PubMed

Analyst. 2023 Sep 25. doi: 10.1039/d3an01237a. Online ahead of print.ABSTRACTRecently, amino acids other than glycine and taurine were found to be conjugated with bile acids by the gut microbiome in mouse and human. As potential diagnostic markers for inflammatory bowel disease and farnesoid X receptor agonists, their physiological effects and mechanisms, however, remain to be elucidated. A tool for the rapid and comprehensive annotation of such new metabolites is required. Thus, we developed a semi-empirical MS/MS library for bile acids conjugated with 18 common amino acids, including alanine, arginine, asparagine, aspartate, glutamine, glutamate, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine. To investigate their fragmentation rules, these amino acids were chemically conjugated with lithocholic acid, deoxycholic acid, and cholic acid, and their accurate-mass MS/MS spectra were acquired. The common fragmentation patterns from the amino acid moieties were combined with 10 general bile acid skeletons to generate a semi-empirical MS/MS library of 180 structures. Software named BAFinder 2.0 was developed to combine the semi-empirical library in negative mode and the characteristic fragments in positive mode for automatic unknown identification. As a proof of concept, this workflow was applied to the LC-MS/MS analysis of the feces of human, beagle dogs, and rats. In total, 171 common amino acid-conjugated bile acids were annotated and 105 of them were confirmed with the retention times of synthesized compounds. To explore other potential bile acid conjugates, user-defined small molecules were in-silico conjugated with bile acids and searched in the fecal dataset. Four novel bile acid conjugates were discovered, including D-Ala-D-Ala, Lys(iso)-Gly, L-2-aminobutyric acid, and ornithine.PMID:37743718 | DOI:10.1039/d3an01237a

Adv Mater. 2023 Sep 24:e2307263. doi: 10.1002/adma.202307263. Online ahead of print.ABSTRACTUnsatisfied tumor accumulation of chemotherapeutic drugs and a complicated immunosuppressive microenvironment diminish the immune response rate and the therapeutic effect. Surface modification of these drugs with target ligands can promote their cellular internalization, but the modified drugs may be subjected to unexpected immune recognition and clearance. Herein, a phenylboronic acid (PBA) group-shieldable dendritic nanomedicine that integrates an immunogenic cell death (ICD)-inducing agent (epirubicin, Epi) and an indoleamine 2,3-dioxgenase 1 (IDO1) inhibitor (NLG919) is reported for tumor chemo-immunotherapy. This NLG919-loaded Epi-conjugated PEGylated dendrimers bridged with boronate bonds (NLG919@Epi-DBP) maintains a stable nanostructure during circulation. Under a moderate acidic condition, the PBA group exposes to the sialic acid residue on the tumor cell membrane to enhance the internalization and penetration of NLG919@Epi-DBP. At pH 5.0, NLG919@Epi-DBP rapidly disassembles to release the incorporated Epi and NLG919. Epi triggers robust ICD of tumor cells that evokes strong immune response. In addition, inhibition of the IDO1 activity downregulates the metabolism of L-tryptophan to kynurenine, leading to a reduction in the recruitment of immunosuppressive cells and modulation of the tumor immune microenvironment. Collectively, this promising strategy has been demonstrated to evoke robust immune response as well as remodel the immunosuppressive microenvironment for an enhanced chemo-immunotherapeutic effect. This article is protected by copyright. All rights reserved.PMID:37743633 | DOI:10.1002/adma.202307263

Int J Biol Macromol. 2023 Sep 22:127044. doi: 10.1016/j.ijbiomac.2023.127044. Online ahead of print.ABSTRACTAtractylodes lancea (Thunb.) is a perennial medicinal herb, with its dry rhizomes are rich in various sesquiterpenoids and polyacetylenes components (including atractylodin, atractylon and β-eudesmol). However, the contents of these compounds are various and germplasms specific, and the mechanisms of biosynthesis in A. lancea are still unknown. In this study, we identified the differentially expressed candidate genes and metabolites involved in the biosynthesis of sesquiterpenoids and polyacetylenes, and speculated the anabolic pathways of these pharmaceutical components by transcriptome and metabolomic analysis. In the sesquiterpenoids biosynthesis, a total of 28 differentially expressed genes (DEGs) and 6 differentially expressed metabolites (DEMs) were identified. The beta-Selinene is likely to play a role in the synthesis of atractylon and β-eudesmol. Additionally, the polyacetylenes biosynthesis showed the presence of 3 DEGs and 4 DEMs. Notably, some fatty acid desaturase (FAB2 and FAD2) significantly down-regulated in polyacetylenes biosynthesis. The gamma-Linolenic acid is likely involved in the biosynthesis of polyacetylenes and thus further synthesis of atractylodin. Overall, these studies have investigated the biosynthetic pathways of atractylodin, atractylon and β-eudesmol in A. lancea for the first time, and present potential new anchor points for further exploration of sesquiterpenoids and polyacetylenes compound biosynthesis pathways in A. lancea.PMID:37742891 | DOI:10.1016/j.ijbiomac.2023.127044

