PubMed

Nat Med. 2022 Nov 10. doi: 10.1038/s41591-022-02046-0. Online ahead of print.ABSTRACTGarrod's concept of 'chemical individuality' has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant-metabolite associations (P < 1.25 × 10-11) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant-metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships.PMID:36357675 | DOI:10.1038/s41591-022-02046-0

Arch Toxicol. 2022 Nov 10. doi: 10.1007/s00204-022-03412-0. Online ahead of print.ABSTRACTThis study aimed to identify the alterations of blood metabolome levels and their association with cardiac dysfunction and cardiac injury following treatment with doxorubicin and trastuzumab. Eight-week-old male Wistar rats were divided into four groups (n = 6 per group) to receive intraperitoneal injection with either: (1) 1 mL of normal saline solution (NSS) at days 0, 4, 8, 15, 22, and 29 (control group for doxorubicin); (2) 3 mg/kg/day of doxorubicin at days 0, 4, 8, 15, 22, and 29 (doxorubicin group); (3) 1 mL of NSS at days 0-6 (control group for trastuzumab); or (4) 4 mg/kg/day of trastuzumab at days 0-6 (trastuzumab group). Four days after the last injected dose, cardiac function was determined. The rats were then euthanized to collect venous blood and the heart for the quantification of 107 serum and 100 cardiac metabolomes using mass spectrometry-based targeted metabolomics. We observed strong relationships between 72 cardiac versus 61 serum metabolomes in doxorubicin and trastuzumab groups. Moreover, significant correlations between cardiac function and the cardiac injury biomarker versus 28 and 58 serum metabolomes were revealed in doxorubicin and trastuzumab-treated rats, respectively. Interestingly, the patterns of both serum and cardiac metabolome alterations differed between doxorubicin and trastuzumab groups. Our findings emphasize the potential role of the constituents of the blood metabolome as non-invasive biomarkers to assess severity and prognosis of heart failure induced by doxorubicin and trastuzumab. These findings may contribute to the development of metabolic-targeted therapy specific for cardioprotection during different phases of cancer treatment.PMID:36357623 | DOI:10.1007/s00204-022-03412-0

Mol Neurobiol. 2022 Nov 11. doi: 10.1007/s12035-022-03107-8. Online ahead of print.ABSTRACTCoumarins are plant-derived polyphenolic compounds belonging to the benzopyrones family, possessing wide-ranging pharmaceutical applications including cytoprotection, which may translate into therapeutic potential for multiple diseases, including Parkinson's disease (PD). Here we demonstrate the neuroprotective potential of a new polyhydroxyl coumarin, N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-2-(7-hydroxy-2-oxo-2H-chromen-4-yl)acetamide (CT51), against the mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+). MPP+'s mechanism of toxicity relates to its ability to inhibit complex I of the mitochondrial electron transport chain (METC), leading to adenosine triphosphate (ATP) depletion, increased reactive oxygen species (ROS) production, and apoptotic cell death, hence mimicking PD-related neuropathology. Dopaminergic differentiated human neuroblastoma cells were briefly pretreated with CT51, followed by toxin exposure. CT51 significantly restored somatic cell viability and neurite processes; hence, the drug targets cell bodies and axons thereby preserving neural function and circuitry against PD-related damage. Moreover, MPP+ emulates the iron dyshomeostasis affecting dopaminergic neurons in PD-affected brains, whilst CT51 was previously revealed as an effective iron chelator that preferentially partitions to mitochondria. We extend these findings by characterising the drug's interactive effects at the METC level. CT51 did not improve mitochondrial coupling efficiency. However, voltammetric measurements and high-resolution respirometry analysis revealed that CT51 acts as an antioxidant agent. Also, the neuronal protection afforded by CT51 associated with downregulating MPP+-induced upregulated expression of hypoxia-inducible factor 1 alpha (HIF-1α), a protein which regulates iron homeostasis and protects against certain forms of oxidative stress after translocating to mitochondria. Our findings support the further development of CT51 as a dual functioning iron chelator and antioxidant antiparkinsonian agent.PMID:36357615 | DOI:10.1007/s12035-022-03107-8

