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Journal of Cancer 2024Tamoxifen is commonly used in the treatment of hormonal-positive breast cancer. However, 30%-40% of tumors treated with tamoxifen develop resistance; therefore, an...
Tamoxifen is commonly used in the treatment of hormonal-positive breast cancer. However, 30%-40% of tumors treated with tamoxifen develop resistance; therefore, an important step to overcome this resistance is to understand the underlying molecular and metabolic mechanisms. In the present work, we used metabolic profiling to determine potential biomarkers of tamoxifen resistance, and gene expression levels of enzymes important to these metabolites and then correlated the expression to the survival of patients receiving tamoxifen. Tamoxifen-resistant cell lines previously developed and characterized in our laboratory were metabolically profiled with nuclear magnetic resonance spectroscopy (NMR) using cryogenic probe, and the findings were correlated with the expression of genes that encode the key enzymes of the significant metabolites. Moreover, the effect of significantly altered genes on the overall survival of patients was assessed using the Kaplan-Meier plotter web tool. We observed a significant increase in the levels of glutamine, taurine, glutathione, and xanthine, and a significant decrease in the branched-chain amino acids, valine, and isoleucine, as well as glutamate and cysteine in the tamoxifen-resistant cells compared to tamoxifen sensitive cells. Moreover, xanthine dehydrogenase and glutathione synthase gene expression were downregulated, whereas glucose-6-phosphate dehydrogenase was upregulated compared to control. Additionally, increased expression of xanthine dehydrogenase was associated with a better outcome for breast cancer patients. Overall, this study sheds light on metabolic pathways that are dysregulated in tamoxifen-resistant cell lines and the potential role of each of these pathways in the development of resistance.
PubMed: 38947399
DOI: 10.7150/jca.96659 -
Food Chemistry: X Oct 2024Differences in main nutritional components in relation to biomarkers of metabolites in purple rice grains at different fillings stages have not been determined...
Differences in main nutritional components in relation to biomarkers of metabolites in purple rice grains at different fillings stages have not been determined previously. This study measured the contents of amino acids, several nutritional indicators, and mineral elements in purple rice grains at five stages following the filling stage. The results revealed that the amino acid, ascorbic acid, total sugar, carotenoid, vitamin B9, cyanidin-3-O-glucoside, peonidin 3-glucoside and seven minerals were highest in the final stage of grain filling. Citric acid, L-isoleucine, trigonelline, and L-glutamate are key metabolites in the metabolic pathway and exhibit strong correlations with various nutritional indicators. Hence, this research preliminarily suggested that trigonelline, L-isoleucine, L-glutamate, and citric acid could be potential biomarkers of nutritional components in purple rice grains during various postfilling stages.
PubMed: 38947340
DOI: 10.1016/j.fochx.2024.101528 -
ACS Central Science Jun 2024A subset of nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs) are encoded in their biosynthetic gene clusters (BGCs) with enzymes annotated as...
A subset of nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs) are encoded in their biosynthetic gene clusters (BGCs) with enzymes annotated as lantibiotic dehydratases. The functions of these putative lantibiotic dehydratases remain unknown. Here, we characterize an NRPS-PKS BGC with a putative lantibiotic dehydratase from the bacterium (). Heterologous expression revealed several metabolites produced by the BGC, and the omission of selected biosynthetic enzymes revealed the biosynthetic pathway toward these compounds. The final product is a bisarginyl ureidopeptide with an enone electrophile. The putative lantibiotic dehydratase catalyzes peptide bond formation to a Thr that extends the peptide scaffold opposite to the NRPS and PKS biosynthetic direction. The condensation domain of the NRPS SnaA catalyzes the formation of a ureido group, and bioinformatics analysis revealed a distinct active site signature EHHXXHDG of ureido-generating condensation (C) domains. This work demonstrates that the annotated lantibiotic dehydratase serves as a separate amide bond-forming machinery in addition to the NRPS, and that the lantibiotic dehydratase enzyme family possesses diverse catalytic activities in the biosynthesis of both ribosomal and nonribosomal natural products.
