PubMed

Food Chem. 2022 Nov 17;405(Pt B):134962. doi: 10.1016/j.foodchem.2022.134962. Online ahead of print.ABSTRACTEpoxiconazole is widely used in agriculture to control plant diseases; however, its effect on the nutritional quality of crops is poorly understood. In the present study, the stereoselective effects of epoxiconazole and its enantiomers on leek metabolites and lipids were clarified using metabolomics and lipidomics based on ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Multivariate analysis revealed significant differences in 123 compounds of leek exposed to chiral epoxiconazole compared to the control group. The order of the degree of influence was (+)-epoxiconazole > racemic-epoxiconazole>(-)-epoxiconazole, indicating significant stereoselectivity. The differential expression of metabolites indicated the activation of stress defense systems, including the antioxidant defense system and signaling pathways and phenylpropanoid metabolism. Alterations in the levels of compounds associated with nutritional quality, such as amino acids, vitamins, phenylpropanoids, flavonoids and lipids indicated changes in the nutritional quality of leek. In general, the nutritional quality of leek decreased after exposure to epoxiconazole.PMID:36413841 | DOI:10.1016/j.foodchem.2022.134962

Anal Chem. 2022 Nov 22. doi: 10.1021/acs.analchem.2c02086. Online ahead of print.ABSTRACTAccurate metabolite characterization plays a vital role in targeted metabolomics. Nonetheless, the library of metabolites is still limited, especially for downstream conjugates, and it is time-consuming to synthesize each of these compounds due to high structural diversity. Herein, a green and smart strategy was developed to expand the scope of targeted metabolomics. The reference standards were synthesized in a one-pot microscale reaction, and the analytical method was tailored using the synthetic products. A group of new metabolites, namely bile acid-amino acid conjugates (BA-AAs), was studied as a proof-of-concept. First, in total 160 BA-AAs were synthesized using a small amount (2 mg each) of bile acids and low-toxic reagents within 4 h. Then, an ultra-high-performance liquid chromatography /Orbitrap-MS method was established to comprehensively profile 202 bile acid derivatives in 20 min. Finally, the method was applied to mice with inflammatory bowel disease (IBD) to discover the accumulation of 70 rare BA-AAs in small intestine and liver, where 55 were first reported from biosamples. These BA-AAs are farnesoid X receptor modulators and might contribute to the development of IBD. Our study demonstrated a feasible approach for the broad-spectrum targeted metabolomics of bile acids.PMID:36413803 | DOI:10.1021/acs.analchem.2c02086

J Agric Food Chem. 2022 Nov 22. doi: 10.1021/acs.jafc.2c04509. Online ahead of print.ABSTRACTThis study was designed to first verify the protective capacity of turmeric powder (TP) as a traditional cooking spice against dextran sulfate sodium (DSS)-induced intestinal inflammation and intestine microbiota imbalance. The DSS-induced mice were fed a standard rodent chow supplemented with or without TP (8%) for 37 days. The results indicated that the pathological phenotype, gut barrier disruption, and colon inflammation of DSS-induced mice were significantly improved through supplementation of TP. In addition, 16S rRNA-based microbiota or targeted metabolomics analysis indicated that TP ameliorated intestinal microbiota dysbiosis caused by DSS and particularly enhanced the abundances of probiotics correlated with tryptophan metabolism, such as Lactobacillus and Bifidobacterium, where the cecal tryptophan was metabolized to indole-3-propionic acid and indole-3-acetic acid. Consumption of TP markedly enhanced the expression levels of colonic aromatic hydrocarbon receptors and further increased the expressions of intestinal tight junction proteins and interleukin-22 in the colitis mice. Collectively, these findings manifest the protective actions of dietary TP consumption against ulcerative colitis via restoring the intestinal microbiota disorders, promoting microbial metabolism, and improving intestinal barrier damage.PMID:36413756 | DOI:10.1021/acs.jafc.2c04509