Nat Commun. 2022 Nov 10;13(1):6806. doi: 10.1038/s41467-022-34535-8.ABSTRACTOur knowledge of the role of the gut microbiome in acute coronavirus disease 2019 (COVID-19) and post-acute COVID-19 is rapidly increasing, whereas little is known regarding the contribution of multi-kingdom microbiota and host-microbial interactions to COVID-19 severity and consequences. Herein, we perform an integrated analysis using 296 fecal metagenomes, 79 fecal metabolomics, viral load in 1378 respiratory tract samples, and clinical features of 133 COVID-19 patients prospectively followed for up to 6 months. Metagenomic-based clustering identifies two robust ecological clusters (hereafter referred to as Clusters 1 and 2), of which Cluster 1 is significantly associated with severe COVID-19 and the development of post-acute COVID-19 syndrome. Significant differences between clusters could be explained by both multi-kingdom ecological drivers (bacteria, fungi, and viruses) and host factors with a good predictive value and an area under the curve (AUC) of 0.98. A model combining host and microbial factors could predict the duration of respiratory viral shedding with 82.1% accuracy (error ± 3 days). These results highlight the potential utility of host phenotype and multi-kingdom microbiota profiling as a prognostic tool for patients with COVID-19.PMID:36357381 | DOI:10.1038/s41467-022-34535-8

J Biol Chem. 2022 Nov 7:102682. doi: 10.1016/j.jbc.2022.102682. Online ahead of print.ABSTRACTLiraglutide, a glucagon-like peptide-1 analog, has beneficial metabolic effects in patients with type 2 diabetes and obesity. Although the high efficacy of liraglutide as an anti-diabetic and anti-obesity drug is well known, liraglutide-induced metabolic alterations in diverse tissues remain largely unexplored. Here, we report the changes in metabolic profiles induced by a two-week subcutaneous injection of liraglutide in diet-induced obese (DIO) mice fed a high-fat diet for eight weeks. Our comprehensive metabolomic analyses of the hypothalamus, plasma, liver, and skeletal muscle showed that liraglutide intervention led to various metabolic alterations in comparison with DIO or non-obese mice. We found that liraglutide remarkably coordinated not only fatty acid metabolism in the hypothalamus and skeletal muscle, but also amino acid and carbohydrate metabolism in plasma and liver. Comparative analyses of metabolite dynamics revealed that liraglutide rewired inter-tissue metabolic correlations. Our study points to a previously unappreciated metabolic alteration by liraglutide in several tissues, which may underlie its therapeutic effects within and across the tissues.PMID:36356900 | DOI:10.1016/j.jbc.2022.102682

Sci Total Environ. 2022 Nov 7:160019. doi: 10.1016/j.scitotenv.2022.160019. Online ahead of print.ABSTRACTCoral bleaching significantly affects the function and health of coral reef ecosystems; however, the mechanisms underlying metabolism and transcription in corals remain unclear. In this study, untargeted metabolomics and metatranscriptomic analyses were performed to analyze the differences between unbleached and bleached Pocillopora corals during the most severe marine heatwaves. Difference analysis showed that bleached corals had significant metabolomic characteristics compared with those in unbleached corals. These differences were significant (p < 0.05) according to partial least squares discriminant analysis (PLS-DA). Kyoto Encyclopedia of Genes and Genomes enrichment (KEGG) analysis revealed that the metabolites were significantly enriched in numerous pathways in bleached or unbleached corals, such as steroid hormone biosynthesis, biosynthesis of unsaturated fatty acids, and pyrimidine metabolism. Bleaching greatly affects coral reproduction as well as the tolerance of coral symbionts to heat stress. In metatranscriptomic analysis, we observed large gene expression differences between unbleached and bleached corals. Three Gene Ontology directed acyclic graphs (DAGs) were constructed to show the significantly differentially expressed genes. Many biological and molecular processes were significantly enriched between bleached corals to unbleached corals, such as metabolic processes, lipid metabolic processes, oxidation-reduction processes, single-organism metabolic processes, and protein metabolic processes. Metabolome and metatranscriptome analyses showed that bleaching caused substantial physiological and genetic damage to corals. This study provides insight into the metabolic and transcriptional changes that occur in corals during bleaching.PMID:36356778 | DOI:10.1016/j.scitotenv.2022.160019

