PubMed

J Physiol Biochem. 2023 Nov 24. doi: 10.1007/s13105-023-00998-6. Online ahead of print.ABSTRACTNonalcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world. New non-invasive diagnostic tools are needed to promptly treat this disease and avoid its complications. This study aimed to find key metabolites and related variables that could be used to predict and diagnose NAFLD. Ninety-eight subjects with NAFLD and 45 controls from the Fatty Liver in Obesity (FLiO) Study (NCT03183193) were analyzed. NAFLD was diagnosed and graded by ultrasound and classified into two groups: 0 (controls) and ≥ 1 (NAFLD). Hepatic status was additionally assessed through magnetic resonance imaging (MRI), elastography, and determination of transaminases. Anthropometry, body composition (DXA), biochemical parameters, and lifestyle factors were evaluated as well. Non-targeted metabolomics of serum was performed with high-performance liquid chromatography coupled to time-of-flight mass spectrometry (HPLC-TOF-MS). Isoliquiritigenin (ISO) had the strongest association with NAFLD out of the determinant metabolites. Individuals with higher concentrations of ISO had healthier metabolic and hepatic status and were less likely to have NAFLD (OR 0.13). Receiver operating characteristic (ROC) curves demonstrated the predictive power of ISO in panel combination with other NAFLD and IR-related variables, such as visceral adipose tissue (VAT) (AUROC 0.972), adiponectin (AUROC 0.917), plasmatic glucose (AUROC 0.817), and CK18-M30 (AUROC 0.810). Individuals with lower levels of ISO have from 71 to 82% more risk of presenting NAFLD compared to individuals with higher levels. Metabolites such as ISO, in combination with visceral adipose tissue, IR, and related markers, constitute a potential non-invasive tool to predict and diagnose NAFLD.PMID:37996653 | DOI:10.1007/s13105-023-00998-6

Sci Rep. 2023 Nov 23;13(1):20613. doi: 10.1038/s41598-023-47456-3.ABSTRACTCrop plants and undomesticated resilient species employ different strategies to regulate their energy resources and growth. Most crop species are sensitive to stress and prioritise rapid growth to maximise yield or biomass production. In contrast, resilient plants grow slowly, are small, and allocate their resources for survival in challenging environments. One small group of plants, termed resurrection plants, survive desiccation of their vegetative tissue and regain full metabolic activity upon watering. However, the precise molecular mechanisms underlying this extreme tolerance remain unknown. In this study, we employed a transcriptomics and metabolomics approach, to investigate the mechanisms of desiccation tolerance in Tripogon loliiformis, a modified desiccation-tolerant plant, that survives gradual but not rapid drying. We show that T. loliiformis can survive rapid desiccation if it is gradually dried to 60% relative water content (RWC). Furthermore, the gene expression data showed that T. loliiformis is genetically predisposed for desiccation in the hydrated state, as evidenced by the accumulation of MYB, NAC, bZIP, WRKY transcription factors along with the phytohormones, abscisic acid, salicylic acid, amino acids (e.g., proline) and TCA cycle sugars during initial drying. Through network analysis of co-expressed genes, we observed differential responses to desiccation between T. loliiformis shoots and roots. Dehydrating shoots displayed global transcriptional changes across broad functional categories, although no enrichment was observed during drying. In contrast, dehydrating roots showed distinct network changes with the most significant differences occurring at 40% RWC. The cumulative effects of the early stress responses may indicate the minimum requirements of desiccation tolerance and enable T. loliiformis to survive rapid drying. These findings potentially hold promise for identifying biotechnological solutions aimed at developing drought-tolerant crops without growth and yield penalties.PMID:37996547 | DOI:10.1038/s41598-023-47456-3

