PubMed

Redox Biol. 2024 Dec 16;79:103464. doi: 10.1016/j.redox.2024.103464. Online ahead of print.ABSTRACTNon-communicable chronic diseases (NCDs) are most commonly characterized by age-related loss of homeostasis and/or by cumulative exposures to environmental factors, which lead to low-grade sustained generation of reactive oxygen species (ROS), chronic inflammation and metabolic imbalance. Nuclear factor erythroid 2-like 2 (NRF2) is a basic leucine-zipper transcription factor that regulates the cellular redox homeostasis. NRF2 controls the expression of more than 250 human genes that share in their regulatory regions a cis-acting enhancer termed the antioxidant response element (ARE). The products of these genes participate in numerous functions including biotransformation and redox homeostasis, lipid and iron metabolism, inflammation, proteostasis, as well as mitochondrial dynamics and energetics. Thus, it is possible that a single pharmacological NRF2 modulator might mitigate the effect of the main hallmarks of NCDs, including oxidative, proteostatic, inflammatory and/or metabolic stress. Research on model organisms has provided tremendous knowledge of the molecular mechanisms by which NRF2 affects NCDs pathogenesis. This review is a comprehensive summary of the most commonly used model organisms of NCDs in which NRF2 has been genetically or pharmacologically modulated, paving the way for drug development to combat NCDs. We discuss the validity and use of these models and identify future challenges.PMID:39709790 | DOI:10.1016/j.redox.2024.103464

Forensic Sci Int. 2024 Dec 17;367:112350. doi: 10.1016/j.forsciint.2024.112350. Online ahead of print.ABSTRACTAccurate detection of cyanide exposure is crucial, particularly in forensic science. However, cyanide's high volatility and potential biochemical conversions in biological samples pose challenges for direct detection, complicating the determination of cause of death. Identifying alternative cyanide metabolites as markers may mitigate false negatives and positives, extending the detection window in poisoning cases. This study aimed to evaluate metabolic changes induced by cyanide exposure in forensic cases using a multi-platform approach, including metabolomics and lipidomics analyses via liquid and gas chromatography coupled with high-resolution mass spectrometry. Results demonstrated clear discrimination between cyanide-exposed and control groups through OPLS-DA models. A total of 92 altered metabolites were identified in cyanide-exposed individuals compared to controls. Significant changes in metabolites primarily included glycerophospholipids (30.7 %), glycerolipids (14 %), fatty acyls (12.9 %), sphingolipids (8.0 %), amino acids and analogs (8.0 %), among others. Cyanide intoxication disrupted multiple metabolic pathways, including mitochondrial β-oxidation, acylcarnitine accumulation, a shift towards gluconeogenesis in amino acid metabolism, and ammonia homeostasis disturbance, affecting both ammonia recycling and the urea cycle. These pathways are essential for cellular energy production. The altered metabolic profiles provide insight into cyanide poisoning pathways, potentially aiding the development of new forensic diagnostic strategies. The area under the receiver operating characteristic curve was used to assess each model's predictive value. Findings suggest that metabolites such as phosphate and 3-hydroxybutyric acid could serve as diagnostic biomarkers in lethal cyanide poisoning cases. Future studies must evaluate these potential biomarkers' effectiveness in different fatal victim cohorts and validate the suggested panel through a targeted approach.PMID:39709742 | DOI:10.1016/j.forsciint.2024.112350

