PubMed

BMC Med. 2023 Jul 27;21(1):275. doi: 10.1186/s12916-023-02967-8.ABSTRACTBACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is an orphan metabolic disease characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C), xanthomas, aortic stenosis, and premature atherosclerotic cardiovascular disease (ASCVD). In addition to LDL-C, studies in experimental models and small clinical populations have suggested that other types of metabolic molecules might also be risk factors responsible for cardiovascular complications in HoFH, but definitive evidence from large-scale human studies is still lacking. Herein, we aimed to comprehensively characterize the metabolic features and risk factors of human HoFH by using metabolic systems strategies.METHODS: Two independent multi-center cohorts with a total of 868 individuals were included in the cross-sectional study. First, comprehensive serum metabolome/lipidome-wide analyses were employed to identify the metabolomic patterns for differentiating HoFH patients (n = 184) from heterozygous FH (HeFH, n = 376) and non-FH (n = 100) subjects in the discovery cohort. Then, the metabolomic patterns were verified in the validation cohort with 48 HoFH patients, 110 HeFH patients, and 50 non-FH individuals. Subsequently, correlation/regression analyses were performed to investigate the associations of clinical/metabolic alterations with typical phenotypes of HoFH. In the prospective study, a total of 84 HoFH patients with available follow-up were enrolled from the discovery cohort. Targeted metabolomics, deep proteomics, and random forest approaches were performed to investigate the ASCVD-associated biomarkers in HoFH patients.RESULTS: Beyond LDL-C, various bioactive metabolites in multiple pathways were discovered and validated for differentiating HoFH from HoFH and non-FH. Our results demonstrated that the inflammation and oxidative stress-related metabolites in the pathways of arachidonic acid and lipoprotein(a) metabolism were independently associated with the prevalence of corneal arcus, xanthomas, and supravalvular/valvular aortic stenosis in HoFH patients. Our results also identified a small marker panel consisting of high-density lipoprotein cholesterol, lipoprotein(a), apolipoprotein A1, and eight proinflammatory and proatherogenic metabolites in the pathways of arachidonic acid, phospholipid, carnitine, and sphingolipid metabolism that exhibited significant performances on predicting first ASCVD events in HoFH patients.CONCLUSIONS: Our findings demonstrate that human HoFH is associated with a variety of metabolic abnormalities and is more complex than previously known. Furthermore, this study provides additional metabolic alterations that hold promise as residual risk factors in HoFH population.PMID:37501168 | DOI:10.1186/s12916-023-02967-8

BMC Plant Biol. 2023 Jul 28;23(1):373. doi: 10.1186/s12870-023-04381-x.ABSTRACTBACKGROUND: Buckwheat (Fagopyrum spp.), belonging to the Polygonaceae family, is an ancient pseudo-cereal with high nutritional and nutraceutical properties. Buckwheat proteins are gluten-free and show balanced amino acid and micronutrient profiles, with higher content of health-promoting bioactive flavonoids that make it a golden crop of the future. Plant metabolome is increasingly gaining importance as a crucial component to understand the connection between plant physiology and environment and as a potential link between the genome and phenome. However, the genetic architecture governing the metabolome and thus, the phenome is not well understood. Here, we aim to obtain a deeper insight into the genetic architecture of seed metabolome in buckwheat by integrating high throughput metabolomics and genotyping-by-sequencing applying an array of bioinformatics tools for data analysis.RESULTS: High throughput metabolomic analysis identified 24 metabolites in seed endosperm of 130 diverse buckwheat genotypes. The genotyping-by-sequencing (GBS) of these genotypes revealed 3,728,028 SNPs. The Genome Association and Prediction Integrated Tool (GAPIT) assisted in the identification of 27 SNPs/QTLs linked to 18 metabolites. Candidate genes were identified near 100 Kb of QTLs, providing insights into several metabolic and biosynthetic pathways.CONCLUSIONS: We established the metabolome inventory of 130 germplasm lines of buckwheat, identified QTLs through marker trait association and positions of potential candidate genes. This will pave the way for future dissection of complex economic traits in buckwheat.PMID:37501129 | DOI:10.1186/s12870-023-04381-x