Sci Rep. 2023 Nov 23;13(1):20535. doi: 10.1038/s41598-023-47783-5.ABSTRACTA multi-class classification model for acute coronary syndrome (ACS) remains to be constructed based on multi-fluid metabolomics. Major confounders may exert spurious effects on the relationship between metabolism and ACS. The study aims to identify an independent biomarker panel for the multiclassification of HC, UA, and AMI by integrating serum and urinary metabolomics. We performed a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based metabolomics study on 300 serum and urine samples from 44 patients with unstable angina (UA), 77 with acute myocardial infarction (AMI), and 29 healthy controls (HC). Multinomial machine learning approaches, including multinomial adaptive least absolute shrinkage and selection operator (LASSO) regression and random forest (RF), and assessment of the confounders were applied to integrate a multi-class classification biomarker panel for HC, UA and AMI. Different metabolic landscapes were portrayed during the transition from HC to UA and then to AMI. Glycerophospholipid metabolism and arginine biosynthesis were predominant during the progression from HC to UA and then to AMI. The multiclass metabolic diagnostic model (MDM) dependent on ACS, including 2-ketobutyric acid, LysoPC(18:2(9Z,12Z)), argininosuccinic acid, and cyclic GMP, demarcated HC, UA, and AMI, providing a C-index of 0.84 (HC vs. UA), 0.98 (HC vs. AMI), and 0.89 (UA vs. AMI). The diagnostic value of MDM largely derives from the contribution of 2-ketobutyric acid, and LysoPC(18:2(9Z,12Z)) in serum. Higher 2-ketobutyric acid and cyclic GMP levels were positively correlated with ACS risk and atherosclerosis plaque burden, while LysoPC(18:2(9Z,12Z)) and argininosuccinic acid showed the reverse relationship. An independent multiclass biomarker panel for HC, UA, and AMI was constructed using the multinomial machine learning methods based on serum and urinary metabolite signatures.PMID:37996510 | DOI:10.1038/s41598-023-47783-5

Nat Commun. 2023 Nov 23;14(1):7674. doi: 10.1038/s41467-023-42862-7.ABSTRACTSporadic Parkinson's Disease (sPD) is a progressive neurodegenerative disorder caused by multiple genetic and environmental factors. Mitochondrial dysfunction is one contributing factor, but its role at different stages of disease progression is not fully understood. Here, we showed that neural precursor cells and dopaminergic neurons derived from induced pluripotent stem cells (hiPSCs) from sPD patients exhibited a hypometabolism. Further analysis based on transcriptomics, proteomics, and metabolomics identified the citric acid cycle, specifically the α-ketoglutarate dehydrogenase complex (OGDHC), as bottleneck in sPD metabolism. A follow-up study of the patients approximately 10 years after initial biopsy demonstrated a correlation between OGDHC activity in our cellular model and the disease progression. In addition, the alterations in cellular metabolism observed in our cellular model were restored by interfering with the enhanced SHH signal transduction in sPD. Thus, inhibiting overactive SHH signaling may have potential as neuroprotective therapy during early stages of sPD.PMID:37996418 | DOI:10.1038/s41467-023-42862-7

FEMS Microbiol Lett. 2023 Nov 23:fnad125. doi: 10.1093/femsle/fnad125. Online ahead of print.ABSTRACTMassive sequencing of the 16S rRNA gene has become a standard first step to describe and compare microbial communities from various samples. Parallel analysis of high numbers of samples makes it relevant to the statistical testing of the influence of natural or experimental factors and variables. However, these descriptions fail to document changes in community or ecosystem functioning. Non-targeted metabolomics are a suitable tool to bridge this gap, yet extractions protocols are different. In this study, prokaryotic community compositions are documented by 16S rRNA gene sequencing after direct DNA extraction, or after metabolites extraction followed by DNA extraction. Results obtained using the V3-V4 region on non-axenic cultures of cyanobacteria, lake water column, biofilm, gut of wild and lab-reared fish, indicate that prior extraction of metabolites does not influence the obtained image of prokaryotic communities. This validates sequential extraction of metabolites followed by DNA as a way to combine 16S rRNA sequencing with metabolome characterization from a single sample. This approach has the potential to complement community structure characterization with a proxy of their functioning, without the uncertainties associated with the use of separate samples.PMID:37996396 | DOI:10.1093/femsle/fnad125

