PubMed

J Agric Food Chem. 2023 Nov 28. doi: 10.1021/acs.jafc.3c05788. Online ahead of print.ABSTRACTTree-crop intercropping is of great significance in food security, land protection, and sustainable agriculture. However, the mechanisms of allelopathy between plant species during intercropping are still limited. This study focuses on the allelopathic effects in the intercropping between Camellia oleifera and Arachis hypogaea L. in southern China. We use different parts of the C. oleifera extract to evaluate their impact on peanut seed germination. The results showed that it has inhibitory effects on peanut germination and growth, with the fruit shell having the strongest inhibitory effect. Three main allelopathic substances affecting A. hypogaea germination and growth were identified using gas chromatography-mass spectrometry (GC-MS) analysis, namely, 2,4-di-tert-butylphenol, hexanal, and benzaldehyde. Transcriptomics and metabolomics analyses revealed their effects on glutathione metabolism pathways and specific gene expression. In summary, this study reveals the allelopathic interaction mechanism between C. oleifera and A. hypogaea, which helps to better understand the role of allelopathy in intercropping practices between trees and crops.PMID:38014643 | DOI:10.1021/acs.jafc.3c05788

J Exp Bot. 2023 Nov 28:erad453. doi: 10.1093/jxb/erad453. Online ahead of print.ABSTRACTExtreme weather conditions lead to significant imbalances in crop productivity, which in turn affect food security. Flooding events cause serious problems to many crop species such as wheat. Although metabolic readjustments under flooding are important for plant regeneration, underlying processes remain poorly understood. Here, we investigated the systemic response of wheat to waterlogging using metabolomics and transcriptomics. A 12-days exposure to excess water triggered nutritional imbalances and disruption of metabolite synthesis and translocation, reflected by reduction of plant biomass and growth performance. Metabolic and transcriptomic profiling in roots, xylem sap and leaves indicated anaerobic fermentation processes as a local response of the roots. Differentially expressed genes and ontological categories revealed that carbohydrate metabolism plays an important role in the systemic response. Analysis of the composition of xylem exudates exhibited decreased root-to-shoot translocation of nutrients, hormones and amino acids. Interestingly, among all metabolites determined in the xylem exudates, alanine was the most abundant. Alanine supplementation to excised leaves lead to increased glucose concentration when leaves derived from waterlogged plants. Our results suggest an important role of alanine not only as an amino-nitrogen donor but also as a vehicle for carbon skeletons to produce glucose de novo and meet the energy demand during waterlogging.PMID:38014629 | DOI:10.1093/jxb/erad453

Circ Genom Precis Med. 2023 Nov 28:e004230. doi: 10.1161/CIRCGEN.123.004230. Online ahead of print.ABSTRACTBACKGROUND: Life's essential 8 (LE8) is a comprehensive construct of cardiovascular health. Yet, little is known about the LE8 score, its metabolic correlates, and its predictive implications among Black Americans and low-income individuals.METHODS: In a nested case-control study of coronary heart disease (CHD) among 299 pairs of Black and 298 pairs of White low-income Americans from the Southern Community Cohort Study, we estimated LE8 score and applied untargeted plasma metabolomics and elastic net with leave-one-out cross-validation to identify metabolite signature (MetaSig) of LE8. Associations of LE8 score and MetaSig with incident CHD were examined using conditional logistic regression. The mediation effect of MetaSig on the LE8-CHD association was also examined. The external validity of MetaSig was evaluated in another nested CHD case-control study among 299 pairs of Chinese adults.RESULTS: Higher LE8 score was associated with lower CHD risk (standardized odds ratio, 0.61 [95% CI, 0.53-0.69]). The MetaSig, consisting of 133 metabolites, showed significant correlation with LE8 score (r=0.61) and inverse association with CHD (odds ratio, 0.57 [0.49-0.65]), robust to adjustment for LE8 score and across participants with different sociodemographic and health status ([odds ratios, 0.42-0.69]; all P<0.05). MetaSig mediated a large portion of the LE8-CHD association: 53% (32%-80%). Significant associations of MetaSig with LE8 score and CHD risk were found in validation cohort (r=0.49; odds ratio, 0.57 [0.46-0.69]).CONCLUSIONS: Higher LE8 score and its MetaSig were associated with lower CHD risk among low-income Black and White Americans. Metabolomics may offer an objective measure of LE8 and its metabolic phenotype relevant to CHD prevention among diverse populations.PMID:38014580 | DOI:10.1161/CIRCGEN.123.004230

