PubMed

Related Articles Metabolic Effects of Acibenzolar-S-Methyl for Improving Heat or Drought Stress in Creeping Bentgrass. Front Plant Sci. 2017;8:1224 Authors: Jespersen D, Yu J, Huang B Abstract Acibenzolar-S-methyl (ASM) is a synthetic functional analog of salicylic acid which can induce systemic acquired resistance in plants, but its effects on abiotic stress tolerance is not well known. The objectives of this study were to examine effects of acibenzolar-S-methyl on heat or drought tolerance in creeping bentgrass (Agrostis stolonifera) and to determine major ASM-responsive metabolites and proteins associated with enhanced abiotic stress tolerance. Creeping bentgrass plants (cv. 'Penncross') were foliarly sprayed with ASM and were exposed to non-stress (20/15°C day/night), heat stress (35/30°C), or drought conditions (by withholding irrigation) in controlled-environment growth chambers. Exogenous ASM treatment resulted in improved heat or drought tolerance, as demonstrated by higher overall turf quality, relative water content, and chlorophyll content compared to the untreated control. Western blotting revealed that ASM application resulted in up-regulation of ATP synthase, HSP-20, PR-3, and Rubisco in plants exposed to heat stress, and greater accumulation of dehydrin in plants exposed to drought stress. Metabolite profiling identified a number of amino acids, organic acids, and sugars which were differentially accumulated between ASM treated and untreated plants under heat or drought stress, including aspartic acid, glycine, citric acid, malic acid, and the sugars glucose, and fructose. Our results suggested that ASM was effective in improving heat or drought tolerance in creeping bentgrass, mainly through enhancing protein synthesis and metabolite accumulation involved in osmotic adjustment, energy metabolism, and stress signaling. PMID: 28744300 [PubMed]

Related Articles Metabolomic Analysis of Alfalfa (Medicago sativa L.) Root-Symbiotic Rhizobia Responses under Alkali Stress. Front Plant Sci. 2017;8:1208 Authors: Song T, Xu H, Sun N, Jiang L, Tian P, Yong Y, Yang W, Cai H, Cui G Abstract Alkaline salts (e.g., NaHCO3 and Na2CO3) causes more severe morphological and physiological damage to plants than neutral salts (e.g., NaCl and Na2SO4) due to differences in pH. The mechanism by which plants respond to alkali stress is not fully understood, especially in plants having symbotic relationships such as alfalfa (Medicago sativa L.). Therefore, a study was designed to evaluate the metabolic response of the root-nodule symbiosis in alfalfa under alkali stress using comparative metabolomics. Rhizobium-nodulized (RI group) and non-nodulized (NI group) alfalfa roots were treated with 200 mmol/L NaHCO3 and, roots samples were analyzed for malondialdehydyde (MDA), proline, glutathione (GSH), superoxide dismutase (SOD), and peroxidase (POD) content. Additionally, metabolite profiling was conducted using gas chromatography combined with time-of-flight mass spectrometry (GC/TOF-MS). Phenotypically, the RI alfalfa exhibited a greater resistance to alkali stress than the NI plants examined. Physiological analysis and metabolic profiling revealed that RI plants accumulated more antioxidants (SOD, POD, GSH), osmolytes (sugar, glycols, proline), organic acids (succinic acid, fumaric acid, and alpha-ketoglutaric acid), and metabolites that are involved in nitrogen fixation. Our pairwise metabolomics comparisons revealed that RI alfalfa plants exhibited a distinct metabolic profile associated with alkali putative tolerance relative to NI alfalfa plants. Data provide new information about the relationship between non-nodulized, rhizobium-nodulized alfalfa and alkali resistance. PMID: 28744296 [PubMed]

