PubMed

J Dairy Sci. 2023 May 8:S0022-0302(23)00216-3. doi: 10.3168/jds.2022-22784. Online ahead of print.ABSTRACTOur objectives were to evaluate the effects of complete replacement of inorganic salts of trace minerals (STM) with organic trace minerals (OTM) in both pre- and postpartum diets on ovarian dynamics, estrous behavior measured by sensors, preimplantation conceptus development, and reproductive performance in dairy cows. Pregnant cows and heifers (n = 273) were blocked by parity and body condition score and randomly assigned to either STM or OTM diets at 45 ± 3 d before their expected calving. Pre- and postpartum diets were formulated to meet 100% of recommended levels of each trace mineral in both treatments, taking into consideration both basal and supplemental levels. The final target concentrations of Co, Cu, Mn, Se, and Zn were, respectively, 0.25, 13.7, 40.0, 0.3, and 40.0 mg/kg in the prepartum diet, and 0.25, 15.7, 40.0, 0.3, and 63.0 mg/kg in the postpartum diet. The STM group was supplemented with Co, Cu, Mn, and Zn sulfates and sodium selenite, while the OTM group was supplemented with Co, Cu, Mn, and Zn proteinates and selenized yeast. Treatments continued until 156 d in milk (DIM) and were assigned to individual cows using automatic feeding gates. Starting at 21 DIM, ultrasonography examinations of the ovaries were performed weekly to determine the presence of a corpus luteum and postpartum resumption of ovarian cyclicity. Cows were presynchronized with 2 injections of PGF2α at 42 and 56 DIM. Estrous behavior was monitored using electronic activity tags that indirectly measured walking activity. Cows detected in estrus after the second PGF2α were inseminated, and those not detected in estrus by 67 DIM were enrolled in a synchronization program. Cows that returned to estrus after artificial insemination (AI) were reinseminated. Pregnancy diagnosis was performed 33 d after AI, and nonpregnant cows were resynchronized. Transcript expression of interferon-stimulated genes in peripheral blood leukocytes was performed in a subgroup of cows (STM, n = 67; OTM, n = 73) on d 19 after AI. A different subgroup of cows (28 STM, 29 OTM) received uterine flushing 15 d after AI for recovery of conceptuses and uterine fluid for analyses of transcriptomics and metabolomics, respectively. In addition, dominant follicle diameter, luteal size and blood flow, and concentration of progesterone in plasma were measured on d 0, 7, and 15 relative to AI. After flushing, PGF2α was given and the dominant follicle was aspirated 2 d later to measure the concentration of trace minerals by mass spectrometry. Estrous behavior, size of the dominant follicle and corpus luteum, concentration of progesterone, time to pregnancy, and proportion of cows pregnant by 100 d of the breeding period did not differ between treatments. A greater proportion of cows supplemented with OTM had a corpus luteum detected before presynchronization (64.3 vs. 75.2%), and primiparous cows supplemented with OTM tended to resume cyclicity earlier than their STM counterparts. Cows supplemented with OTM had a greater concentration of Cu in follicular fluid than cows supplemented with STM (0.89 vs. 0.77 µg/mL, respectively). In pregnant multiparous cows, expression of receptor transporter protein 4 in peripheral blood leukocytes was 42% greater in the OTM group. Conceptuses of the 2 treatments had 589 differentially expressed transcripts, with many indicating advanced conceptus elongation and greater transcript expression of selenoproteins in the OTM group. In pregnant cows, 24 metabolites were more abundant in the uterine fluid of OTM, including spermidine, sucrose, and cholesterol. In conclusion, replacing STM with OTM caused modest improvements to resumption of ovarian cyclicity and important changes in preimplantation conceptus development, but it did not alter conception risk and pregnancy rate.PMID:37164845 | DOI:10.3168/jds.2022-22784