J Pharm Biomed Anal. 2023 Sep 14;236:115722. doi: 10.1016/j.jpba.2023.115722. Online ahead of print.ABSTRACTSeveral Amaranthus vegetables (Amaranthaceae) have been recognized as valuable sources of minerals, vitamins, proteins, and phytonutrients, with health-promoting characteristics. In this study, three edible Amaranthus species, namely A. hybridus (AH), A. blitum (AB), and A. caudatus (AC), were chemically characterized using non-targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique. Further, multivariate chemometric analyses were conducted, including principal component analysis (PCA) and correlation-covariance plot (C-C plot). As a result, forty-one diverse compounds were identified, which varied in distribution and abundance across the investigated species. Amino acids and flavonoid glycosides were the most prevalent metabolites. Other identified compounds comprised nucleoside, chlorogenic acids, hydroxy cinnamoyl amides, and triterpenoid saponins. The most discriminant metabolites were flavonoid glycosides and hydroxy cinnamoyl amides, giving each species a chemotaxonomic identity. Advancing the chemotaxonomy of Amaranthaceae, adenosine nucleoside and N-coumaroyl-ʟ-tryptophan were first reported from this family. Isorhamnetin and tricin glycosides were uniquely identified in AC, offering useful chemotaxonomic markers for this species. Notably, AB and AH profiles shared most metabolites, yet with varying abundance. These include adenosine, nicotiflorin, dicaffeoylquinic acids, and N-trans-feruloyl-4-O-methyldopamine. However, N-coumaroyl-ʟ-tryptophan and kaempferol dirhamnoside were exclusively found in AB, separating it from AH. In conclusion, the applied analytical techniques established molecular fingerprints for the included species, identified specific biomarkers, and investigated their interconnections.PMID:37742505 | DOI:10.1016/j.jpba.2023.115722

J Pharm Biomed Anal. 2023 Sep 20;236:115738. doi: 10.1016/j.jpba.2023.115738. Online ahead of print.ABSTRACTOBJECTIVE: This study aimed to explore the mechanism of total saponin of black ginseng (TSBG) in treating heart failure (HF) in DOX-induced HF model rats.METHODS: Rats with HF induced by the intraperitoneal injection of DOX were treated with TSBG (low dose, 30 mg/kg/day; medium dose, 60 mg/kg/day; high dose, 120 mg/kg/day) and shakubar trivalsartan (80 mg/kg/day, positive control) for four weeks. Serum BNP and ANP levels were tested by ELISA, and pathological tissue sections were examined. Serum metabolites were measured using nontargeted metabolomic techniques. The expression of Akt/mTOR autophagy-associated proteins in heart tissue was detected using Western blot, including Beclin1, p62, LCII and LC3I.RESULTS: Compared with the model group, rats in the TSBG-H group had a significantly lower heart index (p < 0.05), significantly lower serum levels of BNP (p < 0.01) and ANP (p < 0.01) and significantly fewer cardiac histopathological changes. Metabolomic results showed that TSBG significantly back-regulated 12 metabolites (p < 0.05), including cholesterol, histamine, sphinganine, putrescine, arachidonic acid, 3-sulfinoalanine, hypotaurine, gluconic acid and lysoPC (18:0:0). These metabolite changes were involved in taurine and hypotaurine metabolism, arachidonic acid metabolism, sphingolipid metabolism, etc. The protein expression level of p-Akt/Akt and p-mTOR/mTOR was significantly up-regulated (p < 0.001), whereas that of Beclin1, p62 (p < 0.001) and LCII/LC3I was down-regulated (p < 0.05).CONCLUSION: TSBG has an excellent therapeutic effect on DOX-induced HF in rats, probably by regulating the Akt/mTOR autophagy signalling pathway, resulting in the improvement of taurine and hypotaurine metabolism, arachidonic acid metabolism and sphingolipid metabolism, which may provide a reference for elucidating the potential mechanism of action of TSBG against HF.PMID:37742504 | DOI:10.1016/j.jpba.2023.115738