Related Articles Nuclear Magnetic Resonance-Based Metabolomics Approach to Evaluate the Prevention Effect of Camellia nitidissima Chi on Colitis-Associated Carcinogenesis. Front Pharmacol. 2017;8:447 Authors: Li MH, Du HZ, Kong GJ, Liu LB, Li XX, Lin SS, Jia AQ, Yuan ST, Sun L, Wang JS Abstract Colorectal cancer (CRC) is one of the most common malignant tumors worldwide, occurring in the colon or rectum portion of large intestine. With marked antioxidant, anti-inflammation and anti-tumor activities, Camellia nitidissima Chi has been used as an effective treatment of cancer. The azoxymethane/dextran sodium sulfate (AOM/DSS) induced CRC mice model was established and the prevention effect of C. nitidissima Chi extracts on the evolving of CRC was evaluated by examination of neoplastic lesions, histopathological inspection, serum biochemistry analysis, combined with nuclear magnetic resonance (NMR)-based metabolomics and correlation network analysis. C. nitidissima Chi extracts could significantly inhibit AOM/DSS induced CRC, relieve the colonic pathology of inflammation and ameliorate the serum biochemistry, and could significantly reverse the disturbed metabolic profiling toward the normal state. Moreover, the butanol fraction showed a better efficacy than the water-soluble fraction of C. nitidissima Chi. Further development of C. nitidissima Chi extracts as a potent CRC inhibitor was warranted. PMID: 28744216 [PubMed]

Related Articles Circadian Metabolomics in Time and Space. Front Neurosci. 2017;11:369 Authors: Dyar KA, Eckel-Mahan KL Abstract Circadian rhythms are widely known to govern human health and disease, but specific pathogenic mechanisms linking circadian disruption to metabolic diseases are just beginning to come to light. This is thanks in part to the development and application of various "omics"-based tools in biology and medicine. Current high-throughput technologies allow for the simultaneous monitoring of multiple dynamic cellular events over time, ranging from gene expression to metabolite abundance and sub-cellular localization. These fundamental temporal and spatial perspectives have allowed for a more comprehensive understanding of how various dynamic cellular events and biochemical processes are related in health and disease. With advances in technology, metabolomics has become a more routine "omics" approach for studying metabolism, and "circadian metabolomics" (i.e., studying the 24-h metabolome) has recently been undertaken by several groups. To date, circadian metabolomes have been reported for human serum, saliva, breath, and urine, as well as tissues from several species under specific disease or mutagenesis conditions. Importantly, these studies have consistently revealed that 24-h rhythms are prevalent in almost every tissue and metabolic pathway. Furthermore, these circadian rhythms in tissue metabolism are ultimately linked to and directed by internal 24-h biological clocks. In this review, we will attempt to put these data-rich circadian metabolomics experiments into perspective to find out what they can tell us about metabolic health and disease, and what additional biomarker potential they may reveal. PMID: 28744188 [PubMed]

Related Articles Pharmacological PPARγ modulation regulates sebogenesis and inflammation in SZ95 human sebocytes. Biochem Pharmacol. 2017 Aug 15;138:96-106 Authors: Mastrofrancesco A, Ottaviani M, Cardinali G, Flori E, Briganti S, Ludovici M, Zouboulis CC, Lora V, Camera E, Picardo M Abstract The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) controls the expression of genes involved in the regulation of lipid and glucose metabolism, cell proliferation/differentiation as well as inflammatory pathways. Pivotal studies in human sebocytes and isolated sebaceous glands have raised the interesting possibility that compounds acting on PPARγ can modulate sebaceous lipids and inflammation and, as such, may be useful in the treatment of acne. To investigate the role of this receptor in the regulation of lipid synthesis, proliferation and inflammation, we used the SZ95 sebaceous gland cell line stimulated with insulin. In sebocytes, insulin signaling activated the phosphatidylinositide 3-kinase-Akt (PI3K/Akt) and mammalian target of rapamycin (mTOR) pathways, which, in turn, induced high protein/lipid synthesis, increased cell growth and proliferation as well as inflammation. As regards lipogenesis, insulin initially stimulated the formation of unsaturated lipids and then the neosynthesis of lipids. The results showed, that the modulation of PPARγ, counteracted the insulin-induced altered lipogenesis, evident through a decrease in gene expression of key enzymes responsible for the synthesis of fatty acids, and through a reduction of lipid species synthesis analyzed by Oil/Nile Red staining and GC-MS. PPARγ modulation also regulated the insulin-induced proliferation, inhibiting the cell cycle progression and p21WAF1/CIP1 (p21) protein reduction. Moreover, the expression of inflammatory cytokines, induced by insulin or lipopolysaccharide (LPS), was down-modulated. In PPARγ-deficient cells or in the presence of GW9662 antagonist, all these observed effects were abolished, indicating that PPARγ activation plays a role in regulating alteration of lipogenesis, cell proliferation and inflammatory signaling. We demonstrated that selective modulation of PPARγ activity is likely to represent a therapeutic strategy for the treatment of acne. PMID: 28461124 [PubMed - indexed for MEDLINE]