Plant Physiol Biochem. 2023 Apr 29;199:107723. doi: 10.1016/j.plaphy.2023.107723. Online ahead of print.ABSTRACTMelatonin (MT) is essential for plant development and drought adaptation. However, the molecular and metabolic mechanisms underlying MT-induced drought tolerance in maize roots remain largely unclear. Herein, we investigated the effects of MT on drought tolerance in maize roots using integrated transcriptomic and metabolomic analyses, and identified MT-induced genes and metabolites associated with drought resistance. Compared with the untreated control plants, MT application alleviated the deleterious effects of drought on roots, by decreasing the malondialdehyde level and increasing the solute potential, eventually promoting root growth. Transcriptome and metabolome analysis demonstrated that MT significantly upregulates the expression of genes related to flavonoid biosynthesis (PAL, C4H, 4CL, HCT, CHS, CHI, F3'5'H, and DFR), activates drought-responsive transcription factors (ERFs, NACs, MYBs, and bHLHs), and regulates hormone signaling-related genes, especially ethylene response factors (ERF4, ERF81, and ERF110). Moreover, MT increased the accumulation of flavonoid metabolites, particularly apigenin, luteolin, and quercetin, under drought-stress conditions. These findings were further supported by quantitative real-time polymerase chain reaction analysis and total flavonoid measurements. Altogether, our findings suggest that MT promotes maize root growth during drought by regulating flavonoid synthesis pathways, transcription factors, and plant hormone signals. This study provides new insights into the complex mechanisms by which MT enhances crop resistance to drought damage.PMID:37163805 | DOI:10.1016/j.plaphy.2023.107723

J Infect Dis. 2023 May 11:jiad155. doi: 10.1093/infdis/jiad155. Online ahead of print.ABSTRACTBACKGROUND: Natural clearance of Chlamydia trachomatis (Ct) in women commonly occurs in the interval between screening and treatment. In vitro studies show interferon-gamma (IFN-γ)-mediated tryptophan depletion results in Ct clearance, but whether this mechanism occurs in vivo remains unclear. We previously found that women who naturally cleared Ct had lower cervicovaginal levels of tryptophan and IFN-γ compared to women with persisting Ct, suggesting IFN-γ-independent pathways may promote Ct clearance.METHODS: Cervicovaginal lavages from 34 women who did (N = 17) or did not (N = 17) naturally clear Ct were subjected to untargeted high-performance liquid chromatography mass-spectrometry to identify metabolites and metabolic pathways associated with Ct clearance.RESULTS: 375 positively-charged metabolites and 149 negatively-charged metabolites were annotated. Compared to women with persisting Ct infection, Ct natural clearance was associated with increased levels of the oligosaccharides trehalose, sucrose, melezitose, and maltotriose, lower levels of indoline, and lower levels of various amino acids. Metabolites were strongly associated with valine, leucine, and isoleucine biosynthesis pathways.CONCLUSION: The cervicovaginal metabolome in women who did or did not naturally clear Ct is distinct. In women who cleared Ct, depletion of various amino acids, especially valine, leucine, and isoleucine, suggests that amino acids other than tryptophan impact Ct survival in vivo.PMID:37163744 | DOI:10.1093/infdis/jiad155

J Proteome Res. 2023 May 10. doi: 10.1021/acs.jproteome.3c00002. Online ahead of print.ABSTRACTSmall peptides such as dipeptides and tripeptides show various biological activities in organisms. However, methods for identifying dipeptides/tripeptides from complex biological samples are lacking. Here, an annotation strategy involving the derivatization of dipeptides and tripeptides via dansylation was suggested based on liquid chromatography-mass spectrometry (LC-MS) and iterative quantitative structure retention relationship (QSRR) to choose dipeptides/tripeptides by using a small number of standards. First, the LC-autoMS/MS method and initial QSRR model were built based on 25 selected grid-dipeptides and 18 test-dipeptides. To achieve high-coverage detection, dipeptide/tripeptide pools containing abundant dipeptides/tripeptides were then obtained from four dansylated biological samples including serum, tissue, feces, and soybean paste by using the parameter-optimized LC-autoMS/MS method. The QSRR model was further optimized through an iterative train-by-pick strategy. Based on the specific fragments and tR tolerances, 198 dipeptides and 149 tripeptides were annotated. The dipeptides at lower annotation levels were verified by using authentic standards and grid-correlation analysis. Finally, variation in serum dipeptides/tripeptides of three different liver diseases including hepatitis B infection, liver cirrhosis, and hepatocellular carcinoma was characterized. Dipeptides with N-prolinyl, C-proline, N-glutamyl, and N-valinyl generally increased with disease severity. In conclusion, this study provides an efficient strategy for annotating dipeptides/tripeptides from complex samples.PMID:37163573 | DOI:10.1021/acs.jproteome.3c00002