J Pharm Biomed Anal. 2023 Sep 14;236:115719. doi: 10.1016/j.jpba.2023.115719. Online ahead of print.ABSTRACTSepsis arises from an uncontrolled inflammatory response to infection that can lead to organ failure. The gut microbiome is increasingly recognized as a key modulator of sepsis progression. This study investigated whether Coptis chinensis water extract (CCWE) could attenuate sepsis by modulating the gut microbiome and immune response. A rat model of sepsis induced by cecum ligation and perforation was used. 16 S ribosomal ribonucleic acid (rRNA) sequencing, proton nuclear magnetic resonance (1H NMR) metabolomics and flow cytometry assays were used to evaluate microbial, metabolic and immune profiles. CCWE treatment reversed sepsis-induced loss of beneficial bacteria like Firmicutes and Bacteroidetes and restored gut microbial balance. CCWE increased short-chain fatty acids, carnitine and phenylacetate, which provide energy and curb inflammation. By enhancing immune homeostasis and maintaining regulatory T cells (Tregs), CCWE treatment also exerted bidirectional regulation on T cells for initially suppressing hyperactivation then enabling recovery. Overall, CCWE may benefit sepsis by regulating the gut-microbiome-immune axis. By restoring microbiome balance, improving metabolism, and modulating immunity, CCWE treatment shows potential for alleviating sepsis severity and progression. The increases in beneficial bacteria, Tregs, and anti-inflammatory metabolites coupled with decreases in opportunistic pathogens likely contributed collectively to CCWE's protective effects. CCWE may emerge as an alternative or adjunctive option for managing disorders of dangerous inflammation like sepsis. Future research should explore CCWE's mechanisms of action clinically to determine its potential as a safe, effective means of modulating health through natural regulation of the gut microbiome and immune function.PMID:37742503 | DOI:10.1016/j.jpba.2023.115719

J Hazard Mater. 2023 Sep 21;461:132606. doi: 10.1016/j.jhazmat.2023.132606. Online ahead of print.ABSTRACTThe particulate matter (PM) in the air comprises particles containing a complex mixture of pollutants associated with various environmental and public health disturbances. However, studies related to the effects of PM on the skin are still incipient. In this work, the toxicity of particulate material to fibroblast cells derived from the human dermis was investigated using metabolomic analysis for the class of amino acids. For the analysis of amino acids, a new method with high selectivity and resolution based on comprehensive two-dimensional gas chromatography coupled to mass spectrometry (GC×GC-Q-TOFMS/MS) was developed and validated. The exposure impact of PM up to 2.5 µm (PM2.5) on fibroblast cells was shown to be dose-dependent. Metabolomics results indicated that amino acid levels and metabolic pathways in fibroblasts were significantly affected by PM2.5. Given the results, it was possible to correlate these effects to a series of responses, including decreased cellular energy, dysregulation of cellular homeostasis, decreased collagen synthesis, interference with wound healing, and suppression of protein biosynthesis. ENVIRONMENTAL IMPLICATION: Although some progress has been made in air pollution control, the health risk related to PM2.5 exposure remains important. The effects of air pollution on the skin have been extensively studied. However, few studies are related to the impact of PM2.5 on the skin. This study determines the profile of amino acids from fibroblast cells exposed to PM2.5, providing new insight into the damage to skin cells from atmospheric pollution.PMID:37742378 | DOI:10.1016/j.jhazmat.2023.132606