Transl Neurodegener. 2023 Jul 28;12(1):38. doi: 10.1186/s40035-023-00370-0.ABSTRACTMultiple system atrophy (MSA) is a fatal progressive neurodegenerative disease. Biomarkers are urgently required for MSA to improve the diagnostic and prognostic accuracy in clinic and facilitate the development and monitoring of disease-modifying therapies. In recent years, significant research efforts have been made in exploring multidimensional biomarkers for MSA. However, currently few biomarkers are available in clinic. In this review, we systematically summarize the latest advances in multidimensional biomarkers for MSA, including biomarkers in fluids, tissues and gut microbiota as well as imaging biomarkers. Future directions for exploration of novel biomarkers and promotion of implementation in clinic are also discussed.PMID:37501056 | DOI:10.1186/s40035-023-00370-0

Nat Commun. 2023 Jul 27;14(1):4518. doi: 10.1038/s41467-023-40245-6.ABSTRACTGlobally, the lifespan of populations increases but the healthspan is lagging behind. Previous research showed that survival into extreme ages (longevity) clusters in families as illustrated by the increasing lifespan of study participants with each additional long-lived family member. Here we investigate whether the healthspan in such families follows a similar quantitative pattern using three-generational data from two databases, LLS (Netherlands), and SEDD (Sweden). We study healthspan in 2143 families containing index persons with 26 follow-up years and two ancestral generations, comprising 17,539 persons. Our results provide strong evidence that an increasing number of long-lived ancestors associates with up to a decade of healthspan extension. Further evidence indicates that members of long-lived families have a delayed onset of medication use, multimorbidity and, in mid-life, healthier metabolomic profiles than their partners. We conclude that both lifespan and healthspan are quantitatively linked to ancestral longevity, making family data invaluable to identify protective mechanisms of multimorbidity.PMID:37500622 | DOI:10.1038/s41467-023-40245-6

J Dairy Sci. 2023 Jul 25:S0022-0302(23)00428-9. doi: 10.3168/jds.2023-23259. Online ahead of print.ABSTRACTRecent studies have suggested that dietary rumen-protected choline (RPC) supplementation can modulate immune function, attenuate inflammation, and improve performance in periparturient dairy cattle; however, this has yet to be evaluated during a mastitis challenge. Therefore, the objective of this study was to examine the effects of supplementation and dose of RPC on metabolism, inflammation, and performance during an intramammary lipopolysaccharide (LPS) challenge. Parous Holstein cows (parity, mean ± SD, 1.9 ± 1.1 at enrollment) were blocked by calving month and randomly assigned within block to receive either 45 g/d of RPC (20.4 g/d of choline ions; CHOL45, n = 18), 30 g/d of RPC (13.6 g/d of choline ions; CHOL30, n = 21), or no RPC (CON, n = 19) as a top-dress starting 24 d before expected calving until 21 d postpartum. Cows were alternately assigned within treatment group to either receive an intramammary LPS challenge (200 μg in each rear quarter; Escherichia coli O111:B4) or not at 17 DIM. Before the challenge, CHOL45 and CHOL30 cows produced 3.4 and 3.8 (±1.2 SED) kg/d more milk than CON, respectively. Dietary RPC supplementation did not mitigate the milk loss associated with the intramammary LPS challenge; however, CHOL45 and CHOL30 cows produced 3.1 and 3.5 (±1.4 SED) kg/d more milk than CON, respectively in the carryover period (22 to 84 DIM). Dietary RPC supplementation enhanced plasma β-hydroxybutyrate (BHB) concentrations before the LPS challenge, and increased plasma nonesterified fatty acids (NEFA) and acetylcarnitine concentrations during the LPS challenge, potentially reflecting greater adipose tissue mobilization, fatty acid transport and oxidation. Aside from trimethylamine N-oxide and sarcosine, which were increased in CHOL45-LPS as compared with CON-LPS, most other choline metabolite concentrations in plasma were unaffected by treatment, likely because more choline was being secreted in milk. Plasma lactic acid concentrations were decreased in CHOL45-LPS and CHOL30-LPS as compared with CON-LPS, suggesting a reduction in glycolysis or an enhancement in the flux through the lactic acid cycle to support gluconeogenesis. Plasma concentrations of fumaric acid, a byproduct of AA catabolism and the urea cycle, were increased in both choline groups as compared with CON-LPS during the LPS challenge. Cows in the CHOL45 group had greater plasma antioxidant potential before the LPS challenge and reduced plasma methionine sulfoxide concentrations during the LPS challenge compared with CON-LPS, suggesting an improvement in oxidant status. Nevertheless, concentrations of inflammatory markers such as haptoglobin and tumor necrosis factor α (TNFα) were not affected by treatment. Taken together, our data suggest that the effects of dietary RPC supplementation on milk yield could be mediated through metabolic pathways and are unlikely to be related to the resolution of inflammation in periparturient dairy cattle. Lastly, dose responses to dietary RPC supplementation were not found for various economically important outcomes including milk yield, limiting the justification for feeding a greater dietary RPC dose in industry.PMID:37500444 | DOI:10.3168/jds.2023-23259