Allergy. 2023 Nov 28. doi: 10.1111/all.15942. Online ahead of print.ABSTRACTBACKGROUND: While dysregulated sphingolipid metabolism has been associated with risk of childhood asthma, the specific sphingolipid classes and/or mechanisms driving this relationship remain unclear. We aimed to understand the multifaceted role between sphingolipids and other established asthma risk factors that complicate this relationship.METHODS: We performed targeted LC-MS/MS-based quantification of 77 sphingolipids in plasma from 997 children aged 6 years from two independent cohorts (VDAART and COPSAC2010 ). We examined associations of circulatory sphingolipids with childhood asthma, lung function, and three asthma risk factors: functional SNPs in ORMDL3, low vitamin D levels, and reduced gut microbial maturity. Given racial differences between these cohorts, association analyses were performed separately and then meta-analyzed together.RESULTS: We observed elevations in circulatory sphingolipids with asthma phenotypes and risk factors; however, there were differential associations of sphingolipid classes with clinical outcomes and/or risk factors. While elevations from metabolites involved in ceramide recycling and catabolic pathways were associated with asthma and worse lung function [meta p-value range: 1.863E-04 to 2.24E-3], increased ceramide levels were associated with asthma risk factors [meta p-value range: 7.75E-5 to .013], but not asthma. Further investigation identified that some ceramides acted as mediators while some interacted with risk factors in the associations with asthma outcomes.CONCLUSION: This study demonstrates the differential role that sphingolipid subclasses may play in asthma and its risk factors. While overall elevations in sphingolipids appeared to be deleterious overall; elevations in ceramides were uniquely associated with increases in asthma risk factors only; while elevations in asthma phenotypes were associated with recycling sphingolipids. Modification of asthma risk factors may play an important role in regulating sphingolipid homeostasis via ceramides to affect asthma. Further function work may validate the observed associations.PMID:38014461 | DOI:10.1111/all.15942

Am J Physiol Gastrointest Liver Physiol. 2023 Nov 28. doi: 10.1152/ajpgi.00188.2023. Online ahead of print.ABSTRACTDried blood spot (DBS) analysis has existed for >50 years, but application of this technique to fecal analysis remains limited. To address whether dried fecal spots (DFS) could be used to measure fecal bile acids, we collected feces from five subjects for each of the following cohorts: i) healthy individuals, ii) individuals with diarrhea, and iii) Clostridioides difficile-infected patients. Homogenized fecal extracts were loaded onto quantitative DBS (qDBS) devices, dried overnight, and shipped to the bioanalytical lab at ambient temperature. For comparison, source fecal extracts were shipped on dry ice and stored frozen. After four months, frozen fecal extracts and ambient DFS samples were processed and subjected to targeted LC-MS/MS-based metabolomics with stable isotope-labeled standards. We observed no differences in the bile acid levels measured between the traditional extraction and the qDBS-based DFS methods. This pilot data demonstrate that DFS-based analysis is feasible and warrants further development for fecal compounds and microbiome applications.PMID:38014449 | DOI:10.1152/ajpgi.00188.2023

bioRxiv. 2023 Nov 16:2023.11.15.567095. doi: 10.1101/2023.11.15.567095. Preprint.ABSTRACTMetabolomics has gained much attraction due to its potential to reveal molecular disease mechanisms and present viable biomarkers. In this work we used a panel of untargeted serum metabolomes in 602 childhood patients of the COPSAC2010 mother-child cohort. The annotated part of the metabolome consists of 493 chemical compounds curated using automated procedures. Using predicted quantitative-structure-bioactivity relationships for the Tox21 database on nuclear receptors and stress response in cell lines, we created a filtering method for the vast number of quantified metabolites. The metabolites measured in childrens serums used here have predicted potential against the chosen target modelled targets. The targets from Tox21 have been used with quantitative structure-activity relationships (QSARs) and were trained for ~7000 structures, saved as models, and then applied to 493 metabolites to predict their potential bioactivities. The models were selected based on strict accuracy criteria surpassing random effects. After application, 52 metabolites showed potential bioactivity based on structural similarity with known active compounds from the Tox21 set. The filtered compounds were subsequently used and weighted by their bioactive potential to show an association with early childhood hs-CRP levels at six months in a linear model supporting a physiological adverse effect on systemic low-grade inflammation. The significant metabolites were reported.PMID:38014335 | PMC:PMC10680762 | DOI:10.1101/2023.11.15.567095

