PubMed

Front Genet. 2023 Nov 29;14:1278830. doi: 10.3389/fgene.2023.1278830. eCollection 2023.ABSTRACTBackground: Recent evidence has shown that the long non-coding RNA (lncRNA) rPvt1 is elevated in septic myocardial tissues and that its knockdown attenuates sepsis-induced myocardial injury. However, the mechanism underlying the role of rPvt1 in septic myocardial dysfunction has not been elucidated. Methods: In this study, we performed transcriptomic, proteomic, and metabolomic assays and conducted an integrated multi-omics analysis to explore the association between rPvt1 and lipopolysaccharide (Lipopolysaccharide)-induced H9C2 cardiomyocyte injury. LncRNA rPvt1 silencing was achieved using a lentiviral transduction system. Results: Compared to those with the negative control, rPvt1 knockdown led to large changes in the transcriptome, proteome, and metabolome. Specifically, 2,385 differentially expressed genes (DEGs), 272 differentially abundant proteins and 75 differentially expressed metabolites (DEMs) were identified through each omics analysis, respectively. Gene Ontology functional annotation, Kyoto Encyclopedia of Genes and Genomes, Nr, eukaryotic orthologous groups, and Clusters of Orthologous Groups of Proteins pathway analyses were performed on these differentially expressed/abundant factors. The results suggested that mitochondrial energy metabolism might be closely related to the mechanism through which Pvt1 functions. Conclusion: These genes, proteins, metabolites, and their related dysregulated pathways could thus be promising targets for studies investigating the rPvt1-regluatory mechanisms involved in septic myocardial dysfunction, which is important for formulating novel strategies for the prevention, diagnosis and treatment of septic myocardial injury.PMID:38094756 | PMC:PMC10718647 | DOI:10.3389/fgene.2023.1278830

Hortic Res. 2023 Nov 8;10(12):uhad224. doi: 10.1093/hr/uhad224. eCollection 2023 Dec.ABSTRACTIn recent years, multiple advances have been made in understanding the photosynthetic machinery in model organisms. Knowledge transfer to horticultural important fruit crops is challenging and time-consuming due to restrictions in gene editing tools and prolonged life cycles. Here, we characterize a gene encoding a PetM domain-containing protein in tomato. The CRISPR/Cas9 knockout lines of the PetM showed impairment in the chloroplastic electron transport rate (ETR), reduced CO2 assimilation, and reduction of carotenoids and chlorophylls (Chl) under several light conditions. Further, growth-condition-dependent elevation or repression of Chl a/b ratios and de-epoxidation states were identified, underlining possible impairment compensation mechanisms. However, under low light and glasshouse conditions, there were basal levels in CO2 assimilation and ETR, indicating a potential role of the PetM domain in stabilizing the cytochrome b6f complex (Cb6f) under higher light irradiance and increasing its quantum efficiency. This suggests a potential evolutionary role in which this domain might stabilize the site of the Cb6f regulating ratios of cyclic and linear electron transport and its potential importance during the conquest of terrestrial ecosystems during which plants were exposed to higher irradiance. Finally, the results are discussed with regard to metabolism and their implication to photosynthesis from an agronomic perspective.PMID:38094587 | PMC:PMC10716634 | DOI:10.1093/hr/uhad224

Front Plant Sci. 2023 Nov 29;14:1268085. doi: 10.3389/fpls.2023.1268085. eCollection 2023.ABSTRACTCompared with other crops, pennycress (Thlaspi arvense L.) is a niche emerging oil crop. In recent years, research on pennycress has been increasingly reflected in various directions. Pennycress belongs to the Brassicaceae family and was introduced from Eurasia to North America. It has been found worldwide as a cultivated plant and weed. In this paper, we review the advantages of pennycress as a supplementary model plant of Arabidopsis thaliana, oil and protein extraction technology, seed composition analysis based on metabolomics, germplasm resource development, growth, and ecological impact research, abiotic stress, fatty acid extraction optimization strategy, and other aspects of studies over recent years. The main research directions proposed for the future are as follows: (1) assemble the genome of pennycress to complete its entire genome data, (2) optimize the extraction process of pennycress as biodiesel, (3) analyze the molecular mechanism of the fatty acid synthesis pathway in pennycress, and (4) the functions of key genes corresponding to various adversity conditions of pennycress.PMID:38093994 | PMC:PMC10716221 | DOI:10.3389/fpls.2023.1268085

