PubMed

Nanotechnology-based inhalation treatments for lung cancer: state of the art. Nanotechnol Sci Appl. 2015;8:55-66 Authors: Ahmad J, Akhter S, Rizwanullah M, Amin S, Rahman M, Ahmad MZ, Rizvi MA, Kamal MA, Ahmad FJ Abstract Considering the challenges associated with conventional chemotherapy, targeted and local delivery of chemotherapeutics via nanoparticle (NP) carriers to the lungs is an emerging area of interest. Recent studies and growing clinical application in cancer nanotechnology showed the huge potential of NPs as drug carriers in cancer therapy, including in lung carcinoma for diagnosis, imaging, and theranostics. Researchers have confirmed that nanotechnology-based inhalation chemotherapy is viable and more effective than conventional chemotherapy, with lesser side effects. Recently, many nanocarriers have been investigated, including liposomes, polymeric micelles, polymeric NPs, solid lipid NPs, and inorganic NPs for inhalation treatments of lung cancer. Yet, the toxicity of such nanomaterials to the lungs tissues and further distribution to other organs due to systemic absorption on inhalation delivery is a debatable concern. Here, prospect of NPs-based local lung cancer targeting through inhalation route as well as its associated challenges are discussed. PMID: 26640374 [PubMed - as supplied by publisher]

Urinary Metabolites from Mango (Mangifera indica L. cv. Keitt) Galloyl Derivatives and In Vitro Hydrolysis of Gallotannins in Physiological Conditions. Mol Nutr Food Res. 2015 Dec 7; Authors: Barnes RC, Krenek KA, Meibohm B, Mertens-Talcott1 SU, Talcott ST Abstract SCOPE: The absorption, metabolism, and excretion of mango galloyl derivatives (GD) has not yet been investigated in humans, and studies investigating repeated dosages of polyphenols are limited. METHODS AND RESULTS: In this human pilot trial, healthy volunteers (age= 21-38y, n=11) consumed 400g/day of mango-pulp (cv. Keitt) for 10 days, and seven metabolites of gallic acid (GA) were characterized and quantified in urine excreted over a 12 h period. Pyrogallol-O-sulfate and deoxypyrogallol-O-sulfate were found to be significantly more excreted between days 1 and 10 (p < 0.05) from 28.5 mg to 55.4 mg and 23.6 mg to 47.7 mg respectively. Additionally, the in vitro hydrolysis of gallotannins (GTs) was monitored at physiological pH and temperature conditions, and after 4 h a significant (p< 0.05) shift in composition from relativity high to low molecular weight GTs was observed. CONCLUSION: Seven metabolites of GA were identified in the urine of healthy volunteers, and two microbial metabolites were found to be significantly more excreted following 10 days of mango consumption. Mango GTs were also found to release free GA in conditions similar to the intestines. GTs may serve as a pool of pro-GA compounds that can be absorbed or undergo microbial metabolism. This article is protected by copyright. All rights reserved. PMID: 26640139 [PubMed - as supplied by publisher]