Related Articles Dietary supplementation of branched-chain amino acids increases muscle net amino acid fluxes through elevating their substrate availability and intramuscular catabolism in young pigs. Br J Nutr. 2017 Apr;117(7):911-922 Authors: Zheng L, Zuo F, Zhao S, He P, Wei H, Xiang Q, Pang J, Peng J Abstract Branched-chain amino acids (BCAA) have been clearly demonstrated to have anabolic effects on muscle protein synthesis. However, little is known about their roles in the regulation of net AA fluxes across skeletal muscle in vivo. This study was aimed to investigate the effect and related mechanisms of dietary supplementation of BCAA on muscle net amino acid (AA) fluxes using the hindlimb flux model. In all fourteen 4-week-old barrows were fed reduced-protein diets with or without supplemental BCAA for 28 d. Pigs were implanted with carotid arterial, femoral arterial and venous catheters, and fed once hourly with intraarterial infusion of p-amino hippurate. Arterial and venous plasma and muscle samples were obtained for the measurement of AA, branched-chain α-keto acids (BCKA) and 3-methylhistidine (3-MH). Metabolomes of venous plasma were determined by HPLC-quadrupole time-of-flight-MS. BCAA-supplemented group showed elevated muscle net fluxes of total essential AA, non-essential AA and AA. As for individual AA, muscle net fluxes of each BCAA and their metabolites (alanine, glutamate and glutamine), along with those of histidine, methionine and several functional non-essential AA (glycine, proline and serine), were increased by BCAA supplementation. The elevated muscle net AA fluxes were associated with the increase in arterial and intramuscular concentrations of BCAA and venous metabolites including BCKA and free fatty acids, and were also related to the decrease in the intramuscular concentration of 3-MH. Correlation analysis indicated that muscle net AA fluxes are highly and positively correlated with arterial BCAA concentrations and muscle net BCKA production. In conclusion, supplementing BCAA to reduced-protein diet increases the arterial concentrations and intramuscular catabolism of BCAA, both of which would contribute to an increase of muscle net AA fluxes in young pigs. PMID: 28446262 [PubMed - indexed for MEDLINE]

Related Articles Untargeted metabolomic profiling of seminal plasma in nonobstructive azoospermia men: A noninvasive detection of spermatogenesis. Biomed Chromatogr. 2017 Aug;31(8): Authors: Gilany K, Mani-Varnosfaderani A, Minai-Tehrani A, Mirzajani F, Ghassempour A, Sadeghi MR, Amini M, Rezadoost H Abstract Male factor infertility is involved in almost half of all infertile couples. Lack of the ejaculated sperm owing to testicular malfunction has been reported in 6-10% of infertile men, a condition named nonobstructive azoospermia (NOA). In this study, we investigated untargeted metabolomic profiling of the seminal plasma in NOA men using gas chromatography-mass spectrometry and advance chemometrics. In this regard, the seminal plasma fluids of 11 NOA men with TESE-negative, nine NOA men with TESE-positive and 10 fertile healthy men (as a control group) were collected. Quadratic discriminate analysis (QDA) technique was implemented on total ion chromatograms (TICs) for identification of discriminatory retention times. We developed multivariate classification models using the QDA technique. Our results revealed that the developed QDA models could predict the classes of samples using their TIC data. The receiver operating characteristic curves for these models were >0.88. After recognition of discriminatory retention time's asymmetric penalized least square, evolving factor analysis, correlation optimized warping and alternating least squares strategies were applied for preprocessing and deconvolution of the overlapped chromatographic peaks. We could identify 36 discriminatory metabolites. These metabolites may be considered discriminatory biomarkers for different groups in NOA. PMID: 28058728 [PubMed - indexed for MEDLINE]

