PubMed

Related Articles Azadirachtin-A from Azadirachta indica Impacts Multiple Biological Targets in Cotton Bollworm Helicoverpa armigera. ACS Omega. 2019 May 31;4(5):9531-9541 Authors: Dawkar VV, Barage SH, Barbole RS, Fatangare A, Grimalt S, Haldar S, Heckel DG, Gupta VS, Thulasiram HV, Svatoš A, Giri AP Abstract Azadirachtin-A (AzaA) from the Indian neem tree (Azadirachta indica) has insecticidal properties; however, its molecular mechanism remains elusive. The "targeted and nontargeted proteomic profiling", metabolomics, matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) imaging, gene expression, and in silico analysis provided clues about its action on Helicoverpa armigera. Fourth instar H. armigera larvae fed on AzaA-based diet (AzaD) suffered from significant mortality, growth retardation, reduced larval mass, complications in molting, and prolonged development. Furthermore, death of AzaD-fed larvae was observed with various phenotypes like bursting, blackening, and half-molting. Liquid chromatography-mass spectrometry (LC-MS) data showed limited catabolic processing of ingested AzaA and dramatic alternations of primary metabolism in H. armigera. MALDI-TOF imaging indicated the presence of AzaA in midgut of H. armigera. In the gut, out of 79 proteins identified, 34 were upregulated, which were related to digestion, immunity, energy production, and apoptosis mechanism. On the other hand, 45 proteins were downregulated, including those from carbohydrate metabolism, lipid metabolism, and energy transfer. In the hemolymph, 21 upregulated proteins were reported to be involved in immunity, RNA processing, and mRNA-directed protein synthesis, while 7 downregulated proteins were implicated in energy transfer, hydrolysis, lipid metabolism, defense mechanisms, and amino acid storage-related functions. Subsequently, six target proteins were identified using labeled AzaA that interacted with whole insect proteins. In silico analysis suggests that AzaA could be efficiently accommodated in the hydrophobic pocket of juvenile hormone esterase and showed strong interaction with active site residues, indicating plausible targets of AzaA in H. armigera. Quantitative polymerase chain reaction analysis suggested differential gene expression patterns and partly corroborated the proteomic results. Overall, data suggest that AzaA generally targets more than one protein in H. armigera and hence could be a potent biopesticide. PMID: 31460043 [PubMed]

Related Articles Selective Amino Acid-Only in Vivo NMR: A Powerful Tool To Follow Stress Processes. ACS Omega. 2019 May 31;4(5):9017-9028 Authors: Lane D, Soong R, Bermel W, Ning P, Dutta Majumdar R, Tabatabaei-Anaraki M, Heumann H, Gundy M, Bönisch H, Liaghati Mobarhan Y, Simpson MJ, Simpson AJ Abstract In vivo NMR of small 13C-enriched aquatic organisms is developing as a powerful tool to detect and explain toxic stress at the biochemical level. Amino acids are a very important category of metabolites for stress detection as they are involved in the vast majority of stress response pathways. As such, they are a useful proxy for stress detection in general, which could then be a trigger for more in-depth analysis of the metabolome. 1H-13C heteronuclear single quantum coherence (HSQC) is commonly used to provide additional spectral dispersion in vivo and permit metabolite assignment. While some amino acids can be assigned from HSQC, spectral overlap makes monitoring them in vivo challenging. Here, an experiment typically used to study protein structures is adapted for the selective detection of amino acids inside living Daphnia magna (water fleas). All 20 common amino acids can be selectively detected in both extracts and in vivo. By monitoring bisphenol-A exposure, the in vivo amino acid-only approach identified larger fluxes in a greater number of amino acids when compared to published works using extracts from whole organism homogenates. This suggests that amino acid-only NMR of living organisms may be a very sensitive tool in the detection of stress in vivo and is highly complementary to more traditional metabolomics-based methods. The ability of selective NMR experiments to help researchers to "look inside" living organisms and only detect specific molecules of interest is quite profound and paves the way for the future development of additional targeted experiments for in vivo research and monitoring. PMID: 31459990 [PubMed]

