PubMed

J Mass Spectrom Adv Clin Lab. 2023 Feb 17;28:35-46. doi: 10.1016/j.jmsacl.2023.02.002. eCollection 2023 Apr.ABSTRACTThe emerging disciplines of lipidomics and metabolomics show great potential for the discovery of diagnostic biomarkers, but appropriate pre-analytical sample-handling procedures are critical because several analytes are prone to ex vivo distortions during sample collection. To test how the intermediate storage temperature and storage period of plasma samples from K3EDTA whole-blood collection tubes affect analyte concentrations, we assessed samples from non-fasting healthy volunteers (n = 9) for a broad spectrum of metabolites, including lipids and lipid mediators, using a well-established LC-MS-based platform. We used a fold change-based approach as a relative measure of analyte stability to evaluate 489 analytes, employing a combination of targeted LC-MS/MS and LC-HRMS screening. The concentrations of many analytes were found to be reliable, often justifying less strict sample handling; however, certain analytes were unstable, supporting the need for meticulous processing. We make four data-driven recommendations for sample-handling protocols with varying degrees of stringency, based on the maximum number of analytes and the feasibility of routine clinical implementation. These protocols also enable the simple evaluation of biomarker candidates based on their analyte-specific vulnerability to ex vivo distortions. In summary, pre-analytical sample handling has a major effect on the suitability of certain metabolites as biomarkers, including several lipids and lipid mediators. Our sample-handling recommendations will increase the reliability and quality of samples when such metabolites are necessary for routine clinical diagnosis.PMID:36872954 | PMC:PMC9975683 | DOI:10.1016/j.jmsacl.2023.02.002

J Mass Spectrom Adv Clin Lab. 2023 Feb 17;28:47-55. doi: 10.1016/j.jmsacl.2023.02.003. eCollection 2023 Apr.ABSTRACTMass spectrometry focusing on small endogenous molecules has become an integral part of biomarker discovery in the pursuit of an in-depth understanding of the pathophysiology of various diseases, ultimately enabling the application of personalized medicine. While LC-MS methods allow researchers to gather vast amounts of data from hundreds or thousands of samples, the successful execution of a study as part of clinical research also requires knowledge transfer with clinicians, involvement of data scientists, and interactions with various stakeholders. The initial planning phase of a clinical research project involves specifying the scope and design, and engaging relevant experts from different fields. Enrolling subjects and designing trials rely largely on the overall objective of the study and epidemiological considerations, while proper pre-analytical sample handling has immediate implications on the quality of analytical data. Subsequent LC-MS measurements may be conducted in a targeted, semi-targeted, or non-targeted manner, resulting in datasets of varying size and accuracy. Data processing further enhances the quality of data and is a prerequisite for in-silico analysis. Nowadays, the evaluation of such complex datasets relies on a mix of classical statistics and machine learning applications, in combination with other tools, such as pathway analysis and gene set enrichment. Finally, results must be validated before biomarkers can be used as prognostic or diagnostic decision-making tools. Throughout the study, quality control measures should be employed to enhance the reliability of data and increase confidence in the results. The aim of this graphical review is to provide an overview of the steps to be taken when conducting an LC-MS-based clinical research project to search for small molecule biomarkers.PMID:36872952 | PMC:PMC9982001 | DOI:10.1016/j.jmsacl.2023.02.003

Liver Cancer. 2022 Jul 8;12(1):19-31. doi: 10.1159/000525911. eCollection 2023 Feb.ABSTRACTINTRODUCTION: The burden of metabolic (dysfunction) associated fatty liver disease (MAFLD) is rising mirrored by an increase in hepatocellular cancer (HCC). MAFLD and its sequelae are characterized by perturbations in lipid handling, inflammation, and mitochondrial damage. The profile of circulating lipid and small molecule metabolites with the development of HCC is poorly characterized in MAFLD and could be used in future studies as a biomarker for HCC.METHODS: We assessed the profile of 273 lipid and small molecule metabolites by ultra-performance liquid chromatography coupled to high-resolution mass spectrometry in serum from patients with MAFLD (n = 113) and MAFLD-associated HCC (n = 144) from six different centers. Regression models were used to identify a predictive model of HCC.RESULTS: Twenty lipid species and one metabolite, reflecting changes in mitochondrial function and sphingolipid metabolism, were associated with the presence of cancer on a background of MAFLD with high accuracy (AUC 0.789, 95% CI: 0.721-0.858), which was enhanced with the addition of cirrhosis to the model (AUC 0.855, 95% CI: 0.793-0.917). In particular, the presence of these metabolites was associated with cirrhosis in the MAFLD subgroup (p < 0.001). When considering the HCC cohort alone, the metabolic signature was an independent predictor of overall survival (HR 1.42, 95% CI: 1.09-1.83, p < 0.01).CONCLUSION: These exploratory findings reveal a metabolic signature in serum which is capable of accurately detecting the presence of HCC on a background of MAFLD. This unique serum signature will be taken forward for further investigation of diagnostic performance as biomarker of early stage HCC in patients with MAFLD in the future.PMID:36872928 | PMC:PMC9982340 | DOI:10.1159/000525911

