Integrative Molecular Phenotyping
INTEGRATIVE MOLECULAR
PHENOTYPING
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY
DEPARTMENT OF MEDICAL
BIOCHEMISTRY AND BIOPHYSICS
WHEELOCK LABORATORY

PubMed

PubMed
NCBI: db=pubmed; Term=metabolomics
Updated: 2 hours 43 min ago

metabolomics; +23 new citations

Sat, 06/07/2019 - 12:27
23 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 2019/07/06PubMed 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.

Small Molecular Modulators of JMJD1C Preferentially Inhibit Growth of Leukemia Cells.

Fri, 05/07/2019 - 12:17
Small Molecular Modulators of JMJD1C Preferentially Inhibit Growth of Leukemia Cells. Int J Cancer. 2019 Jul 04;: Authors: Xu X, Wang L, Hu L, Dirks WG, Zhao Y, Wei Z, Chen D, Li Z, Wang Z, Han Y, Wei L, Drexler HG, Hu Z Abstract Histone demethylases are promising therapeutic targets as they play fundamental roles for survival of Mixed lineage leukemia rearranged acute leukemia (MLLr AL). Here we focused on the catalytic Jumonji domain of histone H3 lysine 9 (H3K9) demethylase JMJD1C to screen for potential small molecular modulators from 149,519 natural products and 33,765 Chinese medicine components via virtual screening. JMJD1C Jumomji domain inhibitor 4 (JDI-4) and JDI-12 that share a common structural backbone were detected within the top 15 compounds. Surface plasmon resonance analysis showed that JDI-4 and JDI-12 bind to JMJD1C and its family homolog KDM3B with modest affinity. In vitro demethylation assays showed that JDI-4 can reverse the H3K9 demethylation conferred by KDM3B. In vivo demethylation assays indicated that JDI-4 and JDI-12 could induce the global increase of H3K9 methylation. Cell proliferation and colony formation assays documented that JDI-4 and JDI-12 kill MLLr AL and other malignant hematopoietic cells, but not leukemia cells resistant to JMJD1C depletion or cord blood cells. Furthermore, JDI-16, among multiple compounds structurally akin to JDI-4/JDI-12, exhibits superior killing activities against malignant hematopoietic cells compared to JDI-4/JDI-12. Mechanistically, JDI-16 not only induces apoptosis but also differentiation of MLLr AL cells. RNA sequencing and quantitative PCR showed that JDI-16 induced gene expression associated to cell metabolism; targeted metabolomics revealed that JDI-16 downregulates lactic acids, NADP+ and other metabolites. Moreover, JDI-16 collaborates with all-trans retinoic acid to repress MLLr AML cells. In summary, we identified bona fide JMJD1C inhibitors that induce preferential death of MLLr AL cells. This article is protected by copyright. All rights reserved. PMID: 31271662 [PubMed - as supplied by publisher]

Changes in whole metabolites after exenatide treatment in overweight/obese polycystic ovary syndrome patients.

Fri, 05/07/2019 - 12:17
Changes in whole metabolites after exenatide treatment in overweight/obese polycystic ovary syndrome patients. Clin Endocrinol (Oxf). 2019 Jul 04;: Authors: Tang L, Yuan L, Yang G, Wang F, Fu M, Chen M, Liu D Abstract OBJECTIVE: Exenatide is a new agent for diabetes therapy, and its use in polycystic ovary syndrome (PCOS) has gradually increased; however, the clinical benefit and metabolic improvement need further evidence. This research aimed to study the changes in whole metabolites before and after exenatide treatment in overweight/obese PCOS patients to gain a better understanding of exenatide for the treatment of PCOS. METHODS: Sixty-seven women, including 32 with PCOS and 35 age-matched controls, were recruited. The metabolite changes were detected with non-targeted gas chromatography tandem mass spectrometry (NTGC-MS) before and after exenatide treatment, and changes in clinical biochemical characteristics were also observed. RESULTS: A total of 62 metabolites were differentially expressed between the healthy and PCOS groups, and 31 differentially expressed metabolites were detected before and after exenatide treatment. Abnormal lipid metabolism and amino acid metabolism were the main metabolic disorders. Exenatide improved lipid and amino acid metabolism, especially amino acid metabolites. Three types of branched-chain amino acids (valine, leucine, and isoleucine), two types of aromatic amino acids (phenylalanine and tyrosine) and lysine are important potential metabolites for the therapeutic efficacy of exenatide. Many abnormal metabolic disorders are related to insulin resistance, oxidative stress, and even ovulatory dysfunction. Moreover, in this small sample clinical study, we also found that exenatide improved insulin sensitivity, reduced body weight and improved glycolipid metabolism in PCOS. CONCLUSIONS: NTGC-MS-based metabolic pathway analysis revealed that exenatide has a beneficial effect on overweight/obese PCOS patients by regulating metabolic disorders, especially amino acid disorders. This article is protected by copyright. All rights reserved. PMID: 31271659 [PubMed - as supplied by publisher]