PubMed: 38947204
DOI: 10.1021/acscentsci.4c00044 -
Frontiers in Cellular and Infection... 2024The Cecum is a key site for cellulose digestion in nutrient metabolism of intestine, but its mechanisms of microbial and gene interactions has not been fully elucidated...
The Cecum is a key site for cellulose digestion in nutrient metabolism of intestine, but its mechanisms of microbial and gene interactions has not been fully elucidated during pathogenesis of obesity. Therefore, the cecum tissues of the New Zealand rabbits and their contents between the high-fat diet-induced group (Ob) and control group (Co) were collected and analyzed using multi-omics. The metagenomic analysis indicated that the relative abundances of and species were significantly lower, while those of , , , , , , , and species were significantly higher in the Ob as compared to those in Co. Transcriptomic sequencing results showed that the differentially upregulated genes were mainly enriched in pathways, including calcium signaling pathway, PI3K-Akt signaling pathway, and Wnt signaling pathway, while the differentially downregulated genes were mainly enriched in pathways of NF-kappaB signaling pathway and T cell receptor signaling pathway. The comparative analysis of metabolites showed that the glycine, serine, and threonine metabolism and cysteine and methionine metabolism were the important metabolic pathways between the two groups. The combined analysis showed that , , and genes were highly correlated with , and species. Thus, the preliminary study elucidated the microbial and gene interactions in cecum of obese rabbit and provided a basis for further studies in intestinal intervention for human obesity.
Topics: Animals; Rabbits; Diet, High-Fat; Cecum; Obesity; Gastrointestinal Microbiome; Host Microbial Interactions; Metagenomics; Bacteria; Gene Regulatory Networks; Male; Gene Expression Profiling
PubMed: 38947127
DOI: 10.3389/fcimb.2024.1407051 -
Research Square Jun 2024Background and Purpose Impaired cerebral circulation, induced by blood vessel constrictions and microthrombi, leads to delayed cerebral ischemia after subarachnoid...
Background and Purpose Impaired cerebral circulation, induced by blood vessel constrictions and microthrombi, leads to delayed cerebral ischemia after subarachnoid hemorrhage (SAH). 12/15-Lipooxygenase (12/15-LOX) overexpression has been implicated in worsening early brain injury outcomes following SAH. However, it is unknown if 12/15-LOX is important in delayed pathophysiological events after SAH. Since 12/15-LOX produces metabolites that induce inflammation and vasoconstriction, we hypothesized that 12/15-LOX leads to microvessel constriction and microthrombi formation after SAH, and thus 12/15-LOX is an important target to prevent delayed cerebral ischemia. Methods SAH was induced in C57BL/6 and 12/15-LOX mice of both sexes by endovascular perforation. Expression of 12/15-LOX was assessed in brain tissue slices and . C57BL/6 mice were administered either ML351 (12/15-LOX inhibitor) or vehicle. Mice were evaluated for daily neuroscore and euthanized on day five to assess cerebral 12/15-LOX expression, vessel constrictions, platelet activation, microthrombi, neurodegeneration, infarction, cortical perfusion, and for development of delayed deficits. Finally, the effect of 12/15-LOX inhibition on platelet activation was assessed in SAH patient samples using a platelet spreading assay. Results In SAH mice, 12/15-LOX was upregulated in brain vascular cells and there was an increase in 12-S-HETE. Inhibition of 12/15-LOX improved brain perfusion on days 4-5 and attenuated delayed pathophysiological events, including microvessel constrictions, microthrombi, neuronal degeneration, and infarction. Additionally, 12/15-LOX inhibition reduced platelet activation in human and mouse blood samples. Conclusions Cerebrovascular 12/15-LOX overexpression plays a major role in brain dysfunction after SAH by triggering microvessel constrictions and microthrombi formation, which reduces brain perfusion. Inhibiting 12/15-LOX may be a therapeutic target to improve outcomes after SAH.