J Vet Pharmacol Ther. 2023 Mar 5. doi: 10.1111/jvp.13121. Online ahead of print.ABSTRACTCurrent treatment options for feline epilepsy are limited to medications that require administration of multiple doses per day or administration of a capsule or large tablet. Expanding the current treatment options could improve patient and owner compliance and optimize seizure control. Topiramate has been used sparingly in veterinary medicine, and limited pharmacokinetic studies have focused on immediate release formulations in dogs. If effective and safe, topiramate extended-release (XR) could broaden the current treatment options for feline epilepsy. The aims of this two-phase study were to establish single-dose pharmacokinetics for topiramate XR in cats, identify a dosing regimen that maintains steady-state plasma drug concentrations within a reference range extrapolated from human medicine (5-20 μg/mL), and evaluate the safety of topiramate XR in cats following multidose administration. Topiramate XR administered orally at 10 mg/kg once daily for 30 days was sufficient to achieve the desired concentrations in all cats. While no clinically apparent adverse effects were observed, four out of eight cats developed subclinical anemia, calling into question the safety of topiramate XR with chronic administration. Further studies are necessary to better understand the potential adverse effects and overall efficacy of topiramate XR for the treatment of feline epilepsy.PMID:36872425 | DOI:10.1111/jvp.13121

Obesity (Silver Spring). 2023 Mar 5. doi: 10.1002/oby.23687. Online ahead of print.ABSTRACTOBJECTIVE: Liver fat associates with obesity-related metabolic disturbances and may precede incident diseases. Metabolomic profiles of liver fat in the UK Biobank were investigated.METHODS: Regression models assessed the associations between 180 metabolites and proton density liver fat fraction (PDFF) measured 5 years later through magnetic resonance imaging, as the difference (in SD units) of each log metabolite measure with 1-SD higher PDFF among those without chronic disease and not taking statins, and by diabetes and cardiovascular diseases.RESULTS: After accounting for confounders, multiple metabolites were associated positively with liver fat (p < 0.0001 for 152 traits), particularly extremely large and very large lipoprotein particle concentrations, very low-density lipoprotein triglycerides, small high-density lipoprotein particles, glycoprotein acetyls, monounsaturated and saturated fatty acids, and amino acids. Extremely large and large high-density lipoprotein concentrations had strong inverse associations with liver fat. Associations were broadly comparable among those with versus without vascular metabolic conditions, although negative, rather than positive, associations were observed between intermediate-density and large low-density lipoprotein particles among those with BMI ≥25 kg/m2 , diabetes, or cardiovascular diseases. Metabolite principal components showed a 15% significant improvement in risk prediction for PDFF relative to BMI, which was twice as great (but nonsignificant) compared with conventional high-density lipoprotein cholesterol and triglycerides.CONCLUSIONS: Hazardous metabolomic profiles are associated with ectopic hepatic fat and are relevant to risk of vascular-metabolic disease.PMID:36872307 | DOI:10.1002/oby.23687