PLoS One. 2023 May 10;18(5):e0284570. doi: 10.1371/journal.pone.0284570. eCollection 2023.ABSTRACTDuring pregnancy and parturition, female dogs have to cope with various challenges such as providing nutrients for the growth of the fetuses, hormonal changes, whelping, nursing, milk production, and uterine involution. Metabolomic research has been used to characterize the influence of several factors on metabolism such as inter- and intra-individual factors, feeding, aging, inter-breed differences, drug action, behavior, exercise, genetic factors, neuter status, and pathologic processes. Aim of this study was to identify metabolites showing specific changes in blood serum at the different phases of pregnancy and lactation. In total, 27 privately owned female dogs of 21 different breeds were sampled at six time points: during heat, in early, mid and late pregnancy, at the suspected peak of lactation and after weaning. A validated and highly automated canine-specific NMR metabolomics technology was utilized to quantitate 123 measurands. It was evaluated which metabolite concentrations showed significant changes between the different time points. Metabolites were then grouped into five clusters based on concentration patterns and biochemical relationships between the metabolites: high in mid-pregnancy, low in mid-pregnancy, high in late pregnancy, high in lactation, and low in lactation. Several metabolites such as albumin, glycoprotein acetyls, fatty acids, lipoproteins, glucose, and some amino acids show similar patterns during pregnancy and lactation as shown in humans. The patterns of some other parameters such as branched-chain amino acids, alanine and histidine seem to differ between these species. For most metabolites, it is yet unstudied whether the observed changes arise from modified resorption from the intestines, modified production, or metabolism in the maternal or fetal tissues. Hence, further species-specific metabolomic research may support a broader understanding of the physiological changes caused by pregnancy that are likely to be key for the normal fetal growth and development. Our findings provide a baseline of normal metabolic changes during healthy canine pregnancy and parturition. Combined with future metabolomics findings, they may help monitor vital functions of pre-, intra-, and post-partum bitches and may allow early detection of illness.PMID:37163464 | DOI:10.1371/journal.pone.0284570

Infect Drug Resist. 2023 May 3;16:2667-2680. doi: 10.2147/IDR.S405987. eCollection 2023.ABSTRACTBACKGROUND: Mycobacterium tuberculosis (MTB) is a global and highly deleterious pathogen that creates an enormous pressure on global public health. Although several effective drugs have been used to treat tuberculosis, the emergence of multidrug-resistant Mycobacterium tuberculosis (MDR-MTB) has further increased the public health burden. The aim of this study was to describe in depth the metabolic changes in clinical isolates of drug-susceptible Mycobacterium tuberculosis (DS-MTB) and MDR-MTB and to provide clues to the mechanisms of drug resistance based on metabolic pathways.METHODS: Based on the minimum inhibition concentration (MIC) of multiple anti-tuberculosis drugs, two clinical isolates were selected, one DS-MTB isolate (isoniazid MIC=0.06 mg/L, rifampin MIC=0.25 mg/L) and one MDR-MTB isolate (isoniazid MIC=4 mg/L, rifampin MIC=8 mg/L). Through high-throughput metabolomics, the metabolic profiles of the DS-MTB isolate and the MDR-MTB isolate and their cultured supernatants were revealed.RESULTS: Compared with the DS-MTB isolate, 128 metabolites were significantly altered in the MDR-MTB isolate and 66 metabolites were significantly altered in the cultured supernatant. The differential metabolites were significantly enriched in pyrimidine metabolism, purine metabolism, nicotinate and nicotinamide metabolism, arginine acid metabolism, and phenylalanine metabolism. Furthermore, metabolomics analysis of the bacterial cultured supernatants showed a significant increase in 10 amino acids (L-citrulline, L-glutamic acid, L-aspartic acid, L-norleucine, L-phenylalanine, L-methionine, L-tyrosine, D-tryptophan, valylproline, and D-methionine) and a significant decrease in 2 amino acids (L-lysine and L-arginine) in MDR-MTB isolate.CONCLUSION: The present study provided a metabolite alteration profile as well as a cultured supernatant metabolite alteration profile of MDR-MTB clinical isolate, providing clues to the potential metabolic pathways and mechanisms of multidrug resistance.PMID:37163145 | PMC:PMC10164396 | DOI:10.2147/IDR.S405987

medRxiv. 2023 May 2:2023.04.24.23289055. doi: 10.1101/2023.04.24.23289055. Preprint.ABSTRACTBACKGROUND AND AIMS: Life's Essential 8 (LE8) is a comprehensive construct of cardiovascular health. Yet, little is known about LE8 score, its metabolic correlates, and their predictive implications among Black Americans and low-income individuals.METHODS: In a nested case-control study of coronary heart disease (CHD) among 598 Black and 596 White low-income Americans, we estimated LE8 score, conducted untargeted plasma metabolites profiling, and used 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. 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 598 Chinese adults.RESULTS: Higher LE8 score was associated with lower CHD risk [standardized OR (95% CI)=0.61 (0.53-0.69)]. The identified MetaSig, consisting of 133 metabolites, showed strong correlation with LE8 score ( r =0.61) and inverse association with CHD risk [OR (95% CI)=0.57 (0.49-0.65)], robust to adjustment for LE8 score and across participants with different sociodemographic and health status (ORs: 0.42-0.69; all P <0.05). MetaSig mediated a large portion of the LE8-CHD association: 53% (32%-80%) ( P <0.001). Significant associations of MetaSig with LE8 score and CHD risk were found in validation cohort [ r =0.49; OR (95% CI)=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 and comprehensive measure of LE8 score and its metabolic phenotype relevant to CHD prevention among diverse populations.PMID:37163035 | PMC:PMC10168489 | DOI:10.1101/2023.04.24.23289055

