PubMed

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

Food Res Int. 2023 Mar;165:112547. doi: 10.1016/j.foodres.2023.112547. Epub 2023 Feb 3.ABSTRACTIdentifying wine geographical origin and vintage is vital due to the abundance of fraudulent activity associated with wine mislabeling of region and vintage. In this study, an untargeted metabolomic approach based on liquid chromatography/ion mobility quadrupole time-of-flight mass spectrometry (LC-IM-QTOF-MS) was used to discriminate wine geographical origin and vintage. Wines were well discriminated according to region and vintage with orthogonal partial least squares-discriminant analysis (OPLS-DA). The differential metabolites subsequently were screened by OPLS-DA with pairwise modeling. 42 and 48 compounds in positive and negative ionization modes were screened as differential metabolitesfor the discrimination of different wine regions, and 37 and 35 compounds were screened for wine vintage. Furthermore, new OPLS-DA models were performed using these compounds, and the external verification trial showed excellent practicality with an accuracy over 84.2%. This study indicated that LC-IM-QTOF-MS-based untargeted metabolomics was a feasible tool for wine geographical origin and vintage discrimination.PMID:36869536 | DOI:10.1016/j.foodres.2023.112547

Food Res Int. 2023 Mar;165:112527. doi: 10.1016/j.foodres.2023.112527. Epub 2023 Jan 25.ABSTRACTAspergillus oryzae 3.042 and Aspergillus sojae 3.495 are crucial starters for fermented soybean foods since their abundant secreted enzymes. This study aimed to compare the differences in protein secretion between A. oryzae 3.042 and A. sojae 3.495 during the soy sauce koji fermentation and the effect on volatile metabolites to understand the fermentation characteristics of the strains better. Label-free proteomics detected 210 differentially expressed proteins (DEPs) enriched in amino acid metabolism and protein folding, sorting and degradation pathways. Subsequently, extracellular enzyme analysis showed that three peptidases, including peptide hydrolase, dipeptidyl aminopeptidase, and peptidase S41, were up-regulated in A. sojae 3.495. Seven carbohydrases, including α-galactosidase, endo-arabinase, β-glucosidase, α-galactosidase, α-glucuronidase, arabinan-endo 1,5-α-l-arabinase, and endo-1,4-β-xylanase were up-regulated in A. oryzae 3.042, contributing to the difference in enzyme activity. Significantly different extracellular enzymes influenced the content of volatile alcohols, aldehydes and esters such as (R, R)-2,3-butanediol, 1-hexanol, hexanal, decanal, ethyl l-lactate and methyl myristate in both strains, which affected the type of aroma of koji. Overall, this study revealed the differences in molecular mechanisms between A. oryzae 3.042 and A. sojae 3.495 under solid-state fermentation, providing a reference for targeted enhancement strains.PMID:36869527 | DOI:10.1016/j.foodres.2023.112527

Food Res Int. 2023 Mar;165:112520. doi: 10.1016/j.foodres.2023.112520. Epub 2023 Jan 26.ABSTRACTYa'an Tibetan Tea (YATT) is a classic dark tea variety fermented with a unique geographical environment and traditional craftsmanship. Previous research indicates that it is beneficial for obesity and related metabolic disorders, but no systematic research currently reveals its precise mechanisms. This work investigated the preventive effect of YATT on obesity and the corresponding potential mechanisms by performing 16S rRNA gene sequencing and metabolomics studies. Our results demonstrated that YATT could significantly improve the body weight and fat deposition in hypercaloric high-fat diet (HFD)-induced obese rats, enhance antioxidant enzymes activity and reduce inflammation, and reverse the liver damage caused by an HFD. Moreover, 16S rRNA analysis showed that YATT could improve the intestinal microbial disorders caused by the HFD by significantly reversing the increase in Firmicutes/Bacteroidetes（F/B）ratio and the relative abundance of flora associated with the HFD, such as unclassified_Lachnospiraceae and Romboutsia flora. In addition, metabolomic analysis of cecum contents identified 121 differential metabolites, of which 19 were common to all experimental rats fed with and without a high-fat diet. Strikingly, 17 of the most prevalent 19 differential metabolites, including Theobromine, L-Valine, and Diisobutyl phthalate, were considerably reversed by YATT. Enrichment analysis of the metabolic pathways of these differential metabolites indicated that Caffeine metabolism, Phenylalanine metabolism, and Lysine degradation are the potential metabolic pathways responsible for the obesity prevention effect of YATT. Collectively, this work revealed that YATT has good potential for obesity prevention and the improvement of intestinal microbial communities, potentially due to the YATT-induced alterations in the metabolic pathways and functional metabolite levels of caffeine and amino acids. These results inform the material basis of YATT for obesity prevention and its mechanisms and provide essential insights for developing YATT as a healthy beverage for obesity prevention.PMID:36869524 | DOI:10.1016/j.foodres.2023.112520