J Dairy Sci. 2023 Jul 25:S0022-0302(23)00412-5. doi: 10.3168/jds.2022-22890. Online ahead of print.ABSTRACTHeat stress (HS) impairs productivity, health, and welfare in dairy cows, and additionally causes metabolic changes. Hence, specific metabolites could be used as HS biomarkers. Consequently, the aim of the present study was to compare blood metabolite concentrations of German Holstein dairy cows and of their female calves suffering from high temperature-humidity index (THI) during late gestation (cows) or during their first week of life (calves) or not. According to the mean daily THI (mTHI) at the day before blood sampling, animals were classified into 2 groups: high mTHI ≥60 (hmTHI) and low mTHI <60 (lmTHI). To perform a standard cross-sectional 2-group study, cow groups (n = 48) and calf groups (n = 47) were compared separately. Differences in metabolite concentrations between hmTHI and lmTHI animals were inferred based on a targeted metabolomics approach. In the first step, processed metabolomics data were evaluated by multivariate data analysis techniques, and were visualized using the web-based platform MetaboAnalyst V5.0. The most important metabolites with pronounced differences between groups were further analyzed in a second step using linear mixed models. We identified 9 thermally sensitive metabolites for the cows [dodecanedioic acid; 3-indolepropionic acid; sarcosine; triglycerides (14:0_34:0), (16:0_38:7), (18:0_32:1), and (18:0_36:2); phosphatidylcholine aa C38:1; and lysophosphatidylcholine a C20:3] and for the calves [phosphatidylcholines aa C38:1, ae C38:3, ae C36:0, and ae C36:2; cholesteryl esters (17:1) and (20:3); sphingomyelins C18:0 and C18:1; and p-cresol sulfate], most of them related to lipid metabolism. Apart from 2 metabolites (3-indolepropionic acid and sarcosine) in cows, the metabolite plasma concentrations were lower in hmTHI than in lmTHI groups. In our heat-stressed dry cows, results indicate an altered lipid metabolism compared with lactating heat-stressed cows, due to the missing antilipolytic effect of HS. The results also indicate alterations in lipid metabolism of calves due to high mTHI in the first week of life. From a cross-generation perspective, high mTHI directly before calving seems to reduce colostrum quality, with detrimental effects on metabolite concentrations in offspring.PMID:37500442 | DOI:10.3168/jds.2022-22890

J Dairy Sci. 2023 Jul 25:S0022-0302(23)00423-X. doi: 10.3168/jds.2022-23118. Online ahead of print.ABSTRACTLameness in dairy cattle is a highly prevalent condition that impacts on the health and welfare of dairy cows. Prompt detection and implementation of effective treatment is important for managing lameness. However, major limitations are associated with visual assessment of lameness, which is the most commonly used method to detect lameness. The aims of this study were to investigate the use of metabolomics and machine learning to develop novel methods to detect lameness. Untargeted metabolomics using liquid chromatography-mass spectrometry (LC-MS) alongside machine learning models and a stability selection method were utilized to evaluate the predictive accuracy of differences in the metabolomics profile of first-lactation dairy cows before (during the transition period) and at the time of lameness (based on visual assessment using the 0-3 scale of the Agriculture and Horticulture Development Board). Urine samples were collected from 2 cohorts of dairy heifers and stored at -86°C before analysis using LC-MS. Cohort 1 (n = 90) cows were recruited as current first-lactation cows with weekly mobility scores recorded over a 4-mo timeframe, from which newly lame and nonlame cows were identified. Cohort 2 (n = 30) cows were recruited within 3 wk before calving, and lameness events (based on mobility score) were recorded through lactation until a minimum of 70 d in milk (DIM). All cows were matched paired by DIM ± 14 d. The median DIM at lameness identification was 187.5 and 28.5 for cohort 1 and 2, respectively. The best performing machine learning models predicted lameness at the time of lameness with an accuracy of between 81 and 82%. Using stability selection, the prediction accuracy at the time of lameness was 80 to 81%. For samples collected before and after calving, the best performing machine learning model predicted lameness with an accuracy of 71 and 75%, respectively. The findings from this study demonstrate that untargeted LC-MS profiling combined with machine learning methods can be used to predict lameness as early as before calving and before observable changes in gait in first-lactation dairy cows. The methods also provide accuracies for detecting lameness at the time of observable changes in gait of up to 82%. The findings demonstrate that these methods could provide substantial advancements in the early prediction and prevention of lameness risk. Further external validation work is required to confirm these findings are generalizable; however, this study provides the basis from which future work can be conducted.PMID:37500436 | DOI:10.3168/jds.2022-23118