Ecotoxicol Environ Saf. 2024 Dec 21;290:117585. doi: 10.1016/j.ecoenv.2024.117585. Online ahead of print.ABSTRACTCadmium and microplastics, common pollutants, can accumulate in the body, impacting the intestinal barrier and harming livestock breeding. In order to explore the damage mechanism of cadmium and cadmium combined microplastic on the colon of mice, 60 mice were divided into three groups: The control group (0.2 mL of saline), cadmium group (Cd group, 0.2 mL of 4.8 mg/kg/d CdCl2) and mixed group (Mix group, 0.2 mL of mixed solution containing 4.8 mg/kg/d CdCl2 and 10.0 mg/d MPs) were fed for 42 d. The changes of colon histopathology were observed, and the changes of microbial diversity and metabolomics of colon contents were analyzed. Pathological sections of the colon showed abnormal mucosal hyperemia with mixed exposure compared to cadmium exposure. Microbial diversity analysis showed increased abundances of Enterococcus, Adlercreutzia, and Bifidobacterium in the Cd and Mix groups, with Dubosiella being the most significantly increased. Metabolomic analysis indicated significant differences in nucleotide and purine metabolism between the Cd and control groups, and in linoleic acid and bile acid metabolism between the Mix and control groups. The ABC transporter metabolites increased with Cd exposure, while the PPAR pathway metabolites were enriched with MPs exposure. Correlation analysis highlighted several key findings: Pasteurella exhibited a notably negative association with pantothenate. Conversely, Enterococcus demonstrated a significant positive link with palmitoylcarnitine. Additionally, both Adlercreutzia and norank_f_Eggerthellaceae showed a positive correlation with azelaic acid. These findings suggest that Cd and MPs disrupt intestinal microbiota and metabolic pathways, providing insights into potential treatments for such exposures.PMID:39709704 | DOI:10.1016/j.ecoenv.2024.117585

Mol Biol (Mosk). 2024 Jul-Aug;58(4):638-654.ABSTRACTObesity is associated with changes in the gut microbiota, as well as with increased permeability of the intestinal wall. In 130 non-obese volunteers, 57 patients with metabolically healthy obesity (MHO), and 76 patients with metabolically unhealthy obesity (MUHO), bacterial DNA was isolated from stool samples, and the 16S rRNA gene was sequenced. The metabolic profile of the microbiota predicted by PICRUSt2 (https://huttenhower.sph.harvard.edu/picrust/) was more altered in patients with MUHO than MHO. Obesity, especially MUHO, was accompanied by an increase in the ability of the gut microbiota to degrade energy substrates, produce energy through oxidative phosphorylation, synthesize water-soluble vitamins (B1, B6, B7), nucleotides, heme, aromatic amino acids, and protective structural components of cells. Such changes may be a consequence of the microbiota adaptation to the MUHO-specific conditions. Thus, a vicious circle is formed, when MUHO promotes the depletion of the gut microbiome, and further degeneration of the latter contributes to the pathogenesis of metabolic disorders. The concentration of the trefoil factor family (TFF) in the serum of the participants was also determined. In MHO and MUHO patients, the TFF2 and TFF3 levels were increased, but we did not find significant associations of these changes with the metabolic profile of the gut microbiota.PMID:39709568

Gut Microbes. 2025 Dec;17(1):2441356. doi: 10.1080/19490976.2024.2441356. Epub 2024 Dec 22.ABSTRACTThe gut microbiota is a crucial link between diet and cardiovascular disease (CVD). Using fecal metaproteomics, a method that concurrently captures human gut and microbiome proteins, we determined the crosstalk between gut microbiome, diet, gut health, and CVD. Traditional CVD risk factors (age, BMI, sex, blood pressure) explained < 10% of the proteome variance. However, unsupervised human protein-based clustering analysis revealed two distinct CVD risk clusters (low-risk and high-risk) with different blood pressure (by 9 mmHg) and sex-dependent dietary potassium and fiber intake. In the human proteome, the low-risk group had lower angiotensin-converting enzymes, inflammatory proteins associated with neutrophil extracellular trap formation and auto-immune diseases. In the microbial proteome, the low-risk group had higher expression of phosphate acetyltransferase that produces SCFAs, particularly in fiber-fermenting bacteria. This model identified severity across phenotypes in heart failure patients and long-term risk of cardiovascular events in a large population-based cohort. These findings underscore multifactorial gut-to-host mechanisms that may underlie risk factors for CVD.PMID:39709554 | DOI:10.1080/19490976.2024.2441356