Chem Biodivers. 2022 Nov 22. doi: 10.1002/cbdv.202200745. Online ahead of print.ABSTRACTCelery is a vegetable widely consumed as a condiment to prepare diverse dishes around the world. Nevertheless, this plant is susceptible to the attack of several phytopathogens including those of the Fusarium genus which is translated into devastating losses for the production chain. Herein we report on the metabolic changes produced during the celery wilt caused by Fusarium oxysporum which was determined through untargeted 1H NMR metabolomics. The changes in the metabolite content of celery were measured at 16, 24, and 32 days post-inoculation using viable conidia obtained from the native F. oxsyporum strain FO3. Our results demonstrated that the parasitic activity of the fungus reduced the endogenous levels of free sugars (fructose, galactose, glucose isomers, mannose, Myo-inositol, mannitol, and sucrose) amino acids (alanine, aspartate GABA, glutamate, glutamine, histidine, isoleucine, leucine, methionine, proline, threonine, tyrosine, and valine), nucleosides (adenosine, cytidine, guanosine, and uridine) and organic acids (citric acid, fumaric acid, malic acid, and succinic acid). Interestingly, the levels of tyrosine and tryptophan were triggered as a consequence of F. oxysporum infection. This tendency was correlated with an increase in the levels of chlorogenic acid, apiin, and apigenin derivatives, suggesting their involvement in the chemical defense of celery against fungal colonization. According to principal component analysis (PCA) and Orthogonal Projections to Latent Structures Discriminant Analysis (OPLS-DA) methanol was the main differential metabolite and it was considered as a new chemical marker associated with F. oxysporum infection. Our results demonstrate that infected celery plants dramatically reduced their nutritional and nutraceutical contents during Fusarium wilt after 32 days post-inoculation. However, these findings also suggest that the phenylpropanoid pathway is strongly related with the chemical defense of celery against F. oxysporum.PMID:36413469 | DOI:10.1002/cbdv.202200745

J Phys Chem A. 2022 Nov 22. doi: 10.1021/acs.jpca.2c06858. Online ahead of print.ABSTRACTAnalysis of small molecules is essential to metabolomics, natural products, drug discovery, food technology, and many other areas of interest. Current barriers preclude from identifying the constituent molecules in a mixture as overlapping clusters of NMR lines pose a major challenge in resolving signature frequencies for individual molecules. While homonuclear decoupling techniques produce much simplified pure shift spectra, they often affect sensitivity. Conversion of typical NMR spectra to pure shift spectra by signal processing without a priori knowledge about the coupling patterns is essential for accurate analysis. We developed a super-resolved wavelet packet transform based 1H NMR spectroscopy that can be used in high-throughput studies to reliably decouple individual constituents of small molecule mixtures. We demonstrate the efficacy of the method on the model mixtures of saccharides and amino acids in the presence of significant noise.PMID:36413171 | DOI:10.1021/acs.jpca.2c06858

mSystems. 2022 Nov 22:e0090322. doi: 10.1128/msystems.00903-22. Online ahead of print.ABSTRACTCurrently, the regulation of Lactobacillus on intestinal stem cells (ISCs) attracts broad attention, but their active ingredients and the underlying mechanism are worthy of further study. Previously, host intestinal commensal bacteria were verified to drive the differentiation of ISCs. In this study, the strong bacteriostatic activity of Lactobacillus salivarius and Lactobacillus agilis were illustrated, and the components (supernatant, precipitation) of L. salivarius or L. agilis were further demonstrated to decrease the differentiation of ISCs in vivo. Interestingly, antibiotics feeding decreased ISCs differentiation in vivo as well. However, the administration of L. salivarius supernatant following antibiotics feeding was shown to promote ISCs differentiation dramatically when compared with the antibiotics feeding group, indicating that some active ingredients existed in its supernatant to promote ISCs activity. Strikingly, in vitro, the treatment of L. salivarius supernatant was further confirmed to promote the intestinal organoids' size, budding, and LGR5 expression. Next, the metabolomics analysis of Lactobacilli' supernatants suggested that succinate might be a crucial metabolite to promote ISCs activity. Further, the succinate treatment in vitro (1000 μM) and in vivo (50 mM) was confirmed to enhance the expression of LGR5 and PCNA. SLC13A3 (a sodium/dicarboxylate cotransporter) was detected in the intestinal organoids and demonstrated to transport succinate into ISCs, as confirmed by the contact of FITC-succinate with ISCs nucleus. Subsequently, high mitochondrial membrane potential and reactive oxygen species levels appeared in the intestinal organoids upon succinate treatment. Collectively, the promotion of L. salivarius on ISCs activity is associated with succinate-induced mitochondrial energy metabolism. IMPORTANCE In our previous study, Lactobacillus salivarius and Lactobacillus agilis were demonstrated to regulate intestinal stem cell activity in hens, but their active ingredients and the underlying mechanism remain unclear. In this study, L. salivarius supernatant was shown to directly promote intestinal stem cell activity. Furthermore, the succinate (a critical metabolite of L. salivarius) was screened out to promote intestinal stem cell activity. Moreover, the succinate was confirmed to enter intestinal stem cells and induce high mitochondrial energy metabolism, finally promoting intestinal stem cell activity. These findings will advance uncovering the mechanism by which Lactobacillus regulate intestinal stem cell activity in chickens.PMID:36413033 | DOI:10.1128/msystems.00903-22