Clin Transl Med. 2023 Dec;13(12):e1511. doi: 10.1002/ctm2.1511.ABSTRACTBACKGROUND: Hepatocellular carcinoma (HCC) cells undergo reprogramming of glucose metabolism to support uncontrolled proliferation, of which the intrinsic mechanism still merits further investigation. Although regulatory factor X6 (RFX6) is aberrantly expressed in different cancers, its precise role in cancer development remains ambiguous.METHODS: Microarrays of HCC tissues were employed to investigate the expression of RFX6 in tumour and adjacent non-neoplastic tissues. Functional assays were employed to explore the role of RFX6 in HCC development. Chromatin immunoprecipitation, untargeted metabolome profiling and sequencing were performed to identify potential downstream genes and pathways regulated by RFX6. Metabolic assays were employed to investigate the effect of RFX6 on glycolysis in HCC cells. Bioinformatics databases were used to validate the above findings.RESULTS: HCC tissues exhibited elevated expression of RFX6. High RFX6 expression represented as an independent hazard factor correlated to poor prognosis in patients with HCC. RFX6 deficiency inhibited HCC development in vitro and in vivo, while its overexpression exerted opposite functions. Mechanistically, RFX6 bound to the promoter area of phosphoglycerate mutase 1 (PGAM1) and upregulated its expression. The increased PGAM1 protein levels enhanced glycolysis and further promoted the development of HCC.CONCLUSIONS: RFX6 acted as a novel driver for HCC development by promoting aerobic glycolysis, disclosing the potential of the RFX6-PGAM1 axis for therapeutic targeting.PMID:38093528 | DOI:10.1002/ctm2.1511

Adv Sci (Weinh). 2023 Dec 13:e2306576. doi: 10.1002/advs.202306576. Online ahead of print.ABSTRACTSex disparities in serum bile acid (BA) levels and Alzheimer's disease (AD) prevalence have been established. However, the precise link between changes in serum BAs and AD development remains elusive. Here, authors quantitatively determined 33 serum BAs and 58 BA features in 4 219 samples collected from 1 180 participants from the Alzheimer's Disease Neuroimaging Initiative. The findings revealed that these BA features exhibited significant correlations with clinical stages, encompassing cognitively normal (CN), early and late mild cognitive impairment, and AD, as well as cognitive performance. Importantly, these associations are more pronounced in men than women. Among participants with progressive disease stages (n = 660), BAs underwent early changes in men, occurring before AD. By incorporating BA features into diagnostic and predictive models, positive enhancements are achieved for all models. The area under the receiver operating characteristic curve improved from 0.78 to 0.91 for men and from 0.76 to 0.83 for women for the differentiation of CN and AD. Additionally, the key findings are validated in a subset of participants (n = 578) with cerebrospinal fluid amyloid-beta and tau levels. These findings underscore the role of BAs in AD progression, offering potential improvements in the accuracy of AD prediction.PMID:38093507 | DOI:10.1002/advs.202306576

Eur J Med Res. 2023 Dec 13;28(1):586. doi: 10.1186/s40001-023-01490-z.ABSTRACTINTRODUCTION: Cervical cancer threatens women's health seriously. In recent years, the incidence of cervical cancer is on the rise, and the age of onset tends to be younger. Prevention, early diagnosis and specific treatment have become the main means to change the prognosis of cervical cancer patients. Metabolomics research can directly reflect the changes of biochemical processes and microenvironment in the body, which can provide a comprehensive understanding of the changes of metabolites in the process of disease occurrence and development, and provide new ways for the prevention and diagnosis of diseases.OBJECTIVES: The aim of this study is to review the metabolic changes in cervical cancer and the application of metabolomics in the diagnosis and treatment.METHODS: PubMed, Web of Science, Embase and Scopus electronic databases were systematically searched for relevant studies published up to 2022.RESULTS: With the emergence of metabolomics, metabolic regulation and cancer research are further becoming a focus of attention. By directly reflecting the changes in the microenvironment of the body, metabolomics research can provide a comprehensive understanding of the patterns of metabolites in the occurrence and development of diseases, thus providing new ideas for disease prevention and diagnosis.CONCLUSION: With the continuous, in-depth research on metabolomics research technology, it will bring more benefits in the screening, diagnosis and treatment of cervical cancer with its advantages of holistic and dynamic nature.PMID:38093395 | DOI:10.1186/s40001-023-01490-z