Can Galactose Be Converted To Glucose In HepG2 Cells? - Improving the in vitro Mitochondrial Toxicity Assay for the Assessment of Drug Induced Liver Injury.

Fri, 05/07/2019 - 12:17
Can Galactose Be Converted To Glucose In HepG2 Cells? - Improving the in vitro Mitochondrial Toxicity Assay for the Assessment of Drug Induced Liver Injury. Chem Res Toxicol. 2019 Jul 04;: Authors: Xu Q, Liu L, Vu H, Kuhls M, Aslamkhan AG, Liaw A, Yu Y, Kaczor A, Ruth M, Wei C, Imredy J, Lebron J, Pearson K, Gonzalez R, Mitra K, Sistare F Abstract Human hepatocellular carcinoma cells, HepG2, are often used for drug mediated mitochondrial toxicity assessments. Glucose in HepG2 culture media is replaced by galactose to reveal drug-induced mitochondrial toxicity as a marked shift of drug IC50 values for the reduction of cellular ATP. It has been postulated that galactose sensitizes HepG2 mitochondria by the additional ATP consumption demand in the Leloir pathway, which describes the galactose→glucose conversion. However, our NMR metabolomics analysis of HepG2 cells and culture media showed very limited, if any, galactose metabolism. To clarify the role of galactose in HepG2 cellular metabolism, U-13C6-galactose or U-13C6-glucose was added to HepG2 culture media to help specifically track the metabolism of those two sugars. No conversion to U-13C3-lactate was detected when HepG2 cells were incubated with U-13C6-galactose, while an abundance of U-13C3-lactate was produced when HepG2 cells were incubated with U-13C6-glucose. In the absence of glucose, HepG2 cells increased glutamine consumption as a bioenergetics source. Requirement of additional glutamine matched the amount of glucose needed to maintain a steady level of cellular ATP in HepG2 cells. This improved understanding of galactose and glutamine metabolism in HepG2 cells helped optimize the ATP based mitochondrial toxicity assay. The modified assay showed 96% sensitivity and 97% specificity in correctly discriminating compounds known to cause mitochondrial toxicity from those with prior evidences of not being mitochondrial toxicants. The greatest significance of the modified assay was its improved sensitivity in detecting the inhibition of mitochondrial fatty acid β-oxidation (FAO) when glutamine was withheld. By eliminating glutamine, the assay was able to differentially identify inhibitors of FAO and mitochondrial complex II from those of other mitochondrial complexes. Use of this improved assay for an empirical prediction of the likely contribution of mitochondrial toxicity to human DILI (drug induced liver injury) was attempted. Testing of 120 DILI positive and negative compounds representing numerous mechanisms of DILI, the overall prediction of mitochondrial mechanism-related DILI showed 25% sensitivity and 95% specificity. PMID: 31271030 [PubMed - as supplied by publisher]

Multiple metabolic pathways are predictive of ricin intoxication in a rat model.