Zhongguo Zhong Yao Za Zhi. 2023 Feb;48(4):1043-1053. doi: 10.19540/j.cnki.cjcmm.20221024.401.ABSTRACTThis paper aimed to study the effect of Dalbergia cochinchinensis heartwood on plasma endogenous metabolites in rats with ligation of the left anterior descending coronary artery, and to analyze the mechanism of D. cochinchinensis heartwood in improving acute myocardial ischemic injury. The stability and consistency of the components in the D. cochinchinensis heartwood were verified by the establishment of fingerprint, and 30 male SD rats were randomly divided into a sham group, a model group, and a D. cochinchinensis heartwood(6 g·kg~(-1)) group, with 10 rats in each group. The sham group only opened the chest without ligation, while the other groups established the model of ligation. Ten days after administration, the hearts were taken for hematoxylin-eosin(HE) staining, and the content of heart injury indexes in the plasma creatine kinase isoenzyme(CK-MB) and lactate dehydrogenase(LDH), energy metabolism-related index glucose(Glu) content, and vascular endothelial function index nitric oxide(NO) was determined. The endogenous metabolites were detected by ultra-high-performance liquid chromatography-time-of-flight-mass spectrometry(UPLC-Q-TOF-MS). The results showed that the D. cochinchinensis heartwood reduced the content of CK-MB and LDH in the plasma of rats to relieve myocardial injury, reduced the content of Glu in the plasma, improved myocardial energy metabolism, increased the content of NO, cured the vascular endothelial injury, and promoted vasodilation. D. cochinchinensis heartwood improved the increase of intercellular space, myocardial inflammatory cell infiltration, and myofilament rupture caused by ligation of the left anterior descending coronary artery. The metabolomic study showed that the content of 26 metabolites in the plasma of rats in the model group increased significantly, while the content of 27 metabolites decreased significantly. Twenty metabolites were significantly adjusted after the administration of D. cochinchinensis heartwood. D. cochinchinensis heartwood can significantly adjust the metabolic abnormality in rats with ligation of the left anterior descending coronary artery, and its mechanism may be related to the regulation of cardiac energy metabolism, NO production, and inflammation. The results provide a corresponding basis for further explaining the effect of D. cochinchinensis on the acute myocardial injury.PMID:36872275 | DOI:10.19540/j.cnki.cjcmm.20221024.401

Zhongguo Zhong Yao Za Zhi. 2023 Feb;48(3):811-822. doi: 10.19540/j.cnki.cjcmm.20220830.502.ABSTRACTChildren's fever is often accompanied by food accumulation. Traditional Chinese medicine believes that removing food stagnation while clearing heat of children can effectively avoid heat damage. To systematically evaluate the efficacy of Xiaoer Chiqiao Qingre Granules(XRCQ) in clearing heat and removing food accumulation and explore its potential mechanism, this study combined suckling SD rats fed with high-sugar and high-fat diet with injection of carrageenan to induce rat model of fever and food accumulation. This study provided references for the study on the pharmacodynamics and mechanism of XRCQ. The results showed that XRCQ effectively reduced the rectal temperature of suckling rats, improved the inflammatory environment such as the content of interleukin-1β(IL-1β), interleukin-2(IL-2), interferon-γ(IFN-γ), white blood cells, and monocytes. XRCQ also effectively repaired intestinal injury and enhanced intestinal propulsion function. According to the confirmation of its efficacy of clearing heat, the thermolytic mechanism of XRCQ was further explored by non-targeted and targeted metabolomics methods based on LTQ-Orbitrap MS/MS and UPLC-QQQ-MS/MS. Non-target metabolomics analysis of brain tissue samples was performed by QI software combined with SIMCA-P software, and 22 endogenous metabolites that could be significantly regulated were screened out. MetaboAnalyst pathway enrichment results showed that the intervention mechanism was mainly focused on tyrosine metabolism, tricarboxylic acid cycle, inositol phosphate metabolism, and other pathways. At the same time, the results of targeted metabolomics of brain tissue samples showed that XRCQ changed the vitality of digestive system, and inhibited abnormal energy metabolism and inflammatory response, playing a role in clearing heat and removing food stagnation from multiple levels.PMID:36872245 | DOI:10.19540/j.cnki.cjcmm.20220830.502