bioRxiv. 2023 Nov 15:2023.11.10.564562. doi: 10.1101/2023.11.10.564562. Preprint.ABSTRACTHypertrophic cardiomyopathy (HCM) results from pathogenic variants in sarcomeric protein genes, that increase myocyte energy demand and lead to cardiac hypertrophy. But it is unknown whether a common metabolic trait underlies the cardiac phenotype at early disease stage. This study characterized two HCM mouse models (R92W-TnT, R403Q-MyHC) that demonstrate differences in mitochondrial function at early disease stage. Using a combination of cardiac phenotyping, transcriptomics, mass spectrometry-based metabolomics and computational modeling, we discovered allele-specific differences in cardiac structure/function and metabolic changes. TnT-mutant hearts had impaired energy substrate metabolism and increased phospholipid remodeling compared to MyHC-mutants. TnT-mutants showed increased incorporation of saturated fatty acid residues into ceramides, cardiolipin, and increased lipid peroxidation, that could underlie allele-specific differences in mitochondrial function and cardiomyopathy.PMID:38014251 | PMC:PMC10680657 | DOI:10.1101/2023.11.10.564562

bioRxiv. 2023 Nov 15:2023.11.13.566691. doi: 10.1101/2023.11.13.566691. Preprint.ABSTRACTDifferences in affective behavioral expression from early to late adulthood is thought to involve changes in frontal cortical responsiveness to negative valence stimuli. In mice, similar maturational changes in affective behaviors have also been reported but the functional neural circuitry remains unclear. In the present study we investigated age variations in affective behaviors and functional connectivity in male and female C57BL6/J mice. Mice aged 10, 30 and 60 weeks (wo) were tested over 8 weeks for open field activity, sucrose reward preference, social interactions and fear conditioning and functional neuroimaging. Frontal cortical and hippocampal tissues were excised for metabolomics analysis. Our results indicate that young 10wo mice display greater levels of anxiety-like locomotor behavior and develop robust fear conditioning compared to older adult and late middle-aged mice (30-60wo). This was accompanied by greater functional connectivity between a temporal cortical/auditory cortex network and subregions of the anterior cingulate cortex and ventral hippocampus, and a greater network modularity and assortative mixing of nodes in young versus older adult mice. Metabolome analyses identified differences in several essential amino acids between 10wo mice and the other age groups. The results support high 'emotionality' in younger versus older adult mice involving greater prefrontal-hippocampal connectivity.PMID:38014219 | PMC:PMC10680600 | DOI:10.1101/2023.11.13.566691