BMC Med. 2023 Sep 25;21(1):364. doi: 10.1186/s12916-023-03067-3.ABSTRACTBACKGROUND: Epigenetic age is an estimator of biological age based on DNA methylation; its discrepancy from chronologic age warrants further investigation. We recently reported that greater polyphenol intake benefitted ectopic fats, brain function, and gut microbiota profile, corresponding with elevated urine polyphenols. The effect of polyphenol-rich dietary interventions on biological aging is yet to be determined.METHODS: We calculated different biological aging epigenetic clocks of different generations (Horvath2013, Hannum2013, Li2018, Horvath skin and blood2018, PhenoAge2018, PCGrimAge2022), their corresponding age and intrinsic age accelerations, and DunedinPACE, all based on DNA methylation (Illumina EPIC array; pre-specified secondary outcome) for 256 participants with abdominal obesity or dyslipidemia, before and after the 18-month DIRECT PLUS randomized controlled trial. Three interventions were assigned: healthy dietary guidelines, a Mediterranean (MED) diet, and a polyphenol-rich, low-red/processed meat Green-MED diet. Both MED groups consumed 28 g walnuts/day (+ 440 mg/day polyphenols). The Green-MED group consumed green tea (3-4 cups/day) and Mankai (Wolffia globosa strain) 500-ml green shake (+ 800 mg/day polyphenols). Adherence to the Green-MED diet was assessed by questionnaire and urine polyphenols metabolomics (high-performance liquid chromatography quadrupole time of flight).RESULTS: Baseline chronological age (51.3 ± 10.6 years) was significantly correlated with all methylation age (mAge) clocks with correlations ranging from 0.83 to 0.95; p < 2.2e - 16 for all. While all interventions did not differ in terms of changes between mAge clocks, greater Green-Med diet adherence was associated with a lower 18-month relative change (i.e., greater mAge attenuation) in Li and Hannum mAge (beta = - 0.41, p = 0.004 and beta = - 0.38, p = 0.03, respectively; multivariate models). Greater Li mAge attenuation (multivariate models adjusted for age, sex, baseline mAge, and weight loss) was mostly affected by higher intake of Mankai (beta = - 1.8; p = 0.061) and green tea (beta = - 1.57; p = 0.0016) and corresponded with elevated urine polyphenols: hydroxytyrosol, tyrosol, and urolithin C (p < 0.05 for all) and urolithin A (p = 0.08), highly common in green plants. Overall, participants undergoing either MED-style diet had ~ 8.9 months favorable difference between the observed and expected Li mAge at the end of the intervention (p = 0.02).CONCLUSIONS: This study showed that MED and green-MED diets with increased polyphenols intake, such as green tea and Mankai, are inversely associated with biological aging. To the best of our knowledge, this is the first clinical trial to indicate a potential link between polyphenol intake, urine polyphenols, and biological aging.TRIAL REGISTRATION: ClinicalTrials.gov, NCT03020186.PMID:37743489 | DOI:10.1186/s12916-023-03067-3

Anal Bioanal Chem. 2023 Sep 25. doi: 10.1007/s00216-023-04943-w. Online ahead of print.ABSTRACTThe exposure to smoking related products has been evaluated through urine illness risk marker determination through the analysis of urine samples of smokers and vapers. Biomarkers and their metabolites such as N-acetyl-S-(2-cyanoethyl)-L-cysteine (CEMA), N-acetyl-S-(3,4-dihydroxybutyl)-L-cysteine (DHBMA), N-acetyl-S-[1-(hydroxymethyl)-2-propen-1-yl)-L-cysteine (MHBMA), N-acetyl-S-(3-hydroxypropyl)-L-cysteine (3HPMA), 2R-N-acetyl-S-(4-hydroxybutan-2-yl)-L-cysteine (HMPMA), and N-acetyl-S-(3-carboxy-2-propyl)-L-cysteine (CMEMA) together with nicotine and cotinine were identified and quantified by LC-HRMS and LC-MS/MS, and data found normalized to the creatinine level. One hundred two urine samples were collected from smokers, non-smokers, and vapers, spanning an age range from 16 to 79 years. Results obtained showed that CEMA was only detected in urine samples from smokers and MHBMA was in the same order of magnitude in all the urine samples analyzed. HMPMA was found in the urine of vapers at the same order of concentration as in non-smokers. 3HPMA in vapers was lower than in the urine of smokers, presenting an intermediate situation between smokers and non-smokers. On the other hand, DHBMA in vapers can reach similar values to those found for smokers, while CMEMA shows concentrations in the urine of vapers higher than in the case of non-smokers and traditional smokers, requiring new research to link this metabolite to the use of electronic cigarettes and possible alternative metabolomic routes. In general, this study seems to verify that traditional smoking practice constitutes a major source of carcinogenic chemicals compared with substitutive practices, although those practices are not free of potential harm.PMID:37743413 | DOI:10.1007/s00216-023-04943-w

J Sci Food Agric. 2023 Sep 24. doi: 10.1002/jsfa.12990. Online ahead of print.ABSTRACTBACKGROUND: Withering is the first processing procedure of beauty tea, and there are few reports on the impact of withering methods on the quality of beauty tea and its regulatory mechanisms.RESULTS: Through comparison of fresh tea leaves (FT) with the leaves at Indoor natural Withering 18h (IWT-18) and Outdoor Solar Withering 6h (OWT-6), which were collected at the end of the two withering processes, 17282 and 13984 differentially expressed genes (DEGs) were screened and 267 and 154 differential metabolites (DMs) were identified, respectively. Coexpression network revealed that a large number of DEGs and DMs were enriched in phenylpropanoid, flavonoid, and adenosine Triphosphate binding (ABC) transporter pathways, and the number of DMs and DEGs in IWT-18 vs FT exceeded that in OWT-6 vs FT. Both withering methods promoted a significant increase in content of phenylalanine and upregulation of β-glucoside (BGLU) expression in the phenylpropanoid metabolism pathway. The five proanthocyanidins related to theaflavins in the flavonoid synthesis pathway was more significant accumulation in FT vs IWT-18 than in FT vs OWT-6. Meanwhile, both withering methods can affect the ABC transporter pathway to promote the accumulation of amino acids and their derivatives, but different withering methods affect different ABC transporter families. Outdoor withering with more severe abiotic stress has a greater impact on the ABCG family, while indoor withering has a more significant effect on the ABCC family. Sensory evaluation results showed that the dry tea of IWT-18 was slightly better than that of OWT-6 because of longer withering time and more thorough substance transformation.CONCLUSION: In conclusion, the formation of honey flavor in beauty tea may be closely related to the DEGs and DMs in these three pathways. Our research provides theoretical data support for further revealing the mechanism of quality formation during the withering process of beauty tea. This article is protected by copyright. All rights reserved.PMID:37743412 | DOI:10.1002/jsfa.12990

