined networks, we were able to metabolically differentiate these species via their nucleotide metabolism, which cannot be predicted from genomic networks. Additionally, using MINNO, we identified 18 missing reactions from the KEGG database, of which nine were supported by the primary literature. These examples illustrate the use of metabolomics for the empirical refining of genetically constructed networks and show how MINNO can be used to study nonmodel organisms.PMID:38359900 | DOI:10.1021/acs.analchem.3c04501

Dev Cell. 2024 Feb 12:S1534-5807(24)00045-5. doi: 10.1016/j.devcel.2024.01.025. Online ahead of print.ABSTRACTSpatial single-cell omics provides a readout of biochemical processes. It is challenging to capture the transient lipidome/metabolome from cells in a native tissue environment. We employed water gas cluster ion beam secondary ion mass spectrometry imaging ([H2O]n>28K-GCIB-SIMS) at ≤3 μm resolution using a cryogenic imaging workflow. This allowed multiple biomolecular imaging modes on the near-native-state liver at single-cell resolution. Our workflow utilizes desorption electrospray ionization (DESI) to build a reference map of metabolic heterogeneity and zonation across liver functional units at tissue level. Cryogenic dual-SIMS integrated metabolomics, lipidomics, and proteomics in the same liver lobules at single-cell level, characterizing the cellular landscape and metabolic states in different cell types. Lipids and metabolites classified liver metabolic zones, cell types and subtypes, highlighting the power of spatial multi-omics at high spatial resolution for understanding celluar and biomolecular organizations in the mammalian liver.PMID:38359832 | DOI:10.1016/j.devcel.2024.01.025

J Agric Food Chem. 2024 Feb 15. doi: 10.1021/acs.jafc.3c09024. Online ahead of print.ABSTRACTThe microbial fermentation of food has emerged as an efficient means to eliminate pesticide residues in agricultural products; however, the specific degradation characteristics and mechanisms remain unclear. In this study, a Gram-positive bacterium, Aneurinibacillus aneurinilyticus D-21, isolated from fermented Pixian Douban samples exhibited the capability to degrade 45 mg/L of cyfluthrin with an efficiency of 90.37%. Product analysis unveiled a novel cyfluthrin degradation pathway, involving the removal of the cyanide group and ammoniation of the ester bond into an amide. Whole genome analysis discovered the enzymes linked to cyfluthrin degradation, including nitrilase, esterase, carbon-nitrogen ligases, and enzymes associated with aromatic degradation. Additionally, metabolome analysis identified 140 benzenoids distributed across various aromatic metabolic pathways, further substantiating D-21's catabolic capability toward aromatics. This study underscores the exceptional pyrethroid degradation prowess of A. aneurinilyticus D-21, positioning it as a promising candidate for the biotreatment of pesticide residues in food systems.PMID:38359781 | DOI:10.1021/acs.jafc.3c09024

Redox Biol. 2024 Feb 9;70:103081. doi: 10.1016/j.redox.2024.103081. Online ahead of print.ABSTRACTAIMS: Heart failure with preserved ejection fraction (HFpEF) is a devastating health issue although limited knowledge is available for its pathogenesis and therapeutics. Given the perceived involvement of mitochondrial dysfunction in HFpEF, this study was designed to examine the role of mitochondrial dynamics in the etiology of HFpEF.METHOD AND RESULTS: Adult mice were placed on a high fat diet plus l-NAME in drinking water ('two-hit' challenge to mimic obesity and hypertension) for 15 consecutive weeks. Mass spectrometry revealed pronounced changes in mitochondrial fission protein Drp1 and E3 ligase FBXL4 in 'two-hit' mouse hearts. Transfection of FBXL4 rescued against HFpEF-compromised diastolic function, cardiac geometry, and mitochondrial integrity without affecting systolic performance, in conjunction with altered mitochondrial dynamics and integrity (hyperactivation of Drp1 and unchecked fission). Mass spectrometry and co-IP analyses unveiled an interaction between FBXL4 and Drp1 to foster ubiquitination and degradation of Drp1. Truncated mutants of FBXL4 (Delta-Fbox) disengaged interaction between FBXL4 and Drp1. Metabolomic and proteomics findings identified deranged fatty acid and glucose metabolism in HFpEF patients and mice. A cellular model was established with concurrent exposure of high glucose and palmitic acid as a 'double-damage' insult to mimic diastolic anomalies in HFpEF. Transfection of FBXL4 mitigated 'double-damage'-induced cardiomyocyte diastolic dysfunction and mitochondrial injury, the effects were abolished and mimicked by Drp1 knock-in and knock-out, respectively. HFpEF downregulated sarco(endo)plasmic reticulum (SR) Ca2+ uptake protein SERCA2a while upregulating phospholamban, RYR1, IP3R1, IP3R3 and Na+-Ca2+ exchanger with unaltered SR Ca2+ load. FBXL4 ablated 'two-hit' or 'double-damage'-induced changes in SERCA2a, phospholamban and mitochondrial injury.CONCLUSION: FBXL4 rescued against HFpEF-induced cardiac remodeling, diastolic dysfunction, and mitochondrial injury through reverting hyperactivation of Drp1-mediated mitochondrial fission, underscoring the therapeutic promises of FBXL4 in HFpEF.PMID:38359748 | DOI:10.1016/j.redox.2024.103081