Fri, 05/07/2019 - 12:17
Related Articles Multiple metabolic pathways are predictive of ricin intoxication in a rat model. Metabolomics. 2019 Jul 03;15(7):102 Authors: D'Elia RV, Goodchild SA, Winder CL, Southam AD, Weber RJM, Stahl FM, Docx C, Patel V, Green AC, Viant MR, Lukaszewski RA, Dunn WB Abstract INTRODUCTION: Exposure to ricin can be lethal and treatments that are under development have short windows of opportunity for administration after exposure. It is therefore essential to achieve early detection of ricin exposure to provide the best prognosis for exposed individuals. Ricin toxin can be detected in clinical samples via several antibody-based techniques, but the efficacy of these can be limited due to the rapid processing and cellular uptake of toxin in the body and subsequent low blood ricin concentrations. Other diagnostic tools that perform, in an orthogonal manner, are therefore desirable. OBJECTIVES: To determine time-dependent metabolic changes in Sprague-Dawley rats following intravenous exposure to ricin. METHODS: Sprague-Dawley rats were intravenously exposed to ricin and multiple blood samples were collected from each animal for up to 48 h following exposure in two independent studies. Plasma samples were analysed applying HILIC and C18 reversed phase UHPLC-MS assays followed by univariate and multivariate analysis. RESULTS: In Sprague-Dawley rats we have demonstrated that metabolic changes measured in blood can distinguish between rats exposed intravenously to ricin and controls prior to the onset of behavioral signs of intoxication after 24 h. A total of 37 metabolites were significantly altered following exposure to ricin when compared to controls. The arginine/proline, bile acid and triacylglyceride metabolic pathways were highlighted as being important with two triacylglycerides at 8 h post exposure giving an AUROC score of 0.94. At 16 h and 24 h the AUROC score increased to 0.98 and 1.0 with the number of metabolites in the panel increasing to 5 and 7, respectively. CONCLUSIONS: These data demonstrate that metabolites may be a useful tool to diagnose and detect ricin exposure, thus increasing the effectiveness of supportive therapy and future ricin-specific medical treatments. PMID: 31270703 [PubMed - in process]

Differential metabolic responses of shrubs and grasses to water additions in arid karst region, southwestern China.

Fri, 05/07/2019 - 12:17
Related Articles Differential metabolic responses of shrubs and grasses to water additions in arid karst region, southwestern China. Sci Rep. 2019 Jul 03;9(1):9613 Authors: Umair M, Sun N, Du H, Yuan J, Abbasi AM, Wen J, Yu W, Zhou J, Liu C Abstract Increasing precipitation has been predicted to occur in the karst areas in southwestern regions of China. However, it is little known how various plants respond to increasing precipitation in this region. Here we determined the impacts of water addition on leaf metabolites of grasses (Cymbopogon distans and Arundinella sitosa) and shrubs (Carissa spinarum and Bauhinia brachycarpa) in this area. Four levels of water additions (CK, T1, T2 and T3 indicating 0%, +20%, +40% and +60% relative to the current monthly precipitation, respectively) were designed. Sphingolipids substantially increased in the leaves of all four species with increasing water supply which suggests that these plants adopted biochemical strategy to tolerate the wet stress. However, both shrubs showed decreases in valine and threonine (amino acids), threonate, succinate and ascorbic acid (organic acids), galactose and rhamnose (sugars) and epicatchin and oleamides (secondary metabolites) with increasing water supply. Both grasses increased in the total metabolites at T1, but the total metabolites in A. sitosa significantly decreased at T2 and T3 while remains unchanged in C. distans. Tri-carboxylic acid cycle and amino acid metabolism in shrubs and shikimate pathway in grasses were strongly affected with water supply. Overall, shrubs and grasses respond differentially to variation in water addition in terms of metabolomics, which is helpful in understanding how plants respond to climate change. PMID: 31270427 [PubMed - in process]

Adult stem cell deficits drive Slc29a3 disorders in mice.

Fri, 05/07/2019 - 12:17
Related Articles Adult stem cell deficits drive Slc29a3 disorders in mice. Nat Commun. 2019 Jul 03;10(1):2943 Authors: Nair S, Strohecker AM, Persaud AK, Bissa B, Muruganandan S, McElroy C, Pathak R, Williams M, Raj R, Kaddoumi A, Sparreboom A, Beedle AM, Govindarajan R Abstract Mutations exclusively in equilibrative nucleoside transporter 3 (ENT3), the only intracellular nucleoside transporter within the solute carrier 29 (SLC29) gene family, cause an expanding spectrum of human genetic disorders (e.g., H syndrome, PHID syndrome, and SHML/RDD syndrome). Here, we identify adult stem cell deficits that drive ENT3-related abnormalities in mice. ENT3 deficiency alters hematopoietic and mesenchymal stem cell fates; the former leads to stem cell exhaustion, and the latter leads to breaches of mesodermal tissue integrity. The molecular pathogenesis stems from the loss of lysosomal adenosine transport, which impedes autophagy-regulated stem cell differentiation programs via misregulation of the AMPK-mTOR-ULK axis. Furthermore, mass spectrometry-based metabolomics and bioenergetics studies identify defects in fatty acid utilization, and alterations in mitochondrial bioenergetics can additionally propel stem cell deficits. Genetic, pharmacologic and stem cell interventions ameliorate ENT3-disease pathologies and extend the lifespan of ENT3-deficient mice. These findings delineate a primary pathogenic basis for the development of ENT3 spectrum disorders and offer critical mechanistic insights into treating human ENT3-related disorders. PMID: 31270333 [PubMed - in process]

Hyaluronan synthase 2 (HAS2) overexpression diminishes the procatabolic activity of chondrocytes by a mechanism independent of extracellular hyaluronan.