Related Articles Covariation Analysis of Serumal and Urinary Metabolites Suggests Aberrant Glycine and Fatty Acid Metabolism in Chronic Hepatitis B. PLoS One. 2016;11(5):e0156166 Authors: Yang L, Yang X, Kong X, Cao Z, Zhang Y, Hu Y, Tang K Abstract BACKGROUND: Chronic hepatitis b (CHB) is one of the most serious viral diseases threatening human health by putting patients at lifelong risk of cirrhosis and hepatocellular carcinoma (HCC). Although some proofs of altered metabolites in CHB were accumulated, its metabolic mechanism remains poorly understood. Analyzing covariations between metabolites may provide new hints toward underlying metabolic pathogenesis in CHB patients. METHODS: The present study collected paired urine and serum samples from the same subjects including 145 CHB and 23 healthy controls. A large-scale analysis of metabolites' covariation within and across biofluids was systematically done to explore the underlying biological evidences for reprogrammed metabolism in CHB. Randomization and relative ranking difference were introduced to reduce bias caused by different sample size. More importantly, functional indication was interpreted by mapping differentially changed covariations to known metabolic pathways. RESULTS: Our results suggested reprogrammed pathways related to glycine metabolism, fatty acids metabolism and TCA cycle in CHB patients. With further improvement, the covariation analysis combined with network association study would pave new alternative way to interpret functional clues in clinical multi-omics data. PMID: 27228119 [PubMed - indexed for MEDLINE]

Related Articles Peptides in Bronchoalveolar Lavage in Chronic Obstructive Pulmonary Disease. PLoS One. 2016;11(5):e0155724 Authors: Wendt CH, Nelsestuen G, Harvey S, Gulcev M, Stone M, Reilly C Abstract BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous disease with a significant public health burden. Currently there is no biomarker that identifies those at risk of developing COPD, progression of disease or disease phenotypes. We performed metabolomic profiling of bronchoalveolar lavage fluid (BALF) from COPD patients to determine if metabolites correlated with clinical measurements such as lung function, functional status and degree of emphysema. METHODS: Metabolomic components of BALF from 59 subjects with COPD and 20 healthy controls were separated by reversed-phase UPLC and analyzed by ESI-ToF mass spectrometry. We used univariate analysis and multiple regression models to investigate associations between metabolomic features and various clinical variables, such as lung function, functional status as measured by the St. George Respiratory Quotient Score and emphysema as measured by the CT density mask score. RESULTS: We identified over 3900 features by mass spectrometry, many consistent with peptides. Subjects with severe COPD had increased concentration of peptides compared to controls (p < 9.526e-05). The peptide concentration correlated with spirometry, specifically pulmonary function tests associated with airflow obstruction. There was no correlation with CT density, i.e. emphysema, or functional status. CONCLUSIONS: Metabolomic profiling of BALF in COPD patients demonstrated a significant increase in peptides compared to healthy controls that associated strongly to lung function, but not emphysema or functional status. PMID: 27227774 [PubMed - indexed for MEDLINE]