Food Chem. 2023 Mar 3;416:135795. doi: 10.1016/j.foodchem.2023.135795. Online ahead of print.ABSTRACTTo investigate the effects of "golden flora" amount on the sensory quality, metabolites and bioactivities of Fu brick tea (FBT), FBT samples with different "golden flora" amounts were prepared from the same materials by adjusting the water content before pressing. With the increase of "golden flora" in samples, the tea liquor color changed from yellow to orange red and the astringent taste gradually diminished. Targeted analysis demonstrated that (-)-epigallocatechin gallate, (-)-epicatechin gallate, and most amino acids gradually decreased as the increase of "golden flora". Seventy differential metabolites were identified by untargeted analysis. Among them, sixteen compounds including two Fuzhuanins and four EPSFs were positively correlated with "golden flora" amount (P < 0.05). The FBT samples with "golden flora" exhibited significantly higher inhibitory potency on α-amylase and lipase than the samples without "golden flora". Our results provide a theoretical basis of guiding FBT processing based on desired sensory quality and metabolites.PMID:36871505 | DOI:10.1016/j.foodchem.2023.135795

J Pharm Biomed Anal. 2023 Mar 1;228:115320. doi: 10.1016/j.jpba.2023.115320. Online ahead of print.ABSTRACTA new approach is developed for the reliable classification of Calculus bovis along with the identification of willfully contaminated C. bovis species and the quantification of unclaimed adulterants. Guided by a principal component analysis, NMR data mining achieved a near-holistic chemical characterization of three types of authenticated C. bovis, including natural C. bovis (NCB), in vitro cultured C. bovis (Ivt-CCB), and artificial C. bovis (ACB). In addition, species-specific markers used for quality evaluation and species classification were confirmed. That is, the content of taurine in NCB is near negligible, while choline and hyodeoxycholic acid are characteristic for identifying Ivt-CCB and ACB, respectively. Besides, the peak shapes and chemical shifts of H2-25 of glycocholic acid could assist in the recognition of the origins of C. bovis. Based on these discoveries, a set of commercial NCB samples, macroscopically identified as problematic species, was examined with deliberately added sugars and outliers discovered. Absolute quantification of the identified sugars was realized by qHNMR using a single, nonidentical internal calibrant (IC). This study represents the first systematic study of C. bovis metabolomics via an NMR-driven methodology, which advances the toolbox for quality control of TCM and provides a more definitive reference point for future chemical and biological studies of C. bovis as a valuable materia medica.PMID:36871364 | DOI:10.1016/j.jpba.2023.115320

ACS Nano. 2023 Mar 5. doi: 10.1021/acsnano.2c11790. Online ahead of print.ABSTRACTCrop disease represents a serious and increasing threat to global food security. Lanthanum oxide nanomaterials (La2O3 NMs) with different sizes (10 and 20 nm) and surface modifications (citrate, polyvinylpyrrolidone [PVP], and poly(ethylene glycol)) were investigated for their control of the fungal pathogen Fusarium oxysporum (Schl.) f. sp cucumerinum Owen on six-week-old cucumber (Cucumis sativus) in soil. Seed treatment and foliar application of the La2O3 NMs at 20-200 mg/kg (mg/L) significantly suppressed cucumber wilt (decreased by 12.50-52.11%), although the disease control efficacy was concentration-, size-, and surface modification-dependent. The best pathogen control was achieved by foliar application of 200 mg/L PVP-coated La2O3 NMs (10 nm); disease severity was decreased by 67.6%, and fresh shoot biomass was increased by 49.9% as compared with pathogen-infected control. Importantly, disease control efficacy was 1.97- and 3.61-fold greater than that of La2O3 bulk particles and a commercial fungicide (Hymexazol), respectively. Additionally, La2O3 NMs application enhanced cucumber yield by 350-461%, increased fruit total amino acids by 295-344%, and improved fruit vitamin content by 65-169% as compared with infected controls. Transcriptomic and metabolomic analyses revealed that La2O3 NMs: (1) interacted with calmodulin, subsequently activating salicylic acid-dependent systemic acquired resistance; (2) increased the activity and expression of antioxidant and related genes, thereby alleviating pathogen-induced oxidative stress; and (3) directly inhibited in vivo pathogen growth. The findings highlight the significant potential of La2O3 NMs for suppressing plant disease in sustainable agriculture.PMID:36871293 | DOI:10.1021/acsnano.2c11790