Fri, 05/07/2019 - 12:17
Related Articles Hyaluronan synthase 2 (HAS2) overexpression diminishes the procatabolic activity of chondrocytes by a mechanism independent of extracellular hyaluronan. J Biol Chem. 2019 Jul 03;: Authors: Ishizuka S, Tsuchiya S, Ohashi Y, Terabe K, Askew EB, Ishizuka N, Knudson CB, Knudson W Abstract Osteoarthritis (OA) is a progressive degenerative disease of the joints caused in part by a change in the phenotype of resident chondrocytes within affected joints. This altered phenotype, often termed proinflammatory or procatabolic, features enhanced production of endoproteinases and matrix metallo-proteinases (MMPs) as well as secretion of endogenous inflammatory mediators. Degradation and reduced retention of the proteoglycan aggrecan is an early event in OA. Enhanced turnover of hyaluronan (HA) is closely associated with changes in aggrecan. Here, to determine whether experimentally increased HA production promotes aggrecan retention and generates a positive feedback response, we overexpressed HA synthase-2 (HAS2) in chondrocytes via an inducible adenovirus construct (HAS2-OE). HAS2-OE incrementally increased high-molecular-mass HA > 100-fold within the cell-associated and growth medium pools. More importantly, our results indicated that the HAS2-OE expression system inhibits MMP3, MMP13 and other markers of the procatabolic phenotype (such as TNF-stimulated gene 6 protein [TSG6]) and also enhances aggrecan retention. These markers were inhibited in OA-associated chondrocytes and in chondrocytes activated by interleukin-1β (IL-1β), but also chondrocytes activated by lipopolysaccharide (LPS), tumor necrosis factor α (TNFα), or HA oligosaccharides.  However, the enhanced extracellular HA resulting from HAS2-OE did not reduce the pro-catabolic phenotype of neighboring non-transduced chondrocytes as we had expected.    Rather, HA-mediated inhibition of the phenotype occurred only in transduced cells.  In addition, high HA biosynthesis rates, especially in transduced pro-catabolic chondrocytes, resulted in marked changes in chondrocyte dependence on glycolysis versus oxidative phosphorylation for their metabolic energy needs. PMID: 31270213 [PubMed - as supplied by publisher]

Steroyl-CoA Desaturase 1 (SCD1) protects ovarian cancer cells from ferroptotic cell death.

Fri, 05/07/2019 - 12:17
Related Articles Steroyl-CoA Desaturase 1 (SCD1) protects ovarian cancer cells from ferroptotic cell death. Cancer Res. 2019 Jul 03;: Authors: Tesfay L, Paul BT, Konstorum A, Deng Z, Cox AO, Lee J, Furdui CM, Hegde P, Torti FM, Torti SV Abstract Activation of ferroptosis, a recently described mechanism of regulated cell death, dramatically inhibits growth of ovarian cancer cells. Given the importance of lipid metabolism in ferroptosis and the key role of lipids in ovarian cancer, we examined the contribution to ferroptosis of steroyl CoA desaturase (SCD1), an enzyme that catalyzes the rate-limiting step in monounsaturated fatty acid synthesis, in ovarian cancer cells. SCD1 was highly expressed in ovarian cancer tissue, cell lines, and a genetic model of ovarian cancer stem cells. Inhibition of SCD1 induced lipid oxidation and cell death. Conversely, over-expression of SCD1 or exogenous administration of its C16:1 and C18:1 products, palmitoleicic acid or oleate, protected cells from death. Inhibition of SCD1 induced both ferroptosis and apoptosis: inhibition of SCD1 decreased CoQ10, an endogenous membrane antioxidant whose depletion has been linked to ferroptosis, while concomitantly decreasing unsaturated fatty acyl chains in membrane phospholipids and increasing long chain saturated ceramides, changes previously linked to apoptosis. Simultaneous triggering of two death pathways suggests SCD1 inhibition may be an effective component of anti-tumor therapy, since overcoming this dual mechanism of cell death may present a significant barrier to the emergence of drug resistance. Supporting this concept, we observed that inhibition of SCD1 significantly potentiated the anti-tumor effect of ferroptosis inducers in both ovarian cancer cell lines and a mouse orthotopic xenograft model. Our results suggest that the use of combined treatment with SCD1 inhibitors and ferroptosis inducers may provide a new therapeutic strategy for patients with ovarian cancer. PMID: 31270077 [PubMed - as supplied by publisher]

Chitosan Oligosaccharide Ameliorates Nonalcoholic Fatty Liver Disease (NAFLD) in Diet-Induced Obese Mice.