Cardiovasc Diabetol. 2023 Dec 13;22(1):340. doi: 10.1186/s12933-023-02066-1.ABSTRACTBACKGROUND: Olive oil consumption has been inversely associated with the risk of type 2 diabetes (T2D) and cardiovascular disease (CVD). However, the impact of olive oil consumption on plasma metabolites remains poorly understood. This study aims to identify plasma metabolites related to total and specific types of olive oil consumption, and to assess the prospective associations of the identified multi-metabolite profiles with the risk of T2D and CVD.METHODS: The discovery population included 1837 participants at high cardiovascular risk from the PREvención con DIeta MEDiterránea (PREDIMED) trial with available metabolomics data at baseline. Olive oil consumption was determined through food-frequency questionnaires (FFQ) and adjusted for total energy. A total of 1522 participants also had available metabolomics data at year 1 and were used as the internal validation sample. Plasma metabolomics analyses were performed using LC-MS. Cross-sectional associations between 385 known candidate metabolites and olive oil consumption were assessed using elastic net regression analysis. A 10-cross-validation (CV) procedure was used, and Pearson correlation coefficients were assessed between metabolite-weighted models and FFQ-derived olive oil consumption in each pair of training-validation data sets within the discovery sample. We further estimated the prospective associations of the identified plasma multi-metabolite profile with incident T2D and CVD using multivariable Cox regression models.RESULTS: We identified a metabolomic signature for the consumption of total olive oil (with 74 metabolites), VOO (with 78 metabolites), and COO (with 17 metabolites), including several lipids, acylcarnitines, and amino acids. 10-CV Pearson correlation coefficients between total olive oil consumption derived from FFQs and the multi-metabolite profile were 0.40 (95% CI 0.37, 0.44) and 0.27 (95% CI 0.22, 0.31) for the discovery and validation sample, respectively. We identified several overlapping and distinct metabolites according to the type of olive oil consumed. The baseline metabolite profiles of total and extra virgin olive oil were inversely associated with CVD incidence (HR per 1SD: 0.79; 95% CI 0.67, 0.92 for total olive oil and 0.70; 0.59, 0.83 for extra virgin olive oil) after adjustment for confounders. However, no significant associations were observed between these metabolite profiles and T2D incidence.CONCLUSIONS: This study reveals a panel of plasma metabolites linked to the consumption of total and specific types of olive oil. The metabolite profiles of total olive oil consumption and extra virgin olive oil were associated with a decreased risk of incident CVD in a high cardiovascular-risk Mediterranean population, though no associations were observed with T2D incidence.TRIAL REGISTRATION: The PREDIMED trial was registered at ISRCTN ( http://www.isrctn.com/ , ISRCTN35739639).PMID:38093289 | DOI:10.1186/s12933-023-02066-1

J Am Coll Cardiol. 2023 Dec 19;82(25):2350-2473. doi: 10.1016/j.jacc.2023.11.007.NO ABSTRACTPMID:38092509 | DOI:10.1016/j.jacc.2023.11.007