J Cheminform. 2023 Mar 4;15(1):32. doi: 10.1186/s13321-023-00695-y.ABSTRACTMapping the chemical space of compounds to chemical structures remains a challenge in metabolomics. Despite the advancements in untargeted liquid chromatography-mass spectrometry (LC-MS) to achieve a high-throughput profile of metabolites from complex biological resources, only a small fraction of these metabolites can be annotated with confidence. Many novel computational methods and tools have been developed to enable chemical structure annotation to known and unknown compounds such as in silico generated spectra and molecular networking. Here, we present an automated and reproducible Metabolome Annotation Workflow (MAW) for untargeted metabolomics data to further facilitate and automate the complex annotation by combining tandem mass spectrometry (MS2) input data pre-processing, spectral and compound database matching with computational classification, and in silico annotation. MAW takes the LC-MS2 spectra as input and generates a list of putative candidates from spectral and compound databases. The databases are integrated via the R package Spectra and the metabolite annotation tool SIRIUS as part of the R segment of the workflow (MAW-R). The final candidate selection is performed using the cheminformatics tool RDKit in the Python segment (MAW-Py). Furthermore, each feature is assigned a chemical structure and can be imported to a chemical structure similarity network. MAW is following the FAIR (Findable, Accessible, Interoperable, Reusable) principles and has been made available as the docker images, maw-r and maw-py. The source code and documentation are available on GitHub ( https://github.com/zmahnoor14/MAW ). The performance of MAW is evaluated on two case studies. MAW can improve candidate ranking by integrating spectral databases with annotation tools like SIRIUS which contributes to an efficient candidate selection procedure. The results from MAW are also reproducible and traceable, compliant with the FAIR guidelines. Taken together, MAW could greatly facilitate automated metabolite characterization in diverse fields such as clinical metabolomics and natural product discovery.PMID:36871033 | DOI:10.1186/s13321-023-00695-y

J Dairy Sci. 2023 Mar 2:S0022-0302(23)00097-8. doi: 10.3168/jds.2022-22681. Online ahead of print.ABSTRACTSole hemorrhage and sole ulcers, referred to as sole lesions, are important causes of lameness in dairy cattle. We aimed to compare the serum metabolome of dairy cows that developed sole lesions in early lactation with that of cows that remained unaffected. We prospectively enrolled a cohort of 1,169 Holstein dairy cows from a single dairy herd and assessed animals at 4 time points: before calving, immediately after calving, early lactation, and late lactation. Sole lesions were recorded by veterinary surgeons at each time point, and serum samples were collected at the first 3 time points. Cases were defined by the presence of sole lesions in early lactation and further subdivided by whether sole lesions had been previously recorded; unaffected controls were randomly selected to match cases. Serum samples from a case-control subset of 228 animals were analyzed with proton nuclear magnetic resonance spectroscopy. Spectral signals, corresponding to 34 provisionally annotated metabolites and 51 unlabeled metabolites, were analyzed in subsets relating to time point, parity cohort, and sole lesion outcome. We used 3 analytic methods (partial least squares discriminant analysis, least absolute shrinkage and selection operator regression, and random forest) to determine the predictive capacity of the serum metabolome and identify informative metabolites. We applied bootstrapped selection stability, triangulation, and permutation to support the inference of variable selection. The average balanced accuracy of class prediction ranged from 50 to 62% depending on the subset. Across all 17 subsets, 20 variables had a high probability of being informative; those with the strongest evidence of being associated with sole lesions corresponded to phenylalanine and 4 unlabeled metabolites. We conclude that the serum metabolome, as characterized by proton nuclear magnetic resonance spectroscopy, does not appear able to predict sole lesion presence or future development of lesions. A small number of metabolites may be associated with sole lesions although, given the poor prediction accuracies, these metabolites are likely to explain only a small proportion of the differences between affected and unaffected animals. Future metabolomic studies may reveal underlying metabolic mechanisms of sole lesion etiopathogenesis in dairy cows; however, the experimental design and analysis need to effectively control for interanimal and extraneous sources of spectral variation.PMID:36870845 | DOI:10.3168/jds.2022-22681