PubMed: 38947083
DOI: 10.21203/rs.3.rs-4468292/v1 -
MedRxiv : the Preprint Server For... Jun 2024Scarce knowledge about the impact of metabolism-disrupting chemicals (MDCs) on liver injury limits opportunities for intervention. We evaluated pregnancy MDC-mixture...
BACKGROUND AND AIMS
Scarce knowledge about the impact of metabolism-disrupting chemicals (MDCs) on liver injury limits opportunities for intervention. We evaluated pregnancy MDC-mixture associations with liver injury and effect modification by folic acid (FA) supplementation in mother-child pairs.
METHODS
We studied ∼200 mother-child pairs from the Mexican PROGRESS cohort, with measured 43 MDCs during pregnancy (estimated air pollutants, blood/urine metals or metalloids, urine high- and low-molecular-weight phthalate [HMWPs, LMWPs] and organophosphate-pesticide [OP] metabolites), and serum liver enzymes (ALT, AST) at ∼9 years post-parturition. We defined liver injury as elevated liver enzymes in children, and using established clinical scores for steatosis and fibrosis in mothers (i.e., AST:ALT, FLI, HSI, FIB-4). Bayesian Weighted Quantile Sum regression assessed MDC-mixture associations with liver injury outcomes. We further examined chemical-chemical interactions and effect modification by self-reported FA supplementation.
RESULTS
In children, many MDC-mixtures were associated with liver injury outcomes. Per quartile HMWP-mixture increase, ALT increased by 10.1% (95%CI: 1.67%, 19.4%) and AST by 5.27% (95% CI: 0.80%, 10.1%). LMWP-mixtures and air pollutant-mixtures were associated with higher AST and ALT, respectively. Air pollutant and non-essential metal/element associations with liver enzymes were attenuated by maternal cobalt blood concentrations ( -interactions<0.05). In mothers, only the LMWP-mixture was associated with liver injury [OR=1.53 (95%CI: 1.01, 2.28) for HSI>36, and OR=1.62 (95%CI: 1.05, 2.49) for AST:ALT<1]. In mothers and children, most associations were attenuated (null) at FA supplementation≥600mcg/day ( -interactions<0.05).
CONCLUSIONS
Pregnancy MDC exposures may increase liver injury risk, particularly in children. These associations may be attenuated by higher FA supplementation and maternal cobalt levels.
PubMed: 38947077
DOI: 10.1101/2024.06.13.24308903 -
MedRxiv : the Preprint Server For... Jun 2024Triglyceride (TG)/High density lipoprotein cholesterol (HDL-C) ratio (THR) represents a single surrogate predictor of hyperinsulinemia or insulin resistance that is...
Novel Loci ( ) for Triglyceride / High-density Lipoprotein Cholesterol Ratio Longitudinal Change (ΔTHR) among Subjects without Type 2 Diabetes: Evidence from the Long Life Family Study (LLFS) and the Framingham Heart Study (FHS) Offspring Cohort (OS).
AIMS/HYPOTHESIS
Triglyceride (TG)/High density lipoprotein cholesterol (HDL-C) ratio (THR) represents a single surrogate predictor of hyperinsulinemia or insulin resistance that is associated with premature aging processes, risk of diabetes and increased mortality. To identify novel genetic loci for THR change over time (ΔTHR), we conducted genome-wide association study (GWAS) and genome-wide linkage scan (GWLS) among subjects of European ancestry who had complete data from two exams collected about seven years apart from the Long Life Family Study (LLFS, n=1384), a study with familial clustering of exceptional longevity in the US and Denmark.
METHODS
Subjects with diabetes or using medications for dyslipidemia were excluded from this analysis. ΔTHR was derived using growth curve modeling, and adjusted for age, sex, field centers, and principal components (PCs). GWAS was conducted using a linear mixed model accounted for familial relatedness. Our linkage scan was built on haplotype-based IBD estimation with 0.5 cM average spacing.