Sci Total Environ. 2022 Nov 7:159920. doi: 10.1016/j.scitotenv.2022.159920. Online ahead of print.ABSTRACTMixotrophic cultivation was proposed to enhance the biomass and carbon sequestration efficiency of Spirulina in CO2 absorption and microalgae conversion (CAMC) system, and the underlying metabolic mechanism was also explored. The result showed that mixotrophic enhanced the performance of CAMC system, the maximum biomass, total carbon conversion capacity and efficiency was obtained at 0.5 g/L acetate group, which was 60.47 %, 63.06 % and 59.77 % higher than control. Adding 0.5 g/L acetate enhanced the activities of Rubisco and Acetyl-CoA, arrived at 89.59 U/g and 5.16 nmol/g, respectively. Metabolomics analyses suggested that mixotrophic changed metabolic flux and affected intracellular composition. Mixotrophic up-regulated Calvin cycle, glycolysis, and tricarboxylic acid (TCA) cycle, induced more carbon fluxes into central carbon metabolism for the growth of Spirulina. These results suggested that mixotrophic could supply effective energy and carbon skeleton for rapid growth of Spirulina, and provided a theoretical basis for large-scale application of CAMC system.PMID:36356767 | DOI:10.1016/j.scitotenv.2022.159920

Sci Total Environ. 2022 Nov 7:160025. doi: 10.1016/j.scitotenv.2022.160025. Online ahead of print.ABSTRACTMuch attention has been paid to the prevalence of microplastics (MPs) in terrestrial systems. MPs have been shown to affect the physio-biochemical properties of plants. Different MPs may have distinctive behaviors and diverse effects on plant growth. In the present study, the effects of polystyrene (PS), polyethylene (PE), and polypropylene (PP) MPs on physio-biochemical properties, root exudates, and metabolomics of tomato (Lycopersicon esculentum L.) under hydroponic conditions were investigated. Our results show that MPs exposure has adverse effects on tomato growth. MPs exposure had a significant type-dependent effect (p < 0.001) on photosynthetic gas parameters, chlorophyll content, and antioxidant enzyme activities. After exposure to MPs, the content of low molecular weight organic acids in tomato root exudates was significantly increased, which was considered as a strategy to alleviate the toxicity of MPs. In addition, MPs treatment significantly changed the metabolites of tomato root and leaf. Metabolic pathway analysis showed that MPs treatment had a great effect on amino acid metabolism. We also found that plants exposed to PS MPs and PP MPs produced more significant metabolic reprogramming than those exposed to PE MPs. This study provides important implications for the mechanism studies on the toxic effect of various MPs on crops and their future risk assessment.PMID:36356752 | DOI:10.1016/j.scitotenv.2022.160025

Sci Total Environ. 2022 Nov 7:160086. doi: 10.1016/j.scitotenv.2022.160086. Online ahead of print.ABSTRACTGlobal warming further increases the toxic threat of environmental pollutants on organisms. In order to reveal the dimensions of this threat more clearly, it is of great importance that the studies be carried out with temperature differences as close as possible to the temperature values that will represent the global climate projection. In our study, how the toxicity of glyphosate, which is widely used around the world, on zebrafish changes with temperature increases of 0.5° was investigated on behavioral and molecular basis. For this purpose, adult zebrafish were exposed to glyphosate at concentrations of 1 ppm and 5 ppm for 96 h in four environments with a temperature difference of 0.5° (28.5; 29.0; 29.5; 30.0 °C). At the end of the exposure, half of the zebrafish were sampled and remaining half were left for a 10-day recovery process. At the end of the trials, zebrafish were subjected to circadian rhythm and anxiety tests. In addition, histopathological, immunohistochemical and metabolome analyses were performed on brain tissues. As a result, it has been detected that anxiety and circadian rhythm were disrupted in parallel with the increased temperature and glyphosate concentration, and increased histopathological findings and 5-HT4R and GNAT2 immunopositivity in the brain. As a result of metabolome analysis, more than thirty annotated metabolites have been determined due to the synergistic effect of temperature increase and glyphosate exposure. As a conclusion, it was concluded that even a temperature increase of 0.5° caused an increasing effect of glyphosate toxicity in the zebrafish model.PMID:36356745 | DOI:10.1016/j.scitotenv.2022.160086