Biochim Biophys Acta Mol Cell Res. 2023 Nov 21:119643. doi: 10.1016/j.bbamcr.2023.119643. Online ahead of print.ABSTRACTDiet-based models are commonly used to investigate obesity and related disorders. We conducted a comparative profiling of three obesogenic diets HFD, high fat diet; HFHF, high fat high fructose diet; and HFCD, high fat choline deficient diet to assess their impact on the gut microbiome and metabolome. After 20 weeks, we analyzed the gut microbiota and metabolomes of liver, plasma, cecal, and fecal samples. Fecal and plasma bile acids (BAs) and fecal short-chain fatty acids (SCFAs) were also examined. Significant changes were observed in fecal and cecal metabolites, with increased Firmicutes and decreased Bacteroidetes in the HFD, HFHF, and HFCD-fed mice compared to chow and LFD (low fat diet)-fed mice. Most BAs were reduced in plasma and fecal samples of obese groups, except taurocholic acid, which increased in HFCD mice's plasma. SCFAs like acetate and butyrate significantly decreased in obesogenic diet groups, while propionic acid specifically decreased in the HFCD group. Pathway analysis revealed significant alterations in amino acid, carbohydrate metabolism, and nucleic acid biosynthesis pathways in obese mice. Surprisingly, even LFD-fed mice showed distinct changes in microbiome and metabolite profiles compared to the chow group. This study provides insights into gut microbiome dysbiosis and metabolite alterations induced by obesogenic and LFD diets in various tissues. These findings aid in selecting suitable diet models to study the role of the gut microbiome and metabolites in obesity and associated disorders, with potential implications for understanding similar pathologies in humans.PMID:37996062 | DOI:10.1016/j.bbamcr.2023.119643

Environ Pollut. 2023 Nov 21:122996. doi: 10.1016/j.envpol.2023.122996. Online ahead of print.ABSTRACTMicro- and nano-plastics (MNPs) are emerging contaminants found in air, water, and food. Ageing and weathering processes convert aquatic plastics into MNPs which, due to their small size, can be assimilated by organisms. The accumulation of MNPs in aquatic life (e.g., fish, oysters, and crabs) will, in turn, pose risks to the health of ecosystems and human. This study focuses on the uptake, biodistribution, and size-dependent toxicity of polystyrene nano-plastics (PS-NPs) in a commercially important food web, the Australian Bass (Macquaria novemaculeata). Fish were fed artemia containing PS-NPs of various sizes (ranging from 50 nm to 1 μm) for durations of 5 and 7 days. The findings revealed that smaller NPs (50 nm) accumulated in the brain and muscle tissues at higher concentrations, whereas larger NPs (1 μm) were primarily found in the gills and intestines. In addition, an inverse correlation was observed between the size of NPs and the rate of trophic transfer, with smaller PS-NPs resulting in a higher transfer rate from artemia to fish. Polystyrene NPs caused both activation of the enzyme superoxide dismutase and damage to the DNA of fish tissues. These effects were size dependent. Metabolomic analysis revealed that indirect exposure to different-sized PS-NPs resulted in altered metabolic profiles within fish intestines, potentially impacting lipid and energy metabolism. These results offer novel perspectives on the size-specific toxic impacts of NPs on fish and the transfer of plastics through the food chain.PMID:37995956 | DOI:10.1016/j.envpol.2023.122996