Related Articles Metabolomics Profile and Targeted Lipidomics in Multiple Tissues Associated with Feed Efficiency in Beef Steers. ACS Omega. 2019 Feb 28;4(2):3973-3982 Authors: Artegoitia VM, Foote AP, Lewis RM, Freetly HC Abstract A study of multiple tissues was conducted to identify potential metabolic differences in cattle differing in feed efficiency. Individual feed intake and body weight was measured on 144 steers during 105 days on a high-concentrate ration. Steers were selected according to differences in average daily gain (ADG) with those with the greatest ADG (n = 8; 1.96 ± 0.02 kg/day) and least ADG (n = 8; 1.57 ± 0.02 kg/day), whose dry matter intake was within 0.32 SD of the mean intake (10.10 ± 0.05 kg/day). Duodenum, liver, adipose, and longissimus-dorsi were collected at slaughter, and metabolomics profiles were performed by ultra performance liquid chromatography quadrupole-time of-flight mass spectrometry. Principal components analyses, t-tests, and fold changes in tissues profile were used to identify differential metabolites between ADG groups. These were primarily involved in α-linolenic metabolism, which was downregulated in the greatest ADG as compared to least-ADG group in duodenum, adipose, and longissimus-dorsi. However, taurine and glycerophospholipids metabolisms were both upregulated in the greatest ADG compared with least-ADG group in the liver. The phospholipids and cholesterol were quantified in the tissues. Lipid transport and oxidation were the main common metabolic mechanisms associated with cattle feed efficiency. Combining analyses of multiple tissues may offer a powerful approach for defining the molecular basis of differences in performance among cattle for key production attributes. PMID: 31459606 [PubMed]

Related Articles A Novel Role for Triglyceride Metabolism in Foxp3 Expression. Front Immunol. 2019;10:1860 Authors: Howie D, Ten Bokum A, Cobbold SP, Yu Z, Kessler BM, Waldmann H Abstract Lipid metabolism plays a key role in many cellular processes. We show here that regulatory T cells have enhanced lipid storage within subcellular lipid droplets (LD). They also express elevated amounts of both isoforms of diacylglycerol acyl transferase (DGAT1 & 2), enzymes required for the terminal step of triacylglycerol synthesis. In regulatory T-cells (Tregs), the conversion of diacylglycerols to triacylglycerols serves two additional purposes other than lipid storage. First, we demonstrate that it protects T cells from the toxic effects of saturated long chain fatty acids. Second, we show that Triglyceride formation is essential for limiting activation of protein kinase C via free diacyl glycerol moieties. Inhibition of DGAT1 resulted in elevated active PKC and nuclear NFKB, as well as impaired Foxp3 induction in response to TGFβ. Thus, Tregs utilize a positive feedback mechanism to promote sustained expression of Foxp3 associated with control of LD formation. PMID: 31456800 [PubMed - in process]

Related Articles Evidence of a Demethylase-Independent Role for the H3K4-Specific Histone Demethylases in Aspergillus nidulans and Fusarium graminearum Secondary Metabolism. Front Microbiol. 2019;10:1759 Authors: Bachleitner S, Sørensen JL, Gacek-Matthews A, Sulyok M, Studt L, Strauss J Abstract Fungi produce a plethora of secondary metabolites (SMs) involved in cellular protection, defense, and signaling. Like other metabolic processes, transcription of SM biosynthesis genes is tightly regulated to prevent an unnecessary use of resources. Genes involved in SM biosynthesis are usually physically linked, arranged in secondary metabolite gene clusters (SMGCs). Research over the last decades has shown that chromatin structure and posttranslational modifications (PTMs) of histones represent important layers of SMGC regulation. For instance, trimethylation of histone H3 lysine 4 (H3K4me3) is a PTM typically associated with promoter regions of actively transcribed genes. Previously, we have shown that the H3K4me3-specific, JmjC domain-containing histone demethylase KdmB functions not only in repression but also in activation of secondary metabolism in Aspergillus nidulans, suggesting that KdmB has additional functions apart from histone demethylation. In this study, we identified demethylase-independent functions of KdmB in transcriptional regulation of SM gene clusters. Furthermore, we show that this activating and demethylase-independent role of the H3K4 demethylase is also conserved in the phytopathogenic fungus Fusarium graminearum. Lack of FgKdm5 resulted in significant downregulation of five of seven analyzed SMs, whereby only one SMGC depends on a functional JmjC-domain. In A. nidulans strains deficient in H3K4 methylation, i.e., cclA∆, largely phenocopied kdmB∆, while this is not the case for most of the SMs analyzed in Fusarium spp. Notably, KdmB could not rescue the demethylase function in ∆fgkdm5 but restored all demethylase-independent phenotypes. PMID: 31456754 [PubMed]