Int J Biol Macromol. 2023 Mar 2:123863. doi: 10.1016/j.ijbiomac.2023.123863. Online ahead of print.ABSTRACTSynthetic biology is an eco-friendly and sustainable approach for the production of compounds, particularly used when the production processes involve toxic reagents. In this study, we used the silk gland of silkworm to produce indigoidine, a valuable natural blue pigment that cannot be synthesized naturally in animals. We genetically engineered these silkworms by integrating the indigoidine synthetase (idgS) gene from S. lavendulae and the PPTase (Sfp) gene from B. subtilis into the silkworm genome. In the resulting Blue silkworm, indigoidine was detected at a high level in the posterior silk gland (PSG), spanning all developmental stages from larvae to adults, without affecting silkworm growth or development. This synthesized indigoidine was secreted from the silk gland and subsequently stored in the fat body, with only a small fraction being excreted by the Malpighian tubule. Metabolomic analysis revealed that Blue silkworm efficiently synthesized indigoidine by upregulating l-glutamine, the precursor of indigoidine, and succinate, which is related to energy metabolism in the PSG. This study represents the first synthesis of indigoidine in an animal and therefore opens a new avenue for the biosynthesis of natural blue pigments and other valuable small molecules.PMID:36870637 | DOI:10.1016/j.ijbiomac.2023.123863

Environ Pollut. 2023 Mar 2:121349. doi: 10.1016/j.envpol.2023.121349. Online ahead of print.ABSTRACTSerum uric acid elevation has been found in long-term nickel (Ni) exposure occupational workers, but the mechanism is unclear. In this study, the relationship between Ni exposure and uric acid elevation was explored in a cohort of 109 participants composed of a Ni-exposed workers group and a control group. The results showed that Ni concentration (5.70 ± 3.21 μg/L) and uric acid level (355.95 ± 67.87 μmol/L) in the serum were increased in the exposure group with a significant positive correlation (r = 0.413, p < 0.0001). The composition of gut microbiota and metabolome revealed that the abundance of uric acid-lowering bacteria, such as Lactobacillus, Lachnospiraceae_Unclassfied and Blautia were reduced while pathogenic bacteria including Parabacteriadies and Escherichia-Shigella were enriched in Ni group, accompanied by impaired intestinal degradation of purines and upregulated biosynthesis of primary bile acids. Consistent with human results, the mice experiments showed that Ni treatment significantly promotes uric acid elevation and systemic inflammation. Lactobacillus and Blautia in gut microbiota were reduced and inflammation-related taxa Alistipes and Mycoplasma were enriched in the Ni treatment. In addition, LC-MS/MS metabolomic analysis indicated that purine nucleosides were accumulated in mice feces, which increased purine absorption and uric acid elevation in the serum. In summary, this study provides evidence that UA elevation was correlated with heavy metals exposure and highlighted the role of gut microbiota in intestinal purine catabolism and in the pathogenesis of heavy metal-induced hyperuricemia.PMID:36870597 | DOI:10.1016/j.envpol.2023.121349

J Nutr. 2023 Mar 2:S0022-3166(23)35277-5. doi: 10.1016/j.tjnut.2023.02.035. Online ahead of print.ABSTRACTBACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition defined by the build-up of amyloid plaques in the brain and intraneuronal tangles of the protein tau. Autophagy is a cellular cleaning process involved in the degradation of proteins, including proteins directly responsible for amyloid plaques, but its activity is compromised in AD. The mechanistic target of rapamycin complex 1 (mTORC1) inhibits autophagy when activated by amino acids.OBJECTIVES: We therefore hypothesized that reducing amino acid intake by decreasing dietary protein could promote autophagy which in turn could prevent amyloid plaque deposition in mice.METHODS: Homozygote (2-month old) and heterozygote (4-month old) amyloid precursor protein (APP) NL-G-F mice, a model of brain amyloid deposition, were used in this study to test this hypothesis. Male and female mice were fed one of three isocaloric low-protein, control, or high-protein diets for four months and then humanely killed for analysis. Locomotor performance was measured using the inverted screen test and body composition was measured using EchoMRI. Samples were analyzed using western blotting, enzyme-linked immunosorbent assay (ELISA), mass spectrometry, and immunohistochemical staining.RESULTS: mTORC1 activity in the cerebral cortex was inversely co-varied with protein consumption in both homozygote and heterozygote mice. Low-protein diet improved metabolic parameters and restored locomotor performance only in male homozygous mice. Dietary protein adjustment did not impact amyloid deposition in homozygous mice. However, in the heterozygous APP NL-G-F mice, amyloid plaque was lower in male mice consuming the low-protein compared with control diet.CONCLUSIONS: Thus, reducing protein intake reduces mTORC1 activity and may prevent amyloid accumulation, at least in male mice. This study shows that dietary protein is a tool that can be used to change mTORC1 activity and amyloid deposition in the mouse brain and also demonstrates that the murine brain's response to dietary protein is sex specific.PMID:36870538 | DOI:10.1016/j.tjnut.2023.02.035