Sci Total Environ. 2022 Nov 7:160020. doi: 10.1016/j.scitotenv.2022.160020. Online ahead of print.ABSTRACTMicroplastic (MP) contaminants in marine water have become a global public health concern because of their persistence and potentially adverse effects on organisms. MP can affect the growth and metabolism of marine microorganisms and further impact the microbial environmental functions. The molecular impact mechanisms of MP on specific functional microbes with the capability of decomposing methylphosphonate (MPn) to release methane (CH4) in oxygenated water have rarely been reported upon. Herein, we investigated the effects of MP on microbes and concomitant methanogenesis via the microbial degradation of MPn. Furthermore, the specific perturbation was revealed at the molecular level combined with transcriptomics and metabolomics. The results showed that intracellular phosphorus utilization by MPn-degrading strain Burkholderia sp. HQL1813 was enhanced by accelerating the catabolism of MPn. Phosphorus transport-related genes (phnG-M, pstSCAB, phnCDE) were upregulated in the MP exposure groups. Amino acid metabolism, the phosphotransferase system and nucleotide metabolism were also perturbed after MP exposure. Notably, released CH4 increased by 24 %, 29 % and 14 % in the exposure group. In addition, the responses of the strain were dose-independent with increasing MP doses. These findings are beneficial for clarifying the effect of MP on specific functional microbes at the molecular level and their degradation of CH4 by MPn.PMID:36356736 | DOI:10.1016/j.scitotenv.2022.160020

Sci Total Environ. 2022 Nov 7:160039. doi: 10.1016/j.scitotenv.2022.160039. Online ahead of print.ABSTRACTNanopollutants such as nZnO gain importance as contaminants of emerging concern due to their high production volume and potential toxicity. Coastal sediments serve as sinks for nanoparticles but the impacts and the toxicity mechanisms of nZnO in sediment-dwelling organisms are not well understood. We used metabolomics to assess the effects of nZnO-contaminated sediments on a benthic ecosystem engineer, an infaunal polychaete Arenicola marina. The worms were exposed to unpolluted (control) sediment or to the sediment spiked with 100 or 1000 μg Zn kg-1 of nZnO. Oxidative lesions (lipid peroxidation and protein carbonyls) were measured in the body wall as traditional biomarkers of nanopollutant toxicity. Metabolite profiles (including amino acids, tricarboxylic acid (TCA) cycle and urea cycle intermediates) were determined in the body wall and the coelomic fluid. Exposure to nZnO altered metabolism of the lugworms via suppression of the metabolism of gluconeogenic and aromatic amino acids, and altered the TCA cycle likely via suppression of fumarase activity. These metabolic changes may negatively affect carbohydrate metabolism and energy storage, and impair hormonal signaling in the worms. The total pool of free amino acids was also depleted in nZnO exposures with potentially negative consequences for osmoregulation and protein synthesis. Exposure to nZnO led to accumulation of the lipid peroxidation products demonstrating high susceptibility of the cellular membranes to nZnO-induced oxidative stress. The nZnO-induced shifts in the metabolite profiles were more pronounced in the coelomic fluid than the body wall. This finding emphasizes the important metabolic role of the coelomic fluid as well as its suitability for assessing the toxic impacts of nZnO and other metabolic disruptors. The metabolic disruptions caused by environmentally relevant concentrations of nZnO can have negative effects on the organisms' fitness impairing growth and reproduction of the populations of marine bioturbators like the lugworms in nanoparticle-polluted sediments.PMID:36356734 | DOI:10.1016/j.scitotenv.2022.160039