Related Articles Metabolites profiling of date palm (Phoenix dactylifera L.) commercial by-products (pits and pollen) in relation to its antioxidant effect: a multiplex approach of MS and NMR metabolomics. Metabolomics. 2019 Aug 27;15(9):119 Authors: Otify AM, El-Sayed AM, Michel CG, Farag MA Abstract INTRODUCTION: Phoenix dactylifera L. (date palm) is one of the most valued crops worldwide for its economical and nutraceutical applications of its date fruit (pericarp). Currently date pits, considered as a waste product, is employed as coffee substitute post roasting. Whereas, pollen represents another valuable by-product used as a dietary supplement. OBJECTIVES: In this study, a large-scale comparative metabolomics approach was performed for the first characterization and standardization of date palm by-products viz., date pits and pollen. Moreover, roasting impact on date pit metabolite composition was also assessed. METHODS: Metabolites profiling of pits and pollen was determined via a multiplex approach of UPLC-MS and NMR, coupled to multivariate analysis, in relation to its antioxidant activities. RESULTS: Chemical analyses led to the identification of 67 metabolites viz., phenolic acids, flavonols, fatty acids, sphingolipids, steroids and saponins of which 10 are first time to be reported. The enrichment of steroids in date pollen accounts for its fertility promoting properties, whereas date pit was found a rich source for antioxidant polyphenols using metabolomics. PMID: 31456052 [PubMed - in process]

Related Articles Specific diacylglycerols generated by hepatic lipogenesis stimulate the oncogenic androgen receptor activity in male hepatocytes. Int J Obes (Lond). 2019 Aug 27;: Authors: Cheng YW, Chen KW, Kuo HC, Kuo CH, Lin WH, Chen PJ, Yeh SH Abstract BACKGROUND: Obesity-induced hepatocellular carcinoma (HCC) is more prevalent in males than in females, but the underlying mechanism remains unclear. The influence of hepatic androgen receptor (AR) pathway on the gender difference of HCC has been well documented. Here we investigated the role of hepatic lipogenesis, which is elevated in the livers of obese and nonalcoholic fatty liver disease (NAFLD) patients, in stimulating the AR pathway for the male preference of obesity induced HCC. METHODS: Male C57BL/6J mice were fed a fructose-rich high carbohydrate diet (HCD) to induce hepatic lipogenesis. The effect of hepatic lipogenesis on AR was examined by the expression of hydrodynamically injected AR reporter and the endogenous AR target gene; the mechanism was delineated in hepatoma cell lines and validated in male mice. RESULTS: The hepatic lipogenesis induced by a fructose-rich HCD enhanced the transcriptional activity of hepatic AR in male mice, which did not happen when fed a high fat diet. This AR activation was blocked by sh-RNAs or inhibitors targeting key enzymes in lipogenesis, either acetyl-CoA carboxylase subunit alpha (ACCα), or fatty acid synthase (FASN), in vivo and in vitro. Further mechanistic study identified that specific unsaturated fatty acid, the oleic acid (C18:1 n-9), incorporated DAGs produced by hepatic lipogenesis are the key molecules to enhance the AR activity, through activation of Akt kinase, and this novel mechanism is targeted by metformin. CONCLUSIONS: Our study elucidates a novel mechanism underlying the higher risk of HCC in obese/NAFLD males, through specific DAGs enriched by hepatic lipogenesis to increase the transcriptional activity of hepatic AR, a confirmed risk factor for male HCC. PMID: 31455870 [PubMed - as supplied by publisher]

Related Articles Early Life Exposure in Mexico to ENvironmental Toxicants (ELEMENT) Project. BMJ Open. 2019 Aug 26;9(8):e030427 Authors: Perng W, Tamayo-Ortiz M, Tang L, Sánchez BN, Cantoral A, Meeker JD, Dolinoy DC, Roberts EF, Martinez-Mier EA, Lamadrid-Figueroa H, Song PXK, Ettinger AS, Wright R, Arora M, Schnaas L, Watkins DJ, Goodrich JM, Garcia RC, Solano-Gonzalez M, Bautista-Arredondo LF, Mercado-Garcia A, Hu H, Hernandez-Avila M, Tellez-Rojo MM, Peterson KE Abstract PURPOSE: The Early Life Exposure in Mexico to ENvironmental Toxicants (ELEMENT) Project is a mother-child pregnancy and birth cohort originally initiated in the mid-1990s to explore: (1) whether enhanced mobilisation of lead from maternal bone stores during pregnancy poses a risk to fetal and subsequent offspring neurodevelopment; and (2) whether maternal calcium supplementation during pregnancy and lactation can suppress bone lead mobilisation and mitigate the adverse effects of lead exposure on offspring health and development. Through utilisation of carefully archived biospecimens to measure other prenatal exposures, banking of DNA and rigorous measurement of a diverse array of outcomes, ELEMENT has since evolved into a major resource for research on early life exposures and developmental outcomes. PARTICIPANTS: n=1643 mother-child pairs sequentially recruited (between 1994 and 2003) during pregnancy or at delivery from maternity hospitals in Mexico City, Mexico. FINDINGS TO DATE: Maternal bone (eg, patella, tibia) is an endogenous source for fetal lead exposure due to mobilisation of stored lead into circulation during pregnancy and lactation, leading to increased risk of miscarriage, low birth weight and smaller head circumference, and transfer of lead into breastmilk. Daily supplementation with 1200 mg of elemental calcium during pregnancy and lactation reduces lead resorption from maternal bone and thereby, levels of circulating lead. Beyond perinatal outcomes, early life exposure to lead is associated with neurocognitive deficits, behavioural disorders, higher blood pressure and lower weight in offspring during childhood. Some of these relationships were modified by dietary factors; genetic polymorphisms specific for iron, folate and lipid metabolism; and timing of exposure. Research has also expanded to include findings published on other toxicants such as those associated with personal care products and plastics (eg, phthalates, bisphenol A), other metals (eg, mercury, manganese, cadmium), pesticides (organophosphates) and fluoride; other biomarkers (eg, toxicant levels in plasma, hair and teeth); other outcomes (eg, sexual maturation, metabolic syndrome, dental caries); and identification of novel mechanisms via epigenetic and metabolomics profiling. FUTURE PLANS: As the ELEMENT mothers and children age, we plan to (1) continue studying the long-term consequences of toxicant exposure during the perinatal period on adolescent and young adult outcomes as well as outcomes related to the original ELEMENT mothers, such as their metabolic and bone health during perimenopause; and (2) follow the third generation of participants (children of the children) to study intergenerational effects of in utero exposures. TRIAL REGISTRATION NUMBER: NCT00558623. PMID: 31455712 [PubMed - in process]