Mol Metab. 2023 Nov 21:101838. doi: 10.1016/j.molmet.2023.101838. Online ahead of print.ABSTRACTOBJECTIVE: Carbohydrate Response Element Binding Protein (ChREBP) is a glucose 6-phosphate (G6P)-sensitive transcription factor that acts as a metabolic switch to maintain intracellular glucose and phosphate homeostasis. Hepatic ChREBP is well-known for its regulatory role in glycolysis, the pentose phosphate pathway, and de novo lipogenesis. The physiological role of ChREBP in hepatic glycogen metabolism and blood glucose regulation has not been assessed in detail, and ChREBP's contribution to carbohydrate flux adaptations in hepatic Glycogen Storage Disease type 1 (GSD I) requires further investigation.METHODS: The current study aimed to investigate the role of ChREBP as a regulator of glycogen metabolism in response to hepatic G6P accumulation, using a model for acute hepatic GSD type Ib. The immediate biochemical and regulatory responses to hepatic G6P accumulation were evaluated upon G6P transporter inhibition by the chlorogenic acid S4048 in mice that were either treated with a short hairpin RNA (shRNA) directed against ChREBP (shChREBP) or a scrambled shRNA (shSCR). Complementary stable isotope experiments were performed to quantify hepatic carbohydrate fluxes in vivo.RESULTS: ShChREBP treatment normalized the S4048-mediated induction of hepatic ChREBP target genes to levels observed in vehicle- and shSCR-treated controls. In parallel, hepatic shChREBP treatment in S4048-infused mice resulted in a more pronounced accumulation of hepatic glycogen and further reduction of blood glucose levels compared to shSCR treatment. Hepatic ChREBP knockdown modestly increased glucokinase (GCK) flux in S4048-treated mice while it enhanced UDP-glucose turnover as well as glycogen synthase and phosphorylase fluxes. Hepatic GCK mRNA and protein levels were induced by shChREBP treatment in both vehicle- and S4048-treated mice, while glycogen synthase 2 (GYS2) and glycogen phosphorylase (PYGL) mRNA and protein levels were reduced. Finally, knockdown of hepatic ChREBP expression reduced starch domain binding protein 1 (STBD1) mRNA and protein levels while it inhibited acid alpha-glucosidase (GAA) activity, suggesting reduced capacity for lysosomal glycogen breakdown.CONCLUSIONS: Our data show that ChREBP activation controls hepatic glycogen and blood glucose levels in acute hepatic GSD Ib through concomitant regulation of glucose phosphorylation, glycogenesis, and glycogenolysis. ChREBP-mediated control of GCK enzyme levels aligns with corresponding adaptations in GCK flux. In contrast, ChREBP activation in response to acute hepatic GSD Ib exerts opposite effects on GYS2/PYGL enzyme levels and their corresponding fluxes, indicating that GYS2/PYGL expression levels are not limiting to their respective fluxes under these conditions.PMID:37995884 | DOI:10.1016/j.molmet.2023.101838

J Ethnopharmacol. 2023 Nov 21:117472. doi: 10.1016/j.jep.2023.117472. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Cinobufacini injection, an aqueous extract of the toad, is a commonly used anti-tumor animal herbal medicine in clinical practice. It has the effects of detoxifying, reducing swelling, and relieving pain.AIMS OF THE STUDY: To investigate the effects of Cinobufacini injection on hepatocellular carcinoma progression by regulating lipid metabolism and macrophage polarization in the tumor microenvironment and to identify the potential molecular mechanisms.MATERIALS AND METHODS: To establish the axillary transplantation tumor model of hepatocellular carcinoma Hepa1-6 in C57BL/6 mice, and to evaluate the inhibitory effect of Cinobufacini injection on hepatocellular carcinoma in vivo as well as drug delivery security. Combined metabolomics and transcriptomics analysis of the effect of Cinobufagin Injection on tumor microenvironment. An in vitro mouse co-culture model of peritoneal macrophages and Hepa1-6 cells was established to research the effects of Cinobufacini injection on macrophage polarization, hepatocellular carcinoma cell growth, migration, and changes in lipid metabolism. Cinobufacini injection inhibition of the AMPK/SREBP1/FASN signaling pathway regulating cholesterol metabolism and affecting macrophage polarization was examined using qRT-PCR, lentiviral transfection, immunofluorescence, and Western blot.RESULT: In vivo experiments demonstrated that Cinobufacini injection treatment significantly inhibited the growth of Hepa1-6 hepatomas, along with a reduction in cholesterol content and a decrease in the percentage of M2 macrophages in tumor tissue. In vitro, we found that Cinobufacini injection inhibits IL-4-induced M2 macrophage polarization, reduces the cholesterol content of Hepa1-6 cells in a co-culture system, and inhibits the promotion of hepatocellular carcinoma cells by M2 macrophages. In addition, successful overexpression of SREBP1 in Hepa1-6 cells showed more pronounced cellular activity whereas Cinobufacini injection inhibited this change and reduced intracellular lipid levels.CONCLUSION: Cinobufacini injection inhibits cholesterol synthesis within the tumor microenvironment via the AMPK/SERBP1/FASN signaling pathway, which in turn blocks the M2 polarization of macrophages, leading to the weakening of hepatocellular carcinoma growth and migration, and the promotion of its apoptosis. Our findings provide an important Introduction to understanding the molecular mechanism of Cinobufacini injection's anticancer activity and provide reliable theoretical and experimental support for its clinical application.PMID:37995825 | DOI:10.1016/j.jep.2023.117472