J Ethnopharmacol. 2022 Nov 7:115919. doi: 10.1016/j.jep.2022.115919. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Gegen Qinlian decoction (GQD) is traditional Chinese medicine derived from Treatise on febrile diseases and is clinically used for the treatment of acute ulcerative colitis (UC). However, the potential mechanism of GQD treatment for UC remains elusive.AIM OF STUDY: In this study, we aimed to explore the involvement of gut microbiota-related tryptophan metabolism in mediating protective effects of GQD against intestinal barrier damage.MATERIALS AND METHODS: Mice with colitis were treated with 3% dextran sulfate sodium (DSS) for 7 days. The therapeutic effects of GQD in UC mice were examined based on body weight, disease activity index (DAI), organ index, length and pathological changes in the colon. The distribution of fluorescein isothiocyanate dextran (FITC-dextran) in the intestinal tract was observed using small animal imaging, while concentration of FITC-dextran in serum was detected using a fluorescein microplate analyser. Bacterial infiltration in colon tissues was observed by fluorescence in situ hybridisation (FISH), and the bacterial load was further examined in mesenteric lymph nodes (MLNs) through bacterial culture. Subsequently, colonic goblet cells were detected using Alcian blue staining. The tight junctions of the colonic epithelium were observed using transmission electron microscopy, and the expression of tight junction proteins was detected by immunofluorescence (IF) and western blotting. In addition, flow cytometry was used to analyse the proportion of interleukin-22-positive (IL-22+) ILC3 cells in lamina propria lymphocytes, and the content of IL-22 in colon homogenates was determined using an ELISA kit. In addition, targeted tryptophan metabolomics was used to detect the concentration of indole derivatives produced by tryptophan metabolism in faeces, and 16S rDNA was used to investigate the composition and abundance of gut microbiota-related tryptophan metabolism.RESULTS: Administration of GQD significantly alleviated the pathological symptoms, including weight loss, increased DAI score, changes in organ index, colon shortening, and colon pathological injury in UC mice. In addition, GQD reduced the diffusion of FITC-dextran in the intestinal tract, the content of FITC-dextran in serum, and bacterial infiltration in MLNs and colon tissues. Additionally, GQD significantly increased the number of colonic goblet cells, repaired the structure of epithelial tight junctions and increased the expression of tight junction proteins. Furthermore, GQD significantly increased the proportion of IL-22+ ILC3 in the lamina propria, the expression of CYP1A1 protein in colon tissue, and the level of IL-22 in colon homogenates. However, the above protective effects of GQD were inhibited by co-administration of GQD and aryl hydrocarbon receptor (AhR) antagonist. Additionally, GQD restored the content of indole derivatives generated by tryptophan metabolism, regulated the diversity of the gut microbiota, and significantly increased the abundance of genes related to tryptophan metabolism.CONCLUSION: Our results confirmed that GQD repaired the damaged intestinal barrier in UC mice by regulating gut microbiota-related tryptophan metabolism and restoring the generation of indole derivatives to activate AhR-mediated IL-22 production.PMID:36356716 | DOI:10.1016/j.jep.2022.115919

J Ethnopharmacol. 2022 Nov 7:115894. doi: 10.1016/j.jep.2022.115894. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Shuangshen Pingfei formula (SSPF), a Chinese medicine prescription, has been prescribed to alleviate PF. However, little is known about the molecular mechanism underlying PF progression and the regulatory mechanism in SSPF.AIMS OF THE STUDY: To discriminate the molecular alterations underlying the development of pulmonary fibrosis (PF) and reveal the regulatory mechanism of Shuangshen Pingfei formula (SSPF).MATERIALS AND METHODS: An integrated analysis of a time-course pathology combined with proteomics and metabolomics was performed to investigate changes in body weight, survival rate, lung coefficient, histopathology, proteins, and metabolites of lung tissues at different time points upon bleomycin (BLM) exposure and SSPF treatment.RESULTS: The results showed that PF progression was characterized by gradually aggravated fibrosis accompanied by inflammation with extended exposure (7, 14, and 21 days). SSPF significantly attenuated lung fibrosis, as evidenced by increased weight, and reduced lung coefficients and fibrosis scores. Moreover, 368 common differentially expressed proteins (DEPs) were identified, and 102 DEPs were continuously and monotonically upregulated via proteomics among the three BLM treatments. The DEPs were principally involved in extracellular matrix (ECM) remodeling and arginine and proline (AP) metabolic reprogramming. Additionally, metabolomics analyses revealed that BLM exposure mainly affected six metabolism pathways, including 34 differentially regulated metabolites (DRMs). Furthermore, correlation analysis found that several DEPs and DRMs, including L-ornithine, S-adenosyl-L-methionine, ARG, and AOC1, were associated with arginine and proline metabolism, and 8,9-EET, 8,9-DHET, CYP2B, etc., were involved in arachidonic acid (AA) metabolism, suggesting that these two pathways play a critical role in the development of fibrosis. After SSPF treatment, the related protein expression and metabolic disorders were regulated, implying that SSPF provides potential solutions to target these pathways for benefit in the treatment of PF.CONCLUSION: Our data suggest that ECM remodeling, and metabolic reprogramming of AP and AA are distinctive features of PF development. Simultaneously, we confirmed that SSPF could effectively regulate metabolic disorders, indicating its potential clinical application for PF therapy. Our findings using multiple approaches provide a molecular-scale perspective on the mechanisms of PF progression and the amelioration of SSPF.PMID:36356715 | DOI:10.1016/j.jep.2022.115894