BMC Plant Biol. 2024 Dec 21;24(1):1225. doi: 10.1186/s12870-024-05961-1.ABSTRACTPerennial ryegrass (Lolium perenne) is a widely cultivated forage and turf grass species. Salt stress can severely damage the growth of grass plants. The genome-wide molecular mechanisms of salt tolerance have not been well understood in perennial grass species. In this study, the salt sensitive genotype P1 (PI265351, Chile) and the salt tolerant genotype P2 (PI368892, Algeria) of perennial ryegrass were subjected to 200 mM NaCl, and transcriptomics and metabolomics analyses were performed. A total of 5,728 differentially expressed genes (DEGs) were identified through pairwise comparisons. Antioxidant enzyme encoding genes (LpSOD1, LpCAT1), ion channel gene LpCaC1 and transcription factors (LpERFs, LpHSF1 and LpMYB1) were significantly upregulated in P2, suggesting their involvement in regulating expression of salt-responsive genes for salt tolerance. Functional analysis of DEGs revealed that biosynthesis of secondary metabolites, carbohydrate metabolism and signal transduction were the main pathways in response to salt stress. Weighted gene co-expression network analysis (WGCNA) based on RNA-Seq data showed that membrane transport and ABC transporters were significantly correlated with salt tolerance-related traits. The combined transcriptomics and metabolomics analysis demonstrated that the phenylpropanoid biosynthesis pathway was a major secondary metabolic pathway in the salt response of perennial ryegrass. Especially, the tolerant genotype P2 had greater amounts of upregulated phenylpropanoids, flavonoids and anthocyanins and higher expressions of relevant genes in the pathway than the sensitive genotype P1, indicating a role of phenylpropanoid biosynthesis for perennial ryegrass to adapt to salt stress. The results provided insights into the molecular mechanisms of perennial ryegrass adaptation to salinity and laid a base for genetic improvement of salt tolerance in perennial grass species.PMID:39709354 | DOI:10.1186/s12870-024-05961-1

BMC Plant Biol. 2024 Dec 21;24(1):1229. doi: 10.1186/s12870-024-05994-6.ABSTRACTBACKGROUND: Deep sowing has emerged as a vital agricultural strategy, particularly in arid and semi-arid regions, as it allows seeds to access water stored in deeper soil layers. This approach facilitates successful germination and establishment of crops, even in challenging environmental conditions. Previous studies have shown that the length of the maize mesocotyl is an important trait influencing deep-sowing tolerance. Several factors play a crucial role in regulating mesocotyl elongation, primarily including light, hormones, metabolites, and reactive oxygen species (ROS). Therefore, further understanding the regulatory mechanisms of mesocotyl elongation is essential for enhancing maize germination and growth under deep sowing conditions.RESULTS: In this study, we identified a deep sowing-tolerant inbred line, DH65232, which showed significantly increased mesocotyl length compared to B73 under deep sowing conditions. Transcriptome analysis revealed that differentially expressed genes in the mesocotyl of the two inbred lines were mainly enriched in three pathways: hormone regulation, intermediate metabolites, and redox enzymes. Measurements of hormone content and phenotypic analysis following GA3 treatment indicated that GA3 plays a positive role in promoting mesocotyl elongation under deep-sowing stress in the inbred line DH65232. Additionally, untargeted metabolomics revealed that DH65232 exhibited a higher number of differential metabolites related to antioxidant pathway under deep-sowing stress compared to normal sowing. In deep sowing conditions, the determination of POD, CAT, SOD activities, and MDA content in the mesocotyl of B73 and DH65232 shows that DH65232 has a stronger ability to scavenge ROS.CONCLUSIONS: Above all, the inbred line DH65232 exhibits a greater tolerance to deep sowing due to its stronger antioxidant activity. Our study has contributed to a deeper understanding of the complex tolerance mechanisms in maize and provided new insights for the development of new maize varieties under deep sowing conditions.PMID:39709339 | DOI:10.1186/s12870-024-05994-6