bioRxiv. 2023 Apr 28:2023.04.24.538118. doi: 10.1101/2023.04.24.538118. Preprint.ABSTRACTInterplay between metabolism and chromatin signaling have been implicated in cancer initiation and progression. However, whether and how metabolic reprogramming in tumors generates specific epigenetic vulnerabilities remain unclear. Lung adenocarcinoma (LUAD) tumors frequently harbor mutations that cause aberrant activation of the NRF2 antioxidant pathway and drive aggressive and chemo-resistant disease. We performed a chromatin-focused CRISPR screen and report that NRF2 activation sensitized LUAD cells to genetic and chemical inhibition of class I histone deacetylases (HDAC). This association was consistently observed across cultured cells, syngeneic mouse models and patient-derived xenografts. HDAC inhibition causes widespread increases in histone H4 acetylation (H4ac) at intergenic regions, but also drives re-targeting of H4ac reader protein BRD4 away from promoters with high H4ac levels and transcriptional downregulation of corresponding genes. Integrative epigenomic, transcriptomic and metabolomic analysis demonstrates that these chromatin changes are associated with reduced flux into amino acid metabolism and de novo nucleotide synthesis pathways that are preferentially required for the survival of NRF2-active cancer cells. Together, our findings suggest that metabolic alterations such as NRF2 activation could serve as biomarkers for effective repurposing of HDAC inhibitors to treat solid tumors.PMID:37162970 | PMC:PMC10168258 | DOI:10.1101/2023.04.24.538118

Res Sq. 2023 Apr 28:rs.3.rs-2843025. doi: 10.21203/rs.3.rs-2843025/v1. Preprint.ABSTRACTVenetoclax (VEN), in combination with low dose cytarabine (AraC) or a hypomethylating agent, is FDA approved to treat acute myeloid leukemia (AML) in patients who are over the age of 75 or cannot tolerate standard chemotherapy. Despite high response rates to these combination therapies, most patients succumb to the disease due to relapse and/or drug resistance, providing an unmet clinical need for novel therapies to improve AML patient survival. ME-344 is a potent isoflavone with demonstrated inhibitory activity toward oxidative phosphorylation (OXPHOS) and clinical activity in solid tumors. Given that OXPHOS inhibition enhances VEN antileukemic activity against AML, we hypothesized that ME-344 could enhance the anti-AML activity of VEN. Here we report that ME-344 synergized with VEN to target AML cell lines and primary patient samples while sparing normal hematopoietic cells. Cooperative suppression of OXPHOS was detected in a subset of AML cell lines and primary patient samples. Metabolomics analysis revealed a significant reduction of purine biosynthesis metabolites by ME-344. Further, lometrexol, an inhibitor of purine biosynthesis, synergistically enhanced VEN-induced apoptosis in AML cell lines. Interestingly, AML cells with acquired resistance to AraC showed significantly increased purine biosynthesis metabolites and sensitivities to ME-344. Furthermore, synergy between ME-344 and VEN was preserved in these AraC-resistant AML cells. These results translated into significantly prolonged survival upon combination of ME-344 and VEN in NSGS mice bearing parental or AraC-resistant MV4-11 leukemia. This study demonstrates that ME-344 enhances VEN antileukemic activity against preclinical models of AML by suppressing OXPHOS and/or purine biosynthesis.PMID:37162954 | PMC:PMC10168457 | DOI:10.21203/rs.3.rs-2843025/v1