Related Articles Metabolic profiling reveals distinct metabolic alterations in different subtypes of pituitary adenomas and confers therapeutic targets. J Transl Med. 2019 Aug 28;17(1):291 Authors: Feng J, Gao H, Zhang Q, Zhou Y, Li C, Zhao S, Hong L, Yang J, Hao S, Hong W, Zhuang Z, Xu G, Zhang Y Abstract BACKGROUND: Pituitary adenomas are common brain tumors. Although transsphenoidal surgery are able to achieve extensive tumor removal, the rate of recurrence ranges from 5 to 20% depending on the different subtype. Further understanding of these tumors is needed to develop novel strategies to improve the prognosis of patients. But their metabolic characteristics are largely unknown. METHODS: We used metabolomic, transcriptomic, and proteomic approaches to systematically investigate eight subtypes of pituitary adenomas and normal pituitary glands. By blocking IDH2, we investigate IDH2 play an inhibitory role in GH tumor cell growth and tumor secretion. RESULTS: We found that all of the pituitary adenomas displayed downregulated glucose metabolism and glycolysis compared to normal tissues. Together with the differences in amino acids and fatty acids, we categorized these tumors into three clusters. We then re-established the reprogrammed metabolic flux in pituitary adenomas based on multiomic analyses. Take growth hormone-secreting pituitary adenomas as an example, we revealed that IDH2 is a key player in the reprogrammed metabolism of such tumors. By blocking IDH2, we confirmed that IDH2 is a potential target for the inhibition of tumor cell growth and tumor secretion. CONCLUSIONS: Our study first uncovered the metabolic landscape of pituitary adenomas and demonstrated a possible way to inhibit tumor growth by regulating aberrant metabolism. PMID: 31455412 [PubMed - in process]

Related Articles Genetic, clinical and biochemical characterization of a large cohort of patients with hyaline fibromatosis syndrome. Orphanet J Rare Dis. 2019 Aug 27;14(1):209 Authors: Cozma C, Hovakimyan M, Iurașcu MI, Makhseed N, Selim LA, Alhashem AM, Ben-Omran T, Mahmoud IG, Al Menabawy NM, Al-Mureikhi M, Martin M, Demuth L, Yüksel Z, Beetz C, Bauer P, Rolfs A Abstract BACKGROUND: Hyaline fibromatosis syndrome (HFS) is a rare clinical condition in which bi-allelic variants in ANTXR2 are associated with extracellular hyaline deposits. It manifests as multiple skin nodules, patchy hyperpigmentation, joint contractures and severe pain with movement. HFS shows some clinical overlap to Farber disease (FD), a recessive lysosomal storage disorder. RESULTS: We here present the largest cohort of independent, genetically confirmed HFS cases reported to date: in 19 unrelated index patients, we identified ten distinct homozygous ANTXR2 mutations, three of which are novel frame-shift variants. The associated clinical data are consistent with the previous hypothesis of non-truncating variants in the terminal exons 13-17 to confer rather mild phenotypes. The novel observation of gender-dependent disease manifestation in our cohort received support from a meta-analysis of all previously published cases. Untargeted blood-based metabolomics revealed patient samples to be biochemically distinct from control samples. Numerous potential HFS biomarker metabolites could thus be identified. We also found metabolomics profiles of HFS patients to highly overlap with those from FD patients. CONCLUSIONS: Our study extends the mutational spectrum for HFS, suggests gender-dependency of manifestation, and provides pilot metabolomics data for biomarker identification and a better pathomechanistic understanding of the disorder. PMID: 31455396 [PubMed - in process]