J Clin Endocrinol Metab. 2023 Dec 13:dgad731. doi: 10.1210/clinem/dgad731. Online ahead of print.ABSTRACTCONTEXT: Psychological distress has been linked to diabetes risk. Few population-based, epidemiologic studies have investigated the potential molecular mechanisms (e.g., metabolic dysregulation) underlying this association.OBJECTIVE: To evaluate the association between a metabolomic signature for psychological distress and diabetes risk.METHODS: We conducted a nested case-control study of plasma metabolomics and diabetes risk in the Nurses' Health Study, including 728 women (mean age: 55.2 years) with incident diabetes and 728 matched controls. Blood samples were collected between 1989-1990 and incident diabetes was diagnosed between 1992-2008. Based on our prior work, we calculated a weighted plasma metabolite-based distress score (MDS) comprised of 19 metabolites. We used conditional logistic regression accounting for matching factors and other diabetes risk factors to estimate odds ratios (OR) and 95% CI for diabetes risk according to MDS.RESULTS: After adjusting for sociodemographic factors, family history of diabetes, and health behaviors, the OR (95% CI) for diabetes risk across quintiles of the MDS was 1.00 (reference) for Q1, 1.16 (0.77, 1.73) for Q2, 1.30 (0.88, 1.91) for Q3, 1.99 (1.36, 2.92) for Q4, and 2.47 (1.66, 3.67) for Q5. Each SD increase in MDS was associated with 36% higher diabetes risk (95% CI: 1.21, 1.54; p-trend<0.0001). This association was moderately attenuated after additional adjustment for BMI (comparable OR: 1.17; 95% CI: 1.02, 1.35; p-trend=0.02). The MDS explained 17.6% of the association between self-reported psychological distress (defined as presence of depression or anxiety symptoms) and diabetes risk (p=0.04).CONCLUSIONS: MDS was significantly associated with diabetes risk in women. These results suggest that differences in multiple lipid and amino acid metabolites may underlie the observed association between psychological distress and diabetes risk.PMID:38092374 | DOI:10.1210/clinem/dgad731

Environ Pollut. 2023 Dec 11:123129. doi: 10.1016/j.envpol.2023.123129. Online ahead of print.ABSTRACTThe unprecedented proliferation of disposable face masks during the COVID-19 pandemic, coupled with their improper disposal, threatens to exacerbate the already concerning issue of plastic pollution. This study evaluates the role of environmentally weathered masks as potential sources of microplastics (MPs) and nanoplastics (NPs) and assesses their adverse impact on the early life stages of zebrafish. Experimental findings revealed that a single disposable mask could release approximately 1.79 × 109 particles, with nearly 70% measuring less than 1 μm, following 60 days of sunlight exposure and subsequent sand-induced physical abrasion. Remarkably, the MPs/NPs (MNPs) emanating from face masks have the potential to permeate the outer layer (chorion) of zebrafish embryos. Furthermore, due to their minute size, these particles can be consumed by the larvae's digestive system and subsequently circulated to other tissues, including the brain. Exposure to mask-derived MNPs at concentrations of 1 and 10 μg/L led to significant cases of developmental toxicity, incited oxidative stress, and prompted cell apoptosis. A subsequent metabolomics analysis indicated that the accumulation of these plastic particles perturbed metabolic functions in zebrafish larvae, primarily disrupting amino acid and lipid metabolism. The outcomes of this research underscore the accelerating possibility of environmental aging processes and physical abrasion in the release of MNPs from disposable face masks. Most importantly, these results shed light on the possible ecotoxicological risk posed by improperly disposed of face masks.PMID:38092337 | DOI:10.1016/j.envpol.2023.123129

J Ethnopharmacol. 2023 Dec 11:117568. doi: 10.1016/j.jep.2023.117568. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Liansu capsule could alleviate dyspeptic symptoms; however, the mechanisms underlying its role in treating functional dyspepsia (FD) remain unclear.AIM OF THE STUDY: To elucidate the mechanism underlying the efficacy of Liansu capsule in alleviating FD symptoms.MATERIALS AND METHODS: Thirty-six male mice were randomly divided into the following six groups: control, model, low-strength Liansu, moderate-strength Liansu, high-strength Liansu, and domperidone groups. Small intestine propulsion rate, gastric residual rate and histopathological analysis were performed to evaluate efficacy of Liansu capsule. Levels of interleukin-1β, interleukin-6, tumor necrosis factor α, phosphorylation of p65, ghrelin and gastrin were verified by real-time quantitative polymerase chain reaction and immunofluorescence assays. Targeted metabolomic analyses, western blotting and immunofluorescence assays were used to explore the mechanism of Liansu capsule in ameliorating FD.RESULTS: The Liansu capsule significantly ameliorated the symptoms of FD, and markedly increased the levels of ghrelin and gastrin. Moreover, Liansu capsule significantly downregulated the levels of the proinflammatory cytokine interleukin-1β, interleukin-6, tumor necrosis factor α, and inhibited the phosphorylation of p65. Targeted metabolomic analyses showed that Liansu capsule significantly reduced the levels of deoxycholic acid and hyodeoxycholic acid, which were significantly elevated in the model group. Furthermore, these results showed that deoxycholic acid and hyodeoxycholic acid markedly promoted the levels of Takeda G-protein-coupled receptor 5 (TGR5), phosphorylated signal transducer and activator of transcription 3 (STAT3), and Kruppel-like factor 5 (KLF5) in vitro. whereas, Liansu capsule significantly reduced the levels of TGR5, phosphorylated STAT3, and KLF5.CONCLUSION: Our findings indicated that Liansu capsule improved FD by regulating the deoxycholic acid/hyodeoxycholic acid-TGR5-STAT3-KLF5 axis. The findings reveal a novel mechanism underlying the role of Liansu capsule, which may be a promising therapeutic strategy for FD.PMID:38092317 | DOI:10.1016/j.jep.2023.117568