Braz J Microbiol. 2023 May 10. doi: 10.1007/s42770-023-01000-7. Online ahead of print.ABSTRACTContamination of soil by petroleum is becoming increasingly serious in the world today. However, the research on gene functional characteristics, metabolites and distribution of microbial genomes in oil-contaminated soil is limited. Considering that, metagenomic and metabonomic were used to detect microbes and metabolites in oil-contaminated soil, and the changes of functional pathways were analyzed. We found that oil pollution significantly changed the composition of soil microorganisms and metabolites, and promoted the relative abundance of Pseudoxanthomonas, Pseudomonas, Mycobacterium, Immundisolibacter, etc. The degradation of toluene, xylene, polycyclic aromatic hydrocarbon and fluorobenzoate increased in Xenobiotics biodegradation and metabolism. Key monooxygenases and dioxygenase systems were regulated to promote ring opening and degradation of aromatic hydrocarbons. Metabolite contents of polycyclic aromatic hydrocarbons (PAHs) such as 9-fluoronone and gentisic acid increased significantly. The soil microbiome degraded petroleum pollutants into small molecular substances and promoted the bioremediation of petroleum-contaminated soil. Besides, we discovered the complete degradation pathway of petroleum-contaminated soil microorganisms to generate gentisic acid from the hydroxylation of naphthalene in PAHs by salicylic acid. This study offers important insights into bioremediation of oil-contaminated soil from the aspect of molecular regulation mechanism and provides a theoretical basis for the screening of new oil degrading bacteria.PMID:37162704 | DOI:10.1007/s42770-023-01000-7

Chem Res Toxicol. 2023 May 10. doi: 10.1021/acs.chemrestox.3c00007. Online ahead of print.ABSTRACTSyncytialization, the fusion of cytotrophoblasts into an epithelial barrier that constitutes the maternal-fetal interface, is a crucial event of placentation. This process is characterized by distinct changes to amino acid and energy metabolism. A metabolite of the industrial solvent trichloroethylene (TCE), S-(1,2-dichlorovinyl)-l-cysteine (DCVC), modifies energy metabolism and amino acid abundance in HTR-8/SVneo extravillous trophoblasts. In the current study, we investigated DCVC-induced changes to energy metabolism and amino acids during forskolin-stimulated syncytialization in BeWo cells, a human villous trophoblastic cell line that models syncytialization in vitro. BeWo cells were exposed to forskolin at 100 μM for 48 h to stimulate syncytialization. During syncytialization, BeWo cells were also treated with DCVC at 0 (control), 10, or 20 μM. Following treatment, the targeted metabolomics platform, "Tricarboxylic Acid Plus", was used to identify changes in energy metabolism and amino acids. DCVC treatment during syncytialization decreased oleic acid, aspartate, proline, uridine diphosphate (UDP), UDP-d-glucose, uridine monophosphate, and cytidine monophosphate relative to forskolin-only treatment controls, but did not increase any measured metabolite. Notable changes stimulated by syncytialization in the absence of DCVC included increased adenosine monophosphate and guanosine monophosphate, as well as decreased aspartate and glutamate. Pathway analysis revealed multiple pathways in amino acid and sugar metabolisms that were altered with forskolin-stimulated syncytialization alone and DCVC treatment during syncytialization. Analysis of ratios of metabolites within the pathways revealed that DCVC exposure during syncytialization changed metabolite ratios in the same or different direction compared to syncytialization alone. Building off our oleic acid findings, we found that extracellular matrix metalloproteinase-2, which is downstream in oleic acid signaling, underwent the same changes as oleic acid. Together, the metabolic changes stimulated by DCVC treatment during syncytialization suggest changes in energy metabolism and amino acid abundance as potential mechanisms by which DCVC could impact syncytialization and pregnancy.PMID:37162359 | DOI:10.1021/acs.chemrestox.3c00007

J Agric Food Chem. 2023 May 10. doi: 10.1021/acs.jafc.2c08897. Online ahead of print.ABSTRACTThe development and progression of colitis would detrimentally destroy the intestine barrier. However, there remains a paucity of evidence on whether ovalbumin (OVA) can be used as a nutritional food protein to repair the intestinal barrier. In this study, the repairing mechanism of OVA on intestinal barrier was thoroughly investigated by gut microbiota and untargeted metabolomics techniques. The findings demonstrated that OVA reduced intestinal permeability and restored mucin (0.75 ± 0.06) and tight junction (TJ) protein (0.67 ± 0.14) expression in colitis mice caused by 3% dextran sulfate sodium (DSS). In addition, the inflammation response and oxidative stress were also attenuated. The intake of OVA upregulated the abundance of Lactobacillaceae (7.60 ± 3.34%) and Akkermansiaceae (10.39 ± 5.97%). Furthermore, OVA upregulated the abundance of inosine (6.06 ± 0.36%), putrescine (4.14 ± 0.20%), and glycocholic acid (5.59 ± 0.23%) in colitis mice through ATP binding cassette (ABC) transporters and bile secretion pathways. In summary, our findings revealed that OVA could maintain intestinal health, which may provide crucial insights for preventing and treating intestinal diseases.PMID:37161945 | DOI:10.1021/acs.jafc.2c08897