Fri, 05/07/2019 - 12:17
Related Articles Chitosan Oligosaccharide Ameliorates Nonalcoholic Fatty Liver Disease (NAFLD) in Diet-Induced Obese Mice. Mar Drugs. 2019 Jul 02;17(7): Authors: Qian M, Lyu Q, Liu Y, Hu H, Wang S, Pan C, Duan X, Gao Y, Qi LW, Liu W, Wang L Abstract Nonalcoholic fatty liver disease (NAFLD) is a global epidemic, and there is no standard and efficient therapy for it. Chitosan oligosaccharide (COS) is widely known to have various biological effects, and in this study we aimed to evaluate the liver-protective effect in diet-induced obese mice for an enzymatically digested product of COS called COS23 which is mainly composed of dimers and trimers. An integrated analysis of the lipidome and gut microbiome were performed to assess the effects of COS23 on lipids in plasma and the liver as well as on intestinal microbiota. Our results revealed that COS23 obviously attenuated hepatic steatosis and ameliorated liver injury in diet-induced obese mice. The hepatic toxic lipids-especially triglycerides (TGs) and free fatty acids (FFAs)-were decreased dramatically after COS23 treatment. COS23 regulated lipid-related pathways, especially inhibiting the expressions of FFA-synthesis-related genes and inflammation-related genes. Furthermore, COS23 could alter lipid profiles in plasma. More importantly, COS23 also decreased the abundance of Mucispirillum and increased the abundance of Coprococcus in gut microbiota and protected the intestinal barrier by up-regulating the expression of tight-junction-related genes. In conclusion, COS23, an enzymatically digested product of COS, might serve as a promising candidate in the clinical treatment of NAFLD. PMID: 31269758 [PubMed - in process]

A Single Visualization Technique for Displaying Multiple Metabolite-Phenotype Associations.

Fri, 05/07/2019 - 12:17
Related Articles A Single Visualization Technique for Displaying Multiple Metabolite-Phenotype Associations. Metabolites. 2019 Jul 02;9(7): Authors: Henglin M, Niiranen T, Watrous JD, Lagerborg KA, Antonelli J, Claggett BL, Demosthenes EJ, von Jeinsen B, Demler O, Vasan RS, Larson MG, Jain M, Cheng S Abstract To assist with management and interpretation of human metabolomics data, which are rapidly increasing in quantity and complexity, we need better visualization tools. Using a dataset of several hundred metabolite measures profiled in a cohort of ~1500 individuals sampled from a population-based community study, we performed association analyses with eight demographic and clinical traits and outcomes. We compared frequently used existing graphical approaches with a novel 'rain plot' approach to display the results of these analyses. The 'rain plot' combines features of a raindrop plot and a conventional heatmap to convey results of multiple association analyses. A rain plot can simultaneously indicate effect size, directionality, and statistical significance of associations between metabolites and several traits. This approach enables visual comparison features of all metabolites examined with a given trait. The rain plot extends prior approaches and offers complementary information for data interpretation. Additional work is needed in data visualizations for metabolomics to assist investigators in the process of understanding and convey large-scale analysis results effectively, feasibly, and practically. PMID: 31269707 [PubMed]

Human Plasma Metabolomics in Age-Related Macular Degeneration: Meta-Analysis of Two Cohorts.

