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PloS One 2024Development of novel biodosimetry assays and medical countermeasures is needed to obtain a level of radiation preparedness in the event of malicious or accidental mass...
Development of novel biodosimetry assays and medical countermeasures is needed to obtain a level of radiation preparedness in the event of malicious or accidental mass exposures to ionizing radiation (IR). For biodosimetry, metabolic profiling with mass spectrometry (MS) platforms has identified several small molecules in easily accessible biofluids that are promising for dose reconstruction. As our microbiome has profound effects on biofluid metabolite composition, it is of interest how variation in the host microbiome may affect metabolomics based biodosimetry. Here, we 'knocked out' the microbiome of male and female C57BL/6 mice (Abx mice) using antibiotics and then irradiated (0, 3, or 8 Gy) them to determine the role of the host microbiome on biofluid radiation signatures (1 and 3 d urine, 3 d serum). Biofluid metabolite levels were compared to a sham and irradiated group of mice with a normal microbiome (Abx-con mice). To compare post-irradiation effects in urine, we calculated the Spearman's correlation coefficients of metabolite levels with radiation dose. For selected metabolites of interest, we performed more detailed analyses using linear mixed effect models to determine the effects of radiation dose, time, and microbiome depletion. Serum metabolite levels were compared using an ANOVA. Several metabolites were affected after antibiotic administration in the tryptophan and amino acid pathways, sterol hormone, xenobiotic and bile acid pathways (urine) and lipid metabolism (serum), with a post-irradiation attenuative effect observed for Abx mice. In urine, dose×time interactions were supported for a defined radiation metabolite panel (carnitine, hexosamine-valine-isoleucine [Hex-V-I], creatine, citric acid, and Nε,Nε,Nε-trimethyllysine [TML]) and dose for N1-acetylspermidine, which also provided excellent (AUROC ≥ 0.90) to good (AUROC ≥ 0.80) sensitivity and specificity according to the area under the receiver operator characteristic curve (AUROC) analysis. In serum, a panel consisting of carnitine, citric acid, lysophosphatidylcholine (LysoPC) (14:0), LysoPC (20:3), and LysoPC (22:5) also gave excellent to good sensitivity and specificity for identifying post-irradiated individuals at 3 d. Although the microbiome affected the basal levels and/or post-irradiation levels of these metabolites, their utility in dose reconstruction irrespective of microbiome status is encouraging for the use of metabolomics as a novel biodosimetry assay.
Topics: Animals; Mice; Female; Male; Mice, Inbred C57BL; Radiation Exposure; Microbiota; Metabolomics; Metabolome; Radiation, Ionizing
PubMed: 38758927
DOI: 10.1371/journal.pone.0300883 -
Frontiers in Aging 2024Various so-called dietary restriction paradigms have shown promise for extending health and life. All such paradigms rely on (hereafter ) feeding, something virtually... (Review)
Review
Various so-called dietary restriction paradigms have shown promise for extending health and life. All such paradigms rely on (hereafter ) feeding, something virtually never employed in animals whose long-term health we value, either as a control or, except for food restriction itself, for both control and treatment arms of the experiment. Even though the mechanism(s) remain only vaguely understood, compared to -fed animals a host of dietary manipulations, including calorie restriction, low protein, methionine, branched-chain amino acids, and even low isoleucine have demonstrable health benefits in laboratory species in a standard laboratory environment. The remaining challenge is to determine whether these health benefits remain in more realistic environments and how they interact with other health enhancing treatments such as exercise or emerging geroprotective drugs. Here we review the current state of the field of amino acid restriction on longevity of animal models and evaluate its translational potential.
PubMed: 38757144
DOI: 10.3389/fragi.2024.1393216 -
Phytochemistry May 2024(3R,7S)-Jasmonoyl-L-isoleucine (JA-Ile) is a plant hormone that regulates plant defense responses and other physiological functions. The mechanism of attenuation of...
(3R,7S)-Jasmonoyl-L-isoleucine (JA-Ile) is a plant hormone that regulates plant defense responses and other physiological functions. The mechanism of attenuation of JA-Ile signaling in the plant body is essential because prolonged JA-Ile signaling can be detrimental to plant survival. In Arabidopsis thaliana, the cytochrome P450 monooxygenases, CYP94B1/B3/C1, inactivate JA-Ile by converting it into 12-hydroxy-jasmonoyl-L-isoleucine (12-OH-JA-Ile), and CYP94C1 converts 12-OH-JA-Ile into 12-carboxy-jasmonoyl-L-isoleucine (12-COOH-JA-Ile). In the present study, we aimed to identify the cytochrome P450 monooxygenases involved in the catabolic pathway of JA-Ile in tomato leaves. Based on a gene expression screening of SlCYP94 subfamily monooxygenases using qPCR and the time-course of JA-Ile catabolism, we identified SlCYP94B18 and SlCYP94B19 expressed in tomato leaves as candidate monooxygenases catalyzing the two-step catabolism of JA-Ile. An in vitro enzymatic assay using a yeast expression system revealed that these enzymes efficiently converted JA-Ile to 12-OH-JA-Ile, and then to 12-COOH-JA-Ile. SlCYP94B18 and SlCYP94B19 also catalyzed the oxidative catabolism of several JA-amino acid conjugates (JA-AAs), JA-Leu and JA-Val, in tomatoes. These results suggest that SlCYP94B18 and SlCYP94B19 plays a role in the two-step oxidation of JA-AAs, suggesting their broad involvement in regulating jasmonate signaling in tomatoes. Our results contribute to a deeper understanding of jasmonate signaling in tomatoes and may help to improve tomato cultivation and quality.