Eur J Sport Sci. 2023 May 10:1-37. doi: 10.1080/17461391.2023.2213185. Online ahead of print.ABSTRACTA 12-week intervention involving high-intensity interval training (HIIT) with or without citrulline (CIT) supplementation induced adaptations in the serum metabolome of obese older adults through significant changes in 44 metabolites.Changes in 23 metabolites were observed when a CIT supplementation was administered along with a 12-week HIIT intervention.TG (16:1/18:1/16:0) correlated with several adiposity parameters including leptin, triglycerides, legs lean mass.Aspartic acid correlated with several adiposity parameters including leptin, LDL cholesterol as well as android, arms and trunk fat mass.PMID:37161876 | DOI:10.1080/17461391.2023.2213185

Hypertension. 2023 May 10. doi: 10.1161/HYPERTENSIONAHA.123.20901. Online ahead of print.ABSTRACTBACKGROUND: The DASH (Dietary Approaches to Stop Hypertension) diets reduced blood pressure (BP) in the DASH and DASH-Sodium trials, but the underlying mechanisms are unclear. We identified metabolites associated with systolic BP or diastolic BP (DBP) changes induced by dietary interventions (DASH versus control arms) in 2 randomized controlled feeding studies-the DASH and DASH-Sodium trials.METHODS: Metabolomic profiling was conducted in serum and urine samples collected at the end of diet interventions: DASH (n=219) and DASH-Sodium (n=395). Using multivariable linear regression models, associations were examined between metabolites and change in systolic BP and DBP. Tested for interactions between diet interventions and metabolites were the following comparisons: (1) DASH versus control diets in the DASH trial (serum), (2) DASH high-sodium versus control high-sodium diets in the DASH-Sodium trial (urine), and (3) DASH low-sodium versus control high-sodium diets in the DASH-Sodium trial (urine).RESULTS: Sixty-five significant interactions were identified (DASH trial [serum], 12; DASH high sodium [urine], 35; DASH low sodium [urine], 18) between metabolites and systolic BP or DBP. In the DASH trial, serum tryptophan betaine was associated with reductions in DBP in participants consuming the DASH diets but not control diets (P interaction, 0.023). In the DASH-Sodium trial, urine levels of N-methylglutamate and proline derivatives (eg, stachydrine, 3-hydroxystachydrine, N-methylproline, and N-methylhydroxyproline) were associated with reductions in systolic BP or DBP in participants consuming the DASH diets but not control diets (P interaction, <0.05 for all tests).CONCLUSIONS: We identified metabolites that were associated with BP lowering in response to dietary interventions.REGISTRATION: URL: https://www.CLINICALTRIALS: gov; Unique identifier: NCT03403166 (DASH trial). URL: https://www.CLINICALTRIALS: gov; Unique identifier: NCT00000608 (DASH-Sodium trial).PMID:37161796 | DOI:10.1161/HYPERTENSIONAHA.123.20901

Diabetes Obes Metab. 2023 May 10. doi: 10.1111/dom.15104. Online ahead of print.ABSTRACTAIMS: To evaluate the associations of plasma bile acid metabolites, especially in early pregnancy, with gestational diabetes mellitus (GDM) risk among pregnant women.MATERIALS AND METHODS: Plasma concentrations of 15 bile acid metabolites were measured in 645 women at early pregnancy from the Jiashan Birth Cohort using a liquid chromatography-tandem mass spectrometry metabolomics platform. Using logistic and cubic spline models, we examined associations between baseline plasma bile acid metabolites and GDM risk during mid-late pregnancy. A meta-analysis of prospective studies of bile acid and GDM risk was performed.RESULTS: The linear and nonlinear univariate models identified eight metabolites associated with GDM, including cholic acid, taurocholic acid (TCA), glycocholic acid, glycochenodeoxycholic acid, deoxycholic acid, lithocholic acid (LCA), ursodeoxycholic acid and taurolithocholic acid (all P <0.05). Multivariable analysis indicated that TCA and LCA levels were positively (odds ratio [OR] 2.07, 95% confidential interval [CI] 1.05, 3.96; P = 0.030) and negatively (OR 0.83, 95% CI 0.68, 1.01; P = 0.065) associated with GDM, respectively, after adjusting for confounders. The TCA-GDM association showed a positive linear shaped relationship (OR 2.07, 95% CI 1.05, 3.96; P = 0.030); while LCA was negatively related with GDM risk in linearity (OR 0.83, 95% CI 0.68, 1.01; P = 0.065). The meta-analysis of five studies showed a consistent bile acid and GDM association, with a risk ratio (RR) of 2.43 (1.95, 3.03).CONCLUSIONS: This study indicated that, the levels of circulating bile acids in early pregnancy were associated with risk of GDM, independent of GDM risk factors. Most GDM-associated bile acids were primary conjugated and secondary unconjugated bile acids.PMID:37161712 | DOI:10.1111/dom.15104