Trends Biochem Sci. 2024 Dec 20:S0968-0004(24)00273-1. doi: 10.1016/j.tibs.2024.12.001. Online ahead of print.ABSTRACTThe Crabtree effect in yeast, where cells prefer fermentation over respiration in high -glucose environments, is associated with mitochondrial repression, but the molecular mechanisms were previously unclear. Recently, Vengayil et al. revealed that knocking out the ubp3 gene, encoding a deubiquitinase enzyme, mitigates the Crabtree effect by increasing mitochondrial phosphate levels.PMID:39709253 | DOI:10.1016/j.tibs.2024.12.001

Best Pract Res Clin Gastroenterol. 2024 Dec;73:101957. doi: 10.1016/j.bpg.2024.101957. Epub 2024 Nov 14.ABSTRACTAcute liver failure (ALF) is a rare and dynamic syndrome occurring as a sequela of severe acute liver injury (ALI). Its mortality ranges from 50% to 75% based on the aetiology, patients age and severity of encephalopathy at admission. With improvement in intensive care techniques, transplant-free survival in ALF has improved over time. Timely recognition of patients who are unlikely to survive with medical intervention alone is crucial since these individuals may rapidly develop multiorgan failure and render liver transplantation futile. Various predictive models, biomarkers and AI-based models are currently used in clinical practice, each with its fallacies. The King's College Hospital criteria (KCH) were initially established in 1989 to identify patients with acute liver failure (ALF) caused by paracetamol overdose or other causes who are unlikely to improve with conventional treatment and would benefit from a liver transplant. Since then, various models have been developed and validated worldwide. Most models include age, aetiology of liver disease, encephalopathy grade, and liver injury markers like INR, lactate, factor V level, factor VIII/V ratio and serum bilirubin. But none of the currently available models are dynamic and lack accuracy in predicting transplant free survival. There is an increasing interest in developing prognostic serum biomarkers that when used alone or in combination with clinical models enhance the accuracy of predicting outcomes in ALF. Genomics, transcriptomics, proteomics, and metabolomics as well as machine learning and artificial intelligence (AI) algorithms are areas of interest for developing higher-precision predictive models. Overall, the future of prognostic models in ALF is promising, with ongoing research paving the way for more accurate, personalized, and dynamic risk assessment tools that can potentially save lives in this challenging condition. This article summarizes the history of prognostic models in ALF and future trends.PMID:39709212 | DOI:10.1016/j.bpg.2024.101957

Prev Med. 2024 Dec 19:108211. doi: 10.1016/j.ypmed.2024.108211. Online ahead of print.ABSTRACTOBJECTIVE: Physical activity has protective effects on cardiometabolic diseases (CMDs), but the role of metabolism related to physical activity in this process is unclear.METHODS: In the prospective cohort study from UK Biobank between 2006 and 2022, participants free of CMDs at baseline were included (n = 73,990). We identified physical activity-related metabolites and constructed metabolic signature using linear regression and elastic net regression. Association between physical activity, metabolic signature, and CMDs (type 2 diabetes [T2D], coronary heart disease [CHD], and stroke) were explored using Cox and mediation analyses. Interactions between the metabolic signature and genetic susceptibility (categorized into "low" and "high" based on the median of polygenic risk scores) were assessed by additive hazard models and relative excess risk due to interaction (RERI). Multi-state models evaluated the association between metabolic signature and disease progression.RESULTS: We found 58 metabolites were related to physical activity, of which 17 were used to construct metabolic signature. The metabolic signature was associated with reduced risk of T2D (HR = 0.13[0.10-0.16]), CHD (HR = 0.40[0.34-0.47]), and stroke (HR = 0.67[0.53-0.86]), and mediated 40.56 % of the association between physical activity and T2D. The metabolic signature exhibited additive interactions with genetic risk for T2D (RERI = 1.57[1.09-2.05]) and CHD (RERI = 0.27[0.05-0.49]). Finally, the metabolic signature was associated with a reduced risk of transition from CMD to CMM (HR = 0.58[0.42-0.81]).CONCLUSION: Physical activity-related metabolic signature is linked to reduced risks of CMDs and CMM. We once again emphasize the importance of physical activity for CMDs prevention from a metabolic perspective, especially for individuals at high genetic risk.PMID:39708996 | DOI:10.1016/j.ypmed.2024.108211