Cancer Cell. 2023 Nov 16:S1535-6108(23)00365-3. doi: 10.1016/j.ccell.2023.10.009. Online ahead of print.ABSTRACTTrans-differentiation from an adenocarcinoma to a small cell neuroendocrine state is associated with therapy resistance in multiple cancer types. To gain insight into the underlying molecular events of the trans-differentiation, we perform a multi-omics time course analysis of a pan-small cell neuroendocrine cancer model (termed PARCB), a forward genetic transformation using human prostate basal cells and identify a shared developmental, arc-like, and entropy-high trajectory among all transformation model replicates. Further mapping with single cell resolution reveals two distinct lineages defined by mutually exclusive expression of ASCL1 or ASCL2. Temporal regulation by groups of transcription factors across developmental stages reveals that cellular reprogramming precedes the induction of neuronal programs. TFAP4 and ASCL1/2 feedback are identified as potential regulators of ASCL1 and ASCL2 expression. Our study provides temporal transcriptional patterns and uncovers pan-tissue parallels between prostate and lung cancers, as well as connections to normal neuroendocrine cell states.PMID:37995683 | DOI:10.1016/j.ccell.2023.10.009

Plant Physiol Biochem. 2023 Nov 20;205:108201. doi: 10.1016/j.plaphy.2023.108201. Online ahead of print.ABSTRACTAlthough microplastic pollution has been widely studied, the mechanism by which they influence plant photosynthesis and carbon and nitrogen metabolism remains unclear. We aimed to explore the effects of polystyrene microplastics (PS) on photosynthesis and carbon and nitrogen metabolism in cucumber using 5 μm and 0.1 μm PS particles. The PS treatments significantly reduced the stability of cucumber mesophyll cells and photosynthetic parameters and increased the soluble sugar content in cucumber leaves. The 5 μm PS affected the photosynthetic pathway by changing the expression of enzyme genes required for the synthesis of NADPH and ATP, which decreased the photosynthetic capacity in cucumber leaves. However, 0.1 μm PS altered the genes expression of phosphoenolpyruvate carboxykinase (PEPCK) and phosphoenolpyruvate carboxylase (PEPC), which affected the intercellular CO2 concentration and attenuated the negative effects on photosynthetic efficiency. Additionally, PS reduced the expression levels of nitrate/nitrite transporter (NRT) and nitrate reductase (NR), reducing the nitrogen use efficiency in cucumber leaves and mesophyll cells damage through increased accumulation of reduced glutathione (GSH), γ-glutamylcysteine (γ-GC), and citrulline. This study provides a new scientific basis for exploring the effects of microplastics on plant photosynthesis and carbon and nitrogen metabolism.PMID:37995577 | DOI:10.1016/j.plaphy.2023.108201

Aquat Toxicol. 2023 Nov 19;265:106770. doi: 10.1016/j.aquatox.2023.106770. Online ahead of print.ABSTRACTTebuconazole is a triazole fungicide widely used in agricultural crops for control of multiple fungal, mainly foliar and soil-borne diseases. Due to its intense use, this pesticide has been detected on aquatic matrices in different countries, which makes it necessary to identify metabolites capable to be used in its exposure monitoring. The aim of this work was to evaluate tebuconazole metabolites in zebrafish water tanks using liquid chromatography coupled to a high-resolution mass spectrometer (LCHRMS) to highlight analytical targets to monitor tebuconazole exposure in aquatic environments. Two Phase I metabolites, TEB-OH and TEB-COOH, and one Phase II metabolite, TEB-S, were identified. Target metabolomics pointed TEB-S as the most important metabolite for discrimination between treatment and negative control group and potential surrogate for detection and monitoring of tebuconazole exposure in aquatic environments. To the best of our knowledge, this is the first study to suggest the sulphation of tebuconazole (TEB-S) by zebrafish metabolism. Moreover, the use of water samples proved to be a promising approach when compared to the usual biological matrices (e.g. plasma) for evaluating the exposure of aquatic animals to tebuconazole because it is a clean and easy to obtain matrix. Water samples presented a higher concentration of metabolites when compared to plasma samples. The results suggest the applicability of this assay model for the identification of potential biomarkers for monitoring the presence of xenobiotics in water.PMID:37995559 | DOI:10.1016/j.aquatox.2023.106770