Ecotoxicol Environ Saf. 2022 Nov 7;247:114273. doi: 10.1016/j.ecoenv.2022.114273. Online ahead of print.ABSTRACTSterigmatocystin (STE) is a common hepatotoxic and nephrotoxic contaminant in cereals, however, its phytotoxicity and mechanisms are poorly understood. Here, the phytotoxic mechanisms of STE were investigated via the metabolomics of Amaranthus retroflexus L. A total of 140 and 113 differential metabolites were detected in the leaves and stems, respectively, among which amino acids, lipids, and phenolic compounds were significantly perturbed. Valine, leucine, isoleucine, and lysine biosynthesis were affected by STE. These metabolic responses revealed that STE might be toxic to plants by altering the plasma membrane and inducing oxidative damage, which was verified by measuring the relative electrical conductivity and quantification of reactive oxygen species. The elevated amino acids, as well as the decreased of D-sedoheptuiose-7-phosphate indicated increased proteolysis and carbohydrate metabolism restriction. Furthermore, the IAA level also decreased. This study provides a better understanding of the impacts of STE on the public health, environment and food security.PMID:36356529 | DOI:10.1016/j.ecoenv.2022.114273

J Hazard Mater. 2022 Nov 1;443(Pt B):130298. doi: 10.1016/j.jhazmat.2022.130298. Online ahead of print.ABSTRACTGraphene oxide (GO, a popular 2D graphene-based nanomaterial) has developed quickly and has received considerable attention for its applications in environmental protection and pollutant removal. However, significant knowledge gaps still exist about the interaction characteristic and joint toxicity mechanism of GO and cadmium (Cd) on aquatic organisms. In this study, GO showed a high adsorption capacity (120. 6 mg/g) and strong adsorption affinity (KL = 0.85 L/mg) for Cd2+. Integrating multiple analytical methods (e.g., electron microscopy, Raman spectra, and 2D correlation spectroscopy) revealed that Cd2+ is uniformly adsorbed on the GO surface and edge mainly through cation-π interactions. The combined ecological effects of GO and Cd2+ on Chlorella vulgaris were observed. Cd2+ induced more severe growth inhibition, photosynthesis toxicity, ultrastructure damage and plasmolysis than GO. Interestingly, we found that GO nanosheets could augment the algal toxicity of Cd2+ (e.g., chlorophyll b, mitochondrial membrane damage, and uptake). Transcriptomics and metabolomics further explained the underlying mechanism. The results indicated that the regulation of PSI-, PSII-, and metal transport-related genes (e.g., ABCG37 and ZIP4) and the inhibition of metabolic pathways (e.g., amino acid, fatty acid, and carbohydrate metabolism) were responsible for the persistent phytotoxicity. The present work provides mechanistic insights into the roles of coexisting inorganic pollutants on the environmental fate and risk of GO in aquatic ecosystems.PMID:36356516 | DOI:10.1016/j.jhazmat.2022.130298