Signal Transduct Target Ther. 2023 Sep 25;8(1):373. doi: 10.1038/s41392-023-01629-8.ABSTRACTThe role of gut microbiota in modulating the durability of COVID-19 vaccine immunity is yet to be characterised. In this cohort study, we collected blood and stool samples of 121 BNT162b2 and 40 CoronaVac vaccinees at baseline, 1 month, and 6 months post vaccination (p.v.). Neutralisation antibody, plasma cytokine and chemokines were measured and associated with the gut microbiota and metabolome composition. A significantly higher level of neutralising antibody (at 6 months p.v.) was found in BNT162b2 vaccinees who had higher relative abundances of Bifidobacterium adolescentis, Bifidobacterium bifidum, and Roseburia faecis as well as higher concentrations of nicotinic acid (Vitamin B) and γ-Aminobutyric acid (P < 0.05) at baseline. CoronaVac vaccinees with high neutralising antibodies at 6 months p.v. had an increased relative abundance of Phocaeicola dorei, a lower relative abundance of Faecalibacterium prausnitzii, and a higher concentration of L-tryptophan (P < 0.05) at baseline. A higher antibody level at 6 months p.v. was also associated with a higher relative abundance of Dorea formicigenerans at 1 month p.v. among CoronaVac vaccinees (Rho = 0.62, p = 0.001, FDR = 0.123). Of the species altered following vaccination, 79.4% and 42.0% in the CoronaVac and BNT162b2 groups, respectively, recovered at 6 months. Specific to CoronaVac vaccinees, both bacteriome and virome diversity depleted following vaccination and did not recover to baseline at 6 months p.v. (FDR < 0.1). In conclusion, this study identified potential microbiota-based adjuvants that may extend the durability of immune responses to SARS-CoV-2 vaccines.PMID:37743379 | DOI:10.1038/s41392-023-01629-8

Atherosclerosis. 2023 Sep 22:117274. doi: 10.1016/j.atherosclerosis.2023.117274. Online ahead of print.ABSTRACTCardiovascular diseases (CVD) are the leading cause of death worldwide for both men and women, but their prevalence and burden show marked sex differences. The existing knowledge gaps in research, prevention, and treatment for women emphasize the need for understanding the biological mechanisms contributing to the sex differences in CVD. Sex differences in the plasma lipids that are well-known risk factors and predictors of CVD events have been recognized and are believed to contribute to the known disparities in CVD manifestations in men and women. However, the current understanding of sex differences in lipids has mainly come from the studies on routinely measured standard lipids- low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total triglycerides, and total cholesterol, which have been the mainstay of the lipid profiling. Sex differences in individual lipid species, collectively called the lipidome, have until recently been less explored due to the technological challenges and analytic costs. With the technological advancements in the last decade and growing interest in understanding mechanisms of sexual dimorphism in metabolic disorders, many investigators utilized metabolomics and lipidomics based platforms to examine the effect of biological sex on detailed lipidomic profiles and individual lipid species. This review presents an overview of the research on sex differences in the concentrations of circulating lipid species, focusing on findings from the metabolome- and lipidome-wide studies. We also discuss the potential contribution of genetic factors including sex chromosomes and sex-specific physiological factors such as menopause and sex hormones to the sex differences in lipidomic profiles.PMID:37743161 | DOI:10.1016/j.atherosclerosis.2023.117274