Sleep Med. 2023 Nov 19;113:95-102. doi: 10.1016/j.sleep.2023.11.024. Online ahead of print.ABSTRACTIn recent years, there has been an increased interest in elucidating the influence of the gut microbiota on sleep physiology. The gut microbiota affects the central nervous system by modulating neuronal pathways through the neuroendocrine and immune system, the hypothalamus-pituitary-adrenal axis, and various metabolic pathways. The gut microbiota can also influence circadian rhythms. In this study, we observed the gut microbiota composition of patients suffering from narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia. We did not observe any changes in the alpha diversity of the gut microbiota among patient groups and healthy controls. We observed changes in beta diversity in accordance with Jaccard dissimilarities between the control group and groups of patients suffering from narcolepsy type 1 and idiopathic hypersomnia. Our results indicate that both these patient groups differ from controls relative to the presence of rare bacterial taxa. However, after adjustment for various confounding factors such as BMI, age, and gender, there were no statistical differences among the groups. This indicates that the divergence in beta diversity in the narcolepsy type 1 and idiopathic hypersomnia groups did not arise due to sleep disturbances. This study implies that using metabolomics and proteomics approaches to study the role of microbiota in sleep disorders might prove beneficial.PMID:37995475 | DOI:10.1016/j.sleep.2023.11.024

Best Pract Res Clin Obstet Gynaecol. 2023 Nov 18;92:102427. doi: 10.1016/j.bpobgyn.2023.102427. Online ahead of print.ABSTRACTPreeclampsia is a pregnancy-specific disease that has no known precise cause. Integrative biology approach based on multi-omics has been applied to identify upstream pathways and better understand the pathophysiology of preeclampsia. At DNA level, genomics and epigenomics studies have revealed numerous genetic variants associated with preeclampsia, including those involved in regulating blood pressure and immune response. Transcriptomics analyses have revealed altered expression of genes in preeclampsia, particularly those related to inflammation and angiogenesis. At protein level, proteomics studies have identified potential biomarkers for preeclampsia diagnosis and prediction in addition to revealing the main pathophysiological pathways involved in this disease. At metabolite level, metabolomics has highlighted altered lipid and amino acid metabolisms in preeclampsia. Finally, microbiomics studies have identified dysbiosis in the gut and vaginal microbiota in pregnant women with preeclampsia. Overall, omics technologies have improved our understanding of the complex molecular mechanisms underlying preeclampsia. However, further research is warranted to fully integrate and translate these omics findings into clinical practice.PMID:37995432 | DOI:10.1016/j.bpobgyn.2023.102427

Funct Plant Biol. 2023 Nov 24. doi: 10.1071/FP23145. Online ahead of print.ABSTRACTMetabolomic investigations offers a significant foundation for improved comprehension of the adaptability of plants to reconfigure the key metabolic pathways and their response to changing climatic conditions. Their application to ecophysiology and ecotoxicology help to assess potential risks caused by the contaminants, their modes of action and the elucidation of metabolic pathways associated with stress responses. Heavy metal stress is one of the most significant environmental hazards affecting the physiological and biochemical processes in plants. Metabolomic tools have been widely utilised in the massive characterisation of the molecular structure of plants at various stages for understanding the diverse aspects of the cellular functioning underlying heavy metal stress-responsive mechanisms. This review emphasises on the recent progressions in metabolomics in plants subjected to heavy metal stresses. Also, it discusses the possibility of facilitating effective management strategies concerning metabolites for mitigating the negative impacts of heavy metal contaminants on the growth and productivity of plants.PMID:37995340 | DOI:10.1071/FP23145

Cell Rep. 2023 Nov 21;42(12):113463. doi: 10.1016/j.celrep.2023.113463. Online ahead of print.ABSTRACTBrain metastasis cancer-associated fibroblasts (bmCAFs) are emerging as crucial players in the development of breast cancer brain metastasis (BCBM), but our understanding of the underlying molecular mechanisms is limited. In this study, we aim to elucidate the pathological contributions of fucosylation (the post-translational modification of proteins by the dietary sugar L-fucose) to tumor-stromal interactions that drive the development of BCBM. Here, we report that patient-derived bmCAFs secrete high levels of polio virus receptor (PVR), which enhance the invasive capacity of BC cells. Mechanistically, we find that HIF1α transcriptionally upregulates fucosyltransferase 11, which fucosylates PVR, triggering its secretion from bmCAFs. Global phosphoproteomic analysis of BC cells followed by functional verification identifies cell-cell junction and actin cytoskeletal signaling as modulated by bmCAF-secreted, -fucosylated PVR. Our findings delineate a hypoxia- and fucosylation-regulated mechanism by which bmCAFs contribute to the invasiveness of BCBM in the brain.PMID:37995180 | DOI:10.1016/j.celrep.2023.113463