Neurochem Int. 2023 Jul 25:105588. doi: 10.1016/j.neuint.2023.105588. Online ahead of print.ABSTRACTBACKGROUND: Stroke is a significant health issue in the United States, and identifying biomarkers for the prevention and functional recovery after an acute stroke remains the highest priority. This study aims to identify circulating metabolite signatures that may be associated with stroke pathophysiology by performing discovery and validation studies.METHODS: We performed targeted metabolomics profiling of 420 participants of the discovery dataset of Metabolome in an Ischemic Stroke Study (MISS) using high-throughput nuclear magnetic resonance (NMR) spectroscopy. A validation study of significantly altered metabolites was conducted using an independent cohort of 117,988 participants from the UK Biobank, whose metabolomics profiles were generated using the same NMR technology.RESULTS AND CONCLUSION: Our study identified 16 metabolites to be significantly perturbed during acute stroke. Amino acid phenylalanine was significantly increased, while glutamine and histidine were significantly lowered in stroke. Serum levels of apolipoprotein A-1, HDL particles, small HDL particles, essential fatty acids, and phosphatidylcholine were reduced, while ketone bodies like 3-hydroxybutyrate and acetoacetate were markedly increased in stroke. Based on the robust validation in a large independent UK Biobank dataset, some of these analytes may become clinically meaningful biomarkers to predict or prevent stroke in humans.PMID:37499945 | DOI:10.1016/j.neuint.2023.105588

J Sci Food Agric. 2023 Jul 27. doi: 10.1002/jsfa.12885. Online ahead of print.ABSTRACTBACKGROUND: Mandarin wine has high added value which can effectively extend the industry chain of mandarin and bring excellent economic performance. However, innovative fermentation methods are urgently needed to improve the typical taste and flavor characteristics of mandarin wine. In this study, the effect and underlying mechanism of co-fermentation with Saccharomyces cerevisiae and Schizosaccharomyces pombe on the characteristics of mandarin wine was investigated based on an integrated metabolomic and transcriptomic analyses.RESULTS: Compared to fermentation with only S. cerevisiae, the mandarin wine of co-fermentation with S. cerevisiae and Sc. pombe had a higher pH value, lower content of malic acid, and more abundant free amino acids, resulting in better sensory evaluation scores. The introduction of Sc. pombe extended the stage of alcoholic fermentation and enhanced the richness and diversity of volatile compounds, especially the floral and fruity aroma compounds, including ethyl hexanoate, ethyl caprylate, ethyl enanthate, 1-heptanol, and phenylethyl alcohol. Moreover, the significantly differential metabolites and varying genes were mainly found in pathways of glycolysis, pyruvate metabolism, citrate cycle, and amino acids metabolism.CONCLUSION: Co-fermentation with S. cerevisiae and Sc. pombe showed more advantages in producing distinctive taste and flavor of mandarin wine compared to fermentation with only S. cerevisiae. This study can spark new strategies of co-fermentation to improve the sensory quality of mandarin wine. This article is protected by copyright. All rights reserved.PMID:37499161 | DOI:10.1002/jsfa.12885