Food Res Int. 2023 Mar;165:112522. doi: 10.1016/j.foodres.2023.112522. Epub 2023 Jan 26.ABSTRACTOolong tea is one of the most popular tea beverages in China. Tea cultivars, processing technology and origin of production affect the quality and price of oolong teas. To investigate the differences in Huangguanyin oolong tea from different production regions, the chemical components, mineral elements and rare earth elements of Huangguanyin oolong tea produced in Yunxiao (YX) and Wuyishan (WY) were analyzed by using spectrophotometry methods, targeted metabolomics and inductive plasma coupled mass spectrometry (ICP-MS). The results of spectrophotometry methods revealed that there were significant differences in thearubigin, tea polyphenols and water extract between Huangguanyin oolong teas from different production regions. Targeted metabolomics identified a total of 31 chemical components in Huangguanyin oolong teas from the two production regions, of which 14 chemical components were significantly different and contributed to the regional differentiation of Huangguanyin oolong tea. Yunxiao Huangguanyin had relatively higher contents of (-)-Epigallocatechin-3-O-(3-O-methylgallate) (EGCG3″Me), ornithine (Orn) and histidine (His), while Wuyishan Huangguanyin had relatively higher contents of glutamic acid (Glu), γ-aminobutyric acid (GABA), β-aminobutyric acid (β-ABA) and other components. Moreover, ICP-MS identified a total of 15 mineral elements and 15 rare earth elements in Huangguanyin oolong tea from the two production regions, of which 15 elements were significantly different between YX and WY, and contributed to the regional differentiation of Huangguanyin oolong tea. K had a relatively higher content in Yunxiao Huangguanyin, while rare earth elements had relatively higher contents in Wuyishan Huangguanyin. The classification results by the production region showed that the discrimination rate of the support vector machine (SVM) model based on the 14 different chemical components reached 88.89%, while the SVM model based on the 15 elements reached 100%. Therefore, we used targeted metabolomics and ICP-MS techniques to screen and explore the chemical components, mineral elements and rare earth elements differences among two production regions, which indicated the feasibility of Huangguanyin oolong tea classification by production regions in the study. The results will provide some reference for the distinction between the two production regions of Huangguanyin oolong tea.PMID:36869522 | DOI:10.1016/j.foodres.2023.112522

Food Res Int. 2023 Mar;165:112516. doi: 10.1016/j.foodres.2023.112516. Epub 2023 Jan 25.ABSTRACTCompared with traditional staple crops, foxtail millet grain is rich in nutrition and beneficial to human health. Foxtail millet is also tolerance to various abiotic stresses, including drought, making it a good plant for growing in barren land. The study on the composition of metabolites and its dynamics changes during grain development is helpful to understand the process of foxtail millet grain formation. In our study, metabolic and transcriptional analysis were used to uncover the metabolic processes that could influence grain filling in foxtail millet. A total of 2104 known metabolites, belonging to 14 categories, were identified during grain filling. Functional analysis of DAMs and DEGs revealed a stage-specific metabolic properties in foxtail millet grain filling. Some important metabolic processes, such as flavonoid biosynthesis, glutathione metabolism, linoleic acid metabolism, starch and sucrose metabolism and valine, leucine and isoleucine biosynthesis were co-mapped for DEGs and DAMs. Thus, we constructed a gene-metabolite regulatory network of these metabolic pathways to explain their potential functions during grain filling. Our study showed the important metabolic processes during grain filling and focused on the dynamic changes of related metabolites and genes at different stages, which provided a reference for us to better understand and improve foxtail millet grain development and yield.PMID:36869517 | DOI:10.1016/j.foodres.2023.112516