Environ Health Perspect. 2023 Nov;131(11):117011. doi: 10.1289/EHP13217. Epub 2023 Nov 23.ABSTRACTBACKGROUND: Perfluorohexane sulfonate (PFHxS) is a frequently detected per- and polyfluoroalkyl substance in most populations, including in individuals who are pregnant, a period critical for early life development. Despite epidemiological evidence of exposure, developmental toxicity, particularly at realistic human exposures, remains understudied.OBJECTIVES: We evaluated the effect of gestational exposure to human-relevant body burden of PFHxS on fetal and placental development and explored mechanisms of action combining alternative splicing (AS) and gene expression (GE) analyses.METHODS: Pregnant ICR mice were exposed to 0, 0.03, and 0.3μg/kg/day from gestational day 7 to day 17 via oral gavage. Upon euthanasia, PFHxS distribution was measured using liquid chromatography-tandem mass spectrometry. Maternal and fetal phenotypes were recorded, and histopathology was examined for placenta impairment. Multiomics was adopted by combining AS and GE analyses to unveil disruptions in mRNA quality and quantity. The key metabolite transporters were validated by quantitative real-time PCR (qRT-PCR) for quantification and three-dimensional (3D) structural simulation by AlphaFold2. Targeted metabolomics based on liquid chromatography-tandem mass spectrometry was used to detect amino acid and amides levels in the placenta.RESULTS: Pups developmentally exposed to PFHxS exhibited signs of intrauterine growth restriction (IUGR), characterized by smaller fetal weight and body length (p<0.01) compared to control mice. PFHxS concentration in maternal plasma was 5.01±0.54 ng/mL. PFHxS trans-placenta distribution suggested dose-dependent transfer through placental barrier. Histopathology of placenta of exposed dams showed placental dysplasia, manifested with an attenuated labyrinthine layer area and deescalated blood sinus counts and placental vascular development index marker CD34. Combined GE and AS analyses pinpointed differences in genes associated with key biological processes of placental development, proliferation, metabolism, and transport in placenta of exposed dams compared to that of control dams. Further detection of placental key transporter gene expression, protein structure simulation, and amino acid and amide metabolites levels suggested that PFHxS exposure during pregnancy led to impairment of placental amino acid transportation.DISCUSSION: The findings from this study suggest that exposure to human-relevant very-low-dose PFHxS during pregnancy in mice caused IUGR, likely via downregulating of placental amino acid transporters, thereby impairing placental amino acid transportation, resulting in impairment of placental development. Our findings confirm epidemiological findings and call for future attention on the health risk of this persistent yet ubiquitous chemical in the early developmental stage and provide a new approach for understanding gene expression from both quantitative and qualitative omics approaches in toxicological studies. https://doi.org/10.1289/EHP13217.PMID:37995155 | DOI:10.1289/EHP13217

Environ Sci Pollut Res Int. 2023 Nov 23. doi: 10.1007/s11356-023-31044-z. Online ahead of print.ABSTRACTCadmium (Cd) contamination in soil poses a severe threat to plant growth and development. In contrast, silicon (Si) has shown promise in enhancing plant resilience under Cd-induced stress. In this study, we conducted an integrated investigation employing morphological studies, gene expression analysis, and metabolomics to unravel the molecular mechanisms underlying Cd tolerance in maize plants. Our results demonstrate that Si biofortification significantly mitigated Cd stress by reducing Cd accumulation in plant tissues, increasing Si content, and enhancing maize biomass in Cd-stressed plants resulted in a substantial enhancement in shoot dry weight (+ 75%) and root dry weight (+ 30%). Notably, Si treatment upregulated key lignin-related genes (TaPAL, TaCAD, Ta4CL, and TaCOMT) and promoted the accumulation of metabolites (sinapyl alcohol, phenylalanine, p-coumaryl alcohol, cafeyl alcohol, and coniferaldehyde) essential for cell wall strength, particularly under Cd stress conditions. Si application enriched the signal transduction by hormones and increased resistance by induction of biosynthesis genes (TaBZR1, TaLOX3, and TaNCDE1) and metabolites (brassinolide, abscisic acid, and jasmonate) in the roots and leaves under Cd stress. Furthermore, our study provides a comprehensive view of the intricate molecular crosstalk between Si, Cd stress, and plant hormonal responses. We unveil a network of genetic and metabolic interactions that culminate in a multifaceted defense system, enabling maize plants to thrive even in the presence of Cd-contaminated soil. This knowledge not only advances our understanding of the protective role of Si but also highlights the broader implications for sustainable agricultural practices. By harnessing the insights gained from this research, we may pave the way for innovative strategies to fortify crops against environmental stressors, ultimately contributing to the goal of food security in an ever-changing world. In summary, our research offers valuable insights into the protective mechanisms facilitated by Si, which enhance plants' ability to withstand environmental stress, and holds promise for future applications in sustainable agriculture.PMID:37995035 | DOI:10.1007/s11356-023-31044-z