Theriogenology. 2022 Nov 1;195:199-208. doi: 10.1016/j.theriogenology.2022.10.030. Online ahead of print.ABSTRACTEquus members exhibit very divergent karyotype, genetic plasticity, and significant differences in their reproductive physiology. Despite the fact that somatic cell nuclear transfer and intracytoplasmic sperm injection (ICSI) has gained relevance in the last few years in horses, few reports have been published exploring ovum pick up (OPU) and in vitro maturation (IVM) of cumulus-oocyte complexes (COCs) in donkeys. Yet, some donkey species and breeds are considered endangered, and these assisted-reproductive technologies could help to preserve the genetic of valuable individuals. In this study, we tested the hypothesis that supplementation with jenny preovulatory follicular fluid (PFF) during IVM could improve oocyte developmental competence in the donkey. For this, in vitro nuclear maturation rates, cumulus cell expansion, and embryo development after ICSI of donkey COCs matured in culture media supplemented with fetal bovine serum (FBS) or donkey PFF, with a known metabolomic profile, were assessed. Time-lapse imagining was performed after ICSI of horse and donkey oocytes. Eight OPU sessions were done in five jennies with an average recovery rate of 69.2% (n = 45 COCs). Although lower cumulus cells expansion was observed in oocytes of PFF group (P = 0.0010), no significant differences were described in nuclear maturation rates and preimplantation embryo development between groups. Donkey ICSI embryos showed similar morphokinetics to horse ICSI embryos. Our study shows that supplementing IVM media with FBS or donkey PFF supports nuclear maturation and early preimplantation embryo development after ICSI in donkeys. To our knowledge, the present study is the first report of ICSI, time-lapse imaging and in vitro blastocyst production in donkey.PMID:36356490 | DOI:10.1016/j.theriogenology.2022.10.030

Res Vet Sci. 2022 Nov 3;153:127-136. doi: 10.1016/j.rvsc.2022.10.026. Online ahead of print.ABSTRACTFollicular fluid is formed from the transudation of theca and granulosa cells in the growing follicular antrum. Its main function is to provide an optimal intrafollicular microenvironment to modulate oocyte maturation. The aim of this study was to determine the metabolomic profile of preovulatory follicular fluid (PFF) in jennies. For this purpose, PFF was collected from 10 follicles of five jennies in heat. Then, PFF samples were analysed by nuclear magnetic resonance (NMR) and heteronuclear single quantum correlation (2D 1H/13C HSQC). Our study revealed the presence of at least 27 metabolites in the PFF of jennies (including common amino acids, carboxylic acids, amino acid derivatives, alcohols, saccharides, fatty acids, and lactams): 3-hydroxybutyrate, acetate, alanine, betaine, citrate, creatine, creatine phosphate, creatinine, ethanol, formate, glucose, glutamine, glycerol, glycine, hippurate, isoleucine, lactate, leucine, lysine, methanol, phenylalanine, proline, pyruvate, threonine, tyrosine, valine, and τ-methylhistidine. The metabolites found here have an important role in the oocyte development and maturation, since the PFF surrounds the follicle and provides it with the needed nutrients. Our results indicate a unique metabolic profile of the jennies PFF, as it differs from those previously observed in the PFF of the mare, a phylogenetically close species that is taken as a reference for establishing reproductive biotechnology techniques in donkeys. The metabolites found here also differ from those described in the TCM-199 medium enriched with fetal bovine serum (FBS), which is the most used medium for in vitro oocyte maturation in equids. These differences would suggest that the established conditions for in vitro maturation used so far may not be suitable for donkeys. By providing the metabolic composition of jenny PFF, this study could help understand the physiology of oocyte maturation as a first step to establish in vitro reproductive techniques in this species.PMID:36356420 | DOI:10.1016/j.rvsc.2022.10.026