J Agric Food Chem. 2023 Jul 27. doi: 10.1021/acs.jafc.3c01913. Online ahead of print.ABSTRACTCyanobacterial fructose-1,6-/sedoheptulose-1,7-bisphosphatase (Cy-FBP/SBPase) was an important regulatory enzyme in cyanobacterial photosynthesis and was a potential target enzyme for screening to obtain novel inhibitors against cyanobacterial blooms. In this study, we developed a novel pharmacophore screening model based on the catalytic mechanism and substrate structure of Cy-FBP/SBPase and screened 26 S series compounds with different structures and pharmacophore characteristics from the Specs database by computer-assisted drug screening. These compounds exhibited moderate inhibitory activity against Cy-FBP/SBPase, with 9 compounds inhibiting >50% at 100 μM. Among them, compound S5 showed excellent inhibitory activity against both Cy-FBP/SBPase and Synechocystis sp. PCC6803 (IC50 = 6.7 ± 0.7 μM and EC50 = 7.7 ± 1.4 μM). The binding mode of compound S5 to Cy-FBP/SBPase was predicted using the molecular docking theory and validated by sentinel mutation and enzyme activity analysis. Physiochemical, gene transcription level, and metabolomic analyses showed that compound S5 significantly reduced the quantum yield of photosystem II and the maximum electron transfer rate, downregulated transcript levels of related genes encoding the Calvin cycle and photosystem, reduced the photosynthetic efficiency of cyanobacteria, thus inhibited metabolic pathways, such as the Calvin cycle and tricarboxylic acid cycle, and eventually achieved an efficient algicide. In addition, compound S5 had a high safety profile for human-derived cells and zebrafish. In summary, the novel pharmacophore screening model obtained from the current work provides an effective solution to the cyanobacterial bloom problem.PMID:37498729 | DOI:10.1021/acs.jafc.3c01913

Mol Omics. 2023 Jul 27. doi: 10.1039/d3mo00029j. Online ahead of print.ABSTRACTChinese herbal medicine (CHM) exhibits a broad spectrum of clinical applications and demonstrates favorable therapeutic efficacy. Nonetheless, elucidating the underlying mechanism of action (MOA) of CHM in disease treatment remains a formidable task due to its inherent characteristics of multi-level, multi-linked, and multi-dimensional non-linear synergistic actions. In recent years, the concept of a Quality marker (Q-marker) proposed by Liu et al. has significantly contributed to the monitoring and evaluation of CHM products, thereby fostering the advancement of CHM research. Within this study, a Q-marker screening strategy for CHM formulas has been introduced, particularly emphasising efficacy and biological activities, integrating absorption, distribution, metabolism, and excretion (ADME) studies, systems biology, and experimental verification. As an illustrative case, the Q-marker screening of Qianghuo Shengshi decoction (QHSSD) for treating rheumatoid arthritis (RA) has been conducted. Consequently, from a pool of 159 compounds within QHSSD, five Q-markers exhibiting significant in vitro anti-inflammatory effects have been identified. These Q-markers encompass notopterol, isoliquiritin, imperatorin, cimifugin, and glycyrrhizic acid. Furthermore, by employing an integrated analysis of network pharmacology and metabolomics, several instructive insights into pharmacological mechanisms have been gleaned. This includes the identification of key targets and pathways through which QHSSD exerts its crucial roles in the treatment of RA. Notably, the inhibitory effect of QHSSD on AKT1 and MAPK3 activation has been validated through western blot analysis, underscoring its potential to mitigate RA-related inflammatory responses. In summary, this research demonstrates the proposed strategy's feasibility and provides a practical reference model for the systematic investigation of CHM formulas.PMID:37498608 | DOI:10.1039/d3mo00029j

Glycobiology. 2023 Jul 27:cwad055. doi: 10.1093/glycob/cwad055. Online ahead of print.ABSTRACTGlycans play a pivotal role in biology. However, due to the low-affinity of glycan-protein interactions, many interaction pairs remain unknown. Two important glycoproteins involved in B cell biology are the B cell receptor (BCR) and its secreted counterpart, antibodies (Abs). It has been indicated that glycans expressed by these B cell-specific molecules can modulate immune activation via glycan-binding proteins (GBPs). In several autoimmune diseases, an increased prevalence of variable domain glycosylation of IgG autoantibodies has been observed. Especially, the hallmarking autoantibodies in rheumatoid arthritis (RA), anti-citrullinated protein antibodies (ACPA), carry a substantial amount of variable domain glycans (VDGs). The VDGs expressed by these autoantibodies are N-linked, complex-type, α2-6 sialylated and BCRs carrying VDGs have been hypothesized to promote selection of autoreactive B cells via interactions with GBPs. Here, we use the ACPA response as a prototype to study potential in solution and in situ BCR VDG interactors. We employed SiaDAz, a UV-activatable sialic acid analogue carrying a diazirine moiety that can form covalent bonds with proximal GPBs. We show, using oligosaccharide engineering that SiaDAz can be readily incorporated into VDGs of both Abs and BCRs. Our data show that Ab VDGs are able to interact with inhibitory receptor, CD22. Interestingly, although we did not detect this interaction on the cell surface, we captured CD79 β glycan-BCR interactions. These results show the utility of combining photoaffinity labeling and oligosaccharide engineering for identifying Ab and BCR interactions and indicate that VDGs appear not to be lectin cis ligands in our tested conditions.PMID:37498177 | DOI:10.1093/glycob/cwad055