Fri, 05/07/2019 - 12:17
Related Articles Human Plasma Metabolomics in Age-Related Macular Degeneration: Meta-Analysis of Two Cohorts. Metabolites. 2019 Jul 02;9(7): Authors: Laíns I, Chung W, Kelly RS, Gil J, Marques M, Barreto P, Murta JN, Kim IK, Vavvas DG, Miller JB, Silva R, Lasky-Su J, Liang L, Miller JW, Husain D Abstract The pathogenesis of age-related macular degeneration (AMD), a leading cause of blindness worldwide, remains only partially understood. This has led to the current lack of accessible and reliable biofluid biomarkers for diagnosis and prognosis, and absence of treatments for dry AMD. This study aimed to assess the plasma metabolomic profiles of AMD and its severity stages with the ultimate goal of contributing to addressing these needs. We recruited two cohorts: Boston, United States (n = 196) and Coimbra, Portugal (n = 295). Fasting blood samples were analyzed using ultra-high performance liquid chromatography mass spectrometry. For each cohort, we compared plasma metabolites of AMD patients versus controls (logistic regression), and across disease stages (permutation-based cumulative logistic regression considering both eyes). Meta-analyses were then used to combine results from the two cohorts. Our results revealed that 28 metabolites differed significantly between AMD patients versus controls (false discovery rate (FDR) q-value: 4.1 × 10-2-1.8 × 10-5), and 67 across disease stages (FDR q-value: 4.5 × 10-2-1.7 × 10-4). Pathway analysis showed significant enrichment of glycerophospholipid, purine, taurine and hypotaurine, and nitrogen metabolism (p-value ≤ 0.04). In conclusion, our findings support that AMD patients present distinct plasma metabolomic profiles, which vary with disease severity. This work contributes to the understanding of AMD pathophysiology, and can be the basis of future biomarkers and precision medicine for this blinding condition. PMID: 31269701 [PubMed]

The Search for Clinically Useful Biomarkers of Complex Disease: A Data Analysis Perspective.

Fri, 05/07/2019 - 12:17
Related Articles The Search for Clinically Useful Biomarkers of Complex Disease: A Data Analysis Perspective. Metabolites. 2019 Jul 02;9(7): Authors: Considine EC Abstract Unmet clinical diagnostic needs exist for many complex diseases, which (it is hoped) will be solved by the discovery of metabolomics biomarkers. However, at present, no diagnostic tests based on metabolomics have yet been introduced to the clinic. This review is presented as a research perspective on how data analysis methods in metabolomics biomarker discovery may contribute to the failure of biomarker studies and suggests how such failures might be mitigated. The study design and data pretreatment steps are reviewed briefly in this context, and the actual data analysis step is examined more closely. PMID: 31269649 [PubMed]

Comparison of Retention Behavior between Supercritical Fluid Chromatography and Normal-Phase High-Performance Liquid Chromatography with Various Stationary Phases.

Fri, 05/07/2019 - 12:17
Related Articles Comparison of Retention Behavior between Supercritical Fluid Chromatography and Normal-Phase High-Performance Liquid Chromatography with Various Stationary Phases. Molecules. 2019 Jul 02;24(13): Authors: Hirose T, Keck D, Izumi Y, Bamba T Abstract The retention behavior of a wide variety of stationary phases was compared in supercritical fluid chromatography (SFC) and normal-phase high-performance liquid chromatography (NP-HPLC). We also attempted to elucidate the retention behavior in SFC by investigating the selectivity of the different stationary phases. SFC separation conditions with polar stationary phases, such as silica gel (SL) and diol (Diol) phases, operate via adsorptions that include hydrophilic and ionic interactions similar to those in NP-HPLC. Moreover, non-polar stationary phases, such as pentabromophenyl (PBr), pyrenylethyl (PYE), and octadecyl (C18), could be used despite the non-polar mobile phase conditions, because the dispersion and π-π interactions were stronger in SFC than in HPLC. These results reflect the selectivity of the stationary phase and its retention factor, thus providing useful information for the selection of appropriate stationary phases for particular analytes. PMID: 31269632 [PubMed - in process]

A Metal-Polyphenol Network Coated Nanotheranostic System for Metastatic Tumor Treatments.

Fri, 05/07/2019 - 12:17
Related Articles A Metal-Polyphenol Network Coated Nanotheranostic System for Metastatic Tumor Treatments. Small. 2017 12;13(48): Authors: Fan JX, Zheng DW, Mei WW, Chen S, Chen SY, Cheng SX, Zhang XZ Abstract As a characteristic trait of most tumor types, metastasis is the major cause of the death of patients. In this study, a photothermal agent based on gold nanorod is coated with metal (Gd3+ )-organic (polyphenol) network to realize combination therapy for metastatic tumors. This nanotheranostic system significantly enhances antitumor therapeutic effects in vitro and in vivo with the combination of photothermal therapy (PTT) and chemotherapy, also can remarkably prevent the invasion and metastasis due to the presence of polyphenol. After the treatment, an 81% decrease in primary tumor volumes and a 58% decrease in lung metastasis are observed. In addition, the good performance in magnetic resonance imaging, computerized tomography, and photothermal imaging of the nanotheranostic system can realize image-guided therapy. The multifunctional nanotheranostic system will find a great potential in diagnosis and treatment integration in tumor treatments, and broaden the applications of PTT treatment. PMID: 29125688 [PubMed - indexed for MEDLINE]

Metabolomic Profiling of Pompe Disease-Induced Pluripotent Stem Cell-Derived Cardiomyocytes Reveals That Oxidative Stress Is Associated with Cardiac and Skeletal Muscle Pathology.