J Physiol. 2023 Sep 23. doi: 10.1113/JP285124. Online ahead of print.ABSTRACTMitochondria adapt to increased energy demands during muscle contraction by acutely altering metabolite fluxes and substrate oxidation. With age, an impaired mitochondrial metabolic response may contribute to reduced exercise tolerance and decreased skeletal muscle mass, specific force, increased overall fatty depositions in the skeletal muscle, frailty and depressed energy maintenance. We hypothesized that elevated energy stress in mitochondria with age alters the capacity of mitochondria to utilize different substrates following muscle contraction. To test this hypothesis, we used in vivo electrical stimulation to simulate high-intensity intervals (HII) or low intensity steady-state (LISS) exercise in young (5-7 months) and aged (27-29 months) male and female mice to characterize effects of age and sex on mitochondrial substrate utilization in skeletal muscle following contraction. Mitochondrial respiration using glutamate decreased in aged males following HII and glutamate oxidation was inhibited following HII in both the contracted and non-stimulated muscle of aged female muscle. Analyses of the muscle metabolome of female mice indicated that changes in metabolic pathways induced by HII and LISS contractions in young muscle are absent in aged muscle. To test improved mitochondrial function on substrate utilization following HII, we treated aged females with elamipretide (ELAM), a mitochondrially-targeted peptide shown to improve mitochondrial bioenergetics and restore redox status in aged muscle. ELAM removed inhibition of glutamate oxidation and showed increased metabolic pathway changes following HII, suggesting rescuing redox status and improving bioenergetic function in mitochondria from aged muscle increases glutamate utilization and enhances the metabolic response to muscle contraction in aged muscle. KEY POINTS: Acute local contraction of gastrocnemius can systemically alter mitochondrial respiration in non-stimulated muscle. Age-related changes in mitochondrial respiration using glutamate or palmitoyl carnitine following contraction are sex-dependent. Respiration using glutamate after high-intensity contraction is inhibited in aged female muscle. Metabolite level and pathway changes following muscle contraction decrease with age in female mice. Treatment with the mitochondrially-targeted peptide elamipretide can partially rescue metabolite response to muscle contraction.PMID:37742081 | DOI:10.1113/JP285124

J Transl Med. 2023 Sep 23;21(1):662. doi: 10.1186/s12967-023-04537-1.ABSTRACTBACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors constitute the gold standard treatment for type 2 diabetes mellitus (T2DM). Among them, empagliflozin (EMPA) has shown beneficial effects against heart failure. Because cardiovascular diseases (mainly diabetic cardiomyopathy) are the leading cause of death in diabetic patients, the use of EMPA could be, simultaneously, cardioprotective and antidiabetic, reducing the risk of death from cardiovascular causes and decreasing the risk of hospitalization for heart failure in T2DM patients. Interestingly, recent studies have shown that EMPA has positive benefits for people with and without diabetes. This finding broadens the scope of EMPA function beyond glucose regulation alone to include a more intricate metabolic process that is, in part, still unknown. Similarly, this significantly increases the number of people with heart diseases who may be eligible for EMPA treatment.METHODS: This study aimed to clarify the metabolic effect of EMPA on the human myocardial cell model by using orthogonal metabolomics, lipidomics, and proteomics approaches. The untargeted and multivariate analysis mimicked the fasting blood sugar level of T2DM patients (hyperglycemia: HG) and in the average blood sugar range (normal glucose: NG), with and without the addition of EMPA.RESULTS: Results highlighted that EMPA was able to modulate and partially restore the levels of multiple metabolites associated with cellular stress, which were dysregulated in the HG conditions, such as nicotinamide mononucleotide, glucose-6-phosphate, lactic acid, FA 22:6 as well as nucleotide sugars and purine/pyrimidines. Additionally, EMPA regulated the levels of several lipid sub-classes, in particular dihydroceramide and triacylglycerols, which tend to accumulate in HG conditions resulting in lipotoxicity. Finally, EMPA counteracted the dysregulation of endoplasmic reticulum-derived proteins involved in cellular stress management.CONCLUSIONS: These results could suggest an effect of EMPA on different metabolic routes, tending to rescue cardiomyocyte metabolic status towards a healthy phenotype.PMID:37742032 | DOI:10.1186/s12967-023-04537-1

Commun Biol. 2023 Sep 23;6(1):977. doi: 10.1038/s42003-023-05366-0.ABSTRACTCancer cachexia is characterized by weight loss and skeletal muscle wasting. Based on the up-regulation of catabolism and down-regulation of anabolism, here we showed genetic mutation-mediated metabolic reprogramming in the progression of cancer cachexia by screening for metabolites and investigating their direct effect on muscle atrophy. Treatment with 93 μM D-2-hydroxyglutarate (D2HG) resulted in reduced myotube width and increased expression of E3 ubiquitin ligases. Isocitrate Dehydrogenase 1 (IDH1) mutant patients had higher D2HG than non-mutant patients. In the in vivo murine cancer cachexia model, mutant IDH1 in CT26 cancer cells accelerated cachexia progression and worsened overall survival. Transcriptomics and metabolomics revealed a distinct D2HG-induced metabolic imbalance. Treatment with the IDH1 inhibitor ivosidenib delayed the progression of cancer cachexia in murine GL261 glioma model and CT26 colorectal carcinoma models. These data demonstrate the contribution of IDH1 mutation mediated D2HG accumulation to the progression of cancer cachexia and highlight the individualized treatment of IDH1 mutation associated cancer cachexia.PMID:37741882 | DOI:10.1038/s42003-023-05366-0