Evidence-based pharmacogenetics: Is it possible? Int J Risk Saf Med. 2015 Nov 27;27 Suppl 1:S97-8 Authors: Sychev DA, Malova EU Abstract BACKGROUND: For improving quality, safety and efficiency of care, health systems perform a paradigm change towards personalized medicine, also referred to as genomic medicine. It uses combined knowledge (genomics, transcriptomics, proteomics, metabolomics) about a person to predict disease susceptibility, disease prognosis or treatment response and thereby to improve the person's health. The last decade has witnessed a steady embrace of personalized medicine by senior government officials, industry leadership and health care providers [1]. On the 12th December of 2013 Russian President Vladimir Putin in his annual address to the Federal Assembly said: "The Ministry of Health and the Russian Academy of Sciences must give priority to fundamental and applied research in medicine, including genomic studies" [2]. A year earlier, in 2012 the Ministry of Health of the Russian Federation, headed by Veronika Skvortsova established the strategy of personalized medicine development in Russia [3]. But still a lot of work is focused on using clinical research findings to aid the delivery of optimum clinical care to patients. Pharmacogenetic testing (using genetic information to guide drug therapy) is an actively developing field of personalized medicine and its current state indicates that it can be usefully introduced into clinical practice in the nearest future. In Russia pharmacogenetic testing is already used for personalizing prescription of certain drugs [4]. OBJECTIVE: To assess the extent of genetic testing use for improving use of medicines. METHODS: PubMed and E-Library searches for the period of 2004-2015. RESULTS: The number of publications retrieved in PubMed search for the term "pharmacogenetics" for 2004 year was 538 and was more than 15500 publications for 2015. 800 Russian-language publications in total were retrieved using a domestic scientific database E-Library search for the term "pharmacogenetics" for 2015 year. The sharp rise in the number of publications (including Russia) reflects growing interest not only among scientists, but also among practitioners. However evidence that is actually available on some key topics may not be of sufficiently high quality to support confident conclusions. As a rule, retrospective cohort studies, also known as historical cohort studies, are carried out. The number of randomized, prospective studies is not large, though in recent years, there has been an increase in their number. However, surrogate outcomes are commonly used in the mentioned studies as trial end points. The main reason for this is the lack of sponsorship. Quite often studies are not interesting for pharmaceutical companies and are carried out within the confines of the small grants. Nevertheless, systematic reviews and meta-analyses of some pharmacogenetic tests provide the high level of evidence (pharmacogenetic testing for clopidogrel, abacavir and antineoplastic drugs) so they appear even in clinical guidelines with the evidence level IIb. It is important to mention that for certain drugs FDA has already approved pharmacogenetic testing [5]. CONCLUSIONS: Evidence is often inconsistent. This leads to the fact that clinical use of pharmacogenetic testing seems to be most appropriate for the management of patients with high risk of adverse drug reactions. PMID: 26639733 [PubMed - in process]

geoRge: a computational tool to detect the presence of stable isotope labeling in LC/MS-based untargeted metabolomics. Anal Chem. 2015 Dec 6; Authors: Capellades J, Navarro M, Samino S, Garcia-Ramirez M, Hernandez C, Simo R, Vinaixa M, Yanes O Abstract Studying the flow of chemical moieties through the complex set of metabolic reactions that happen in the cell is essential to understanding the alterations in homeostasis that occur in disease. Recently, LC/MS-based untargeted metabolomics and isotopically labeled metabolites have been used to facilitate the unbiased mapping of labeled moieties through metabolic pathways. However, due to the complexity of the resulting experimental datasets few computational tools are available for data analysis. Here we introduce geoRge, a novel computational approach capable of analyzing untargeted LC/MS data from stable isotope-labeling experiments. geoRge is written in the open language R and runs on the output structure of the widespreadly-used XCMS package. Unlike other existing tools, geoRge benefits from the fact that mass spectral peaks originated from labeled metabolites show higher intensity and may even appear anew in the mass spectra. We demonstrate that a statistical comparison between unlabeled and labeled samples that identifies significant up-regulated features in the labeled samples is more robust method for tracking stable isotopes than iterating over all MS signal data using the theoretical mass difference between the light and heavy stable isotopes. The automated untargeted isotope annotation and relative quantification capabilities of geoRge are demonstrated by the analysis of LC/MS data from a human retinal pigment epithelium cell line (ARPE-19) grown on normal and high glucose concentrations mimicking diabetic retinopathy conditions in vitro. To ensure data traceability and reproducibility, and enabling for comparison with other existing and future approaches, raw LC/MS files have been deposited in MetaboLights (MTBLS213) and geoRge is available as an R script at https://github.com/jcapelladesto/geoRge. PMID: 26639619 [PubMed - as supplied by publisher]