bioRxiv. 2023 Nov 16:2023.11.14.566937. doi: 10.1101/2023.11.14.566937. Preprint.ABSTRACTTelomerase reverse transcriptase (TERT) is essential for glioblastoma (GBM) proliferation. Delineating metabolic vulnerabilities induced by TERT can lead to novel GBM therapies. We previously showed that TERT upregulates glutathione (GSH) pool size in GBMs. Here, we show that TERT acts via the FOXO1 transcription factor to upregulate expression of the catalytic subunit of glutamate-cysteine ligase (GCLC), the rate-limiting enzyme of de novo GSH synthesis. Inhibiting GCLC using siRNA or buthionine sulfoximine (BSO) reduces synthesis of 13 C-GSH from [U- 13 C]-glutamine and inhibits clonogenicity. However, GCLC inhibition does not induce cell death, an effect that is associated with elevated [U- 13 C]-glutamine metabolism to glutamate and pyrimidine nucleotide biosynthesis. Mechanistically, GCLC inhibition activates MYC and leads to compensatory upregulation of two key glutamine-utilizing enzymes i.e., glutaminase (GLS), which generates glutamate from glutamine, and CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotatase), the enzyme that converts glutamine to the pyrimidine nucleotide precursor dihydroorotate. We then examined the therapeutic potential of inhibiting GLS and CAD in combination with GCLC. 6-diazo-5-oxy-L-norleucin (DON) is a potent inhibitor of glutamine-utilizing enzymes including GLS and CAD. The combination of BSO and DON suppresses GSH and pyrimidine nucleotide biosynthesis and is synergistically lethal in GBM cells. Importantly, in vivo stable isotope tracing indicates that combined treatment with JHU-083 (a brain-penetrant prodrug of DON) and BSO abrogates synthesis of GSH and pyrimidine nucleotides from [U- 13 C]-glutamine and induces tumor shrinkage in mice bearing intracranial GBM xenografts. Collectively, our studies exploit a mechanistic understanding of TERT biology to identify synthetically lethal metabolic vulnerabilities in GBMs.SIGNIFICANCE: Using in vivo stable isotope tracing, metabolomics, and loss-of-function studies, we demonstrate that TERT expression is associated with metabolic alterations that can be synergistically targeted for therapy in glioblastomas.PMID:38014170 | PMC:PMC10680720 | DOI:10.1101/2023.11.14.566937

Res Sq. 2023 Nov 17:rs.3.rs-3600439. doi: 10.21203/rs.3.rs-3600439/v1. Preprint.ABSTRACTBackground The INSPIRE randomized clinical trial demonstrated that a high protein diet (HPRO) combined with neuromuscular electrical stimulation (NMES) attenuates muscle atrophy and may improve functional outcomes after aSAH. Using an untargeted metabolomics approach, we sought to identify specific metabolites mediating these effects. Methods Blood samples were collected from subjects on admission prior to randomization to either standard of care (SOC; N=12) or HPRO+NMES (N=12) and at 7 days as part of the INSPIRE protocol. Untargeted metabolomics were performed for each plasma sample. Paired fold changes were calculated for each metabolite among subjects in the HPRO+NMES group at baseline and 7 days after intervention. Changes in metabolites from baseline to 7 days were compared for the HPRO+NMES and SOC groups. Sparse partial least squared discriminant analysis (sPLS-DA) identified metabolites discriminating each group. Pearson's correlation coefficients were calculated between each metabolite and total protein per day, nitrogen balance, and muscle volume Multivariable models were developed to determine associations between each metabolite and muscle volume. Results A total of 18 unique metabolites were identified including pre and post treatment and differentiating SOC vs HPRO+NMES. Of these, 9 had significant positive correlations with protein intake: N-acetylserine (ρ=0.61, P =1.56x10 -3 ), N-acetylleucine (ρ=0.58, P =2.97x10 -3 ), β-hydroxyisovaleroylcarnitine (ρ=0.53, P =8.35x10 -3 ), tiglyl carnitine (ρ=0.48, P =0.0168), N-acetylisoleucine (ρ=0.48, P =0.0183), N-acetylthreonine (ρ=0.47, P =0.0218), N-acetylkynurenine (ρ=0.45, P =0.0263), N-acetylvaline (ρ=0.44, P =0.0306), and urea (ρ=0.43, P =0.0381). In multivariable regression models, N-acetylleucine was significantly associated with preserved temporalis [OR 1.08 (95%CI 1.01, 1.16)] and quadricep [OR 1.08 (95%CI 1.02, 1.15)] muscle volume. Quinolinate was also significantly associated with preserved temporalis [OR 1.05 (95%CI 1.01, 1.09)] and quadricep [OR 1.04 (95%CI 1.00, 1.07)] muscle volume. N-acetylserine, N-acetylcitrulline, and b-hydroxyisovaleroylcarnitine were also associated with preserved temporalis or quadricep volume. Conclusions Metabolites defining the HPRO+NMES intervention mainly consisted of amino acid derivatives. These metabolites had strong correlations with protein intake and were associated with preserved muscle volume.PMID:38014126 | PMC:PMC10680941 | DOI:10.21203/rs.3.rs-3600439/v1