Microbiol Res. 2022 Oct 31;266:127242. doi: 10.1016/j.micres.2022.127242. Online ahead of print.ABSTRACTPochonia chlamydosporia is a soil-dwelling fungus and biological control agent of nematodes, active ingredient in commercial bionematicides. The fungus is also endophytically associated with the roots of several plant species, promoting their growth and inducing systemic resistance. In this study, different pathways and tomato defense metabolites were studied to identify mechanisms induced by P. chlamydosporia that contribute to the control of Meloidogyne javanica, at early and late developmental stages. Some defense responses activated by the fungus appeared related to the nematode life cycle. Among the evaluated biochemical analysis, root colonization of P. chlamydosporia showed an increase in the concentration of phenolic compounds, such as chlorogenic acid. In addition, the expression of some host plant genes was also modified. The interaction of the fungus with roots parasitized by M. javanica resulted in the highest expression of Phenylalanine Ammonia-Lyase (PAL), Chalcone synthase (LECHS 2), and Protease Inhibitor (PI1) genes at 24 days post-inoculation. At the second sampling time (44 days), there was an increase in the expression of the Respiratory Burst Oxidase Homolog (RBOH) gene. Fungus reduced the expression of the ACC-oxidase and Pathogenesis-Related Proteins 1 (PR-1) genes in roots. Moreover, P. chlamydosporia inoculation changed metabolites and phytohormone profiles of the gall formed by M. javanica. Plant defense response appeared to involve the jasmonic acid and phytosphingosine cascades. With this analysis, it was possible to propose new molecular mechanisms induced by the fungus that contribute to the control of M. javanica.PMID:36356349 | DOI:10.1016/j.micres.2022.127242

Toxins (Basel). 2022 Nov 5;14(11):765. doi: 10.3390/toxins14110765.ABSTRACTThe traditional Chinese herbal medicine Eupatorium fortunei Turcz. (E. fortunei) has been widely adopted to treat nausea, diabetes, siriasis, and poor appetite. However, E. fortunei contains multiple pyrrolizidine alkaloids (PAs). This study aimed to investigate the hepatotoxicity of total alkaloids in E. fortunei (EFTAs) and identify the toxic mechanisms of EFTAs on hepatocytes. Liquid chromatography with a tandem mass spectrometry assay with reference standards indicated that EFTAs mainly consisted of eight PAs whose content accounted for 92.38% of EFTAs. EFTAs markedly decreased mouse body and liver weights and increased the contents of AST and ALT. The histopathological assays demonstrated that, after exposition to EFTAs, the structures of hepatocytes were damaged and the fibrosis and apoptosis in hepatocytes were accelerated. Moreover, EFTAs increased the serum level of inflammatory cytokines and aggravated circulating oxidative stress. A combination of hepatic proteomics and metabolomics was used to investigate the toxic mechanisms of EFTAs. The study revealed that EFTAs seriously disrupted glycerophospholipid metabolism by upregulating the contents of lysophosphatidylglycerol acyltransferase 1 and phosphatidylinositol and downregulating the contents of choline/ethanolamine kinase beta, choline-ethanolamine phosphotransferase 1, phospholipase D4, 1-acylglycerophosphocholine, phosphatidylcholine, and dihydroxyacetone phosphate in the liver, resulting in detrimental inflammation, fibrosis, and apoptosis. This study revealed that EFTAs induced severe hepatotoxicity by disrupting glycerophospholipid metabolism.PMID:36356015 | DOI:10.3390/toxins14110765

Toxics. 2022 Oct 22;10(11):632. doi: 10.3390/toxics10110632.ABSTRACTAir pollution constitutes an environmental problem that it is known to cause many serious adverse effects on the cardiovascular and respiratory systems. The chemical characterization of particulate matter (PM) is key for a better understanding of the associations between chemistry and toxicological effects. In this work, the chemical composition and biological effects of fifteen PM10 air filter samples from three air quality stations in Catalonia with contrasting air quality backgrounds were investigated. Three-dimensional (3D) lung cancer cell cultures were exposed to these sample extracts, and cytotoxicity, reactive oxygen species (ROS) induction, metabolomics, and lipidomics were explored. The factor analysis method Multivariate Curve Resolution-Alternating Least-Squares (MCR-ALS) was employed for an integrated interpretation of the associations between chemical composition and biological effects, which could be related to urban traffic emission, biomass burning smoke, and secondary aerosols. In this pilot study, a novel strategy combining new approach methodologies and chemometrics provided new insights into the biomolecular changes in lung cells associated with different sources of air pollution. This approach can be applied in further research on air pollution toxicity to improve our understanding of the causality between chemistry and its effects.PMID:36355924 | DOI:10.3390/toxics10110632