Gut Microbes. 2023 Dec;15(2):2257273. doi: 10.1080/19490976.2023.2257273. Epub 2023 Sep 23.ABSTRACTMaternal secretor status has been shown to be associated with the presence of specific fucosylated human milk oligosaccharides (HMOs), and the impact of maternal secretor status on infant gut microbiota measured through 16s sequencing has previously been reported. None of those studies have confirmed exclusive breastfeeding nor investigated the impact of maternal secretor status on gut microbial fermentation products. The present study focused on exclusively breastfed (EBF) Indonesian infants, with exclusive breastfeeding validated through the stable isotope deuterium oxide dose-to-mother (DTM) technique, and the impact of maternal secretor status on the infant fecal microbiome and metabolome. Maternal secretor status did not alter the within-community (alpha) diversity, between-community (beta) diversity, or the relative abundance of bacterial taxa at the genus level. However, infants fed milk from secretor (Se+) mothers exhibited a lower level of fecal succinate, amino acids and their derivatives, and a higher level of 1,2-propanediol when compared to infants fed milk from non-secretor (Se-) mothers. Interestingly, for infants consuming milk from Se+ mothers, there was a correlation between the relative abundance of Bifidobacterium and Streptococcus, and between each of these genera and fecal metabolites that was not observed in infants receiving milk from Se- mothers. Our findings indicate that the secretor status of the mother impacts the gut microbiome of the exclusively breastfed infant.PMID:37741856 | DOI:10.1080/19490976.2023.2257273

Gut Microbes. 2023 Dec;15(2):2256749. doi: 10.1080/19490976.2023.2256749. Epub 2023 Sep 23.ABSTRACTGestational diabetes mellitus (GDM) is an increasing public health concern that significantly increases the risk of early childhood allergic diseases. Altered maternal milk glycobiome may strongly affect gut microbiota and enteric-specific Treg cell-mediated development of immune tolerance in GDM infants. In this study, we found that, compared with healthy Chinese mothers, mothers with GDM had significantly lower levels of total and specific human milk oligosaccharides (HMOs) in their colostrum that subsequently increased with extension of lactation. This alteration in HMO profiles significantly delayed colonization of Lactobacillus and Bifidobacterium spp. in their breast-fed infants, resulting in a distinct gut microbial structure and metabolome. Further experiments in GDM mouse models indicated that decreased contents of milk oligosaccharides, mainly 3'-sialyllactose (3'-SL), in GDM maternal mice reduced colonization of bacteria, such as L. reuteri and L. johnsonii, in the neonatal gut, which impeded development of RORγt+ regulatory T (Treg) cell-mediated immune tolerance. Treatment of GDM neonates with 3'-SL, Lactobacillus reuteri (L. reuteri) and L. johnsonii promoted the proliferation of enteric Treg cells and expression of transcription factor RORγt, which may have contributed to compromising ovalbumin (OVA)-induced allergic responses. In vitro experiments showed that 3'-SL, metabolites of L. johnsonii, and lysates of L. reuteri stimulated differentiation of mouse RORγt+ Treg cells through multiple regulatory effects on Toll-like receptor, MAPK, p53, and NOD-like receptor signaling pathways. This study provides new ideas for the development of gut microbiota and immune tolerance in GDM newborns.PMID:37741825 | DOI:10.1080/19490976.2023.2256749