A rapid and reliable method for discriminating rice products from different regions using MCX-based solid-phase extraction and DI-MS/MS-based metabolomics approach. J Chromatogr B Analyt Technol Biomed Life Sci. 2017 Jul 18;1061-1062:185-192 Authors: Lim DK, Mo C, Long NP, Lim J, Kwon SW Abstract The expansion of the global rice marketplace ultimately raises concerns about authenticity control. Several analytical methods for differentiating the geographical origin of rice have been developed, yet a high-throughput method is still in demand. In this study, we developed a rapid approach using direct infusion-mass spectrometry (DI-MS) to distinguish rice products from different countries. Specifically, the elimination of the matrix effect by a polytetrafluoroethylene (PTFE) filter, a mixed-mode cation exchange (MCX) solid-phase extraction (SPE) with 20% methanol, and an MCX SPE with 100% methanol were measured. Afterward, partial least squares discriminant analysis and random forests were applied to seek the optimal discrimination method. The results revealed that the combination of MCX SPE with 100% methanol and DI-MS in positive ion mode (accuracy=1.000, R(2)=0.916, Q(2)=0.720, B/W-based p-value=0.015) or the combination of MCX SPE with 20% methanol and targeted DI-MS/MS in positive ion mode (accuracy=1.000, R(2)=0.931, Q(2)=0.849, B/W-based p-value=0.002) showed the excellent discriminatory ability. Furthermore, differentially expressed metabolites including sodiated lysophosphatidylcholine, lysophosphatidylcholine, lysophosphatidylethanolamines and lysophosphatidylglycerol classes were found. In conclusion, our study provides a rapid and reliable platform for geographical discrimination of white rice and will contribute to the authenticity control of rice products. PMID: 28743095 [PubMed - as supplied by publisher]

Dynamics of lipids and metabolites during the cell cycle of Chlamydomonas reinhardtii. Plant J. 2017 Jul 25;: Authors: Jüppner J, Mubeen U, Leisse A, Caldana C, Brust H, Steup M, Herrmann M, Steinhauser D, Giavalisco P Abstract Metabolites and lipids are the final products of enzymatic processes, distinguishing the different cellular functions and activities of single cells or whole tissues. Understanding these cellular functions within a well-established model system, requires a systemic collection of molecular and physiological information. In the current report, the green algae Chlamydomonas reinhardtii was selected to establish a comprehensive workflow for the detailed multi-omics analysis of a synchronously growing cell culture system. Next to the implementation and benchmarking of the synchronous cell culture, a two-phase extraction method was adopted for the analysis of proteins, lipids, metabolites and starch from a single sample aliquot of as little as 10 - 50 million Chlamydomonas cells. In a proof of concept study, primary metabolites and lipids were sampled throughout the diurnal cell cycle. The results of these time-resolved measurements showed that single compounds were not only coordinated between each other in different pathways, but that these complex metabolic signatures have the potential to be used as biomarkers of various cellular processes. Taken together the developed workflow including the synchronized growth of the photoautotrophic cell culture, in combination with comprehensive extraction methods and detailed metabolic phenotyping has the potential for the in-depth analysis of complex cellular processes, providing essential information for the understanding of complex biological systems. This article is protected by copyright. All rights reserved. PMID: 28742931 [PubMed - as supplied by publisher]

Health effects of dietary oxidized tyrosine and dityrosine administration in mice with nutrimetabolomic strategies. J Agric Food Chem. 2017 Jul 25;: Authors: Yang Y, Zhang H, Yan B, Zhang T, Gao Y, Shi Y, Le G Abstract This study aims to investigate the health effects of long-term dietary oxidized tyrosine (O-Tyr) and its main product (dityrosine) administration on mice metabolism. Mice received daily intragastric administration of either O-Tyr (320 μg/kg body weight), dityrosine (Dityr, 320 μg/kg body weight) or saline for consecutive six weeks. Urine and plasma samples were analyzed by NMR-based metabolomics strategies. Body weight, clinical chemistry, oxidative damage indexes and histopathological data were obtained as complementary information. O-Tyr and Dityr exposure changed many systemic metabolic processes, including reduced choline bioavailability, led to fat accumulation in liver, induced hepatic injury and renal dysfunction, resulted in changes in gut microbiota functions, elevated risk factor for cardiovascular disease, altered amino acid metabolism, induced oxidative stress responses, and inhibited energy metabolism. These findings implied that it is absolutely essential to reduce the generation of oxidation protein products in food system through improving modern food processing methods. PMID: 28742334 [PubMed - as supplied by publisher]