Environ Sci Technol. 2023 Jul 27. doi: 10.1021/acs.est.3c01566. Online ahead of print.ABSTRACTAs the concentration of microplastics/microspheres (MPs) in coastal and estuarine regions increases, the likelihood of disease outbreaks and epidemics also rises. Our study investigated the impact of polyvinyl chloride MPs (PVC-MPs) on white spot syndrome virus (WSSV) infection in shrimp. The results revealed that PVC-MPs obviously increased WSSV replication in vivo, leading to a high mortality rate among the larvae and facilitating the horizontal transmission of WSSV. Furthermore, the data of WSSV loads detected together with qPCR, agarose gel electrophoresis, and flow cytometry approaches indicated that PVC-MPs could interact with the virus to prolong survival and maintain the virulence of WSSV at different temperatures and pH values. In terms of host resistance, metabolomics and transcriptomics analysis demonstrated that exposure to PVC-MPs upregulated metabolic concentrations and gene expressions associated with phospholipid metabolism that were associated with innate immunity responses. Particularly, PVC-MPs stimulated the synthesis of phosphatidylcholine (PC) and induced lipid peroxidation. The inhibition of PC on Stimulator of Interferon Genes (STING) translocation from the endoplasmic reticulum to the Golgi apparatus reduces expression of the innate immunity genes (IFN-like genes Vago4 and Vago5) regulated by STING signaling pathways, resulting in a significant decrease in the shrimp's resistance to WSSV infection. Notably, a recovery operation in which the exposed larvae were transferred to a MPs-free aquatic environment led to decreased WSSV infectivity over time, indicating the restoration of antiviral properties in shrimp. Overall, these findings highlight that MPs promote shrimp susceptibility to WSSV in two aspects: host immune defense and viral virulence.PMID:37498082 | DOI:10.1021/acs.est.3c01566

J Agric Food Chem. 2023 Jul 27. doi: 10.1021/acs.jafc.3c00009. Online ahead of print.ABSTRACTHexanal is a phytochemical with antimicrobial activity. However, its antibacterial effect and mechanism against Vibrio parahaemolyticus (V. parahaemolyticus) remain unclear. The study aims to elucidate the associated mechanism using tandem mass tag quantitative proteomics and non-targeted metabolomics. Hexanal treatment reduced intracellular ATP concentration, increased membrane permeability, and destroyed the morphology and ultrastructure of V. parahaemolyticus cells. Proteomics and metabolomics data indicated that 572 differentially expressed proteins (DEPs) and 241 differential metabolites (DMs) were identified in hexanal-treated V. parahaemolyticus. These DEPs and DMs were involved in multiple biological pathways including amino acid metabolism, purine and pyrimidine biosynthesis, etc. Bioinformatics analysis revealed that hexanal damaged the structure and function of cell membranes, inhibited nucleotide metabolism, and disturbed carbohydrate metabolism and tricarboxylic acid cycle (TCA) cycle, which ultimately resulted in growth inhibition and bacterial death. The study is conducive to better understand the mode of action of hexanal against V. parahaemolyticus and offers experimental foundation for the application of hexanal as the antibacterial agent in the seafood-associated industry.PMID:37498004 | DOI:10.1021/acs.jafc.3c00009

Mov Disord. 2023 Jul 27. doi: 10.1002/mds.29566. Online ahead of print.ABSTRACTBACKGROUND: Glycoprotein nonmetastatic melanoma protein B (GPNMB) has been demonstrated to mediate pathogenicity in Parkinson's disease (PD) through interactions with α-synuclein, and plasma GPNMB tended to be a novel biomarker for PD.OBJECTIVE: The goal of this study was to investigate whether plasma GPNMB could act as a potential biomarker for the clinical diagnosis and severity monitoring of multiple system atrophy (MSA), another typical synucleinopathy.METHODS: Plasma GPNMB levels in patients with MSA, patients with PD, and healthy control subjects (HCs) were quantified using enzyme-linked immunosorbent assays.RESULTS: A total of 204 patients with MSA, 65 patients with PD, and 207 HCs were enrolled. The plasma GPNMB levels in patients with MSA were similar to those in HCs (P = 0.251) but were significantly lower than those in patients with PD (P = 0.003). Moreover, there was no significant correlation detected between the plasma GPNMB levels and disease severity scores of patients with MSA.CONCLUSIONS: No evidence was detected for the biomarker potential of plasma GPNMB in MSA. © 2023 International Parkinson and Movement Disorder Society.PMID:37497669 | DOI:10.1002/mds.29566