Food Res Int. 2023 Mar;165:112393. doi: 10.1016/j.foodres.2022.112393. Epub 2022 Dec 28.ABSTRACTThe health-promoting activities of procyanidin extracts from hawthorn (HPCs) are closely related to their digestive behaviors, absorption, and colonic metabolism, all of which remain unknown for now and thus hinder further exploration. This study aims to explore the dynamic changes of HPCs during in vitro digestion and fermentation, as well as their Caco-2 permeability, focusing mainly on the interaction between gut microbiota and HPCs. The results showed that the digested HPC samples had characteristic absorption peaks at 280 nm, and there were absorption peaks in the stretching vibration zone, including OH and CC on the benzene ring, which suggested that procyanidins were the main components in HPCs after in vitro digestion. Meanwhile, HPCs had the highest stability in the oral phase. However, the total procyanidin content of HPCs decreased during gastrointestinal digestion, and flavan-3-ol dimers and trimers in HPCs are partially degraded into epicatechin. Uptake of epicatechin (4.07 %), procyanidin B2 (2.15 %), and procyanidin B5 (39.44 %) through Caco-2 monolayer was also observed in HPC treatment, while there was still a large portion of procyanidins that was not absorbed. Subsequent fermentation resulted in a decrease in pH along with the production of short-chain fatty acids (SCFAs), mainly due to the degradation and utilization of HPC, as indicated by a reduction of total procyanidins. Furthermore, the HPCs modulated gut microbial populations: down-regulated the abundances of Bacteroides, Fusobacterium, Enterococcus, Parabacteroides, and Bilophila, and up-regulated Escherichia-Shigella, Klebsiella, Turicibacter, Actinobacillus, Roseburia, and Blautia. Ultimately, epicatechin and procyanidin B2, B5 and C1 were converted into phenolic acids through the metabolism of Bacteroides, Sutterella, Butyrobacter and Blautia. 4-ethylbenzoic acid, 4-hydroxyphenylpropionic acid, 3,4-dihydroxyphenyl acetic acid were confirmed as the significant metabolites in the fermentation. These results elucidated the potential mechanisms of HPCs metabolism and their beneficial effects on gut microbiota and colonic phenolic acids production.PMID:36869464 | DOI:10.1016/j.foodres.2022.112393

Food Res Int. 2023 Mar;165:112376. doi: 10.1016/j.foodres.2022.112376. Epub 2023 Jan 2.ABSTRACTUntargeted metabolomics with the combination of ion mobility separation coupled to high resolution mass spectrometry (IMS-HRMS) was applied to investigate the impact of resveratrol and pterostilbene supplementation on the metabolic fingerprint of the Wistar rats liver with induced liver steatosis. RP-LC and HILIC in both ionisation modes were employed to analyse the liver samples (n = 40) from Wistar rats fed with a high-fat and high-fructose diet, supplemented or not with resveratrol and pterostilbene. After univariate and multivariate statistical analysis, 34 metabolites were highlighted in the different diets and elucidated. Despite the structural similarity, different alterations in liver metabolism were observed by the supplementations. Resveratrol treatment was characterised by the alteration in metabolism of 17 lysophospholipids, while pterostilbene affected some vitamins and derivatives, among others. IMS has demonstrated great potential in the elucidation process thanks to the additional structural descriptor the CCS (Å2), providing more confidence in the identification.PMID:36869462 | DOI:10.1016/j.foodres.2022.112376