Related Articles 1H-NMR metabolomics reveals the Glabrescione B exacerbation of glycolytic metabolism beside the cell growth inhibitory effect in glioma. Cell Commun Signal. 2019 Aug 28;17(1):108 Authors: D'Alessandro G, Quaglio D, Monaco L, Lauro C, Ghirga F, Ingallina C, De Martino M, Fucile S, Porzia A, Di Castro MA, Bellato F, Mastrotto F, Mori M, Infante P, Turano P, Salmaso S, Caliceti P, Di Marcotullio L, Botta B, Ghini V, Limatola C Abstract BACKGROUND: Glioma is the most common and primary brain tumors in adults. Despite the available multimodal therapies, glioma patients appear to have a poor prognosis. The Hedgehog (Hh) signaling is involved in tumorigenesis and emerged as a promising target for brain tumors. Glabrescione B (GlaB) has been recently identified as the first direct inhibitor of Gli1, the downstream effector of the pathway. METHODS: We established the overexpression of Gli1 in murine glioma cells (GL261) and GlaB effect on cell viability. We used 1H-nuclear magnetic resonance (NMR) metabolomic approach to obtain informative metabolic snapshots of GL261 cells acquired at different time points during GlaB treatment. The activation of AMP activated protein Kinase (AMPK) induced by GlaB was established by western blot. After the orthotopic GL261 cells injection in the right striatum of C57BL6 mice and the intranasal (IN) GlaB/mPEG5kDa-Cholane treatment, the tumor growth was evaluated. The High Performance Liquid Chromatography (HPLC) combined with Mass Spectrometry (MS) was used to quantify GlaB in brain extracts of treated mice. RESULTS: We found that GlaB affected the growth of murine glioma cells both in vitro and in vivo animal model. Using an untargeted 1H-NMR metabolomic approach, we found that GlaB stimulated the glycolytic metabolism in glioma, increasing lactate production. The high glycolytic rate could in part support the cytotoxic effects of GlaB, since the simultaneous blockade of lactate efflux with α-cyano-4-hydroxycinnamic acid (ACCA) affected glioma cell growth. According to the metabolomic data, we found that GlaB increased the phosphorylation of AMPK, a cellular energy sensor involved in the anabolic-to-catabolic transition. CONCLUSIONS: Our results indicate that GlaB inhibits glioma cell growth and exacerbates Warburg effect, increasing lactate production. In addition, the simultaneous blockade of Gli1 and lactate efflux amplifies the anti-tumor effect in vivo, providing new potential therapeutic strategy for this brain tumor. PMID: 31455353 [PubMed - in process]

Related Articles Integrating molecular characterization and metabolites profile revealed CtCHI1's significant role in Carthamus tinctorius L. BMC Plant Biol. 2019 Aug 27;19(1):376 Authors: Guo D, Gao Y, Liu F, He B, Jia X, Meng F, Zhang H, Guo M Abstract BACKGROUND: As a traditional Chinese herb, safflower (Carthamus tinctorius L.) is valued for its florets to prevent cardiovascular and cerebrovascular diseases. Basing on previous chemical analysis, the main active compounds are flavonoids in its florets. Although flavonoid biosynthetic pathway has been well-documented in many model species, unique biosynthetic pathway remains to be explored in safflower. Of note, as an important class of transitional enzymes, chalcone isomerase (CHI) has not been characterized in safflower. RESULTS: According to our previous research, CHIs were identified in a safflower transcriptome library built by our lab. To characterize CHI in safflower, a CHI gene named CtCHI1 was identified. A multiple sequences alignment and phylogenetic tree demonstrate that CtCHI1 shares 92% amino acid identity and close relationship with CHI to Saussurea medusa. Additionally, subcellular localization analysis indicated CtCHI1-GFP fusion protein was mainly in the cell nucleus. Further, we purified CtCHI1 protein from E. coli which can effectively catalyze isomerization of 2',4',4,6'-tetrahydroxychalcone into naringenin in vitro. Via genetic engineer technology, we successfully obtained transgenic tobacco and safflower lines. In transgenic tobacco, overexpression of CtCHI1 significantly inhibited main secondary metabolites accumulation, including quercetin (~ 79.63% for ovx-5 line) and anthocyanins (~ 64.55% for ovx-15 line). As shown in transgenic safflower, overexpression of CtCHI1 resulted in upstream genes CtPAL3 and CtC4H1 increasing dramatically (up to ~ 3.9fold) while Ct4CL3, CtF3H and CtDFR2 were inhibited. Also, comparing the whole metabolomics database by PCA and PLS-DA between transgenic and control group, 788 potential differential metabolites were marked and most of them displayed up-regulated trends. In parallel, some isolated secondary metabolites, such as hydroxysafflor yellow A (HSYA), rutin, kaempferol-3-O-β-rutinoside and dihydrokaempferol, accumulated in transgenic safflower plants. CONCLUSIONS: In this study, we found that CtCHI1 is an active, functional, catalytic protein. Moreover, CtCHI1 can negatively and competitively regulate anthocyanins and quercetin pathway branches in tobacco. By contrast, CtCHI1 can positively regulate flavonol and chalcone metabolic flow in safflower. This research provides some clues to understand CHI's differential biochemical functional characterization involving in flavonoid pathway. More molecular mechanisms of CHI remain to be explored in the near future. PMID: 31455221 [PubMed - in process]