Biotechnol Adv. 2024 Dec 19:108506. doi: 10.1016/j.biotechadv.2024.108506. Online ahead of print.ABSTRACTGene therapy is poised to transition from niche to mainstream medicine, with recombinant adeno-associated virus (rAAV) as the vector of choice. However, robust, scalable, industrialized production is required to meet demand and provide affordable patient access, which has not yet materialized. Closing the chasm between demand and supply requires innovation in biomanufacturing to achieve the essential step change in rAAV product yield and quality. Omics provides a rich source of mechanistic knowledge that can be applied to HEK293, the most commonly used cell line for rAAV production. In this review, the findings from a growing number of diverse studies that apply genomics, epigenomics, transcriptomics, proteomics, and metabolomics to HEK293 bioproduction are explored. Learnings from CHO-Omics, application of omics approaches to improve CHO bioproduction, provide a framework to explore the potential of "HEK-Omics" as a multi-omics-informed approach providing actionable mechanistic insights for improved transient and stable production of rAAV and other recombinant products in HEK293.PMID:39708987 | DOI:10.1016/j.biotechadv.2024.108506

Microb Pathog. 2024 Dec 19:107246. doi: 10.1016/j.micpath.2024.107246. Online ahead of print.ABSTRACTSepsis remains a life-threatening condition with high mortality rates despite current therapeutic approaches. While Huang-Lian-Jie-Du Decoction (HLJDD), a traditional Chinese medicine formula, has been historically used to treat inflammatory conditions, its therapeutic potential in sepsis and underlying mechanisms remain unexplored. This study investigated HLJDD's comprehensive effects on sepsis pathophysiology using a rat cecal ligation and puncture (CLP) model. HLJDD significantly improved survival rates and demonstrated sophisticated immunomodulatory effects through temporal regulation of the biphasic immune response characteristic of sepsis. In early sepsis, HLJDD suppressed pro-inflammatory cytokines (IL-1β, IL-6) while maintaining defensive inflammation. During late sepsis, it counteracted immunosuppression by reducing IL-10 levels and CD4+CD25+ T cell populations while protecting CD4+ and CD8+ T cells from apoptosis. Notably, HLJDD demonstrated dynamic regulation of the gut microbiota-metabolite axis. It enhanced beneficial bacterial populations (Firmicutes, Lactobacillus) while suppressing potentially pathogenic species (Bacteroides, Parabacteroides). Metabolomic analysis revealed time-dependent modulation of short-chain fatty acids, with elevated levels at 12 h followed by strategic reduction at 18-30 h, coordinating with changes in SCFA-producing bacteria. This temporal metabolic regulation corresponded with improved intestinal barrier function and balanced immune responses. The study unveils HLJDD's novel mechanism of action through synchronized modulation of immune responses, gut microbiota, and metabolite profiles, presenting a multi-target therapeutic approach that addresses the complex pathophysiology of sepsis. These findings provide a strong foundation for further clinical investigation of HLJDD as an innovative treatment strategy for sepsis.PMID:39708977 | DOI:10.1016/j.micpath.2024.107246