Cell Mol Gastroenterol Hepatol. 2023 Dec 11:S2352-345X(23)00216-3. doi: 10.1016/j.jcmgh.2023.12.003. Online ahead of print.ABSTRACTBACKGROUND & AIMS: A long immune-tolerant (IT) phase lasting for decades and delayed HBeAg seroconversion (HBe-SC) in patients with chronic hepatitis B (CHB) increase the risk of liver diseases. Early entry into the immune-active (IA) phase and HBe-SC confers a favorable clinical outcome with an unknown mechanism. We aimed to identify factor(s) triggering IA-entry and HBe-SC in the natural history of CHB.METHODS: To study the relevance of gut microbiota evolution in the risk of CHB activity, fecal samples were collected from CHB patients (n=102) in different disease phases. A hepatitis B virus (HBV)-hydrodynamic injection (HDI) mouse model was therefore established in several mouse strains and germ-free mice, and multiplatform metabolomic and bacteriologic assays were performed.RESULTS: Ruminococcus gnavus was the most abundant species in CHB patients in the IT-phase, whereas Akkermansia muciniphila was predominantly enriched in IA patients and associated with ALT-flares, HBeAg loss and early HBe-SC. HBV-HDI mouse models recapitulated this human finding. Increased cholesterol-to-bile acids (BAs) metabolism was found in IT patients, since R. gnavus encodes bile salt hydrolase to deconjugate primary BAs and augment BAs total pool for facilitating HBV persistence and prolonging the IT course. A. muciniphila counteracted this activity through the direct removal of cholesterol. The secretome metabolites of A. muciniphila, which contained small molecules structurally similar to apigenin, lovastatin, ribavirin, etc., inhibited the growth and the function of R. gnavus to allow HBV elimination.CONCLUSIONS: R. gnavus and A. muciniphila play opposite roles in HBV infection. A. muciniphila metabolites, which benefit the elimination of HBV, may contribute to future anti-HBV strategies.PMID:38092311 | DOI:10.1016/j.jcmgh.2023.12.003

Cell Signal. 2023 Dec 11:111009. doi: 10.1016/j.cellsig.2023.111009. Online ahead of print.ABSTRACTAIMS: Glucokinase (GCK) acts as the glucose sensor in maintaining glucose homeostasis. The inactivating mutation of the GCK gene leads to glucokinase-maturity onset diabetes of the young (GCK-MODY). This study aims to gain further insights into the molecular alterations triggered by GCK partial inactivation in hepatocytes, potentially underlying the favorable prognosis of GCK-MODY.MAIN METHODS: A GCK knockdown HepG2 cell model was established, and the integration of proteomics and metabolomics was used to gain a comprehensive understanding of the molecular pathway changes caused by GCK inactivation in the liver.KEY FINDINGS: Proteomic analysis identified 257 differential proteins. KEGG pathway enrichment analysis showed that protein expression changes in the GCK knockdown group were significantly enriched in central carbon metabolism, the TCA cycle, amino acid metabolism and the oxidative phosphorylation pathway. Among them, enzymes in the TCA cycle (PC, IDH2, SDH) were significantly downregulated in GCK-knockdown group. Targeted metabolomics revealed that in the GCK knockdown hepatocytes, TCA cycle intermediates were significantly decreased, including pyruvate, oxaloacetate, citrate and succinic acid, and three metabolites increased including glycine, betaine and homocysteine. These metabolic alterations in turn reduced the accumulation of reactive oxygen species in GCK knockdown hepatocytes. Correlation analysis indicated that TCA cycle metabolites were positively correlated with proteins involved in the TCA cycle, carbon metabolism, glycolysis, Ras signaling, fibrosis and inflammation.SIGNIFICANCE: In conclusion, GCK knockdown reduced TCA cycle flux and oxidative stress in hepatocytes by influencing the levels of key transcription factors and enzymes, providing a comprehensive understanding of the effects of GCK partial inactivation on liver metabolism and molecular mechanisms.PMID:38092300 | DOI:10.1016/j.cellsig.2023.111009