Related Articles Metabolite profiling of non-sterile rhizosphere soil. Plant J. 2017 Jul 25;: Authors: Pétriacq P, Williams A, Cotton TEA, McFarlane AE, Rolfe SA, Ton J Abstract Rhizosphere chemistry is the sum of root exudation chemicals, their breakdown products and microbial products of soil-derived chemicals. To date, most studies about root exudation chemistry are based on sterile cultivation systems, which limits the discovery of microbial breakdown products that act as semiochemicals and shape microbial rhizosphere communities. Here, we present a method for untargeted metabolic profiling of non-sterile rhizosphere soil. We have developed an experimental growth system that enables collection and analysis of rhizosphere chemicals from different plant species. High-throughput sequencing of 16S rRNA genes demonstrated that plants in the growth system support a microbial rhizosphere effect. To collect a range of (a)polar chemicals from the system, we developed extraction methods that do not cause detectable damage to root cells or soil-inhabiting microbes, thus preventing contamination with cellular metabolites. Untargeted metabolite profiling by UPLC-Q-TOF mass spectrometry, followed by uni- and multivariate statistical analyses identified a wide range of secondary metabolites that are enriched in plant-containing soil compared to control soil without roots. We show that the method is suitable for profiling rhizosphere chemistry of maize in agricultural soil, demonstrating applicability to different plant-soil combinations. Our study provides a robust method for comprehensive metabolite profiling of non-sterile rhizosphere soil, which represents a technical advance towards the establishment of causal relationships between the chemistry and microbial composition of the rhizosphere. This article is protected by copyright. All rights reserved. PMID: 28742258 [PubMed - as supplied by publisher]

Related Articles GPR55 receptor antagonist decreases glycolytic activity in PANC-1 pancreatic cancer cell line and tumor xenografts. Int J Cancer. 2017 Jul 25;: Authors: Bernier M, Catazaro J, Singh NS, Wnorowski A, Boguszewska-Czubara A, Jozwiak K, Powers R, Wainer IW Abstract The Warburg effect is a predominant metabolic pathway in cancer cells characterized by enhanced glucose uptake and its conversion to L-lactate and is associated with upregulated expression of HIF-1α and activation of the EGFR-MEK-ERK, Wnt-β-catenin and PI3K-AKT signaling pathways. (R,R')-4'-methoxy-1-naphthylfenoterol ((R,R')-MNF) significantly reduces proliferation, survival, and motility of PANC-1 pancreatic cancer cells through inhibition of the GPR55 receptor. We examined (R,R')-MNF's effect on glycolysis in PANC-1 cells and tumors. Global NMR metabolomics was used to elucidate differences in the metabolome between untreated and (R,R')-MNF-treated cells. LC/MS analysis was used to quantify intracellular concentrations of β-hydroxybutyrate, carnitine and L-lactate. Changes in target protein expression were determined by Western blot analysis. Data was also obtained from mouse PANC-1 tumor xenografts after administration of (R,R')-MNF. Metabolomics data indicate that (R,R')-MNF altered fatty acid metabolism, energy metabolism, and amino acid metabolism and increased intracellular concentrations of β-hydroxybutyrate and carnitine while reducing L-lactate content. The cellular content of phosphoinositide-dependent kinase-1 and hexokinase 2 was reduced consistent with diminished PI3K-AKT signaling and glucose metabolism. The presence of the GLUT8 transporter was established and found to be attenuated by (R,R')-MNF. Mice treated with (R,R')-MNF had significant accumulation of L-lactate in tumor tissue relative to vehicle-treated mice, together with reduced levels of the selective L-lactate transporter MCT4. Lower intratumoral levels of EGFR, pyruvate kinase M2, β-catenin, hexokinase 2 and P-glycoprotein were also observed. The data suggest that (R,R')-MNF reduces glycolysis in PANC-1 cells and tumors through reduced expression and function at multiple controlling sites in the glycolytic pathway. This article is protected by copyright. All rights reserved. PMID: 28741686 [PubMed - as supplied by publisher]