J Ethnopharmacol. 2024 Dec 19:119271. doi: 10.1016/j.jep.2024.119271. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Tinospora crispa (L.) Hook.f. & Thomson (T. crispa), is widely distributed in Xishuangbanna, Yunnan Province, China. According to the "Selected Medicinal Plants of Yunnan", T. crispa is recognized for its versatile medicinal properties, including promoting diuresis, reducing swelling, relieving pain, relaxing tendons, and promoting blood circulation, suggesting that their extracts can be used to exhibit a range of beneficial activities such as immune regulation, blood sugar reduction, and anti-inflammatory effects. In the Dai ethnic areas of China, T. crispa is commonly employed in the herbal prescription of treatment of hyperuricemia and gouty arthritis. However, further study is needed to enucleate the potential pharmacological mechanism of T. crispa.AIM OF THE STUDY: This study aimed to investigate the effects and mechanisms of T. crispa vines extract (TC) in alleviating hyperuricemia.MATERIALS AND METHODS: A hyperuricemia mouse model was established through intraperitoneal injection of potassium oxonate to evaluate the hypouricemic effects of TC. To explore the underlying mechanisms of TC, network pharmacology analysis was employed. Additionally, a series of experimental approaches-including serum biomarker assays, ELISA, reverse transcription-quantitative PCR (RT-qPCR), histopathological staining, metabolomics analysis and western blotting-were performed to assess the capability of TC in modulating uric acid levels.RESULTS: TC treatment markedly lowered serum biomarkers by inhibiting xanthine oxidase (XOD) activity and modulating the expression of urate transporters, while also alleviating renal injury in hyperuricemic mice. Through bioinformatics and network pharmacology analyses, the NOD-like receptor signaling pathway was identified as a critical mechanism underlying the therapeutic impact of TC. Metabolomics analysis uncovered 14 differential metabolites and seven metabolic pathways linked to the anti-hyperuricemic action of TC. Further experimental validation confirmed that TC attenuated renal inflammation and suppressed activation of the NLRP3/caspase-1/IL-1β signaling pathway.CONCLUSION: Our findings demonstrate that TC exerts a significant uric acid-lowering effect in hyperuricemic mice. This therapeutic effect can be attributed to the suppression of uric acid synthesis and the modulation of urate transporters. Moreover, the inhibition of the NLRP3/caspase-1/IL-1β signaling pathway further contributes to the regulatory action of TC on uric acid homeostasis.PMID:39708936 | DOI:10.1016/j.jep.2024.119271

Mol Cell Proteomics. 2024 Dec 19:100897. doi: 10.1016/j.mcpro.2024.100897. Online ahead of print.ABSTRACTHistone post-translational modifications (PTMs) regulate gene expression patterns through epigenetic mechanisms. The 5 histone proteins (H1, H2A, H2B, H3, and H4) are extensively modified, with over 75 distinct modification types spanning more than 200 sites. Despite strong advances in mass spectrometry-based approaches, identification and quantification of modified histone peptides remains challenging due to factors such as isobaric peptides, pseudo-isobaric PTMs, and low stoichiometry of certain marks. Here we describe the development of a new high-throughput method to identify and quantify over 150 modified histone peptides by liquid chromatography-mass spectrometry (LC-MS). Fast gradient microflow liquid chromatography and variable window SWATH data-independent acquisition on a new quadrupole time-of-flight platform is compared to a previous method using nanoflow LC-MS on an Orbitrap hybrid. Histones extracted from cells treated with either a histone deacetylase inhibitor (HDACi) or TGF-beta 1 were analyzed by data-independent acquisition (DIA) on two mass spectrometers: an Orbitrap Exploris 240 with a 55-minute nanoflow LC gradient, and the SCIEX ZenoTOF 7600 with a 10-minute microflow gradient. To demonstrate the reproducibility and speed advantage of the method, 100 consecutive injections of one sample were performed in less than 2 days on the QTOF platform. The result is the comprehensive characterization of histone PTMs achieved in less than 20 minutes of total run time using only 200 ng of sample. Results for drug-treated histone samples are comparable to those produced by the previous method and can be achieved using less than one-third of the instrument time.PMID:39708910 | DOI:10.1016/j.mcpro.2024.100897