25 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/08/28PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

20 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/08/27PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Related Articles Metformin and Dipeptidase Peptidyl-4 Inhibitor Differentially Modulate the Intestinal Microbiota and Plasma Metabolome of Metabolically Dysfunctional Mice. Can J Diabetes. 2019 May 27;: Authors: Ryan PM, Patterson E, Carafa I, Mandal R, Wishart DS, Dinan TG, Cryan JF, Tuohy KM, Stanton C, Ross RP Abstract OBJECTIVES: Recent evidence indicates that gut microbiota is altered considerably by a variety of commonly prescribed medications. This study assessed the impact of 2 antidiabetic therapeutics on gut microbiota and markers of cardiometabolic disease in metabolically dysfunctional mice. METHODS: C57BL/6 mice were fed a high-fat diet for 24 weeks while receiving 1 of 2 antidiabetic therapeutics-metformin or dipeptidase peptidyl-4 (DPP-4) inhibitor, PKF-275-055-for the final 12 weeks. Mice were assessed for weight gain, glucose and cholesterol metabolism, and adiposity. In addition, cecal microbiota was analyzed by 16S compositional sequencing, and plasma metabolome was analyzed by liquid chromatography with tandem mass spectrometry. RESULTS: Both therapeutics had similar metabolic effects, attenuating mesenteric adiposity and improving cholesterol metabolism and insulin sensitivity. However, multivariate analyses of microbiota and metabolomics data revealed clear divergence of the therapeutic groups. Although both metformin and PKF-275-055 mice displayed significantly decreased Firmicutes/Bacteroidetes ratios, only metformin harboured metabolic health-associated Akkermansia, Parabacteroides and Christensenella. Paradoxically, metformin also reduced α diversity, a metric frequently associated with host metabolic fitness. PKF-275-055 mice displayed elevated levels of butyrate-producing Ruminococcus and acetogen Dorea, with reduced levels of certain plasma sphingomyelin, phosphatidylcholine and lysophosphatidylcholine entities. In turn, metformin reduced levels of acylcarnitines, a functional group associated with systemic metabolic dysfunction. Finally, several associations were identified between metabolites and altered taxa. CONCLUSIONS: This study represents the first direct comparison of the microbiota-modifying effects of metformin and a DPP-4 inhibitor, and proposes several putative microbial targets both in terms of novel therapeutic development and adverse effect prevention. PMID: 31445961 [PubMed - as supplied by publisher]

Related Articles Endometrium and endometriosis tissue mitochondrial energy metabolism in a nonhuman primate model. Reprod Biol Endocrinol. 2019 Aug 24;17(1):70 Authors: Atkins HM, Bharadwaj MS, O'Brien Cox A, Furdui CM, Appt SE, Caudell DL Abstract BACKGROUND: Endometriosis is the growth of uterine lining (endometrium) outside of the uterus. In other chronic inflammatory diseases, mitochondrial dysfunction is suspected of playing a role in disease pathogenesis. However, little is known about endometriosis mitochondrial function or its effects on tissue metabolism. The objectives of this study were to analyze mitochondrial function in nonhuman primate (NHP) endometrium and endometriosis tissue and to identify the metabolic features of these tissues that may contribute to disease. METHODS: Mitochondrial function in endometriosis tissue and endometrium was measured using mitochondrial respirometry analysis to determine if changes in oxidative phosphorylation exist in endometrium and endometriosis tissue compared to control endometrium from clinically healthy NHPs. Targeted metabolomics and multidimensional statistical analysis were applied to quantify key metabolites in energy and amino acid biosynthesis pathways. RESULTS: Mitochondrial respirometry assays showed endometrium from NHPs with endometriosis had reduced complex II-mediated oxygen consumption rates (OCR) across all energy states (basal, p = 0.01; state 3, p = 0.02; state 3u, p = 0.04; state 4o, p = 0.008) and endometriosis tissue had reduced state 3, complex I-mediated OCR (p = 0.02) and respiratory control rates (p = 0.01) compared to normal endometrium. Targeted metabolomics performed on tissue revealed carnitine (p = 0.001), creatine phosphate (p = 0.01), NADH (p = 0.0001), FAD (p = 0.001), tryptophan (p = 0.0009), and malic acid (p = 0.005) were decreased in endometriosis tissue compared to normal endometrium samples. FAD (p = 0.004), tryptophan (p = 0.0004) and malic acid (p = 0.03) were significantly decreased in endometrium from NHPs with endometriosis compared to normal endometrium. Significant metabolites identified in endometriosis and endometrium samples from animals with endometriosis were part of amino acid biosynthesis or energy metabolism pathways. CONCLUSIONS: Here, endometrial mitochondrial energy production and metabolism were decreased in endometrium and endometriosis tissue. Decreased mitochondrial energy production may be due to oxidative stress-induced damage to mitochondrial DNA or membranes, a shift in cell metabolism, or decreased energy substrate; however, the exact cause remains unknown. Additional research is needed to determine the implications of reduced mitochondrial energy production and metabolism on endometriosis and endometrium. PMID: 31445519 [PubMed - in process]