Sci Total Environ. 2023 Dec 11:169190. doi: 10.1016/j.scitotenv.2023.169190. Online ahead of print.ABSTRACTThe bisindolic alkaloid caulerpin (CAU) is a bioactive compound isolated from green algae of the genus Caulerpa that are highly invasive in the Mediterranean Sea. On the other side, the purine alkaloid caffeine (CAF) is one of the most globally consumed psychoactive substances and a widespread anthropogenic water pollutant. Both compounds display a large panel of biological properties and are well known to accumulate in the tissues of aquatic organisms and, in certain circumstances, co-occur in the human diet. On this premise, the present study aimed to investigate possible synergistic interactions between CAU and CAF by using the bivalve Mytilus galloprovincialis as a model organism. Mussels were exposed to CAF via medium while they were fed food enriched with CAU. After treatments, biochemical analysis confirmed the toxic potential of CAF, with increased AChE activity and lipid peroxidation. Also, histopathological alterations were observed in the gills and digestive tubules. The NMR-based metabolomic analysis detected higher levels of free amino acids under CAF treatments. Conversely, the food administration of CAU did not affect the above toxicological biomarkers. In addition, we did not observe any cumulative effect between CAF and CAU toward increased cellular damage and neurotoxicity. On the other hand, a possible action of CAU in decreasing CAF toxicity could be hypothesized based on our results. This hypothesis is supported by the activity of CAU as an agonist of peroxisome proliferator-activated receptors (PPARs). PPARs mediate xenobiotic detoxification via cytochromes P450, which is involved in CAF metabolism. Overall, the results obtained not only rule out any cumulative adverse effects of CAF and CAU but also encourage further research to evaluate the possible use of CAU, a compound easily obtained through the valorization of biomass from invasive species, as a food additive to improve the clearance of xenobiotics.PMID:38092204 | DOI:10.1016/j.scitotenv.2023.169190

J Nutr. 2023 Dec 11:S0022-3166(23)72798-3. doi: 10.1016/j.tjnut.2023.12.011. Online ahead of print.ABSTRACTBACKGROUND: Provision of zinc supplementation to young children has been associated with reduced infectious morbidity and better growth outcomes. However, the metabolic pathways underlying these outcomes are unclear, and metabolomic data from humans undergoing zinc supplementation, particularly infants, are generally lacking.OBJECTIVE: To examine the effect of zinc supplementation on metabolic profiles in Tanzanian infants ages 6 weeks and 6 months METHODS: Blood samples were collected at age 6 weeks and 6 months from 50 Tanzanian infants who were enrolled in a randomized placebo-controlled trial of zinc supplementation (5 mg oral daily). Metabolomic analysis using an ultrahigh-performance liquid chromatography/tandem mass spectroscopy (UPLC-MS/MS) platform were performed to identify potential metabolomic profiles and biomarkers associated with zinc supplementation. Principal component analysis (PCA) was used to summarize metabolomic data from all samples. Two-way repeated measures ANOVAs with compound symmetry covariance structures were used to compare metabolome levels over time between infants in the two treatment arms.RESULTS: In PCA, our samples tended to be more separated by child age (6 weeks versus 6 months) than by zinc supplementation status. We found that zinc supplementation affected a variety of metabolites associated with amino acid, lipid, nucleotide, and xenobiotic metabolism, including indoleacetate in the tryptophan metabolism pathway,3-methoxytrosine and 4-hydrxoyphenylphruvate in the tyrosine pathway, eicosanedioate, 2-aminooctanoate, and N-acetyl-2-aminooctanoate in the fatty acid pathway, and N6-succinyladenosine in the purine metabolism pathway. Compared to the relatively small number of metabolites associated with zinc supplements, many infant metabolites changed significantly from age 6 weeks to 6 months.CONCLUSIONS: Zinc supplementation, despite having overall clinical benefits, appears to induce limited metabolomic changes in blood metabolites in young infants. Future larger studies may be warranted to further examine metabolic pathways associated with zinc supplementation.PMID:38092153 | DOI:10.1016/j.tjnut.2023.12.011