RESULTS
Heritability of ΔTHR was moderate (46%). Our GWAS identified a significant locus at the ( =1.58e-9) for ΔTHR; this gene locus has been reported before influencing baseline THR levels. Our GWLS found evidence for a significant linkage with a logarithm of the odds (LODs) exceeding 3 on (LODs=4.1). Using a subset of 25 linkage enriched families (pedigree-specific LODs>0.1), we assessed sequence elements under and identified two novel variants ( -rs114108468, =5e-6, MAF=1.8%; -rs16864075, =3e-6, MAF=8%; accounted for ∼28% and ∼29% of the linkage, respectively, and 57% jointly). While the former variant was associated with ( =7e-5) / ( =3.49e-2) RNA transcriptional levels, the latter variant was not associated with ( =0.23) RNA transcriptional levels. Replication in FHS OS observed modest effect of these loci on ΔTHR. Of 188 metabolites from 13 compound classes assayed in LLFS, we observed multiple metabolites (e.g., DG.38.5, PE.36.4, TG.58.3) that were significantly associated with the variants ( <3e-4).
CONCLUSIONS
Our linkage-guided sequence analysis approach permitted our discovery of two novel gene variants -rs114108468 and -rs16864075 on for ΔTHR among subjects without diabetes selected for exceptional survival and healthy aging.
PubMed: 38947029
DOI: 10.1101/2024.06.18.24309120 -
AJOG Global Reports Aug 2024Intrahepatic cholestasis of pregnancy has been linked to sudden stillbirth. The suddenness of the stillbirths in these cases have led clinicians to suspect that the...
BACKGROUND
Intrahepatic cholestasis of pregnancy has been linked to sudden stillbirth. The suddenness of the stillbirths in these cases have led clinicians to suspect that the pathogenesis of stillbirth in women with intrahepatic cholestasis of pregnancy is not related to asphyxia but rather to an undefined etiology. One leading hypothesis relates certain bile acid metabolites to myocardial injury.
OBJECTIVE
The purpose of this study was to determine whether cord blood troponin I levels are increased in fetuses born to mothers with a diagnosis of intrahepatic cholestasis of pregnancy.
STUDY DESIGN
A prospective, case-control study was performed at a single institution between 2017 to 2019 in which 87 pregnant patients with a diagnosis of intrahepatic cholestasis of pregnancy (total bile acids ≥10 μmol/L) were enrolled as cases and 122 randomly selected pregnant patients (asymptomatic with intrapartum total bile acids <10 μmol/L) were enrolled as controls. Cord blood troponin I levels were measured at delivery in both groups using a commercially available chemiluminescent immunoassay. Values ≤0.04 ng/mL were considered negative. Values >0.04 ng/mL were considered positive. The primary outcome was the presence of elevated troponin levels in both cases and controls as a surrogate marker for cardiac status. Our secondary outcomes included neonatal intensive care unit stay, low Apgar scores, neonatal acidosis, and hypoxia indicated by cord blood pH and base excess levels at the time of birth. Chi square and tests were performed to compare social and obstetrical variables. A value of <.05 was considered significant. A stratification by total bile acids range of <40 μmol/L, 40 to 100 μmol/L, and >100 μmol/L was performed to assess the relationship between the different severities of intrahepatic cholestasis of pregnancy (by risk of fetal demise with those with total bile acids of >100 μmol/L considered at greatest risk) and the likelihood of a positive troponin I result. Finally, a logistic regression analysis was performed to determine if levels of ≥10 μmol/L were associated with elevated troponin levels.
RESULTS
The mean gestational age at delivery was 38.96±1.47 and 37.71±1.59 weeks of gestation in the controls and cases respectively (<.001). The mean total bile acids values were 5.2±1.28 ng/mL and 43.2±40.62 ng/mL in the controls and cases respectively (<.001). Cord blood troponin I was positive in 15 of 122 (12.30%) controls and in 20 of 87 (22.99%) cases. (<.001). When further stratified by total bile acids levels of <40, 40 to 100, and >100 μmol/L, we found a positive correlation between higher total bile acids levels and a positive troponin I test (=.002). When controlling for gestational age at delivery, maternal age, and body mass index, higher total bile acids levels were associated with a positive troponin I level (adjusted odds ratio, 1.015; 95% confidence interval, 1.004-1.026).