Fri, 05/07/2019 - 12:17
Related Articles Metabolomic Profiling of Pompe Disease-Induced Pluripotent Stem Cell-Derived Cardiomyocytes Reveals That Oxidative Stress Is Associated with Cardiac and Skeletal Muscle Pathology. Stem Cells Transl Med. 2017 01;6(1):31-39 Authors: Sato Y, Kobayashi H, Higuchi T, Shimada Y, Ida H, Ohashi T Abstract Pompe disease (PD) is a lysosomal storage disease that is caused by a deficiency of the acid α-glucosidase, which results in glycogen accumulation in the lysosome. The major clinical symptoms of PD include skeletal muscle weakness, respiratory failure, and cardiac hypertrophy. Based on its severity and symptom onset, PD is classified into infantile and late-onset forms. Lysosomal accumulation of glycogen can promote many types of cellular dysfunction, such as autophagic dysfunction, endoplasmic reticulum stress, and abnormal calcium signaling within skeletal muscle. However, the disease mechanism underlying PD cardiomyopathy is not fully understood. Several researchers have shown that PD induced pluripotent stem cell (iPSC)-derived cardiomyocytes successfully replicate the disease phenotype and are useful disease models. We have analyzed the metabolomic profile of late-onset PD iPSC-derived cardiomyocytes and found that oxidative stress and mitochondrial dysfunction are likely associated with cardiac complications. Furthermore, we have validated that these disease-specific changes were also observed in the cardiomyocytes and skeletal muscle of a genetically engineered murine PD model. Oxidative stress may contribute to skeletal muscle and cardiomyocyte dysfunction in PD mice; however, NF-E2-related factor 2 was downregulated in cardiomyocytes and skeletal muscle, despite evidence of oxidative stress. We hypothesized that oxidative stress and an impaired antioxidative stress response mechanism may underlie the molecular pathology of late-onset PD. Stem Cells Translational Medicine 2017;6:31-39. PMID: 28170191 [PubMed - indexed for MEDLINE]

Macrophages and Metabolism in the Tumor Microenvironment.

Thu, 04/07/2019 - 12:01
Macrophages and Metabolism in the Tumor Microenvironment. Cell Metab. 2019 Jul 02;30(1):36-50 Authors: Vitale I, Manic G, Coussens LM, Kroemer G, Galluzzi L Abstract Tumor-associated macrophages (TAMs) constitute a plastic and heterogeneous cell population of the tumor microenvironment (TME) that can account for up to 50% of some solid neoplasms. Most often, TAMs support disease progression and resistance to therapy by providing malignant cells with trophic and nutritional support. However, TAMs can mediate antineoplastic effects, especially in response to pharmacological agents that boost their phagocytic and oxidative functions. Thus, TAMs and their impact on the overall metabolic profile of the TME have a major influence on tumor progression and resistance to therapy, de facto constituting promising targets for the development of novel anticancer agents. Here, we discuss the metabolic circuitries whereby TAMs condition the TME to support tumor growth and how such pathways can be therapeutically targeted. PMID: 31269428 [PubMed - in process]

Cell-Based Metabolomics for Untargeted Screening and Prioritization of Vertebrate-Active Stressors in Streams Across the United States.