J Nutr. 2023 Dec 11:S0022-3166(23)72797-1. doi: 10.1016/j.tjnut.2023.12.010. Online ahead of print.ABSTRACTBACKGROUND: Folic acid (FA) is the oxidized form of folate found in supplements and FA-fortified foods. Most FA is reduced by dihydrofolate reductase to 5-methyltetrahydrofolate (5mTHF); the latter is the form of folate naturally found in foods. Ingestion of FA increases plasma levels of both 5mTHF and unmetabolized FA (UMFA). Limited information is available on downstream metabolic effects of supplemental FA intake, including potential effects associated with UMFA.OBJECTIVE: We aimed to assess the metabolic effects of FA-supplementation, and the associations of plasma 5mTHF and UMFA with the metabolome in FA-naïve Bangladeshi adults.METHODS: Sixty participants were selected from the Folic Acid and Creatine Trial (FACT); half received 800 μg FA/day for 12 weeks and half placebo. Plasma metabolome profiles were measured by high-resolution mass spectrometry, including 170 identified metabolites and 26,541 metabolic features. Penalized regression methods were used to assess the associations of targeted metabolites with FA-supplementation, 5mTHF, and UMFA. Pathway analyses were conducted using Mummichog.RESULTS: In penalized models of identified metabolites, FA-supplementation was associated with higher choline. Changes in 5mTHF concentrations were positively associated with metabolites involved in amino acid metabolism (5-hydroxyindoleacetic acid, acetylmethionine, creatinine, guanidinoacetate, hydroxyproline/n-acetylalanine) and two fatty acids (docosahexaenoic acid and linoleic acid). Changes in 5mTHF concentrations were negatively associated with acetylglutamate, acetyllysine, carnitine, propionyl carnitine, cinnamic acid, homogentisate, arachidonic acid and nicotine. UMFA concentrations were associated with lower levels of arachidonic acid. Together, metabolites selected across all models were related to lipids, aromatic amino acid metabolism, and the urea cycle. Analyses of nontargeted metabolic features identified additional pathways associated with FA supplementation.CONCLUSION: In addition to the recapitulation of several expected metabolic changes associated with 5mTHF, we observed additional metabolites/pathways associated with FA-supplementation. Further studies are needed to confirm these associations and assess their potential implications for human health.CLINICAL TRIAL REGISTRY: This trial was registered at https://clinicaltrials.gov as NCT01050556.PMID:38092151 | DOI:10.1016/j.tjnut.2023.12.010

Int J Biol Macromol. 2023 Dec 11:128727. doi: 10.1016/j.ijbiomac.2023.128727. Online ahead of print.ABSTRACTDicranostigma leptopodum (Maxim) Fedde (DLF) is a renowned medicinal plant in China, known to be rich in alkaloids. However, the unavailability of a reference genome has impeded investigation into its plant metabolism and genetic breeding potential. Here we present a high-quality chromosomal-level genome assembly for DLF, derived using a combination of Nanopore long-read sequencing, Illumina short-read sequencing and Hi-C technologies. Our assembly genome spans a size of 621.81 Mb with an impressive contig N50 of 93.04 Mb. We show that the species-specific whole-genome duplication (WGD) of DLF and Papaver somniferum corresponded to two rounds of WGDs of Papaver setigerum. Furthermore, we integrated comprehensive homology searching, gene family analyses and construction of a gene-to-metabolite network. These efforts led to the discovery of co-expressed transcription factors, including NAC and bZIP, alongside sanguinarine (SAN) pathway genes CYP719 (CFS and SPS). Notably, we identified P6H as a promising gene for enhancing SAN production. By providing the first reference genome for Dicranostigma, our study confirms the genomic underpinning of SAN biosynthesis and establishes a foundation for advancing functional genomic research on Papaveraceae species. Our findings underscore the pivotal role of high-quality genome assemblies in elucidating genetic variations underlying the evolutionary origin of secondary metabolites.PMID:38092109 | DOI:10.1016/j.ijbiomac.2023.128727