CONCLUSION
Elevated troponin I was more likely to be found in patients with intrahepatic cholestasis of pregnancy than in those without intrahepatic cholestasis of pregnancy. When stratified by total bile acids levels, a positive troponin I level was more likely to be found with higher levels of total bile acids. In addition, as total bile acids levels increased, they were more likely to be associated with a positive troponin I level. Although there were no stillbirths in our cohort, our findings suggest a potential relationship between cardiac injury and high levels of total bile acids demonstrated by the presence of elevated troponin I levels in cord blood at the time of birth.
PubMed: 38946940
DOI: 10.1016/j.xagr.2024.100356 -
Frontiers in Microbiology 2024As a symbiotic probiotic for the host, (CB) has the potential to strengthen the body's immune system and improve intestinal health. However, the probiotic mechanism of...
INTRODUCTION
As a symbiotic probiotic for the host, (CB) has the potential to strengthen the body's immune system and improve intestinal health. However, the probiotic mechanism of CB is not completely understood. The CBX 2021 strain isolated by our team from a health pig independently exhibits strong butyric acid production ability and stress resistance. Therefore, this study comprehensively investigated the efficacy of CBX 2021 in pigs and its mechanism of improving pig health.
METHODS
In this study, we systematically revealed the probiotic effect and potential mechanism of the strain by using various methods such as microbiome, metabolites and transcriptome through animal experiments and cell experiments .
RESULTS
Our study showed that CBX 2021 improved growth indicators such as daily weight gain in weaned piglets and also reduced diarrhea rates. Meanwhile, CBX 2021 significantly increased immunoglobulin levels in piglets, reduced contents of inflammatory factors and improved the intestinal barrier. Subsequently, 16S rRNA sequencing showed that CBX 2021 treatment implanted more butyric acid-producing bacteria (such as ) in piglets and reduced the number of potentially pathogenic bacteria (like ). With significant changes in the microbial community, CBX 2021 improved tryptophan metabolism and several alkaloids synthesis in piglets. Further experiments showed that CBX 2021 adhesion directly promoted the proliferation of a porcine intestinal epithelial cell line (IPEC-J2). Moreover, transcriptome analysis revealed that bacterial adhesion increased the expression of intracellular G protein-coupled receptors, inhibited the Notch signaling pathway, and led to a decrease in intracellular pro-inflammatory molecules.
DISCUSSION
These results suggest that CBX 2021 may accelerate piglet growth by optimizing the intestinal microbiota, improving metabolic function and enhancing intestinal health.
PubMed: 38946904
DOI: 10.3389/fmicb.2024.1394332 -
Frontiers in Microbiology 2024Bacterial endophytes dwelling in medicinal plants represent an as yet underexplored source of bioactive natural products with the potential to be developed into drugs...
Bacterial endophytes dwelling in medicinal plants represent an as yet underexplored source of bioactive natural products with the potential to be developed into drugs against various human diseases. For the first time, several spp. were isolated from the rare and endangered traditional medicinal plant ssp. , also known as Edelweiss. In the search for novel natural products, nine endophytic spp. from Edelweiss were investigated via genome sequencing and analysis, followed by fermentation in different media and investigation of secondary metabolomes. A total of 214 secondary metabolite biosynthetic gene clusters (BGCs), of which 35 are presumably unique, were identified by the bioinformatics tool antiSMASH in the genomes of these isolates. LC-MS analyses of the secondary metabolomes of these isolates revealed their potential to produce both known and presumably novel secondary metabolites, whereby most of the identified molecules could be linked to their cognate BGCs. This work sets the stage for further investigation of endophytic streptomycetes from Edelweiss aimed at the discovery and characterization of novel bioactive natural products.
PubMed: 38946903
DOI: 10.3389/fmicb.2024.1408479