Biomed Chromatogr. 2023 May 9:e5683. doi: 10.1002/bmc.5683. Online ahead of print.ABSTRACTRheumatoid arthritis (RA) is an autoimmune disease with a 0.5% prevalence worldwide. Inflammation, periosteal proliferation, and joint destruction are the main clinical symptoms of RA. Typhonii Rhizoma (TR) is the dry tuber of the Araceae plant Typhonium giganteum Engl, and possesses many uses such as dispelling obstructive wind-phlegm, and relieving pain. TR is used for the clinical treatment of arthromyodynia and RA. However, the mechanism of action remains unclear. In this study, we first evaluated the effects of TR in type II collagen-induced RA model rats. Secondly, in serum metabolomics, TR could ameliorate 11 potential metabolites in RA model rats and reversed RA through pentose and glucuronate interconversions, sphingolipid metabolism, glycerophospholipid metabolism, and tryptophan metabolism. To further explore the mechanisms of TR, 40 chemical constituents in TR were used to established a component-target interaction network. Some key genes were verified by in vitro pharmacological tests by integrating the results from the network pharmacology and metabolomics. The verification results showed that the mechanisms of TR against RA may be related to the inhibition of the production of inflammatory cytokines and the expression and function of HIF1-α. This study serves as a theoretical basis for the treatment of RA with TR.PMID:37161606 | DOI:10.1002/bmc.5683

J Exp Clin Cancer Res. 2023 May 10;42(1):118. doi: 10.1186/s13046-023-02686-1.ABSTRACTBACKGROUND: The failure of novel therapies effective in preclinical animal models largely reflects the fact that current models do not really mimic the pathological/therapeutic features of glioblastoma (GBM), in which the most effective temozolomide chemoradiotherapy (RT/TMZ) regimen can only slightly extend survival. How to improve RT/TMZ efficacy remains a major challenge in clinic.METHODS: Syngeneic G422TN-GBM model mice were subject to RT/TMZ, surgery, piperlongumine (PL), αPD1, glutathione. Metabolomics or transcriptomics data from G422TN-GBM and human GBM were used for gene enrichment analysis and estimation of ROS generation/scavenging balance, oxidative stress damage, inflammation and immune cell infiltration. Overall survival, bioluminescent imaging, immunohistochemistry, and immunofluorescence staining were used to examine therapeutic efficacy and mechanisms of action.RESULTS: Here we identified that glutathione metabolism was most significantly altered in metabolomics analysis upon RT/TMZ therapies in a truly refractory and reliable mouse triple-negative GBM (G422TN) preclinical model. Consistently, ROS generators/scavengers were highly dysregulated in both G422TN-tumor and human GBM. The ROS-inducer PL synergized surgery/TMZ, surgery/RT/TMZ or RT/TMZ to achieve long-term survival (LTS) in G422TN-mice, but only one LTS-mouse from RT/TMZ/PL therapy passed the rechallenging phase (immune cure). Furthermore, the immunotherapy of RT/TMZ/PL plus anti-PD-1 antibody (αPD1) doubled LTS (50%) and immune-cured (25%) mice. Glutathione completely abolished PL-synergistic effects. Mechanistically, ROS reduction was associated with RT/TMZ-resistance. PL restored ROS level (mainly via reversing Duox2/Gpx2), activated oxidative stress/inflammation/immune responses signature genes, reduced cancer cell proliferation/invasion, increased apoptosis and CD3+/CD4+/CD8+ T-lymphocytes in G422TN-tumor on the basis of RT/TMZ regimen.CONCLUSION: Our findings demonstrate that PL reverses RT/TMZ-reduced ROS and synergistically resets tumor microenvironment to cure GBM. RT/TMZ/PL or RT/TMZ/PL/αPD1 exacts effective immune cure in refractory GBM, deserving a priority for clinical trials.PMID:37161450 | DOI:10.1186/s13046-023-02686-1