bioRxiv. 2023 Nov 16:2023.11.15.567158. doi: 10.1101/2023.11.15.567158. Preprint.ABSTRACTFatty acid esters of hydroxy fatty acids (FAHFAs) are endogenous bioactive lipids known for their anti-inflammatory and anti-diabetic properties. Despite their therapeutic potential, little is known about the sex-specific variations in FAHFA metabolism. This study investigated the role of Androgen Dependent TFPI Regulating Protein (ADTRP), a FAHFA hydrolase. Additionally, tissue-specific differences in FAHFA levels, focusing on the perigonadal white adipose tissue (pgWAT), subcutaneous white adipose tissue (scWAT), brown adipose tissue (BAT), plasma, and liver, were evaluated using metabolomics and lipidomics. We found that female mice exhibited higher FAHFA levels in pgWAT, scWAT, and BAT compared to males. FAHFA levels were inversely related to Adtrp mRNA, which showed significantly lower expression in females compared with males in pgWAT and scWAT. However, no significant differences between the sexes were observed in plasma and liver FAHFA levels. Adtrp deletion had minimal impact on both sexes' metabolome and lipidome of pgWAT. However, we discovered higher endogenous levels of triacylglycerol estolides containing FAHFAs, a FAHFA metabolic reservoir, in the pgWAT of female mice. These findings suggest that sex-dependent differences in FAHFA levels occur primarily in specific WAT depots and may modulate local insulin sensitivity in adipocytes. However, further investigations are warranted to fully comprehend the underlying mechanisms and implications of sex effects on FAHFA metabolism in humans.PMID:38014093 | PMC:PMC10680750 | DOI:10.1101/2023.11.15.567158

Res Sq. 2023 Nov 15:rs.3.rs-3597052. doi: 10.21203/rs.3.rs-3597052/v1. Preprint.ABSTRACTThiamine (Vitamin B1) is an essential micronutrient and a co-factor for metabolic functions related to energy metabolism. We determined the association between whole blood thiamine pyrophosphate (TPP) concentrations and plasma metabolites using high resolution metabolomics in critically ill patients. Methods Cross-sectional study performed in Erciyes University Hospital, Kayseri, Turkey and Emory University, Atlanta, GA, USA. Participants were ≥ 18 years of age, with an expected length of ICU stay longer than 48 hours, receiving furosemide therapy for at least 6 months before ICU admission. Results Blood for TPP and metabolomics was obtained on the day of ICU admission. Whole blood TPP concentrations were measured using high-performance liquid chromatography (HPLC). Liquid chromatography/mass spectrometry was used for plasma high-resolution metabolomics. Data was analyzed using regression analysis of TPP levels against all plasma metabolomic features in metabolome-wide association studies. We also compared metabolomic features from patients in the highest TPP concentration tertile to patients in the lowest TPP tertile as a secondary analysis. We enrolled 76 participants with a median age of 69 (range, 62.5-79.5) years. Specific metabolic pathways associated with whole blood TPP levels, using both regression and tertile analysis, included pentose phosphate, fructose and mannose, branched chain amino acid, arginine and proline, linoleate, and butanoate pathways. Conclusions Plasma high-resolution metabolomics analysis showed that whole blood TPP concentrations are significantly associated with metabolites and metabolic pathways linked to the metabolism of energy, amino acids, lipids, and the gut microbiome in adult critically ill patients.PMID:38014088 | PMC:PMC10680934 | DOI:10.21203/rs.3.rs-3597052/v1

medRxiv. 2023 Nov 13:2023.11.13.23298467. doi: 10.1101/2023.11.13.23298467. Preprint.ABSTRACTThe influence of genotype on defining the human gut microbiome has been extensively studied, but definite conclusions have not yet been found. To fill this knowledge gap, we leverage data from children enrolled in the Vitamin D Antenatal Asthma Reduction Trial (VDAART) from 6 months to 8 years old. We focus on a pool of 12 genes previously found to be associated with the gut microbiome in independent studies, establishing a Bonferroni corrected significance level of p-value < 2.29 × 10 -6 . We identified significant associations between SNPs in the FHIT gene (known to be associated with obesity and type 2 diabetes) and obesity-related microbiome features, and the children's BMI through their childhood. Based on these associations, we defined a set of SNPs of interest and a set of taxa of interest. Taking a multi-omics approach, we integrated plasma metabolome data into our analysis and found simultaneous associations among children's BMI, the SNPs of interest, and the taxa of interest, involving amino acids, lipids, nucleotides, and xenobiotics. Using our association results, we constructed a quadripartite graph where each disjoint node set represents SNPs in the FHIT gene, microbial taxa, plasma metabolites, or BMI measurements. Network analysis led to the discovery of patterns that identify several genetic variants, microbial taxa and metabolites as new potential markers for obesity, type 2 diabetes, or insulin resistance risk.PMID:38014043 | PMC:PMC10680902 | DOI:10.1101/2023.11.13.23298467