J Agric Food Chem. 2022 Nov 22. doi: 10.1021/acs.jafc.2c06287. Online ahead of print.ABSTRACTNitrogen (N) and potassium (K) have significant effects on apple peel color. To further understand the molecular mechanism of N-K regulation of apple color, we analyzed the apple peel under different N and K treatments using isotope labeling, transcriptomics, and metabolomics. Under high N treatments, fruit red color and anthocyanin content decreased significantly. High N decreased the 13C distribution rate and increased the Ndff values of fruits, while K increased the expression of MdSUTs and MdSOTs and promoted 13C transportation to fruits. Anthocyanin-targeted metabonomics and transcriptome analysis revealed that high N downregulated the expression of structural genes related to the anthocyanin synthesis pathway (MdPAL, Md4CL, MdF3H, MdANS, and MdUFGT) and their regulators (MdMYBs and MdbHLHs), and also decreased some metabolites contents. K alleviated this inhibition and seven anthocyanins were regulated by N-K. Our results improve the understanding of the synergistic regulation of apple fruit coloring by N-K.PMID:36412927 | DOI:10.1021/acs.jafc.2c06287

J Funct Biomater. 2022 Nov 6;13(4):223. doi: 10.3390/jfb13040223.ABSTRACTAmino sugars N-acetylglucosamine (GlcNAc) and glucosamine (GlcN) are abundant sources of carbon and nitrogen in the oral cavity. The aim of this study was to investigate the effects of GlcNAc metabolism on the genomics and biochemistry of a saliva-derived microbial community, and on the surface integrity of human teeth and restorative surfaces. Pooled cell-containing saliva (CCS) was used to establish a microcosm biofilm in vitro in a biofilm medium (BM) containing 5 different carbohydrates. The microbial composition of each biofilm was analyzed by 16S rRNA amplicon sequencing, and the concentrations of eight organic acids were determined for selected sugars by targeted metabolomics. Meanwhile, extracted human teeth and polished titanium and ceramic disks were submerged in BM supplemented with 1% of glucose or GlcNAc, inoculated with CCS and Streptococcus mutans UA159, and incubated for 30 days. To mimic the effects of other microbial byproducts, the specimens were immersed in 10 mM hydrogen peroxide and 10 mM ammonium hydroxide for 30 days. The surface of each specimen was evaluated by profilometry for roughness (Ra) and imaged by scanning electron microscopy. The pH of the biofilm supernatant was significantly higher for the medium containing GlcNAc (p < 0.0001), and was higher in samples containing teeth than the two restorative disks for media containing the same sugar. For both teeth and titanium specimens, the samples treated with glucose-biofilm presented higher roughness values (Ra) than those with GlcNAc-biofilm and every other group. SEM images of the teeth and titanium disks largely supported the profilometry results, with glucose-biofilm samples demonstrating the largest deviation from the reference. For ceramic disks, slightly higher Ra values were obtained for the ammonia group. These findings provide the first direct evidence to support the ability of amino sugars to significantly reduce the cariogenic potential of oral biofilms by altering their biochemistry and bacterial composition. Additionally, amino sugar metabolism appears to be less detrimental to teeth and restorative surfaces than glucose metabolism.PMID:36412864 | DOI:10.3390/jfb13040223