BMC Plant Biol. 2023 May 10;23(1):245. doi: 10.1186/s12870-023-04258-z.ABSTRACTBACKGROUND: Cotton is an important industrial crop and a pioneer crop for saline-alkali land restoration. However, the molecular mechanism underlying the cotton response to salt is not completely understood.METHODS: Here, we used metabolome data and transcriptome data to analyze the salt tolerance regulatory network of cotton and metabolic biomarkers.RESULTS: In this study, cotton was stressed at 400 m M NaCl for 0 h, 3 h, 24 h and 48 h. NaCl interfered with cotton gene expression, altered metabolite contents and affected plant growth. Metabolome analysis showed that NaCl stress increased the contents of amino acids, sugars and ABA, decreased the amount of vitamin and terpenoids. K-means cluster analysis of differentially expressed genes showed that the continuously up-regulated genes were mainly enriched in metabolic pathways such as flavonoid biosynthesis and amino acid biosynthesis.CONCLUSION: The four metabolites of cysteine (Cys), ABA(Abscisic acid), turanose, and isopentenyladenine-7-N-glucoside (IP7G) were consistently up-regulated under salt stress, which may indicate that they are potential candidates for cotton under salt stress biomarkers. Combined transcriptome and metabolome analysis revealed accumulation of cysteine, ABA, isopentenyladenine-7-N-glucoside and turanose were important for salt tolerance in cotton mechanism. These results will provide some metabolic insights and key metabolite biomarkers for salt stress tolerance, which may help to understanding of the metabolite response to salt stress in cotton and develop a foundation for cotton to grow better in saline soil.PMID:37161359 | DOI:10.1186/s12870-023-04258-z

Oncogene. 2023 May 9. doi: 10.1038/s41388-023-02703-9. Online ahead of print.ABSTRACTVimentin is highly expressed in metastatic cancers, and its expression correlates with poor patient prognoses. However, no causal in vivo studies linking vimentin and non-small cell lung cancer (NSCLC) progression existed until now. We use three complementary in vivo models to show that vimentin is required for the progression of NSCLC. First, we crossed LSL-KrasG12D; Tp53fl/fl mice (KPV+/+) with vimentin knockout mice (KPV-/-) to demonstrate that KPV-/- mice have attenuated tumor growth and improved survival compared with KPV+/+ mice. Next, we therapeutically treated KPV+/+ mice with withaferin A (WFA), an agent that disrupts vimentin intermediate filaments (IFs). We show that WFA suppresses tumor growth and reduces tumor burden in the lung. Finally, luciferase-expressing KPV+/+, KPV-/-, or KPVY117L cells were implanted into the flanks of athymic mice to track cancer metastasis to the lung. In KPVY117L cells, vimentin forms oligomers called unit-length filaments but cannot assemble into mature vimentin IFs. KPV-/- and KPVY117L cells fail to metastasize, suggesting that cell-autonomous metastasis requires mature vimentin IFs. Integrative metabolomic and transcriptomic analysis reveals that KPV-/- cells upregulate genes associated with ferroptosis, an iron-dependent form of regulated cell death. KPV-/- cells have reduced glutathione peroxidase 4 (GPX4) levels, resulting in the accumulation of toxic lipid peroxides and increased ferroptosis. Together, our results demonstrate that vimentin is required for rapid tumor growth, metastasis, and protection from ferroptosis in NSCLC.PMID:37161053 | DOI:10.1038/s41388-023-02703-9

Sci Rep. 2023 May 9;13(1):7489. doi: 10.1038/s41598-023-34593-y.ABSTRACTSample preparation in untargeted metabolomics should allow reproducible extractions of as many molecules as possible. Thus, optimizing sample preparation is crucial. This study compared six different extraction procedures to find the most suitable for extracting zebrafish larvae in the context of an infection model. Two one-phase extractions employing methanol (I) and a single miscible phase of methanol/acetonitrile/water (II) and two two-phase methods using phase separation between chloroform and methanol/water combinations (III and IV) were tested. Additional bead homogenization was used for methods III and IV (III_B and IV_B). Nine internal standards and 59 molecules of interest (MoInt) related to mycobacterial infection were used for method evaluation. Two-phase methods (III and IV) led to a lower feature count, higher peak areas of MoInt, especially amino acids, and higher coefficients of variation in comparison to one-phase extractions. Adding bead homogenization increased feature count, peak areas, and CVs. Extraction I showed higher peak areas and lower CVs than extraction II, thus being the most suited one-phase method. Extraction III and IV showed similar results, with III being easier to execute and less prone to imprecisions. Thus, for future applications in zebrafish larvae metabolomics and infection models, extractions I and III might be chosen.PMID:37161044 | DOI:10.1038/s41598-023-34593-y