Related Articles Metabolomics for predicting hyperglycemia in pregnancy: a protocol for a systematic review and potential meta-analysis. Syst Rev. 2019 Aug 24;8(1):218 Authors: Nicolosi BF, Leite DF, Mayrink J, Souza RT, Cecatti JG, Calderon IMP Abstract BACKGROUND: Hyperglycemia in pregnancy (HIP) has been recently differentiated between diabetes in pregnancy (DIP) and gestational diabetes mellitus (GDM). The proposed protocol is relevant, and clinical concern is due to the higher risk of adverse pregnancy outcomes (APO) and long-term effects on both the mother and the fetus. Fasting plasma glucose level (FPG) and oral glucose tolerance test (OGTT) are current diagnostic tools. However, controversy persists concerning diagnostic criteria, cut-off points, and even selective or universal screening. The objective of this systematic review is to assess the performance of metabolomic markers in the prediction of HIP. METHODS: This is a protocol for a systematic review with potential meta-analysis. The primary outcome is GDM, defined as glucose intolerance identified in the second and third trimesters of pregnancy (any FPG ≥ 92 mg/dL and < 126 mg/dL OR when 75-g OGTT shows one altered value among these: FPG ≥ 92 mg/dL or 1-h post glucose load ≥ 180 mg/dL or 2-h post glucose load ≥ 153 mg/dL); the secondary outcome is HIP, defined as hyperglycemia detected in the first trimester of pregnancy (any FPG ≥ 126 mg/dL). A detailed systematic literature search will be carried out in electronic databases and conference abstracts, using the keywords "gestational diabetes mellitus," "metabolomics," "pregnancy," and "screening" (and their variations). We will include original peer-reviewed articles published from Jan 1, 1999, to Dec 31, 2018. Original studies including diabetes diagnosed before pregnancy (T2DM and T1DM), multiple pregnancies, and congenital malformations will be excluded. All results regarding samples, participant characteristics, metabolomic techniques, and diagnostic accuracy measures will be retrieved and analyzed. Since this is a systematic review, no ethical approval is necessary. DISCUSSION: This systematic review may have the potential to provide significant evidence-based findings on the prediction performance of metabolomics. There are short and long-term repercussions for the mother and the newborn. Therefore, both may benefit from an accurate prediction technique for HIP. SYSTEMATIC REVIEW REGISTRATION: This protocol was registered in the PROSPERO platform under number CRD42018100175 . PMID: 31445518 [PubMed - in process]