Endocrinology. 2022 Nov 22:bqac191. doi: 10.1210/endocr/bqac191. Online ahead of print.ABSTRACTAndrogens regulate broad physiologic and pathologic processes, including external genitalia development, prostate cancer progression, and anti-inflammatory effects in both cancer and asthma. In prostate cancer, several lines of evidence have implicated dietary and endogenous fatty acids in cell invasion, angiogenesis, and treatment resistance. However, the role of fatty acids in steroidogenesis and the mechanisms by which alterations in this pathway occur are not well understood. Here, we show that, of a panel of fatty acids tested, arachidonic acid and its specific metabolite 5-hydroxyeicosatetraenoic acid (5-HETE) regulate androgen metabolism. Arachidonic acid is metabolized to 5-HETE and reduces androgens by inducing AKR1C2 and AKR1C3 expression in human prostate, breast, and lung epithelial cells. Finally, we provide evidence that these effects require the expression of the antioxidant response sensor, nuclear factor erythroid 2-related factor 2 (Nrf2). Our findings identify an interconnection between conventional fatty acid metabolism and steroid metabolism that has broad relevance to androgen physiology and inflammatory regulation.PMID:36412122 | DOI:10.1210/endocr/bqac191

Biomed Pharmacother. 2022 Dec;156:113986. doi: 10.1016/j.biopha.2022.113986. Epub 2022 Nov 8.ABSTRACTMutations in the gene encoding the RNA/DNA-binding protein Fused in Sarcoma (FUS) have been detected in familial amyotrophic lateral sclerosis (ALS) patients. FUS has been found to be a critical component of the oxidative damage repair complex that might explain its role in neurodegeneration. Here, we examined what impact antioxidant treatment with thiamine (vitamine B1), or its more bioavailable derivative O,S-dibenzoylthiamine (DBT), would have on the hallmarks of pathology in the FUS[1-359]-transgenic mouse model of ALS. From 8-weeks old, in the pre-symptomatic phase of disease, animals received either thiamine, DBT (200 mg/kg/day), or vehicle for 6 weeks. We examined physiological, behavioral, molecular and histological outcomes, as well as the serum metabolome using nuclear magnetic resonance (NMR). The DBT-treated mice displayed improvements in physiological outcomes, motor function and muscle atrophy compared to vehicle, and the treatment normalized levels of brain glycogen synthase kinase-3β (GSK-3β), GSK-3β mRNA and IL-1β mRNA in the spinal cord. Analysis of the metabolome revealed an increase in the levels of choline and lactate in the vehicle-treated FUS mutants alone, which is also elevated in the cerebrospinal fluid of ALS patients, and reduced glucose and lipoprotein concentrations in the FUS[1-359]-tg mice, which were not the case in the DBT-treated mutants. The administration of thiamine had little impact on the outcome measures, but it did normalize circulating HDL levels. Thus, our study shows that DBT therapy in FUS mutants is more effective than thiamine and highlights how metabolomics may be used to evaluate therapy in this model.PMID:36411653 | DOI:10.1016/j.biopha.2022.113986

Biomed Pharmacother. 2022 Dec;156:113923. doi: 10.1016/j.biopha.2022.113923. Epub 2022 Oct 29.ABSTRACTMalignant tumors are non-communicable diseases that affect human life health and quality of life. Anti-tumour-related research has also been the focus and difficulty in oncology research. With the rise of metabolomics, tumour biology, and the theory of tumour reprogramming, amino acid metabolic reprogramming has become a new target for antitumor research. Amino acids provide biomolecules such as nucleotides for tumour cell proliferation, invasion, and immune escape processes. They are also essential metabolites for immune cell activation and antitumor effects in the tumour microenvironment. Abnormal changes in amino acid metabolism are closely related to tumour development and immunity. Some essential proteins or critical enzymes in their metabolic pathways can be used for tumour diagnosis and prognosis assessment markers. Therefore, this paper reviews the effects of amino acid metabolism on tumour cell proliferation and the abnormal alterations of amino acid metabolism during the tumour metabolic cycle and analyzes and prospects the tumour therapeutic drugs targeting amino acid metabolism. This paper provides theoretical references for the in-depth study of the regulation of amino acid metabolism on tumour development and its possible therapeutic targets.PMID:36411616 | DOI:10.1016/j.biopha.2022.113923