Related Articles Multiple Hepatic Regulatory Variants at the GALNT2 GWAS Locus Associated with High-Density Lipoprotein Cholesterol. Am J Hum Genet. 2015 Dec 3;97(6):801-15 Authors: Roman TS, Marvelle AF, Fogarty MP, Vadlamudi S, Gonzalez AJ, Buchkovich ML, Huyghe JR, Fuchsberger C, Jackson AU, Wu Y, Civelek M, Lusis AJ, Gaulton KJ, Sethupathy P, Kangas AJ, Soininen P, Ala-Korpela M, Kuusisto J, Collins FS, Laakso M, Boehnke M, Mohlke KL Abstract Genome-wide association studies (GWASs) have identified more than 150 loci associated with blood lipid and cholesterol levels; however, the functional and molecular mechanisms for many associations are unknown. We examined the functional regulatory effects of candidate variants at the GALNT2 locus associated with high-density lipoprotein cholesterol (HDL-C). Fine-mapping and conditional analyses in the METSIM study identified a single locus harboring 25 noncoding variants (r(2) > 0.7 with the lead GWAS variants) strongly associated with total cholesterol in medium-sized HDL (e.g., rs17315646, p = 3.5 × 10(-12)). We used luciferase reporter assays in HepG2 cells to test all 25 variants for allelic differences in regulatory enhancer activity. rs2281721 showed allelic differences in transcriptional activity (75-fold [T] versus 27-fold [C] more than the empty-vector control), as did a separate 780-bp segment containing rs4846913, rs2144300, and rs6143660 (49-fold [AT(-) haplotype] versus 16-fold [CC(+) haplotype] more). Using electrophoretic mobility shift assays, we observed differential CEBPB binding to rs4846913, and we confirmed this binding in a native chromatin context by performing chromatin-immunoprecipitation (ChIP) assays in HepG2 and Huh-7 cell lines of differing genotypes. Additionally, sequence reads in HepG2 DNase-I-hypersensitivity and CEBPB ChIP-seq signals spanning rs4846913 showed significant allelic imbalance. Allelic-expression-imbalance assays performed with RNA from primary human hepatocyte samples and expression-quantitative-trait-locus (eQTL) data in human subcutaneous adipose tissue samples confirmed that alleles associated with increased HDL-C are associated with a modest increase in GALNT2 expression. Together, these data suggest that at least rs4846913 and rs2281721 play key roles in influencing GALNT2 expression at this HDL-C locus. PMID: 26637976 [PubMed - in process]

Related Articles Whole-genome duplication increases tumor cell sensitivity to MPS1 inhibition. Oncotarget. 2015 Nov 30; Authors: Jemaà M, Manic G, Lledo G, Lissa D, Reynes C, Morin N, Chibon F, Sistigu A, Castedo M, Vitale I, Kroemer G, Abrieu A Abstract Several lines of evidence indicate that whole-genome duplication resulting in tetraploidy facilitates carcinogenesis by providing an intermediate and metastable state more prone to generate oncogenic aneuploidy. Here, we report a novel strategy to preferentially kill tetraploid cells based on the abrogation of the spindle assembly checkpoint (SAC) via the targeting of TTK protein kinase (better known as monopolar spindle 1, MPS1). The pharmacological inhibition as well as the knockdown of MPS1 kills more efficiently tetraploid cells than their diploid counterparts. By using time-lapse videomicroscopy, we show that tetraploid cells do not survive the aborted mitosis due to SAC abrogation upon MPS1 depletion. On the contrary diploid cells are able to survive up to at least two more cell cycles upon the same treatment. This effect might reflect the enhanced difficulty of cells with whole-genome doubling to tolerate a further increase in ploidy and/or an elevated level of chromosome instability in the absence of SAC functions. We further show that MPS1-inhibited tetraploid cells promote mitotic catastrophe executed by the intrinsic pathway of apoptosis, as indicated by the loss of mitochondrial potential, the release of the pro-apoptotic cytochrome c from mitochondria, and the activation of caspases. Altogether, our results suggest that MPS1 inhibition could be used as a therapeutic strategy for targeting tetraploid cancer cells. PMID: 26637805 [PubMed - as supplied by publisher]

Towards merging untargeted and targeted methods in mass spectrometry-based metabolomics and lipidomics. Anal Chem. 2015 Dec 4; Authors: Cajka T, Fiehn O Abstract Advances in mass spectrometry (MS) and data processing have led to discoveries in regulation of cellular metabolism by using metabolomics and lipidomics approaches. Mass spectrometry is by far the dominating analytical platform in metabolomics and lipidomics, surpassing the use of nuclear magnetic resonance (NMR) at a 5:2 ratio according to our citation analysis. PMID: 26637011 [PubMed - as supplied by publisher]