Food Res Int. 2023 Mar;165:112350. doi: 10.1016/j.foodres.2022.112350. Epub 2022 Dec 25.ABSTRACTThe purpose of this study was to reveal the relationship between core microorganisms and flavor substances in the fermentation process of corn wine. Microbial diversity, volatile and non-volatile flavor substances were detected by high-throughput sequencing (HTS), headspace solid phase micro-extraction gas chromatography-mass spectrometry (HS-SPME/GC-MS) and gas chromatography time of flight mass spectrometry (GC-TOF-MS). High performance liquid chromatography (HPLC) was used to detect organic acids in corn wine fermentation, and its physiochemical properties were tracked. The results showed that physiochemical factors changed obviously with fermentation time. Bacillus, Prevotella_9, Acinetobacter and Gluconobacter were the predominant bacterial. Rhizopus and Saccharomyces were the dominant fungi. Acetic acid and succinic acid were important organic acids in corn wine. According to variable importance of projection (VIP) > 1 and P < 0.05, 24 volatile flavor substances with significant difference were screened out from 52 volatile flavor substances. Similarly, 25 non-volatile flavor substances with significant differences were screened out from the 97 reliable metabolites identified by 223 chromatographic peaks. Eight key metabolic pathways were enriched from 25 non-volatile flavor substances according to path influence values > 0.1 and P < 0.05. Based on Two-way Orthogonal Partial Least Squares (O2PLS) model and Pearson correlation coefficient, Saccharomyces, Rhizopus, uncultured_bacterium, Aneurinibacillus, Wickerhamomyces and Gluconobacter may be the potential volatile flavor-contributing microorganism genus in corn wine. The Pearson correlation coefficient showed that Saccharomyces was significantly positively correlated with malic acid, oxalic acid, valine and isoleucine, and Rhizopus was positively correlated with glucose-1-phosphate and alanine. These findings enhanced our understanding of the formation mechanism of flavor substances in corn wine and provided the theoretical basis for stabilizing flavor quality of corn wine.PMID:36869445 | DOI:10.1016/j.foodres.2022.112350

Microbiome. 2023 Mar 3;11(1):40. doi: 10.1186/s40168-023-01492-3.ABSTRACTBACKGROUND: Postpartum dairy cows experiencing excessive lipolysis are prone to severe immunosuppression. Despite the extensive understanding of the gut microbial regulation of host immunity and metabolism, its role during excessive lipolysis in cows is largely unknown. Herein, we investigated the potential links between the gut microbiome and postpartum immunosuppression in periparturient dairy cows with excessive lipolysis using single immune cell transcriptome, 16S amplicon sequencing, metagenomics, and targeted metabolomics.RESULTS: The use of single-cell RNA sequencing identified 26 clusters that were annotated to 10 different immune cell types. Enrichment of functions of these clusters revealed a downregulation of functions in immune cells isolated from a cow with excessive lipolysis compared to a cow with low/normal lipolysis. The results of metagenomic sequencing and targeted metabolome analysis together revealed that secondary bile acid (SBA) biosynthesis was significantly activated in the cows with excessive lipolysis. Moreover, the relative abundance of gut Bacteroides sp. OF04 - 15BH, Paraprevotella clara, Paraprevotella xylaniphila, and Treponema sp. JC4 was mainly associated with SBA synthesis. The use of an integrated analysis showed that the reduction of plasma glycolithocholic acid and taurolithocholic acid could contribute to the immunosuppression of monocytes (CD14+MON) during excessive lipolysis by decreasing the expression of GPBAR1.CONCLUSIONS: Our results suggest that alterations in the gut microbiota and their functions related to SBA synthesis suppressed the functions of monocytes during excessive lipolysis in transition dairy cows. Therefore, we concluded that altered microbial SBA synthesis during excessive lipolysis could lead to postpartum immunosuppression in transition cows. Video Abstract.PMID:36869370 | DOI:10.1186/s40168-023-01492-3