J Hazard Mater. 2023 Dec 8;465:133202. doi: 10.1016/j.jhazmat.2023.133202. Online ahead of print.ABSTRACTWheat is susceptible to atmospheric ozone (O3) pollution, thus the increasing O3 is a serious threat to wheat production. γ-aminobutyric acid (GABA) is found to play key roles in the tolerance of plants to stress. However, few studies elaborated the function of GABA in response of wheat to O3. Here, we incorporated metabolome and transcriptome data to provide a more comprehensive insight on the role of GABA in enhancing the O3-tolerance of wheat. In our study, there were 31, 23, and 32 differentially accumulated flavonoids in the carbon-filtered air with GABA, elevated O3 with or without GABA treatments compared to the carbon-filtered air treatment, respectively. Elevated O3 triggered the accumulation of dihydroflavone, flavonols, and flavanols. Exogenous GABA enhanced dihydroflavone and dihydroflavonol, and also altered the expression of genes encoding some key enzymes in the flavonoid synthesis pathway. Additionally, GABA stimulated proline accumulation and antioxidant enzyme activities under elevated O3, resulting in the less accumulation of H2O2 and malondialdehyde. Consequently, GABA alleviated the grain yield loss from 19.6% to 9.6% induced by elevated O3. Our study provided comprehensive insight into the role of GABA in the alleviating the detrimental effects of elevated O3 on wheat, and a new avenue to mitigate O3 damage to the productivity of crops.PMID:38091801 | DOI:10.1016/j.jhazmat.2023.133202

Nat Rev Genet. 2023 Dec 13. doi: 10.1038/s41576-023-00674-x. Online ahead of print.ABSTRACTModern health care faces several serious challenges, including an ageing population and its inherent burden of chronic diseases, rising costs and marginal quality metrics. By assessing and optimizing the health trajectory of each individual using a data-driven personalized approach that reflects their genetics, behaviour and environment, we can start to address these challenges. This assessment includes longitudinal phenome measures, such as the blood proteome and metabolome, gut microbiome composition and function, and lifestyle and behaviour through wearables and questionnaires. Here, we review ongoing large-scale genomics and longitudinal phenomics efforts and the powerful insights they provide into wellness. We describe our vision for the transformation of the current health care from disease-oriented to data-driven, wellness-oriented and personalized population health.PMID:38093095 | DOI:10.1038/s41576-023-00674-x

Cell Mol Life Sci. 2023 Dec 13;81(1):8. doi: 10.1007/s00018-023-05041-x.ABSTRACTCystatin F, a cysteine peptidase inhibitor, is a potent modulator of NK cytotoxicity. By inhibiting granule-mediated cytotoxicity pathway, cystatin F induces formation of non-functional NK cell stage, called split-anergy. We show that N-glycosylation determines the localization and cellular function of cystatin F. Cystatin F mostly exhibited high-mannose glycosylation in U-937 cells, both high-mannose and complex glycosylation in NK-92 and primary NKs, and predominantly complex glycosylation in super-charged NKs. Manipulating N-glycosylation with kifunensine increased high-mannose glycosylation of cystatin F and lysosome localisation, which decreased cathepsin C activity and reduced NK cytotoxicity. Mannose-6-phosphate could significantly reduce the internalization of extracellular cystatin F. By comparing NK cells with different cytotoxic potentials, we found that high-mannose cystatin F was strongly associated with lysosomes and cathepsin C in NK-92 cell line. In contrast, in highly cytotoxic super-charged NKs, cystatin F with complex glycosylation was associated with the secretory pathway and less prone to inhibit cathepsin C. Modulating glycosylation to alter cystatin F localisation could increase the cytotoxicity of NK cells, thereby enhancing their therapeutic potential for treating cancer patients.PMID:38092995 | DOI:10.1007/s00018-023-05041-x