J Small Anim Pract. 2023 Nov 27. doi: 10.1111/jsap.13688. Online ahead of print.ABSTRACTOBJECTIVES: This study used hydrogen nuclear magnetic resonance spectroscopy for the first time to examine differences in the metabolomic profile of stifle joint synovial fluid from dogs with cranial cruciate ligament rupture with and without meniscal injuries, in order to identify biomarkers of meniscal injury. Identifying a biomarker of meniscal injury could then ultimately be used to design a minimally invasive diagnostic test for meniscal injuries in dogs.MATERIALS AND METHODS: Stifle joint synovial fluid was collected from dogs undergoing stifle joint surgery or arthrocentesis for lameness investigations. We used multi-variate statistical analysis using principal component analysis and univariate statistical analysis using one-way analysis of variance and analysis of co-variance to identify differences in the metabolomic profile between dogs with cranial cruciate ligament rupture and meniscal injury, cranial cruciate ligament rupture without meniscal injury, and neither cranial cruciate ligament rupture nor meniscal injury, taking into consideration clinical variables.RESULTS: A total of 154 samples of canine synovial fluid were included in the study. Sixty-four metabolites were annotated to the hydrogen nuclear magnetic resonance spectroscopy spectra. Six spectral regions were found to be significantly altered (false discovery rate adjusted P-value <0.05) between groups with cranial cruciate ligament rupture with and without meniscal injury, including three attributed to nuclear magnetic resonance mobile lipids [mobile lipid -CH3 (P=0.016), mobile lipid -n(CH3 )3 (P=0.017), mobile unsaturated lipid (P=0.031)].CLINICAL SIGNIFICANCE: We identified an increase in nuclear magnetic resonance mobile lipids in the synovial fluid of dogs with meniscal injury which are of interest as potential biomarkers of meniscal injury.PMID:38013167 | DOI:10.1111/jsap.13688

J Biol Chem. 2023 Nov 25:105500. doi: 10.1016/j.jbc.2023.105500. Online ahead of print.ABSTRACTThe aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor known for mediating the effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. TCDD induces non-alcoholic fatty liver disease (NAFLD)-like pathologies including simple steatosis that can progress to steatohepatitis with fibrosis and bile duct proliferation in male mice. Dose-dependent progression of steatosis to steatohepatitis with fibrosis by TCDD has been associated with metabolic reprogramming, including the disruption of amino acid metabolism. Here, we used targeted metabolomic analysis to reveal dose-dependent changes in the level of ten serum and eleven hepatic amino acids in mice upon treatment with TCDD. Bulk RNAseq and protein analysis showed TCDD repressed CPS1, OTS, ASS1, ASL, and GLUL, all of which are associated with the urea cycle and glutamine biosynthesis. Urea and glutamine are end products of the detoxification and excretion of ammonia, a toxic byproduct of amino acid catabolism. Furthermore, we found that the catalytic activity of OTC, a rate-limiting step in the urea cycle was also dose-dependently repressed. These results are consistent with an increase in circulating ammonia. Collectively, the repression of the urea and glutamate-glutamine cycles increased circulating ammonia levels and the toxicity of TCDD.PMID:38013089 | DOI:10.1016/j.jbc.2023.105500