Diagnosis and treatment of small intestinal bacterial overgrowth. Expert Rev Gastroenterol Hepatol. 2015 Dec 4;:1-13 Authors: Ponziani FR, Gerardi V, Gasbarrini A Abstract A huge number of bacteria are hosted in the gastrointestinal tract, following a gradient increasing towards the colon. Gastric acid secretion and intestinal clearance provide the qualitative and quantitative partitioning of intestinal bacteria; small intestinal bacteria overgrowth (SIBO) occurs when these barrier mechanisms fail. Diagnosis of SIBO is challenging due to the low specificity of symptoms, the frequent association with other diseases of the gastrointestinal tract and the absence of optimal objective diagnostic tests. The therapeutic approach to SIBO is oriented towards resolving predisposing conditions, and is supported by antibiotic treatment to restore the normal small intestinal microflora and by modifications of dietary habits for symptomatic relief. In the near future, metagenomics and metabolomics will help to overcome the uncertainties of SIBO diagnosis and the pitfalls of therapeutic management, allowing the design of a personalized strategy based on the direct insight into the small intestinal microbial community. PMID: 26636484 [PubMed - as supplied by publisher]

Metabolomics and Type 2 Diabetes: Translating Basic Research into Clinical Application. J Diabetes Res. 2016;2016:3898502 Authors: Klein MS, Shearer J Abstract Type 2 diabetes (T2D) and its comorbidities have reached epidemic proportions, with more than half a billion cases expected by 2030. Metabolomics is a fairly new approach for studying metabolic changes connected to disease development and progression and for finding predictive biomarkers to enable early interventions, which are most effective against T2D and its comorbidities. In metabolomics, the abundance of a comprehensive set of small biomolecules (metabolites) is measured, thus giving insight into disease-related metabolic alterations. This review shall give an overview of basic metabolomics methods and will highlight current metabolomics research successes in the prediction and diagnosis of T2D. We summarized key metabolites changing in response to T2D. Despite large variations in predictive biomarkers, many studies have replicated elevated plasma levels of branched-chain amino acids and their derivatives, aromatic amino acids and α-hydroxybutyrate ahead of T2D manifestation. In contrast, glycine levels and lysophosphatidylcholine C18:2 are depressed in both predictive studies and with overt disease. The use of metabolomics for predicting T2D comorbidities is gaining momentum, as are our approaches for translating basic metabolomics research into clinical applications. As a result, metabolomics has the potential to enable informed decision-making in the realm of personalized medicine. PMID: 26636104 [PubMed - in process]

Challenges of Inversely Estimating Jacobian from Metabolomics Data. Front Bioeng Biotechnol. 2015;3:188 Authors: Sun X, Länger B, Weckwerth W Abstract Inferring dynamics of metabolic networks directly from metabolomics data provides a promising way to elucidate the underlying mechanisms of biological systems, as reported in our previous studies (Weckwerth, 2011; Sun and Weckwerth, 2012; Nägele et al., 2014) by a differential Jacobian approach. The Jacobian is solved from an overdetermined system of equations as JC + CJ(T)  = -2D, called Lyapunov Equation in its generic form, where J is the Jacobian, C is the covariance matrix of metabolomics data, and D is the fluctuation matrix. Lyapunov Equation can be further simplified as the linear form Ax = b. Frequently, this linear equation system is ill-conditioned, i.e., a small variation in the right side b results in a big change in the solution x, thus making the solution unstable and error-prone. At the same time, inaccurate estimation of covariance matrix and uncertainties in the fluctuation matrix bring biases to the solution x. Here, we first reviewed common approaches to circumvent the ill-conditioned problems, including total least squares, Tikhonov regularization, and truncated singular value decomposition. Then, we benchmarked these methods on several in silico kinetic models with small to large perturbations on the covariance and fluctuation matrices. The results identified that the accuracy of the reverse Jacobian is mainly dependent on the condition number of A, the perturbation amplitude of C, and the stiffness of the kinetic models. Our research contributes a systematical comparison of methods to inversely solve Jacobian from metabolomics data. PMID: 26636075 [PubMed - as supplied by publisher]