PubMed: 38750708
DOI: 10.1016/j.phytochem.2024.114141 -
Gut Microbes 2024Exposing C-section infants to the maternal vaginal microbiome, coined "vaginal seeding", partially restores microbial colonization. However, whether vaginal seeding... (Randomized Controlled Trial)
Randomized Controlled Trial
Exposing C-section infants to the maternal vaginal microbiome, coined "vaginal seeding", partially restores microbial colonization. However, whether vaginal seeding decreases metabolic disease risk is unknown. Therefore, we assessed the effect of vaginal seeding of human infants on adiposity in a murine model. Germ-free mice were colonized with transitional stool from human infants who received vaginal seeding or control (placebo) seeding in a double-blind randomized trial. There was a reduction in intraabdominal adipose tissue (IAAT) volume in male mice that received stool from vaginally seeded infants compared to control infants. Higher levels of isoleucine and lower levels of nucleic acid metabolites were observed in controls and correlated with increased IAAT. This suggests that early changes in the gut microbiome and metabolome caused by vaginal seeding have a positive impact on metabolic health.
Topics: Animals; Humans; Female; Mice; Adiposity; Gastrointestinal Microbiome; Male; Vagina; Fecal Microbiota Transplantation; Feces; Double-Blind Method; Intra-Abdominal Fat; Infant; Infant, Newborn
PubMed: 38743047
DOI: 10.1080/19490976.2024.2353394 -
Molecular Therapy : the Journal of the... May 2024Altered Branched Chain Amino Acids (BCAA), including leucine, isoleucine and valine, are frequently observed in patients with advanced cancer. We evaluated the efficacy...
Altered Branched Chain Amino Acids (BCAA), including leucine, isoleucine and valine, are frequently observed in patients with advanced cancer. We evaluated the efficacy of Chimeric Antigen Receptor (CAR) T cell-mediated cancer cell lysis potential in the immune microenvironment of BCAA supplementation and deletion. BCAA supplementation increased cancer cell killing percentage, while accelerating BCAA catabolism and deceasing BCAA transporter decreased cancer cell lysis efficacy. We thus designed BCKDK engineering CAR T cells for the reprogramming of BCAA metabolism in the tumor microenvironment based on the genotype and phenotype modification. BCKDK overexpression (OE) in CAR-T cells significantly improved cancer cell lysis, while BCKDK knockout (KO) resulted in inferior lysis potential. In an in vivo experiment, BCKDK-OE CAR-T cells treatment significantly prolonged the survival of mice bearing NALM6-GL cancer cells, with the differentiation of central memory cells and the increasing proportion of CAR-T cells in peripheral circulation. BCKDK-KO CAR-T cells treatment resulted in shorter survival and decreasing percentage of CAR-T cells in peripheral circulation. In conclusion, BCKDK engineered CAR-T cells exert distinct phenotype for the superior anticancer efficiency.
PubMed: 38734897
DOI: 10.1016/j.ymthe.2024.05.017 -
Pharmacological Research May 2024In recent years several experimental observations demonstrated that the gut microbiome plays a role in regulating positively or negatively metabolic homeostasis....
In recent years several experimental observations demonstrated that the gut microbiome plays a role in regulating positively or negatively metabolic homeostasis. Indole-3-propionic acid (IPA), a Tryptophan catabolic product mainly produced by C. Sporogenes, has been recently shown to exert either favorable or unfavorable effects in the context of metabolic and cardiovascular diseases. We performed a study to delineate clinical and multiomics characteristics of human subjects characterized by low and high IPA levels. Subjects with low IPA blood levels showed insulin resistance, overweight, low-grade inflammation, and features of metabolic syndrome compared to those with high IPA. Metabolomics analysis revealed that IPA was negatively correlated with leucine, isoleucine, and valine metabolism. Transcriptomics analysis in colon tissue revealed the enrichment of several signaling, regulatory, and metabolic processes. Metagenomics revealed several OTU of ruminococcus, alistipes, blautia, butyrivibrio and akkermansia were significantly enriched in IPA group while in IPA group Escherichia-Shigella, megasphera, and Desulfovibrio genus were more abundant. Next, we tested the hypothesis that treatment with IPA in a mouse model may recapitulate the observations of human subjects, at least in part. We found that a short treatment with IPA (4 days at 20/mg/kg) improved glucose tolerance and Akt phosphorylation in the skeletal muscle level, while regulating blood BCAA levels and gene expression in colon tissue, all consistent with results observed in human subjects stratified for IPA levels. Our results suggest that treatment with IPA may be considered a potential strategy to improve insulin resistance in subjects with dysbiosis.