Int J Biol Macromol. 2024 Dec 19:138833. doi: 10.1016/j.ijbiomac.2024.138833. Online ahead of print.ABSTRACTFresh-cut fruit, with nutrition and convenience, has a broad market demand. However, its shelf life is shortened due to its tissue damage. Therefore, the development of cost-effective and eco-friendly multifunctional packaging materials to extend the shelf life of fresh-cut fruits is urgently needed. A cornstarch-based film (CS film) was successfully prepared using V-type corn starch as an ethylene scavenger and kiwifruit peel extract (KPE) as an antioxidant. The film containing 4.00 % (v/v) KPE had a DPPH radical scavenging capability of 52.1 % ± 2.4 % and ABTS radical scavenging capability of 70.4 % ± 4.4 %. The amount of ethylene harvested was 17.27 cm3 g-1. In addition, the malondialdehyde content of fresh-cut kiwifruits covered by CS film decreased by 42.82 % compared with PE film after 72 h, and the hardness increased 71.20 %. And the CS film could regulate ethylene and oxygen concentration, and extending the fresh life of kiwifruit from 3 days to 15 days. Metabolomics and transcriptomic analyses revealed that the CS film regulated ethylene self-promotion and the balance of reactive oxygen species metabolism. As a result, these reduced sugar synthesis and metabolism, which helped to maintain the freshness of fresh-cut kiwifruit. These findings can serve as a reference for developing techniques to preserve the packaging of fresh-cut fruits.PMID:39708893 | DOI:10.1016/j.ijbiomac.2024.138833

Cell Rep Med. 2024 Dec 11:101878. doi: 10.1016/j.xcrm.2024.101878. Online ahead of print.ABSTRACTMalignant rhabdoid tumor (MRT) is one of the most aggressive childhood cancers for which no effective treatment options are available. Reprogramming of cellular metabolism is an important hallmark of cancer, with various metabolism-based drugs being approved as a cancer treatment. In this study, we use patient-derived tumor organoids (tumoroids) to map the metabolic landscape of several pediatric cancers. Combining gene expression analyses and metabolite profiling using mass spectrometry, we find nucleotide biosynthesis to be a particular vulnerability of MRT. Treatment of MRT tumoroids with de novo nucleotide synthesis inhibitors methotrexate (MTX) and BAY-2402234 lowers nucleotide levels in MRT tumoroids and induces apoptosis. Lastly, we demonstrate in vivo efficacy of MTX in MRT patient-derived xenograft (PDX) mouse models. Our study reveals nucleotide biosynthesis as an MRT-specific metabolic vulnerability, which can ultimately lead to better treatment options for children suffering from this lethal pediatric malignancy.PMID:39708810 | DOI:10.1016/j.xcrm.2024.101878

Cell Stem Cell. 2024 Dec 12:S1934-5909(24)00413-2. doi: 10.1016/j.stem.2024.11.014. Online ahead of print.ABSTRACTFatty acid oxidation is of uncertain importance in most stem cells. We show by 14C-palmitate tracing and metabolomic analysis that hematopoietic stem/progenitor cells (HSPCs) engage in long-chain fatty acid oxidation that depends upon carnitine palmitoyltransferase 1a (CPT1a) and hydroxyacyl-CoA dehydrogenase (HADHA) enzymes. CPT1a or HADHA deficiency had little or no effect on HSPCs or hematopoiesis in young adult mice. Young HSPCs had the plasticity to oxidize other substrates, including glutamine, and compensated for loss of fatty acid oxidation by decreasing pyruvate dehydrogenase phosphorylation, which should increase function. This metabolic plasticity declined as mice aged, when CPT1a or HADHA deficiency altered hematopoiesis and impaired hematopoietic stem cell (HSC) function upon serial transplantation. A high-fat diet increased fatty acid oxidation and reduced HSC function. This was rescued by CPT1a or HADHA deficiency, demonstrating that increased fatty acid oxidation can undermine HSC function. Long-chain fatty acid oxidation is thus dispensable in young HSCs but necessary during aging and deleterious with a high-fat diet.PMID:39708796 | DOI:10.1016/j.stem.2024.11.014