J Adv Res. 2023 Sep 21:S2090-1232(23)00259-X. doi: 10.1016/j.jare.2023.09.010. Online ahead of print.ABSTRACTINTRODUCTION: Micro- and nanoplastics (MNPs) are emerging environmental pollutants that have raised serious concerns about their potential impact on ecosystem and organism health. Despite increasing efforts to investigate the impacts of micro- and nanoplastics (MNPs) on biota little is known about their potential impacts on terrestrial organisms, especially insects, at environmental concentrations.OBJECTIVES: To address this gap, we used an insect model, silkworm Bombyx mori to examine the potential long-term impacts of different sizes of polystyrene (PS) MNPs at environmentally realistic concentrations (0.25 to 1.0 μg/mL).METHODS: After exposure to PS-MNPs over most of the larval lifetime (from second to last instar), the endpoints were examined by an integrated physiological (growth and survival) and multiomics approach (metabolomics, 16S rRNA, and transcriptomics).RESULTS: Our results indicated that dietary exposures to PS-MNPs had no lethal effect on survivorship, but interestingly, increased host body weight. Multiomics analysis revealed that PS-MNPs exposure significantly altered multiple pathways, particularly lipid metabolism, leading to enriched energy reserves. Furthermore, the exposure changed the structure and composition of the gut microbiome and increased the abundance of gut bacteria Acinetobacter and Enterococcus. Notably, the predicted functional profiles and metabolite expressions were significantly correlated with bacterial abundance. Importantly, these observed effects were particle size-dependent and were ranked as PS-S (91.92 nm) > PS-M (5.69 µm) > PS-L (9.7 µm).CONCLUSION: Overall, PS-MNPs at environmentally realistic concentrations exerted stimulatory effects on energy metabolism that subsequently enhanced body weight in silkworms, suggesting that chronic PS-MNPs exposure might trigger weight gain in animals and humans by influencing host energy and microbiota homeostasis.PMID:37741508 | DOI:10.1016/j.jare.2023.09.010

J Ethnopharmacol. 2023 Sep 21:117205. doi: 10.1016/j.jep.2023.117205. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Spleen Yang Deficiency Syndrome (SYDS), which is a syndrome commonly treated with Traditional Chinese Medicine (TCM), manifests as overall metabolic dysfunction caused mainly by digestive system disorders. Atractylodes lancea (Thunb.) DC. (AL) is a widely used traditional herb with the efficacy of eliminate dampness and strengthen the spleen, Atractylodes oil (AO) is a medicinal component of AL and can be used to treat various gastrointestinal disorders. However, its effects on SYDS and underlying mechanisms have not been clarified to date.AIM OF THE STUDY: The present study aimed to investigate the efficacy of AO in the improvement of the symptoms of SYDS in rat and the underlying mechanism by integrating transcriptomics, and metabolomics.MATERIALS AND METHODS: The SYDS rats induced by reserpine were treated with AO. The protective effect of AO on SYDS rats was evaluated by serum biochemical detection, histopathological analyses. Enzyme-linked immunosorbent assay (ELISA), colorimetric assay and immunofluorescence (IF) were performed to determine the levels of relevant indicators of mitochondrial function and energy metabolism in the liver. Liver metabolites and transcript levels were assessed by non-targeted metabolomics and transcriptomics to analyze potential molecular mechanisms and targets. The expression of the corresponding proteins was verified using Western blotting.RESULTS: AO not only regulated the digestion, absorption function and oxidative stress status of SYDS rats, but also improved mitochondrial function and alleviated energy metabolism disorders in SYDS rats. Metabolomic and transcriptomic analyses demonstrated that AO regulation is mainly exerted in amino acid metabolism, unsaturated fatty acid metabolism, TCA cycle as well as PPAR and AMPK signaling pathways. In addition, The AMPK signaling pathway was verified and AO promoted AMPK phosphorylation and the expression of SIRT1, PGC-1α, and PPARα in SYDS rats.CONCLUSIONS: The therapeutic effect of AO on SYDS is potentially attributable to activation of the AMPK/SIRT1/PGC-1α signaling pathway, which enhances transport and regulation of energy metabolism.PMID:37741473 | DOI:10.1016/j.jep.2023.117205

Chemosphere. 2023 Sep 21:140246. doi: 10.1016/j.chemosphere.2023.140246. Online ahead of print.ABSTRACTSuperworm (larve of Zophobas atratus) could consume foams of expanded polystyrene plastics. However, there is no sufficient understanding of the impact of microplastics on superworms and the degradation pathways of polystyrene. Herein, we explored the weight and survival change of superworms while fed with polystyrene microplastics, and found that survival rate and mean weight would reduce. In terms of gut microbial community structure of surperworms, significant shifts were detected with the relative abundance of Hafnia-Obesumbacterium sp. increasing. In addition, we domesticated two microbiota from the gut of superworms, and confirmed their ability to degrade PS in vitro. The last but most important, 1291 metabolites were identified by HPLC-TOF-MS/MS, and six metabolites related to polystyrene degradation were identified through comparative metabolomic analysis. According to the content and pathways of these metabolites, three metabolic pathways of polystyrene were (a) styrene-phenylacetyl-CoA-L-2-aminoadipic acid; (b) styrene-phenylacetyl-CoA-benzaldehyde; (c) styrene-2-hydroxyacetophenone. These results would help to further screen bacteria of PS degradation and investigate PS metabolic pathways in invertebrates.PMID:37741374 | DOI:10.1016/j.chemosphere.2023.140246