Thu, 04/07/2019 - 12:01
Cell-Based Metabolomics for Untargeted Screening and Prioritization of Vertebrate-Active Stressors in Streams Across the United States. Environ Sci Technol. 2019 Jul 03;: Authors: Collette TW, Ekman D, Zhen H, Nguyen H, Bradley PM, Teng Q Abstract The U.S. Geological Survey and the U.S. Environmental Protection Agency have assessed contaminants in 38 streams across the U.S., using an extensive suite of target-chemical analysis methods along with a variety of biological effects tools. Here we report zebrafish liver (ZFL) cell-culture based NMR metabolomic analysis of these split stream samples. We used this untargeted approach to evaluate the sites according to overall impact on the ZFL metabolome and found that neither the total number of organics detected at the sites, nor their cumulative concentrations, were good predictors of these impacts. Further, we used partial-least squares regression to compare ZFL endogenous metabolite profiles to values for 455 potential stressors (organics, inorganics, and physical properties) measured in these waters and found that the profiles covaried with at most 280 of the stressors, which were subsequently ranked into quartiles based on the strength of their covariance. While contaminants of emerging concern (CECs) were well represented in the top, most strongly, covarying quartile - suggesting considerable potential for eliciting biological responses at these sites - there was even higher representation of various well-characterized legacy contaminants (e.g., PCBs). These results emphasize the importance of complementing chemical analysis with untargeted bioassays to help focus regulatory efforts on the most significant ecosystem threats. PMID: 31268696 [PubMed - as supplied by publisher]

A Digital Method to Quantify Type I IFN.

Thu, 04/07/2019 - 12:01
A Digital Method to Quantify Type I IFN. J Interferon Cytokine Res. 2019 Jul 03;: Authors: Rius-Rocabert S, Presa JL, Esteban-Rubio S, Ayuso-Sacido A, Nistal-Villan E Abstract Interferon (IFN), the first ever-described cytokine, has a potent activity against viruses. Soon since its discovery, quantification of IFN has been an important issue. Most of the traditional methods to measure IFN biological activity rely on indirect methods that quantify dyes retained by IFN-protected cells against a lytic virus, or by techniques that indirectly quantify viral replication by measuring the expression level of viral-encoded reporter proteins such as the green fluorescent protein (GFP). In both cases, the IFN units are determined by the quantification of an effective dose 50, defined as the IFN dose that prevents 50% cell death of 50% reduction of the maximal amount of GFP intensity. In this study we propose the use of an alternative approach to measure IFN activity by calculating the minimal IFN dose 50 as the amount of IFN able to completely protect 50% of the cells from infection measured by the total absence of virus-dependent GFP signal in a cell culture plate. This sensitive approach could be used to easily quantify the Z value to determine IFN bioassay robustness. We believe that this approximation could be interesting to be considered by the IFN community. PMID: 31268382 [PubMed - as supplied by publisher]

Mitochondrial activity contributes to impaired renal metabolic homeostasis and renal pathology in STZ-induced diabetic mice.

Thu, 04/07/2019 - 12:01
Mitochondrial activity contributes to impaired renal metabolic homeostasis and renal pathology in STZ-induced diabetic mice. Am J Physiol Renal Physiol. 2019 Jul 03;: Authors: Wu M, Li S, Yu X, Chen W, Ma H, Shao C, Zhang Y, Zhang A, Huang S, Jia Z Abstract Diabetic nephropathy (DN) has become the main cause of end-stage renal disease worldwide while the efficacy of current therapeutic strategies on DN remains unsatisfactory. Recent researches reported the involvement of metabolic re-arrangement in the pathological process of DN, and of all the disturbances in metabolism, mitochondria serve as key regulatory hubs. In the present study, high-resolution mass spectrometry-based none-target metabolomics was employed to uncover the metabolic characteristics of early diabetic kidney with or without the inhibition of mitochondrial activity. At first, we observed a moderate enhancement of mitochondrial complex-1 activity in diabetic kidney, which was completely normalized by a specific mitochondrial complex-1 inhibitor rotenone (ROT). Meanwhile, metabolomics data indicated over-activated pentose phosphate pathway, purine and pyrimidine metabolism, hexosamine biosynthetic pathway, and Kreb cycle, which were strikingly corrected by ROT. In addition, ROT also strikingly corrected imbalanced redox homeostasis possibly by increasing the ratio of antioxidant metabolites GSH and NAPDH against their oxidative form. In agreement with the improved metabolic status and oxidative response, ROT attenuated glomerular and tubular injury efficiently. The fibrotic markers (fibronectin, α-SMA, collagen I and collagen III), inflammatory factors (TNF-ᵯC;, IL-1ᵯD;, and ICAM-1) and oxidative stress were all markedly blocked by ROT. In vitro, ROT dose-dependently attenuated high glucose-induced proliferation and extracellular matrix production in mesangial cells. Collectively, these findings revealed that the overactivation of mitochondrial activity in kidney could contribute to the metabolic disorders and the pathogenesis of early diabetic nephropathy. PMID: 31268353 [PubMed - as supplied by publisher]

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