Plant Physiol Biochem. 2024 Nov 27;219:109355. doi: 10.1016/j.plaphy.2024.109355. Online ahead of print.ABSTRACTFlowers belonging to the Iris genus, with a predominant display of blue hues, showcase a variety of blue polymorphisms across different species. This study focused on analyzing the L∗, a∗, and b∗ color values of Iris typhifolia, I. lactea, I. laevigata, and I. sanguinea. Notably, I. lactea exhibited the highest L∗ value, indicating a brighter hue, while I. typhifolia and I. laevigata displayed larger a∗ values, suggesting a shift towards a reddish tone. I. sanguinea, conversely, presented the most profound blue with the lowest b∗ value. Our research delved into understanding the influence of anthocyanin components on these color variations and explored the regulatory role of the dihydroflavonol-4-reductase (DFR) gene. The findings underscore delphinidin as the primary blue pigment, with the additional presence of petunidin in I. typhifolia and I. laevigata introducing a purplish-red hue. Flavonoids were identified as contributors to enhancing the brightness of I. lactea's color. The study elucidates that blue polymorphism predominantly arises from varying proportions of delphinidin pigments, closely linked to substrate selection by Asp type DFRs. Following the expression of different DFR genes from the two blue Iris species, significant substrate selection differences were observed. These findings lay a foundation for future efforts to enhance flower colors in Irises and other related species by offering DFR as a target candidate gene.PMID:39708701 | DOI:10.1016/j.plaphy.2024.109355

J Environ Manage. 2024 Dec 20;373:123795. doi: 10.1016/j.jenvman.2024.123795. Online ahead of print.ABSTRACTAnaerobic digestion of food waste is increasingly utilized for bioenergy generation, producing a byproduct known as food waste digestate (FWD), which has potential applications as a fertilizer within the circular economy. However, accumulating numerous pollutants in FWD poses significant challenges to environmental management and human health. The complex nature of these pollutants complicates both targeted and non-targeted chemical analyses, making safety evaluations difficult. To address this, we developed a toxicity evaluation protocol based on comprehensive cellular effects to assess the safety profile of FWD. Our study found that human FHC cells were significantly more sensitive to FWD solutions, with 1.2-, 1.8-, and 1.7-fold greater sensitivity than GES-1, HepG2, and HEK293 cells. We identified oxidative stress levels and the activation of the NF-κB signaling pathway as crucial and sensitive indicators of FWD-induced toxicity. Metabolomics analysis revealed that FWD triggered the activation of the inflammatory mediator regulation of the transient receptor potential channels pathway, indicating a cellular response aimed at mitigating damage through immune repair mechanisms. By comprehensively assessing these cellular and molecular indicators, we can better predict the potential human and environmental risks associated with FWD. This knowledge is essential for establishing safety guidelines and appropriate dilution ratios for FWD reutilization, enhancing environmental management practices within a circular economy framework.PMID:39708690 | DOI:10.1016/j.jenvman.2024.123795

Food Chem. 2024 Dec 18;469:142565. doi: 10.1016/j.foodchem.2024.142565. Online ahead of print.ABSTRACTBesides aroma, the tastes of Pixian Broad Bean Paste (PBBP) are also important, however, they have not yet been thoroughly elucidated. Therefore, this study employed sensory and untargeted metabolomics approaches to investigate taste characteristics, molecular basis and their metabolic pathways of PBBP from three different manufacturers and two grades. Results showed PBBP was predominantly characterized by strong sour, umami and salty tastes, and significant differences were observed in samples from different manufacturers and grades (p < 0.05), especially higher sourness, saltiness and umami in premium PBBP. Based on non-volatiles, 55 key differential metabolites were identified through orthogonal partial least square discriminant analysis (OPLS-DA, P value<0.05, VIP value>1.0) and Pearson correlation analysis (|ρ| > 0.7). These key differential metabolites responsible for taste differences were metabolized by 36 crucial KEGG pathways (P value<0.05, impact value>0.05). These results could expand our understandings of PBBP taste compounds and their metabolisms, and provide theoretical evidences for further quality improvement.PMID:39708645 | DOI:10.1016/j.foodchem.2024.142565