PubMed: 38734193
DOI: 10.1016/j.phrs.2024.107207 -
Molecules (Basel, Switzerland) Apr 2024The production of peanut oil in the industrial sector necessitates the utilization of diverse raw materials to generate consistent batches with stable flavor profiles,...
The production of peanut oil in the industrial sector necessitates the utilization of diverse raw materials to generate consistent batches with stable flavor profiles, thereby leading to an increased focus on understanding the correlation between raw materials and flavor characteristics. In this study, sensory evaluations, headspace solid-phase micro-extraction gas chromatography mass spectrometry (HS-SPME-GC-MS), odor activity value (OAV) calculations, and correlation analysis were employed to investigate the flavors and main contributing amino acids of hot-pressed oils derived from different peanut varieties. The results confirmed that the levels of alcohols, aldehydes, and heterocyclic compounds in peanut oil varied among nine different peanut varieties under identical processing conditions. The OAVs of 25 key aroma compounds, such as methylthiol, 3-ethyl-2,5-dimethylpyrazine, and 2,3-glutarone, exceeded a value of 1. The sensory evaluations and flavor content analysis demonstrated that pyrazines significantly influenced the flavor profile of the peanut oil. The concentrations of 11 amino acids showed a strong correlation with the levels of pyrazines. Notably, phenylalanine, lysine, glutamic acid, arginine, and isoleucine demonstrated significant associations with both pyrazine and nut flavors. These findings will provide valuable insights for enhancing the sensory attributes of peanut oil and selecting optimal raw peanuts for its production.
Topics: Amino Acids; Arachis; Odorants; Gas Chromatography-Mass Spectrometry; Peanut Oil; Volatile Organic Compounds; Flavoring Agents; Pyrazines; Solid Phase Microextraction; Taste; Hot Temperature
PubMed: 38731439
DOI: 10.3390/molecules29091947 -
Animals : An Open Access Journal From... Apr 2024The present study aims to determine the effect of miscellaneous meals (rapeseed meal, cottonseed meal, and sunflower meal) replacing soybean meal in feed on growth...
The present study aims to determine the effect of miscellaneous meals (rapeseed meal, cottonseed meal, and sunflower meal) replacing soybean meal in feed on growth performance, apparent digestibility of nutrients, serum biochemical parameters, serum free amino acid content, microbiota composition and SCFAs content in growing pigs (25-50 kg). A total of 72 (Duroc × Landrace × Yorkshire) growing pigs with initial weights of 25.79 ± 0.23 kg were randomly divided into three treatments. The pigs were fed corn-soybean meal (CON), corn-soybean-miscellaneous meals (CSM), and corn-miscellaneous meals (CMM). Each treatment included six replicates with four pigs per pen (n = 24, 12 barrows and 12 gilts). Soybean meal accounted for 22.10% of the basal diet in the CON group. In the CSM group, miscellaneous meals partially replaced soybean meal with a mixture of 4.50% rapeseed meal, 3.98% cottonseed meal, and 4.50% sunflower meal. In the CMM group, miscellaneous meals entirely replaced soybean meal with a mixture of 8.50% rapeseed meal, 8.62% cottonseed meal, and 8.5% sunflower. The results showed that compared with the CON, the CSM and CMM groups significantly improved the average daily gain (ADG) of growing pigs during the 25-50 kg stage ( < 0.05) but had no effects on average daily feed intake (ADFI) and average daily feed intake/average daily gain (F/G) ( > 0.05). Moreover, the CMM group significantly reduced nutrient apparent digestibility of gross energy compared with the CON group. The serum biochemical parameters results showed that the CSM group significantly improved the contents of total protein (TP) compared with the CON group ( < 0.05). The CMM group significantly improved the contents of total protein (TP), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) compared with the CON group in serum ( < 0.05). In comparison with the CON group, the CMM group also significantly improved lysine (Lys), threonine (Thr), valine (Val), isoleucine (Ile), leucine (Leu), phenylalanine (Phe), arginine (Arg), and citrulline (Cit) levels in serum ( < 0.05). However, the CMM group significantly decreased non-essential amino acid content glycine (Gly) in serum compared with CON ( < 0.05), while compared with the CON group, the CSM and CMM groups had no significant effects on the relative abundance, the alpha-diversity, or the beta-diversity of fecal microbiota. Moreover, compared with the CON group, the CSM group significantly increased butyric acid and valeric acid contents of short-chain fatty acids (SCFAs) in feces ( < 0.05). In contrast to the CON group, the CMM group significantly reduced the contents of SCFAs in feces, including acetic acid, propionic acid, and isobutyric acid ( < 0.05). Collectively, the results of the present study indicate that miscellaneous meals (rapeseed meal, cottonseed meal, and sunflower meal) can partially replace the soybean meal and significantly improve the growth performance of growing pigs during the 25-50 kg stage. Thus, miscellaneous meals are a suitable protein source as basal diets to replace soybean meals for 25-50 kg growing pigs. These results can be helpful to further develop miscellaneous meals as a functional alternative feed ingredient to soybean meal.