J Ethnopharmacol. 2023 Nov 25:117494. doi: 10.1016/j.jep.2023.117494. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: The herbal pair Alpinia officinarum-Cyperus rotundus (HPAC) has an extended history of use in the treatment of gastric ulcers, and its curative effect is definite.AIM OF THE STUDY: To explore the material basis and holistic mechanism of HPAC on ethanol-induced gastric ulcers.MATERIALS AND METHODS: Three chemometrics, GRA, OPLS, and BCA, were used to construct the spectrum-effect relationship between the HPLC fingerprints of HPAC extracts and the bioactivity indices (cell viability; the levels of TNF-α, IL-6, COX-2, and PGE2; and wound healing rate) against GES-1 cell damage to screen the bioactive ingredients. The bioactive components were isolated and validated in vitro. Simultaneously, the effects of HPAC with concentrated bioactive ingredients was tested on ethanol-induced gastric ulcers in vivo, and the mechanism was investigated using transcriptomics and metabolomics. The mechanism was further validated by Western blotting. Finally, the contents of the main components of HPAC were determined before and after compatibility.RESULTS: Twelve bioactive components were screened, and the structures of nine compounds were confirmed. An in vitro verification test showed that DPHA and galangin could protect GES-1 cells from injury, and that their content increased after compatibility. The CH2Cl2 fraction of HPAC (HP-CH2Cl2) can protect mice from ethanol-induced gastric mucosal injury by reducing hemorrhage and decreasing inflammatory cell infiltration. Western blot analysis indicated that this fraction may up-regulate TRPV1 protein and down-regulate PI3K and AKT proteins.CONCLUSIONS: DPHA and galangin may be the bioactive components against ethanol-induced GES-1 cell injury. HP-CH2Cl2 may exert gastroprotective effects by regulating PI3K, AKT and TRPV1 proteins.PMID:38012972 | DOI:10.1016/j.jep.2023.117494

J Transl Med. 2023 Nov 27;21(1):860. doi: 10.1186/s12967-023-04747-7.ABSTRACTBACKGROUND: Prostate cancer (PC) is a heterogenous multifocal disease ranging from indolent to lethal states. For improved treatment-stratification, reliable approaches are needed to faithfully differentiate between high- and low-risk tumors and to predict therapy response at diagnosis.METHODS: A metabolomic approach based on high resolution magic angle spinning nuclear magnetic resonance (HR MAS NMR) analysis was applied on intact biopsies samples (n = 111) obtained from patients (n = 31) treated by prostatectomy, and combined with advanced multi- and univariate statistical analysis methods to identify metabolomic profiles reflecting tumor differentiation (Gleason scores and the International Society of Urological Pathology (ISUP) grade) and subtypes based on tumor immunoreactivity for Ki67 (cell proliferation) and prostate specific antigen (PSA, marker for androgen receptor activity).RESULTS: Validated metabolic profiles were obtained that clearly distinguished cancer tissues from benign prostate tissues. Subsequently, metabolic signatures were identified that further divided cancer tissues into two clinically relevant groups, namely ISUP Grade 2 (n = 29) and ISUP Grade 3 (n = 17) tumors. Furthermore, metabolic profiles associated with different tumor subtypes were identified. Tumors with low Ki67 and high PSA (subtype A, n = 21) displayed metabolite patterns significantly different from tumors with high Ki67 and low PSA (subtype B, n = 28). In total, seven metabolites; choline, peak for combined phosphocholine/glycerophosphocholine metabolites (PC + GPC), glycine, creatine, combined signal of glutamate/glutamine (Glx), taurine and lactate, showed significant alterations between PC subtypes A and B.CONCLUSIONS: The metabolic profiles of intact biopsies obtained by our non-invasive HR MAS NMR approach together with advanced chemometric tools reliably identified PC and specifically differentiated highly aggressive tumors from less aggressive ones. Thus, this approach has proven the potential of exploiting cancer-specific metabolites in clinical settings for obtaining personalized treatment strategies in PC.PMID:38012666 | DOI:10.1186/s12967-023-04747-7