Front Endocrinol (Lausanne). 2022 Nov 3;13:1014670. doi: 10.3389/fendo.2022.1014670. eCollection 2022.ABSTRACTOBJECTIVE: This meta-analysis of randomized controlled trials (RCTs) was conducted to assess the efficacy of probiotics in the treatment of metabolic-associated fatty liver disease (MAFLD) mainly in terms of liver function, glucose and lipid metabolism, and inflammation.METHODS: RCTs were searched on PubMed, Web of Science, Embase, and the Cochrane Library until June 2022. A meta-analysis was performed on the therapeutic efficacy of probiotics on liver function, glucose and lipid metabolism, and inflammatory biomarkers by using RevMan 5.4 software.RESULTS: A total of 772 patients from 15 studies were included in the analysis. The methodological quality varied across studies. We found that adding probiotic therapies could reduce the levels of alanine aminotransferase [mean difference (MD): -11.76 (-16.06, -7.46), p < 0.00001], aspartate aminotransferase (MD: -9.08 (-13.60, -4.56), p < 0.0001], γ-glutamyltransferase [MD: -5.67 (-6.80, -4.54), p < 0.00001] and homeostasis model assessment-insulin resistance [MD: -0.62 (-1.08, -0.15), p = 0.01], in patients with MAFLD compared with those in control individuals. However, there was no statistically significant improvement in the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, C-reactive protein and tumor necrosis factor α among patients with MAFLD. Subgroup analyses showed that other key factors, such as age, participants' baseline body mass index, and the duration of intervention, may influence probiotic therapy outcomes.CONCLUSION: There is promising evidence that probiotic supplementation can reduce liver enzyme levels and regulate glycometabolism in patients with MAFLD. Further rigorous and long-term trials exploring these novel therapeutic perspectives are warranted to confirm these results.PMID:36407321 | PMC:PMC9670148 | DOI:10.3389/fendo.2022.1014670

Front Cell Infect Microbiol. 2022 Oct 28;12:945750. doi: 10.3389/fcimb.2022.945750. eCollection 2022.ABSTRACTCrithidia fasiculata belongs to the trypanosomatidae order of protozoan parasites, bearing close relation to other kinetoplastid parasites such as Trypanosoma brucei and Leishmania spp. As an early diverging lineage of eukaryotes, the study of kinetoplastid parasites has provided unique insights into alternative mechanisms to traditional eukaryotic metabolic pathways. Crithidia are a monogenetic parasite for mosquito species and have two distinct lifecycle stages both taking place in the mosquito gut. These consist of a motile choanomastigote form and an immotile amastigote form morphologically similar to amastigotes in Leishmania. Owing to their close relation to Leishmania, Crithidia are a growing research tool, with continuing interest in its use as a model organism for kinetoplastid research with the added benefit that they are non-pathogenic to humans and can be grown with no special equipment or requirements for biological containment. Although comparatively little research has taken place on Crithidia, similarities to other kinetoplast species has been shown in terms of energy metabolism and genetics. Crithidia also show similarities to kinetoplastids in their production of the monosaccharide D-arabinopyranose similar to Leishmania, which is incorporated into a lipoarabinogalactan a major cell surface GPI-anchored molecule. Additionally, Crithidia have been used as a eukaryotic expression system to express proteins from other kinetoplastids and potentially other eukaryotes including human proteins allowing various co- and post-translational protein modifications to the recombinant proteins. Despite the obvious usefulness and potential of this organism very little is known about its lipid metabolism. Here we describe a detailed lipidomic analyses and demonstrate the possible placidity of Crithidia's lipid metabolis. This could have important implications for biotechnology approaches and how other kinetoplastids interact with, and scavenge nutrients from their hosts.PMID:36405970 | PMC:PMC9671073 | DOI:10.3389/fcimb.2022.945750