Food Funct. 2023 Jul 27. doi: 10.1039/d3fo01797d. Online ahead of print.ABSTRACTAsparagus is a perennial herb and is widely used as food and medicine in China. In this study, untargeted metabolomics analysis was applied to compare the chemical differences between the edible and inedible parts of asparagus, as well as the inedible parts of white and green asparagus. A total of 342 compounds were identified in the asparagus extracts, and 24 steroid saponins, 31 oxylipins and 36 LysoGPLs were identified for the first time in asparagus. Metabolomics analysis showed that the inedible part of white asparagus is rich in steroidal saponins, oxylipins and alkaloids, while the inedible part of green asparagus is rich in flavonoids, phenolic acids, LysoGPLs and amino acids. The inedible part of white asparagus showed significantly higher inhibitory effects on breast cancer 4T-1 cells than that of green asparagus. Network pharmacology analysis and molecular docking showed that the biological difference is related to higher levels of steroidal saponins and oxylipins in the inedible part of white asparagus. This study is useful for the wasted resource utilization of inedible parts of asparagus.PMID:37497633 | DOI:10.1039/d3fo01797d

J Proteome Res. 2023 Jul 27. doi: 10.1021/acs.jproteome.3c00382. Online ahead of print.ABSTRACTThe lipid metabolism adaptations of estrogen and progesterone receptor-positive breast cancer tumors from a mouse syngeneic model are investigated in relation to differences across the transition from hormone-dependent (HD) to hormone-independent (HI) tumor growth and the acquisition of endocrine therapy (ET) resistance (HIR tumors). Results are articulated with reported polar metabolome results to complete a metabolic picture of the above transitions and suggest markers of tumor progression and aggressiveness. Untargeted nuclear magnetic resonance metabolomics was used to analyze tumor and mammary tissue lipid extracts. Tumor progression (HD-HI-HIR) was accompanied by increased nonesterified cholesterol forms and phospholipids (phosphatidylcholine, phosphatidylethanolamine, sphingomyelins, and plasmalogens) and decreased relative contents of triglycerides and fatty acids. Predominating fatty acids became shorter and more saturated on average. These results were consistent with gradually more activated cholesterol synthesis, β-oxidation, and phospholipid biosynthesis to sustain tumor growth, as well as an increase in cholesterol (possibly oxysterol) forms. Particular compound levels and ratios were identified as potential endocrine tumor HD-HI-HIR progression markers, supporting new hypotheses to explain acquired ET resistance.PMID:37497607 | DOI:10.1021/acs.jproteome.3c00382

Int J Biol Sci. 2023 Jul 9;19(11):3576-3594. doi: 10.7150/ijbs.85133. eCollection 2023.ABSTRACTIncreasing evidence suggests that immunometabolism has started to unveil the role of metabolism in shaping immune function and autoimmune diseases. In this study, our data show that purinergic receptor P2Y12 (P2RY12) is highly expressed in concanavalin A (ConA)-induced immune hepatitis mouse model and serves as a potential metabolic regulator in promoting metabolic reprogramming from oxidative phosphorylation to glycolysis in T cells. P2RY12 deficiency or inhibition of P2RY12 with P2RY12 inhibitors (clopidogrel and ticagrelor) are proved to reduce the expression of inflammatory mediators, cause CD4+ and CD8+ effector T cells hypofunction and protect the ConA-induced immune hepatitis. A combined proteomics and metabolomics analysis revealed that P2RY12 deficiency causes redox imbalance and leads to reduced aerobic glycolysis by downregulating the expression of hexokinase 2 (HK2), a rate-limiting enzyme of the glycolytic pathway, indicating that HK2 might be a promising candidate for the treatment of diseases associated with T cell activation. Further analysis showed that P2RY12 prevents HK2 degradation by activating the PI3K/Akt pathway and inhibiting lysosomal degradation. Our findings highlight the importance of the function of P2RY12 for HK2 stability and metabolism in the regulation of T cell activation and suggest that P2RY12 might be a pivotal regulator of T cell metabolism in ConA-induced immune hepatitis.PMID:37497007 | PMC:PMC10367548 | DOI:10.7150/ijbs.85133