Correlation between maximum standardized uptake values on FDG-PET and microenvironmental factors in patients with clinical stage IA radiologic pure-solid lung adenocarcinoma. Lung Cancer. 2019 Aug 09;136:57-64 Authors: Ichikawa T, Aokage K, Miyoshi T, Tane K, Suzuki K, Makinoshima H, Tsuboi M, Ishii G Abstract OBJECTIVES: The purpose of this study was to investigate whether fluorodeoxyglucose (FDG) accumulation is associated with the expression of microenvironmental factors in radiological pure-solid lung adenocarcinoma. METHODS: We selected 50 cases involving patients with clinical stage IA radiological pure-solid lung adenocarcinoma who were examined with 18 F-FDG positron emission tomography (18 F-FDG PET) prior to surgery and whose FDG-PET maximal standardized uptake values (SUVmax) were calculated. Tumor specimens were analyzed by immunohistochemistry (IHC) for phosphorylated AKT (pAKT), glucose transporter type 1 (GLUT-1), carbonic anhydrase IX (CA IX), podoplanin-positive cancer associated fibroblasts (PDPN + CAFs), and CD204-positive tumor-associated macrophages (CD204+ TAMs). We compared the clinicopathological characteristics and the immunophenotypes between two groups with high and low SUVmax. RESULTS: A multivariate analysis revealed that SUVmax was an independently significant prognostic factor (P = .03). The 5-year overall survival (OS) and recurrence free survival (RFS) rates of the SUV max high and low groups were 68.0% versus 100% ((P = .002; OS) 54.3% versus 90.8% (P < .001; RFS)), respectively. Vascular invasion, pleural invasion, and the prevalence of solid predominant subtype tumors were more frequent in the SUVmax high group. Additionally, the expression levels of GLUT-1 and pAKT in cancer cells were significantly higher in this group (P < .001, and P < .001 respectively). Furthermore, the numbers of the tumor-promoting stromal cells, i.e., PDPN + CAFs and CD204+ TAMs, were also significantly higher in the SUVmax high group (P = .001, and P < .001 respectively). CONCLUSION: Our results indicated that a close association exists between the SUVmax and expressions of not only metabolism associated markers in cancer cells but also of tumor promoting markers in stromal cells among patients with clinical stage IA adenocarcinoma with radiologically pure-solid nodules. PMID: 31445355 [PubMed - as supplied by publisher]

Malvidin 3-Glucoside Modulated Gut Microbial Dysbiosis and Global Metabolome Disrupted in a Murine Colitis Model Induced by Dextran Sulfate Sodium. Mol Nutr Food Res. 2019 Aug 24;:e1900455 Authors: Liu F, Wang TTY, Tang Q, Xue C, Li RW, Wu VCH Abstract SCOPE: This study aimed to elucidate the mechanisms of the anthocyanin malvidin 3-glucoside (MV) in alleviating gut dysbiosis using a murine colitis model induced by dextran sulfate sodium (DSS). METHODS AND RESULTS: The effect of MV on the structure and function of the colon microbiome and microbial metabolism was evaluated using 16S rRNA gene sequencing, global metabolomics, and a network algorithm based on the random-matrix theory. MV ingestion improved histopathological scores and increased IL10 expression in the colon mucosa of colitis mice. While DSS had a profound effect on the gut microbiome and significantly decreased both microbial richness and evenness, MV further reduced evenness but promoted microbial interactions and restored the Firmicutes/Bacteroidetes ratio repressed by DSS. Moreover, MV reduced the abundance of pathogenic bacteria, such as Ruminococcus gnavus, in colitis mice and had a strong modulatory effect on microbial co-occurrence patterns and gut metabolites. In addition, MV reversed several key inflammatory mediators, including sphingolipid metabolites, from elevated levels in DSS colitis mice. As a bioactive ingredient, MV exerted its effect on the gut microbiome in a mechanism that differed from the whole blueberry. CONCLUSION: MV ingestion ameliorated intestinal inflammation by modulating colon epithelium integrity, gut microbiome, and key inflammatory mediators. This article is protected by copyright. All rights reserved. PMID: 31444937 [PubMed - as supplied by publisher]

Related Articles Circulating metabolites in progression to islet autoimmunity and type 1 diabetes. Diabetologia. 2019 Aug 23;: Authors: Lamichhane S, Kemppainen E, Trošt K, Siljander H, Hyöty H, Ilonen J, Toppari J, Veijola R, Hyötyläinen T, Knip M, Orešič M Abstract AIMS/HYPOTHESIS: Metabolic dysregulation may precede the onset of type 1 diabetes. However, these metabolic disturbances and their specific role in disease initiation remain poorly understood. In this study, we examined whether children who progress to type 1 diabetes have a circulatory polar metabolite profile distinct from that of children who later progress to islet autoimmunity but not type 1 diabetes and a matched control group. METHODS: We analysed polar metabolites from 415 longitudinal plasma samples in a prospective cohort of children in three study groups: those who progressed to type 1 diabetes; those who seroconverted to one islet autoantibody but not to type 1 diabetes; and an antibody-negative control group. Metabolites were measured using two-dimensional GC high-speed time of flight MS. RESULTS: In early infancy, progression to type 1 diabetes was associated with downregulated amino acids, sugar derivatives and fatty acids, including catabolites of microbial origin, compared with the control group. Methionine remained persistently upregulated in those progressing to type 1 diabetes compared with the control group and those who seroconverted to one islet autoantibody. The appearance of islet autoantibodies was associated with decreased glutamic and aspartic acids. CONCLUSIONS/INTERPRETATION: Our findings suggest that children who progress to type 1 diabetes have a unique metabolic profile, which is, however, altered with the appearance of islet autoantibodies. Our findings may assist with early prediction of the disease. PMID: 31444528 [PubMed - as supplied by publisher]