EBioMedicine. 2023 Mar 2;90:104503. doi: 10.1016/j.ebiom.2023.104503. Online ahead of print.ABSTRACTBACKGROUND: Type 2 diabetes (T2D) and coronary artery disease (CAD) both have known genetic determinants, but the mechanisms through which their associated genetic variants lead to disease onset remain poorly understood.METHODS: We used large-scale metabolomics data in a two-sample reverse Mendelian randomization (MR) framework to estimate effects of genetic liability to T2D and CAD on 249 circulating metabolites in the UK Biobank (N = 118,466). We examined the potential for medication use to distort effect estimates by conducting age-stratified metabolite analyses.FINDINGS: Using inverse variance weighted (IVW) models, higher genetic liability to T2D was estimated to decrease high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) (e.g., HDL-C: -0.05 SD; 95% CI -0.07 to -0.03, per doubling of liability), whilst increasing all triglyceride groups and branched chain amino acids (BCAAs). IVW estimates for CAD liability suggested an effect on reducing HDL-C as well as raising very-low density lipoprotein cholesterol (VLDL-C) and LDL-C. In pleiotropy-robust models, T2D liability was still estimated to increase BCAAs, but several estimates for higher CAD liability reversed and supported decreased LDL-C and apolipoprotein-B. Estimated effects of CAD liability differed substantially by age for non-HDL-C traits, with higher CAD liability lowering LDL-C only at older ages when statin use was common.INTERPRETATION: Overall, our results support largely distinct metabolic features of genetic liability to T2D and CAD, illustrating both challenges and opportunities for preventing these commonly co-occurring diseases.FUNDING: Wellcome Trust [218495/Z/19/Z], UK MRC [MC_UU_00011/1; MC_UU_00011/4], the University of Bristol, Diabetes UK [17/0005587], World Cancer Research Fund [IIG_2019_2009].PMID:36870196 | DOI:10.1016/j.ebiom.2023.104503

Appl Biochem Biotechnol. 2023 Mar 4. doi: 10.1007/s12010-023-04419-8. Online ahead of print.ABSTRACTGlobally 80% type 2 diabetes mellitus (T2DM) patients suffer nonalcoholic fatty liver disease (NAFLD). The interplay of gut microbiota and endogenous metabolic networks has not yet been reported in the setting of T2DM with NAFLD. As such, this study utilized 16S rRNA gene sequencing to assess the changes in intestinal flora and nuclear magnetic resonance spectroscopy (1H NMR) to identify potential metabolites in a T2DM with NAFLD rat model. Spearman correlation analysis was performed to explore the relationship between gut microbiota and metabolites. Results revealed that among T2DM with NAFLD rats, diversity indexes of intestinal microbiota were distinctly decreased while levels of 18 bacterial genera within the intestinal tract were significantly altered. In addition, levels of eight metabolites mainly involved in the synthesis and degradation of ketone bodies, the TCA cycle, and butanoate metabolism were altered. Correlation analysis revealed that gut bacteria such as Blautia, Ruminococcus torques group, Allobaculum, and Lachnoclostridium strongly associate with 3-hydroxybutyrate, acetone, acetoacetate, 2-oxoglutarate, citrate, creatinine, hippurate, and allantoin. Our findings can provide a basis for future development of targeted treatments.PMID:36870027 | DOI:10.1007/s12010-023-04419-8