Heliyon. 2023 Jul 8;9(7):e18045. doi: 10.1016/j.heliyon.2023.e18045. eCollection 2023 Jul.ABSTRACTParkinson's disease (PD) is the second most common neurodegenerative disease, with an increasing prevalence as the population ages, posing a serious threat to human health, but the pathogenesis remains uncertain. Acanthopanax senticosus (Rupr. et Maxim.) Harms (ASH) (aqueous ethanol extract), a Chinese herbal medicine, provides obvious and noticeable therapeutic effects on PD. To further investigate the ASH's mechanism of action in treating PD, the structural and functional gut microbiota, as well as intestinal metabolite before and after ASH intervention in the PD mice model, were examined utilizing metagenomics and fecal metabolomics analysis. α-syn transgenic mice were randomly divided into a model and ASH groups, with C57BL/6 mice as a control. The ASH group was gavaged with ASH (45.5 mg/kg/d for 20d). The time of pole climbing and autonomous activity were used to assess motor ability. The gut microbiota's structure, composition, and function were evaluated using Illumina sequencing. Fecal metabolites were identified using UHPLC-MS/MS to construct intestinal metabolites. The findings of this experiment demonstrate that ASH may reduce the climbing time of PD model mice while increasing the number of autonomous movements. The results of metagenomics analysis revealed that ASH could up-regulated Firmicutes and down-regulated Actinobacteria at the phylum level, while Clostridium was up-regulated and Akkermansia was down-regulated at the genus level; it could also recall 49 species from the phylum Firmicutes, Actinobacteria, and Tenericutes. Simultaneously, metabolomics analysis revealed that alpha-Linolenic acid metabolism might be a key metabolic pathway for ASH to impact in PD. Furthermore, metagenomics function analysis and metabolic pathway enrichment analysis revealed that ASH might influence unsaturated fatty acid synthesis and purine metabolism pathways. These metabolic pathways are connected to ALA, Palmitic acid, Adenine, and 16 species of Firmicutes, Actinobacteria, and Tenericutes. Finally, these results indicate that ASH may alleviate the movement disorder of the PD model, which may be connected to the regulation of gut microbiota structure and function as well as the modulation of metabolic disorders by ASH.PMID:37496895 | PMC:PMC10366437 | DOI:10.1016/j.heliyon.2023.e18045

Front Plant Sci. 2023 Jul 11;14:1216826. doi: 10.3389/fpls.2023.1216826. eCollection 2023.ABSTRACTSweet orange 'Newhall' (C. sinensis) is a popular fruit in high demand all over the world. Its peel and pulp are rich in a variety of nutrients and are widely used in catering, medicine, food and other industries. Grafting is commonly practiced in citrus production. Different rootstock types directly affect the fruit quality and nutritional flavor of citrus. However, the studies on citrus metabolites by grafting with different rootstocks are very limited, especially for amino acids (AAs). The preliminary test showed that there were significant differences in total amino acid content of two rootstocks (Poncirus trifoliata (CT) and C. junos Siebold ex Tanaka (CJ)) after grafting, and total amino acid content in the peel was higher than flesh. However, the molecular mechanism affecting amino acid differential accumulation remains unclear. Therefore, this study selected peel as the experimental material to reveal the amino acid components and differential accumulation mechanism of sweet orange 'Newhall' grafted with different rootstocks through combined transcriptome and metabolome analysis. Metabolome analysis identified 110 amino acids (AAs) and their derivatives in sweet orange 'Newhall' peels, with L-valine being the most abundant. L-asparagine was observed to be affected by both developmental periods and rootstock grafting. Weighted gene co-expression network analysis (WGCNA) combined with Redundancy Analysis (RDA) revealed eight hub structural genes and 41 transcription factors (TFs) that significantly influenced amino acid biosynthesis in sweet orange 'Newhall' peels. Our findings further highlight the significance of rootstock selection in enhancing the nutritional value of citrus fruits and might contribute to the development of functional citrus foods and nutritional amino acid supplements.PMID:37496860 | PMC:PMC10366444 | DOI:10.3389/fpls.2023.1216826