Related Articles The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol. 2017 Jul 25;: Authors: Fridman WH, Zitvogel L, Sautès-Fridman C, Kroemer G Abstract Immunotherapy is currently the most rapidly advancing area of clinical oncology, and provides the unprecedented opportunity to effectively treat, and even cure, several previously untreatable malignancies. A growing awareness exists of the fact that the success of chemotherapy and radiotherapy, in which the patient's disease can be stabilized well beyond discontinuation of treatment (and occasionally is cured), also relies on the induction of a durable anticancer immune response. Indeed, the local immune infiltrate undergoes dynamic changes that accompany a shift from a pre-existing immune response to a therapy-induced immune response. As a result, the immune contexture, which is determined by the density, composition, functional state and organization of the leukocyte infiltrate of the tumour, can yield information that is relevant to prognosis, prediction of a treatment response and various other pharmacodynamic parameters. Several complementary technologies can be used to explore the immune contexture of tumours, and to derive biomarkers that could enable the adaptation of individual treatment approaches for each patient, as well as monitoring a response to anticancer therapies. PMID: 28741618 [PubMed - as supplied by publisher]

Related Articles The Pharmacogenomic and Metabolomic Predictors of ACE Inhibitor and Angiotensin II Receptor Blocker Effectiveness and Safety. Cardiovasc Drugs Ther. 2017 Jul 24;: Authors: Flaten HK, Monte AA Abstract Hypertension (HTN) is the most common chronic disease in the USA. Hypertensive patients frequently require repeat primary care visits to find an effective drug or drug combination to control their disease. Currently, patients are prescribed drugs for HTN based on race, age, and comorbidities and although the current guidelines are reasonable starting points for prescribing, 50% of hypertensive patients still fail to achieve target blood pressures. Despite numerous strategies to improve compliance, drug effectiveness, and optimization of initial drug choice, effectiveness has remained largely unchanged over the past two decades. Therefore, it is important to pursue alternative strategies to more effectively treat patients and to decrease medical costs. Additional precision medicine work is needed to identify factors associated with effectiveness of commonly used antihypertensive medications. The objective of this manuscript is to present a comprehensive review of the pharmacogenomic and metabolomic factors associated with ACEI and ARB effectiveness and safety. PMID: 28741243 [PubMed - as supplied by publisher]

Related Articles p38 MAPK signaling and phosphorylations in the BRCT1 domain regulate XRCC1 recruitment to sites of DNA damage. Sci Rep. 2017 Jul 24;7(1):6322 Authors: de Sousa MML, Bjørås KØ, Hanssen-Bauer A, Solvang-Garten K, Otterlei M Abstract XRCC1 is a scaffold protein involved in base excision repair and single strand break repair. It is a phosphoprotein that contains more than 45 phosphorylation sites, however only a few of these have been characterized and connected to specific kinases and functions. Mitogen activated protein kinases (MAPK) are mediators of cellular stress responses, and here we demonstrate that p38 MAPK signaling is involved in phosphorylation of XRCC1 and regulation of recruitment to oxidative stress. Inhibition of p38 MAPK caused a marked pI shift of XRCC1 towards a less phosphorylated state. Inhibition of p38 also increased the immediate accumulation of XRCC1 at site of DNA damage in a poly(ADP)-ribose (PAR) dependent manner. These results suggest a link between PARylation, p38 signaling and XRCC1 recruitment to DNA damage. Additionally, we characterized two phosphorylation sites, T358 and T367, located within, or close to, the phosphate-binding pocket of XRCC1, which is important for interaction with PAR. Mutation of these sites impairs recruitment of XRCC1 to DNA damage and binding to PARP1/PAR. Collectively, our data suggest that phosphorylation of T358 and T367 and p38 signaling are important for proper regulation of XRCC1 recruitment to DNA damage and thereby avoidance of potential toxic and mutagenic BER-intermediates. PMID: 28740101 [PubMed - in process]