Phytother Res. 2022 Nov 21. doi: 10.1002/ptr.7670. Online ahead of print.ABSTRACTThe mechanism of SARS-CoV-2 spike protein-mediated perturbations of metabolic pathways and modulation of antcin A, a steroid-like compound isolated from Taiwanofungus camphoratus, are not studied. Here, we investigated the metabolic alteration by SARS-CoV-2 spike protein and the regulatory effect of antcin A on SARS-CoV-2 spike protein-induced metabolic changes in the Phorbol 12-myristate 13-acetate (PMA)-induced human monocytes (THP-1) using proton nuclear magnetic resonance (1 H-NMR) and MetaboAnalyst 5.0 software. The cytotoxic potential of SARS-CoV-2 spike protein, antcin A, and dexamethasone was assessed by MTT assay. The metabolomic perturbations and their relation to human coronaviruses' receptors were evaluated by qPCR. This study indicated that the altered metabolites mediated by SARS-CoV-2 protein, such as methionine, phosphoenolpyruvic acid, canadine, glutamine, ethanolamine, and phenylalanine, were significantly reversed by antcin A. In addition, antcin A significantly inhibited SARS-CoV-2 spike protein-mediated up-regulation of TLR-4 and ACE2 receptors, while GRP78 inhibition was not statistically significant. This is the first study to use 1 H-NMR to investigate SARS-CoV-2 spike protein-induced metabolomic changes in PMA-induced THP-1 cells. Antcin A significantly reversed metabolomic alters while dexamethasone failed to fix them. Therefore, we believe that antcin A could be a potential candidate for therapeutic agents for viral infections related to a metabolic abnormality.PMID:36411492 | DOI:10.1002/ptr.7670

Eur J Med Res. 2022 Nov 21;27(1):256. doi: 10.1186/s40001-022-00895-6.ABSTRACTBACKGROUND: Despite the wide clinical application of checkpoint inhibitor immunotherapy in lung adenocarcinoma, its limited benefit to patients remains puzzling to researchers. One of the mechanisms of immunotherapy resistance may be the dysregulation of lactate metabolism in the immunosuppressive tumor microenvironment (TME), which can inhibit dendritic cell maturation and prevent T-cell invasion into tumors. However, the key genes related to lactate metabolism and their influence on the immunotherapeutic effects in lung adenocarcinoma have not yet been investigated in depth.METHODS: In this study, we first surveyed the dysregulated expression of genes related to lactate metabolism in lung adenocarcinoma and then characterized their biological functions. Using machine learning methods, we constructed a lactate-associated gene signature in The Cancer Genome Atlas cohort and validated its effectiveness in predicting the prognosis and immunotherapy outcomes of patients in the Gene Expression Omnibus cohorts.RESULTS: A 7-gene signature based on the metabolomics related to lactate metabolism was found to be associated with multiple important clinical features of cancer and was an independent prognostic factor.CONCLUSIONS: These results suggest that rather than being simply a metabolic byproduct of glycolysis, lactate in the TME can affect immunotherapy outcomes. Therefore, the mechanism underlying this effect of lactate is worthy of further study.PMID:36411477 | DOI:10.1186/s40001-022-00895-6