J Transl Med. 2023 Mar 3;21(1):169. doi: 10.1186/s12967-023-03935-9.ABSTRACTBACKGROUND: Chemotherapy (CT) is central to the treatment of triple negative breast cancer (TNBC), but drug toxicity and resistance place strong restrictions on treatment regimes. Fasting sensitizes cancer cells to a range of chemotherapeutic agents and also ameliorates CT-associated adverse effects. However, the molecular mechanism(s) by which fasting, or short-term starvation (STS), improves the efficacy of CT is poorly characterized.METHODS: The differential responses of breast cancer or near normal cell lines to combined STS and CT were assessed by cellular viability and integrity assays (Hoechst and PI staining, MTT or H2DCFDA staining, immunofluorescence), metabolic profiling (Seahorse analysis, metabolomics), gene expression (quantitative real-time PCR) and iRNA-mediated silencing. The clinical significance of the in vitro data was evaluated by bioinformatical integration of transcriptomic data from patient data bases: The Cancer Genome Atlas (TCGA), European Genome-phenome Archive (EGA), Gene Expression Omnibus (GEO) and a TNBC cohort. We further examined the translatability of our findings in vivo by establishing a murine syngeneic orthotopic mammary tumor-bearing model.RESULTS: We provide mechanistic insights into how preconditioning with STS enhances the susceptibility of breast cancer cells to CT. We showed that combined STS and CT enhanced cell death and increased reactive oxygen species (ROS) levels, in association with higher levels of DNA damage and decreased mRNA levels for the NRF2 targets genes NQO1 and TXNRD1 in TNBC cells compared to near normal cells. ROS enhancement was associated with compromised mitochondrial respiration and changes in the metabolic profile, which have a significant clinical prognostic and predictive value. Furthermore, we validate the safety and efficacy of combined periodic hypocaloric diet and CT in a TNBC mouse model.CONCLUSIONS: Our in vitro, in vivo and clinical findings provide a robust rationale for clinical trials on the therapeutic benefit of short-term caloric restriction as an adjuvant to CT in triple breast cancer treatment.PMID:36869333 | DOI:10.1186/s12967-023-03935-9

Pharm Res. 2023 Mar 3. doi: 10.1007/s11095-023-03488-y. Online ahead of print.ABSTRACTINTRODUCTION: The emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) posed a severe challenge to tuberculosis (TB) management. The treatment of MDR-TB involves second-line anti-TB agents, most of which are injectable and highly toxic. Previous metabolomics study of the Mtb membrane revealed that two antimicrobial peptides, D-LAK120-A and D-LAK120-HP13, can potentiate the efficacy of capreomycin against mycobacteria.AIMS: As both capreomycin and peptides are not orally available, this study aimed to formulate combined formulations of capreomycin and D-LAK peptides as inhalable dry powder by spray drying.METHODS AND RESULTS: A total of 16 formulations were prepared with different levels of drug content and capreomycin to peptide ratios. A good production yield of over 60% (w/w) was achieved in most formulations. The co-spray dried particles exhibited spherical shape with a smooth surface and contained low residual moisture of below 2%. Both capreomycin and D-LAK peptides were enriched at the surface of the particles. The aerosol performance of the formulations was evaluated with Next Generation Impactor (NGI) coupled with Breezhaler®. While no significant difference was observed in terms of emitted fraction (EF) and fine particle fraction (FPF) among the different formulations, lowering the flow rate from 90 L/min to 60 L/min could reduce the impaction at the throat and improve the FPF to over 50%.CONCLUSIONS: Overall, this study showed the feasibility of producing co-spray dried formulation of capreomycin and antimicrobial peptides for pulmonary delivery. Future study on their antibacterial effect is warranted.PMID:36869245 | DOI:10.1007/s11095-023-03488-y

Commun Med (Lond). 2023 Mar 3;3(1):35. doi: 10.1038/s43856-023-00265-1.ABSTRACTBACKGROUND: Cavernous angiomas (CAs) affect 0.5% of the population, predisposing to serious neurologic sequelae from brain bleeding. A leaky gut epithelium associated with a permissive gut microbiome, was identified in patients who develop CAs, favoring lipid polysaccharide producing bacterial species. Micro-ribonucleic acids along with plasma levels of proteins reflecting angiogenesis and inflammation were also previously correlated with CA and CA with symptomatic hemorrhage.METHODS: The plasma metabolome of CA patients and CA patients with symptomatic hemorrhage was assessed using liquid-chromatography mass spectrometry. Differential metabolites were identified using partial least squares-discriminant analysis (p < 0.05, FDR corrected). Interactions between these metabolites and the previously established CA transcriptome, microbiome, and differential proteins were queried for mechanistic relevance. Differential metabolites in CA patients with symptomatic hemorrhage were then validated in an independent, propensity matched cohort. A machine learning-implemented, Bayesian approach was used to integrate proteins, micro-RNAs and metabolites to develop a diagnostic model for CA patients with symptomatic hemorrhage.RESULTS: Here we identify plasma metabolites, including cholic acid and hypoxanthine distinguishing CA patients, while arachidonic and linoleic acids distinguish those with symptomatic hemorrhage. Plasma metabolites are linked to the permissive microbiome genes, and to previously implicated disease mechanisms. The metabolites distinguishing CA with symptomatic hemorrhage are validated in an independent propensity-matched cohort, and their integration, along with levels of circulating miRNAs, enhance the performance of plasma protein biomarkers (up to 85% sensitivity and 80% specificity).CONCLUSIONS: Plasma metabolites reflect CAs and their hemorrhagic activity. A model of their multiomic integration is applicable to other pathologies.PMID:36869161 | DOI:10.1038/s43856-023-00265-1