Plant Mol Biol. 2023 Nov 23. doi: 10.1007/s11103-023-01390-0. Online ahead of print.ABSTRACTIn response to herbivory, Capsicum annuum leaves adapt their specialized metabolome that may protect the plant against herbivore feeding either directly or indirectly through volatile metabolites acting as cues for natural enemies of the herbivore. The volatile blend of spider-mite infested leaves differs from non-challenged leaves predominantly by a higher contribution of mono- and sesquiterpenes. In addition to these terpenoids released into the headspace, the terpenoid composition of the leaves alters upon herbivory. All this suggests an important role for terpenoids and their biosynthetic machinery in the defence against herbivory. Here, we show that the C. annuum genome contains a terpene synthase (TPS) gene family of 103 putative members of which structural analysis revealed that 27 encode functional enzymes. Transcriptome analysis showed that several TPS loci were differentially expressed upon herbivory in leaves of two C. annuum genotypes, that differ in susceptibility towards spider mites. The relative expression of upstream biosynthetic genes from the mevalonate and the methylerythritol phosphate pathway also altered upon herbivory, revealing a shift in the metabolic flux through the terpene biosynthetic module. The expression of multiple genes potentially acting downstream of the TPSs, including cytochrome P450 monooxygenases, UDP-glucosyl transferases, and transcription factors strongly correlated with the herbivory-induced TPS genes. A selection of herbivory-induced TPS genes was functionally characterized through heterologous expression and the products that these enzymes catalysed matched with the volatile and non-volatile terpenoids induced in response to herbivory.PMID:37995005 | DOI:10.1007/s11103-023-01390-0

Clin Ter. 2023 Nov-Dec;174(Suppl 2(6)):256-262. doi: 10.7417/CT.2023.2496.ABSTRACTBACKGROUND: Mast cells are immune cells that mediate hypersensi-tivity and allergic reactions in the body, secreting histamine and other inflammatory molecules. They have been associated with different inflammatory conditions such as obesity and other adipose tissue di-sorders. Lipedema is a chronic disease characterized by an abnormal accumulation of adipose tissue on the legs and arms, pain, and other symptoms. Mast cells may play a role in the pathology of lipedema.OBJECTIVE: Pilot study to determine levels of histamine and its metabolites in lipedema subcutaneous adipose tissue (SAT) biopsy samples, and to test sodium cromoglycate for the treatment of mast cells in women with lipedema.METHODS: Biopsies from lipedema and control SAT were collected and analyzed histologically for the presence of mast cells. Mass spec-trometry was used to measure the levels of histamine, a key marker of mast cells, and its metabolites in SAT in women with lipedema and controls, and after a group of women with lipedema were administered oral and topical doses of sodium cromoglycate for two weeks.RESULTS: Histological examination of biopsies from lipedema patients confirmed the presence of mast cells. Metabolomic analysis revealed high levels of histamine and its metabolites in samples from women with lipedema compared to controls. Following a two-week treatment period, lipedema tissue samples exhibited reduced levels of histamine, suggesting a reduction of mast cell activity.CONCLUSION: Sodium cromoglycate has the ability to stabilize mast cells and reduce histamine levels in lipedema patients, which could be useful in lowering the symptoms of lipedema.PMID:37994773 | DOI:10.7417/CT.2023.2496