Related Articles An integrated strategy by using target tissue metabolomics biomarkers as pharmacodynamic surrogate indices to screen antipyretic components of Qingkaikling injection. Sci Rep. 2017 Jul 24;7(1):6310 Authors: Zhang Z, Lu F, Liu H, Zhao H, Liu Y, Fu S, Wang M, Xie Z, Yu H, Huang Z, Zhang Y, Gao X Abstract Traditional Chinese medicine (TCM) treatment can be valuable therapeutic strategies. However, the active components and action mechanisms that account for its therapeutic effects remain elusive. Based on the hypothesis that the components of a formula which exert effect would be measurable in target tissue, a target tissue metabolomics-based strategy was proposed for screening of antipyretic components in Qingkaikling injection (QKLI). First, we detected the components of QKLI which could reach its target tissue (hypothalamus) by determining the hypothalamus microdialysate and discovered that only baicalin and geniposide could be detected. Then, by conducting hypothalamus metabolomics studies, 14 metabolites were screened as the potential biomarkers that related to the antipyretic mechanisms of QKLI and were used as its pharmacodynamic surrogate indices. Subsequently, the dynamic concentration of baicalin and geniposide in hypothalamus microdialysates and biomarkers in hypothalamus were measured and correlated with each other. The results indicated that only baicalin shown a good correlation with these biomarkers. Finally, a network pharmacology approach was established to validate the antipyretic activity of baicalin and the results elucidated its antipyretic mechanisms as well. The integrated strategy proposed here provided a powerful means for identifying active components and mechanisms contributing to pharmacological effects of TCM. PMID: 28740079 [PubMed - in process]

Related Articles Plasma N-acetylputrescine, cadaverine and 1,3-diaminopropane: potential biomarkers of lung cancer used to evaluate the efficacy of anticancer drugs. Oncotarget. 2017 Jul 17;: Authors: Liu R, Li P, Bi CW, Ma R, Yin Y, Bi K, Li Q Abstract Polyamines have been widely investigated as potential biomarkers for various types of cancers, including lung cancer, which is one of the most common causes of death from cancer worldwide. This study was carried out to evaluate the value of polyamines that serve as early diagnostic and cancer progression markers as well as drug evaluation for lung cancer (squamous cell carcinoma of lung, SCCL). SCCL was induced in Wistar rats by intratracheal instillation of 3-methylcholanthrene and treated with three different anti-cancer drugs, Aidi injections, fluorouracil, and a combination of them. After carcinogenesis for 28, 70 and 98 days and therapy for 28 and 56 days, the polyamine levels in plasma of SCCL, healthy and treated rats were determined using a UHPLC-MS/MS assay base on the means of targeted metabolomics. Results showed that increased N-acetylputrescine, cadaverine and 1,3-diaminopropane levels were associated with progression of SCCL. The levels of cadaverine and 1,3-diaminopropane returned to normal after administration of the three different kinds of anticancer drug. In addition, the suitability of using N-acetylputrescine, cadaverine and 1,3-diaminopropane as biomarkers was confirmed by PLS-DA and ROC analysis. It can provide an innovative and effective way for the clinical diagnosis, prevention and treatment of lung cancer, and stimulate a theoretical basis for the design and development of new anticancer drugs. At the same time, this increased the clinical options for polyamines as cancer biomarkers. PMID: 28740003 [PubMed - as supplied by publisher]

Related Articles MetaboQC: A tool for correcting untargeted metabolomics data with mass spectrometry detection using quality controls. Talanta. 2017 Nov 01;174:29-37 Authors: Calderón-Santiago M, López-Bascón MA, Peralbo-Molina Á, Priego-Capote F Abstract Nowadays most metabolomic studies involve the analysis of large sets of samples to find a representative metabolite pattern associated to the factor under study. During a sequence of analyses the instrument signals can be subjected to the influence of experimental variability sources. Implementation of quality control (QC) samples to check the contribution of experimental variability is the most common approach in metabolomics. This practice is based on the filtration of molecular entities experiencing a variation coefficient higher than that measured in the QC data set. Although other robust correction algorithms have been proposed, none of them has provided an easy-to-use and easy-to-install tool capable of correcting experimental variability sources. In this research an R-package -the MetaboQC- has been developed to correct intra-day and inter-days variability using QCs analyzed within a pre-set sequence of experiments. MetaboQC has been tested in two data sets to assess the correction effects by comparing the metabolites variability before and after application of the proposed tool. As a result, the number of entities in QCs significantly different between days was reduced from 86% to 19% in the negative ionization mode and from 100% to 13% in the positive ionization mode. Furthermore, principal component analysis allowed detecting the filtration of instrumental variability associated to the injection order. PMID: 28738582 [PubMed - in process]