Mol Nutr Food Res. 2023 Nov 27:e2200578. doi: 10.1002/mnfr.202200578. Online ahead of print.ABSTRACTSCOPE: Cinnamaldehyde (CAH), a phytochemical constituent isolated from cinnamon, is gaining attention due to its nutritional and medicinal benefits. This study aimed to investigate the potential role of CAH in the treatment of ulcerative colitis (UC).METHODS AND RESULTS: Integrated metabolomics and gut microbiome analysis are performed for 2,4,6-trinitrobenzenesulfonic acid (TNBS) induced UC rats. The effect of CAH on colonic inflammation, lipid peroxidation, metabolic profiles, and gut microbiota is systematically explored. It finds that CAH improves the colitis-related symptoms, decreases disease activity index, increases the colon length and body weight, and alleviates histologic inflammation of UC rats. These therapeutic effects of CAH are due to suppression of inflammation and lipid peroxidation. Moreover, multi-omics analysis reveals that CAH treatment cause changes in plasma metabolome and gut microbiome in UC rats. CAH regulates lipid metabolic processes, especially phosphatidylcholines, lysophosphatidylcholines, and polyunsaturated fatty acids. Meanwhile, CAH modulates the gut microbial structure by restraining pathogenic bacteria (such as Helicobacter) and increasing probiotic bacteria (such as Bifidobacterium and Lactobacillus).CONCLUSIONS: These results indicate that CAH exerts a beneficial role in UC by synergistic modulating the balance in gut microbiota and the associated metabolites, and highlights the nutritional and medicinal value of CAH in UC management.PMID:38012477 | DOI:10.1002/mnfr.202200578

Support Care Cancer. 2023 Nov 28;31(12):724. doi: 10.1007/s00520-023-08183-7.ABSTRACTPURPOSE: Growing recognition of the gut microbiome as an influential modulator of cancer treatment efficacy and toxicity has led to the emergence of clinical interventions targeting the microbiome to enhance cancer and health outcomes. The highly modifiable nature of microbiota to endogenous, exogenous, and environmental inputs enables interventions to promote resilience of the gut microbiome that have rapid effects on host health, or response to cancer treatment. While diet, probiotics, and faecal microbiota transplant are primary avenues of therapy focused on restoring or protecting gut function in people undergoing cancer treatment, the role of physical activity and exercise has scarcely been examined in this population.METHODS: A narrative review was conducted to explore the nexus between cancer care and the gut microbiome in the context of physical activity and exercise as a widely available and clinically effective supportive care strategy used by cancer survivors.RESULTS: Exercise can facilitate a more diverse gut microbiome and functional metabolome in humans; however, most physical activity and exercise studies have been conducted in healthy or athletic populations, primarily using aerobic exercise modalities. A scarcity of exercise and microbiome studies in cancer exists.CONCLUSIONS: Exercise remains an attractive avenue to promote microbiome health in cancer survivors. Future research should elucidate the various influences of exercise modalities, intensities, frequencies, durations, and volumes to explore dose-response relationships between exercise and the gut microbiome among cancer survivors, as well as multifaceted approaches (such as diet and probiotics), and examine the influences of exercise on the gut microbiome and associated symptom burden prior to, during, and following cancer treatment.PMID:38012463 | DOI:10.1007/s00520-023-08183-7

Nat Immunol. 2023 Nov 27. doi: 10.1038/s41590-023-01665-0. Online ahead of print.ABSTRACTFew cancers can be targeted efficiently by engineered T cell strategies. Here, we show that γδ T cell antigen receptor (γδ TCR)-mediated cancer metabolome targeting can be combined with targeting of cancer-associated stress antigens (such as NKG2D ligands or CD277) through the addition of chimeric co-receptors. This strategy overcomes suboptimal γ9δ2 TCR engagement of αβ T cells engineered to express a defined γδ TCR (TEGs) and improves serial killing, proliferation and persistence of TEGs. In vivo, the NKG2D-CD28WT chimera enabled control only of liquid tumors, whereas the NKG2D-4-1BBCD28TM chimera prolonged persistence of TEGs and improved control of liquid and solid tumors. The CD277-targeting chimera (103-4-1BB) was the most optimal co-stimulation format, eradicating both liquid and solid tumors. Single-cell transcriptomic analysis revealed that NKG2D-4-1BBCD28TM and 103-4-1BB chimeras reprogram TEGs through NF-κB. Owing to competition with naturally expressed NKG2D in CD8+ TEGs, the NKG2D-4-1BBCD28TM chimera mainly skewed CD4+ TEGs toward adhesion, proliferation, cytotoxicity and less exhausted signatures, whereas the 103-4-1BB chimera additionally shaped the CD8+ subset toward a proliferative state.PMID:38012415 | DOI:10.1038/s41590-023-01665-0