Food Res Int. 2023 Mar;165:112563. doi: 10.1016/j.foodres.2023.112563. Epub 2023 Feb 3.ABSTRACTGut microbes and microbial metabolites derived from polysaccharides mediate beneficial effects related to polysaccharides consumption. Lycium barbarum polysaccharide (LBP) is the main bioactive components in L. barbarum fruits and possesses considerable health-promoting effects. In the present study, we aimed to investigate whether LBP supplementation influenced host metabolic responses and gut microbiota in healthy mice, and to identify bacterial taxa associated with the observed beneficial effects. Our results indicated that mice supplied with LBP at 200 mg/kg BW showed lower serum total cholesterol (TC), triglyceride (TG), and liver TG levels. LBP supplementation strengthened the antioxidant capacity of liver, supported the growth of Lactobacillus and Lactococcus, and stimulated short-chain fatty acids (SCFAs) production. Serum metabolomic analysis revealed that fatty acid degradation pathways were enriched, and RT-PCR further confirmed that LBP up-regulated the expression of liver genes involved in fatty acid oxidation. The Spearman's correlation analysis indicated that some serum and liver lipid profiles and hepatic SOD activity were associated with Lactobacillus, Lactococcus, Ruminococcus, Allobaculum and AF12. Collectively, these findings provide new evidence for the potential preventive effect of LBP consumption on hyperlipidemia and nonalcoholic fatty liver disease.PMID:36869545 | DOI:10.1016/j.foodres.2023.112563

Food Res Int. 2023 Mar;165:112560. doi: 10.1016/j.foodres.2023.112560. Epub 2023 Feb 2.ABSTRACTDysregulation of nicotinamide adenine dinucleotide (NAD+) homeostasis by increased activity of NAD+ consumers or reduced NAD+ biosynthesis plays an important role in the onset of prevalent, often age-related, diseases, such as diabetes, neuropathies or nephropathies. To counteract such dysregulation, NAD+ replenishment strategies can be used. Among these, administration of vitamin B3 derivatives (NAD+ precursors) has garnered attention in recent years. However, the high market price of these compounds and their limited availability, pose important limitations to their use in nutritional or biomedical applications. To overcome these limitations, we have designed an enzymatic method for the synthesis and purification of (1) the oxidized NAD+ precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), (2) their reduced forms NMNH and NRH, and (3) their deaminated forms nicotinic acid mononucleotide (NaMN) and nicotinic acid riboside (NaR). Starting from NAD+ or NADH as substrates, we use a combination of three highly overexpressed soluble recombinant enzymes; (a) a NAD+ pyrophosphatase, (b) an NMN deamidase, and (c) a 5'-nucleotidase, to produce these six precursors. Finally, we validate the activity of the enzymatically produced molecules as NAD+ enhancers in cell culture.PMID:36869544 | DOI:10.1016/j.foodres.2023.112560

Food Res Int. 2023 Mar;165:112555. doi: 10.1016/j.foodres.2023.112555. Epub 2023 Feb 7.ABSTRACTThe global market of chocolate has increased worldwide during the last decade and is expected to reach a value of USD 200 billion by 2028. Chocolate is obtained from different varieties of Theobroma cacao L, a plant domesticated more than 4000 years ago in the Amazon rainforest. However, chocolate production is a complex process requiring extensive post-harvesting, mainly involving cocoa bean fermentation, drying, and roasting. These steps have a critical impact on chocolate quality. Standardizing and better understanding cocoa processing is, therefore, a current challenge to boost the global production of high-quality cocoa worldwide. This knowledge can also help cocoa producers improve cocoa processing management and obtain a better chocolate. Several recent studies have been conducted to dissect cocoa processing via omics analysis. A vast amount of data has been produced regarding omics studies of cocoa processing performed worldwide. This review systematically analyzes the current data on cocoa omics using data mining techniques and discusses opportunities and gaps for cocoa processing standardization from this data. First, we observed a recurrent report in metagenomics studies of species of the fungi genus Candida and Pichia as well as bacteria from the genus Lactobacillus, Acetobacter, and Bacillus. Second, our analyzes of the available metabolomics data showed clear differences in the identified metabolites in cocoa and chocolate from different geographical origin, cocoa type, and processing stage. Finally, our analysis of peptidomics data revealed characteristic patterns in the gathered data including higher diversity and lower size distribution of peptides in fine-flavor cocoa. In addition, we discuss the current challenges in cocoa omics research. More research is still required to fill gaps in central matter in chocolate production as starter cultures for cocoa fermentation, flavor evolution of cocoa, and the role of peptides in the development of specific flavor notes. We also offer the most comprehensive collection of multi-omics data in cocoa processing gathered from different research articles.PMID:36869541 | DOI:10.1016/j.foodres.2023.112555