Epigenetics Chromatin. 2022 Nov 21;15(1):35. doi: 10.1186/s13072-022-00470-7.ABSTRACTBACKGROUND: Three-dimensional (3D) cell culture has emerged as an alternative approach to 2D flat culture to model more accurately the phenotype of solid tissue in laboratories. Culturing cells in 3D more precisely recapitulates physiological conditions of tissues, as these cells reduce activities related to proliferation, focusing their energy consumption toward metabolism and homeostasis.RESULTS: Here, we demonstrate that 3D liver spheroids are a suitable system to model chromatin dynamics and response to epigenetics inhibitors. To delay necrotic tissue formation despite proliferation arrest, we utilize rotating bioreactors that apply active media diffusion and low shearing forces. We demonstrate that the proteome and the metabolome of our model resemble typical liver functions. We prove that spheroids respond to sodium butyrate (NaBut) treatment, an inhibitor of histone deacetylases (HDACi), by upregulating histone acetylation and transcriptional activation. As expected, NaBut treatment impaired specific cellular functions, including the energy metabolism. More importantly, we demonstrate that spheroids reestablish their original proteome and transcriptome, including pre-treatment levels of histone acetylation, metabolism, and protein expression once the standard culture condition is restored after treatment. Given the slow replication rate (> 40 days) of cells in 3D spheroids, our model enables to monitor the recovery of approximately the same cells that underwent treatment, demonstrating that NaBut does not have long-lasting effects on histone acetylation and gene expression. These results suggest that our model system can be used to quantify molecular memory on chromatin.CONCLUSION: Together, we established an innovative cell culture system that can be used to model anomalously decondensing chromatin in physiological cell growth and rule out epigenetics inheritance if cells recover the original phenotype after treatment. The transient epigenetics effects demonstrated here highlight the relevance of using a 3D culture model system that could be very useful in studies requiring long-term drug treatment conditions that would not be possible using a 2D cell monolayer system.PMID:36411440 | DOI:10.1186/s13072-022-00470-7

Sci Rep. 2022 Nov 21;12(1):19982. doi: 10.1038/s41598-022-24214-5.ABSTRACTChemical communication in elephants has been well studied at the chemical and behavioural levels. Pheromones have been identified in the Asian elephant (Elephas maximus), including (Z)-7-dodecenyl acetate and frontalin, and their specific effects on the sexual behaviour of elephants have been accurately documented. In contrast, our knowledge on the proteins mediating detection of pheromones in elephants remains poor and superficial, with only three annotated and reliable entries in sequence databases, two of them being odorant-binding proteins (OBPs), and the third a member of von Ebner's gland (VEG) proteins. Proteomic analysis of trunk wash extract from African elephant (Loxodonta africana) identified one of the OBPs (LafrOBP1) as the main component. We therefore expressed LafrOBP1 and its Asian elephant orthologue in yeast Pichia pastoris and found that both recombinant proteins, as well as the natural LafrOBP1 are tuned to (Z)-7-dodecenyl acetate, but have no affinity for frontalin. Both the natural and recombinant LafrOBP1 carry post-translational modifications such as O-glycosylation, phosphorylation and acetylation, but as these modifications affect only a very small amount of the protein, we cannot establish their potential effects on the ligand-binding properties of OBP1.PMID:36411331 | DOI:10.1038/s41598-022-24214-5

Nat Cancer. 2022 Nov 21. doi: 10.1038/s43018-022-00463-1. Online ahead of print.ABSTRACTThe pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG-asparaginase sensitizes tumors to mitochondrial targeting with phenformin.PMID:36411320 | DOI:10.1038/s43018-022-00463-1

Nat Commun. 2022 Nov 21;13(1):7024. doi: 10.1038/s41467-022-34422-2.ABSTRACTEnvironmental exposures during early life play a critical role in life-course health, yet the molecular phenotypes underlying environmental effects on health are poorly understood. In the Human Early Life Exposome (HELIX) project, a multi-centre cohort of 1301 mother-child pairs, we associate individual exposomes consisting of >100 chemical, outdoor, social and lifestyle exposures assessed in pregnancy and childhood, with multi-omics profiles (methylome, transcriptome, proteins and metabolites) in childhood. We identify 1170 associations, 249 in pregnancy and 921 in childhood, which reveal potential biological responses and sources of exposure. Pregnancy exposures, including maternal smoking, cadmium and molybdenum, are predominantly associated with child DNA methylation changes. In contrast, childhood exposures are associated with features across all omics layers, most frequently the serum metabolome, revealing signatures for diet, toxic chemical compounds, essential trace elements, and weather conditions, among others. Our comprehensive and unique resource of all associations ( https://helixomics.isglobal.org/ ) will serve to guide future investigation into the biological imprints of the early life exposome.PMID:36411288 | DOI:10.1038/s41467-022-34422-2

Trends Plant Sci. 2022 Nov 18:S1360-1385(22)00294-1. doi: 10.1016/j.tplants.2022.10.009. Online ahead of print.NO ABSTRACTPMID:36411181 | DOI:10.1016/j.tplants.2022.10.009