PubMed: 38731358
DOI: 10.3390/ani14091354 -
Journal of Thrombosis and Haemostasis :... May 2024Direct oral factor Xa inhibitors are widely used as alternatives to conventional vitamin K antagonists in managing venous thromboembolism and nonvalvular atrial...
BACKGROUND
Direct oral factor Xa inhibitors are widely used as alternatives to conventional vitamin K antagonists in managing venous thromboembolism and nonvalvular atrial fibrillation. Unfortunately, bleeding-related adverse events remain a major concern in clinical practice. In case of bleeding or emergency surgery, rapid-onset reversal agents may be required to counteract the anticoagulant activity.
OBJECTIVES
The ability of factor Xa variants to bypass the direct oral factor Xa inhibitors was assessed.
METHODS
Human factor Xa variants were generated through substitution of phenylalanine 174 (F174) for either alanine, isoleucine, or serine. Factor Xa variants were stably expressed in HEK293 cells and purified to homogeneity using ion-exchange chromatography.
RESULTS
F174-substituted human factor X variants demonstrated efficacy in restoring thrombin generation in plasma containing direct factor Xa inhibitors (apixaban, rivaroxaban, edoxaban). Their ability to bypass the anticoagulant effects stems from a significant reduced sensitivity for the direct factor Xa inhibitors, due to a decrease in binding affinity determined using molecular dynamics simulations and free energy computation. Furthermore, F174 modification resulted in a partial loss of inhibition by tissue factor pathway inhibitor, enhancing the procoagulant effect of F174-substituted factor X. Consequently, the F174A- and F174S-substituted factor X variants effectively counteracted the effects of two widely used anticoagulants, apixaban and rivaxoraban, in plasma of atrial fibrillation and venous thromboembolism patients.
CONCLUSIONS
These human factor X variants have the potential to serve as a rescue reversal strategy to overcome the effect of direct factor Xa inhibitors in case of life-threatening bleeding events or emergency surgical interventions.
PubMed: 38729577
DOI: 10.1016/j.jtha.2024.04.022 -
Food Science & Nutrition May 2024Amino acid-related disorders are caused by a defect in the metabolic pathways of amino acid groups. These patients must follow a lifelong protein diet. The objective of...
Amino acid-related disorders are caused by a defect in the metabolic pathways of amino acid groups. These patients must follow a lifelong protein diet. The objective of this study was to produce a low-protein cocoa powder (LPP) with enzymatic hydrolysis and precipitation method. First, the solubility of cocoa powder was increased by heat and enzyme treatments (Amylase, Viscozyme, and Alcalase). Then, the protein level was decreased by isoelectric precipitation. According to the obtained results, the solubility of cocoa powder rose from 28.61% to 50.69%. Protein content decreased by almost 40% and significant reductions in the amino acid profile were also provided; the highest ones were detected in methionine (100%), lysine (73.65%), leucine (53.64%), alanine (46.17%), and isoleucine (44.73%) levels. LPP had high phenolic content (25.10 mg/g GAE) and the changes in the antioxidant activities were not significant ( > .05). Moreover, chocolate production with LPP and control powder was also carried out under laboratory conditions. Hardness (1732.52 g), moisture content (0.60%), and water activity (0.37) of chocolate samples produced with low-protein cocoa powder (LPC) were lower than those of the control sample. The Casson model well fitted to the rheological data ( > .990) and chocolate samples showed elastic behavior. The removal of proteins from the cocoa was verified with Fourier transform infrared spectroscopy analyses. The melting temperatures of chocolates (31.84 and 31.54°C for control and LPC samples, respectively) did not change with the applied process. As a conclusion, it was revealed that the production of low-protein cocoa powder and chocolate is feasible for patients with amino acid disorders with this study.
PubMed: 38726434
DOI: 10.1002/fsn3.3997