Food Chem. 2024 Feb 8;444:138684. doi: 10.1016/j.foodchem.2024.138684. Online ahead of print.ABSTRACTA research platform for food authentication was set up by combining stable isotope ratio analysis, metabolomics by gas and liquid mass-spectrometry and NMR investigations, chemometric analyses for food excellences. This multi-analytical approach was tested on samples of elephant garlic (Allium ampeloprasum L.), a species belonging to the same genus of common garlic (Allium ampeloprasum L.), mainly produced in southern Tuscany-(Allium ampeloprasum). The isotopic composition allowed the product to be geographically characterized. Flavonoids, like (+)-catechin, cinnamic acids, quercetin glycosides were identified. The samples showed also a significant amount of dipeptides, sulphur-containing metabolites and glutathione, the latter of which could be considered a molecular marker of the analyzed elephant garlic. For nutraceutical profiling to reach quality labels, extracts were investigated in specific biological assays, displaying interesting vasorelaxant properties in rat aorta by mediating nitric oxide release from the endothelium and exhibited positive inotropic and negative chronotropic effects in rat perfused heart.PMID:38359701 | DOI:10.1016/j.foodchem.2024.138684

Food Chem. 2024 Feb 10;445:138705. doi: 10.1016/j.foodchem.2024.138705. Online ahead of print.ABSTRACTWe are undergoing a food transformation with the introduction of plant-based meat analogues, but little is known about their chemical characteristics. This study aimed to elucidate the Maillard reactions in plant-based meat burger alternatives (PBMBA). For this purpose, NMR-based metabolomics and targeted MS analysis of Maillard and dehydroalanine pathway markers were conducted on six PBMBA prototypes with different proportions of high-moisture protein extrudates, low-moisture extrudates and pea protein on a commercial PBMBA and on a meat burger before and after cooking. Results revealed that higher levels of Maillard reaction markers were present in PBMBAs in the uncooked state, with lower levels formed during cooking compared with conventional meat. The metabolite profile disclosed that the distinct pattern of the Maillard reaction could be attributed to different substrate availability, but data also revealed that pre-processing of the plant protein affects the presence of Maillard reaction products in PBMBAs.PMID:38359568 | DOI:10.1016/j.foodchem.2024.138705

Proc Natl Acad Sci U S A. 2024 Feb 20;121(8):e2307430121. doi: 10.1073/pnas.2307430121. Epub 2024 Feb 15.ABSTRACTBlood metabolite levels are affected by numerous factors, including preanalytical factors such as collection methods and geographical sites. These perturbations have caused deleterious consequences for many metabolomics studies and represent a major challenge in the metabolomics field. It is important to understand these factors and develop models to reduce their perturbations. However, to date, the lack of suitable mathematical models for blood metabolite levels under homeostasis has hindered progress. In this study, we develop quantitative models of blood metabolite levels in healthy adults based on multisite sample cohorts that mimic the current challenge. Five cohorts of samples obtained across four geographically distinct sites were investigated, focusing on approximately 50 metabolites that were quantified using 1H NMR spectroscopy. More than one-third of the variation in these metabolite profiles is due to cross-cohort variation. A dramatic reduction in the variation of metabolite levels (90%), especially their site-to-site variation (95%), was achieved by modeling each metabolite using demographic and clinical factors and especially other metabolites, as observed in the top principal components. The results also reveal that several metabolites contribute disproportionately to such variation, which could be explained by their association with biological pathways including biosynthesis and degradation. The study demonstrates an intriguing network effect of metabolites that can be utilized to better define homeostatic metabolite levels, which may have implications for improved health monitoring. As an example of the potential utility of the approach, we show that modeling gender-related metabolic differences retains the interesting variance while reducing unwanted (site-related) variance.PMID:38359289 | DOI:10.1073/pnas.2307430121