J Nutr Biochem. 2023 Mar 1:109307. doi: 10.1016/j.jnutbio.2023.109307. Online ahead of print.ABSTRACTNon-alcoholic fatty liver disease (NAFLD) pathogenesis remains poorly understood due to the complex metabolic and inflammatory changes in the liver. This study aimed to elucidate hepatic events related to inflammation and lipid metabolism and their linkage with metabolic alterations during NAFLD in American lifestyle-induced obesity syndrome (ALIOS) diet-fed mice. 48 JaxC57BL/6J male mice were fed with ALIOS diet (n=24) or control chow diet (n=24) for 8, 12, and 16 weeks. At the end of each timepoint, 8 mice were sacrificed where plasma and liver were collected. Hepatic fat accumulation was followed using magnetic resonance imaging and confirmed with histology. Further, targeted gene expression and non-targeted metabolomics analysis were conducted. Our results showed higher hepatic steatosis, body weight, energy consumption, and liver mass in ALIOS diet-fed mice compared to control mice. ALIOS diet altered expression of genes related to inflammation (Tnfa and IL-6) and lipid metabolism (Cd36, Fasn, Scd1, Cpt1a, and Ppara). Metabolomics analysis indicated decrease of lipids containing polyunsaturated fatty acids such as LPE(20:5) and LPC(20:5) with increase of other lipid species such as LPI(16:0) and LPC(16:2) and peptides such as alanyl-phenylalanine and glutamyl-arginine. We further observed novel correlations between different metabolites including sphingolipid, lysophospholipids, peptides, and bile acid with inflammation, lipid uptake and synthesis. Together with the reduction of antioxidant metabolites and gut microbiota-derived metabolites contribute to NAFLD development and progression. The combination of non-targeted metabolomics with gene expression in future studies can further identify key metabolic routes during NAFLD which could be the targets of potential novel therapeutics.PMID:36868506 | DOI:10.1016/j.jnutbio.2023.109307

J Nutr Biochem. 2023 Mar 1:109308. doi: 10.1016/j.jnutbio.2023.109308. Online ahead of print.ABSTRACTColorectal cancer (CRC) is one of the most common and deadly cancers worldwide. Grape pomace (GP) is a rich source of bioactive compounds with anti-inflammatory, and anticancer effects. We recently found that dietary GP had protective effects against CRC development in the azoxymethane (AOM)/dextran sulfate sodium (DSS) CRC mouse model through suppression of cell proliferation and modulation of DNA methylation. However, the underlying molecular mechanisms associated with changes in metabolites remain unexamined. This study profiled fecal metabolomic changes in a mouse CRC model in response to GP supplementation using gas chromatography-mass spectrometry (GC-MS) based metabolomic analysis. A total of 29 compounds showed significant changes due to GP supplementation, including bile acids, amino acids, fatty acids, phenols/flavonoids, glycerolipids, carbohydrates, organic acids, and others. The major changes in metabolites of feces include increased deoxycholic acid (DCA) and decreased amino acid content. Dietary GP upregulated the expression of farnesoid X receptor (FXR) downstream genes while decreasing fecal urease activity. DNA repair enzyme MutS Homolog 2 (MSH2) was upregulated by GP supplementation. Consistently, γ-H2AX, as a DNA damage marker, decreased in GP supplemented mice. Moreover, MDM2, a protein in the ataxia telangiectasia mutated (ATM) signaling, was decreased by GP supplementation. These data provided valuable metabolic clues for unraveling the protective effects of GP supplementation against CRC development.PMID:36868505 | DOI:10.1016/j.jnutbio.2023.109308