From Genetics to Functional Genomics: Improvement in Drought Signaling and Tolerance in Wheat. Front Plant Sci. 2015;6:1012 Authors: Budak H, Hussain B, Khan Z, Ozturk NZ, Ullah N Abstract Drought being a yield limiting factor has become a major threat to international food security. It is a complex trait and drought tolerance response is carried out by various genes, transcription factors (TFs), microRNAs (miRNAs), hormones, proteins, co-factors, ions, and metabolites. This complexity has limited the development of wheat cultivars for drought tolerance by classical breeding. However, attempts have been made to fill the lost genetic diversity by crossing wheat with wild wheat relatives. In recent years, several molecular markers including single nucleotide polymorphisms (SNPs) and quantitative trait loci (QTLs) associated with genes for drought signaling pathways have been reported. Screening of large wheat collections by marker assisted selection (MAS) and transformation of wheat with different genes/TFs has improved drought signaling pathways and tolerance. Several miRNAs also provide drought tolerance to wheat by regulating various TFs/genes. Emergence of OMICS techniques including transcriptomics, proteomics, metabolomics, and ionomics has helped to identify and characterize the genes, proteins, metabolites, and ions involved in drought signaling pathways. Together, all these efforts helped in understanding the complex drought tolerance mechanism. Here, we have reviewed the advances in wide hybridization, MAS, QTL mapping, miRNAs, transgenic technique, genome editing system, and above mentioned functional genomics tools for identification and utility of signaling molecules for improvement in wheat drought tolerance. PMID: 26635838 [PubMed - as supplied by publisher]

Molecular and Translational Classifications of DAMPs in Immunogenic Cell Death. Front Immunol. 2015;6:588 Authors: Garg AD, Galluzzi L, Apetoh L, Baert T, Birge RB, Bravo-San Pedro JM, Breckpot K, Brough D, Chaurio R, Cirone M, Coosemans A, Coulie PG, De Ruysscher D, Dini L, de Witte P, Dudek-Peric AM, Faggioni A, Fucikova J, Gaipl US, Golab J, Gougeon ML, Hamblin MR, Hemminki A, Herrmann M, Hodge JW, Kepp O, Kroemer G, Krysko DV, Land WG, Madeo F, Manfredi AA, Mattarollo SR, Maueroder C, Merendino N, Multhoff G, Pabst T, Ricci JE, Riganti C, Romano E, Rufo N, Smyth MJ, Sonnemann J, Spisek R, Stagg J, Vacchelli E, Vandenabeele P, Vandenberk L, Van den Eynde BJ, Van Gool S, Velotti F, Zitvogel L, Agostinis P Abstract The immunogenicity of malignant cells has recently been acknowledged as a critical determinant of efficacy in cancer therapy. Thus, besides developing direct immunostimulatory regimens, including dendritic cell-based vaccines, checkpoint-blocking therapies, and adoptive T-cell transfer, researchers have started to focus on the overall immunobiology of neoplastic cells. It is now clear that cancer cells can succumb to some anticancer therapies by undergoing a peculiar form of cell death that is characterized by an increased immunogenic potential, owing to the emission of the so-called "damage-associated molecular patterns" (DAMPs). The emission of DAMPs and other immunostimulatory factors by cells succumbing to immunogenic cell death (ICD) favors the establishment of a productive interface with the immune system. This results in the elicitation of tumor-targeting immune responses associated with the elimination of residual, treatment-resistant cancer cells, as well as with the establishment of immunological memory. Although ICD has been characterized with increased precision since its discovery, several questions remain to be addressed. Here, we summarize and tabulate the main molecular, immunological, preclinical, and clinical aspects of ICD, in an attempt to capture the essence of this phenomenon, and identify future challenges for this rapidly expanding field of investigation. PMID: 26635802 [PubMed - as supplied by publisher]

Integrated 'Omics', Targeted Metabolite and Single-cell Analyses of Arctic Snow Algae Functionality and Adaptability. Front Microbiol. 2015;6:1323 Authors: Lutz S, Anesio AM, Field K, Benning LG Abstract Snow algae are poly-extremophilic microalgae and important primary colonizers and producers on glaciers and snow fields. Depending on their pigmentation they cause green or red mass blooms during the melt season. This decreases surface albedo and thus further enhances snow and ice melting. Although the phenomenon of snow algal blooms has been known for a long time, large aspects of their physiology and ecology sill remain cryptic. This study provides the first in-depth and multi-omics investigation of two very striking adjacent green and red snow fields on a glacier in Svalbard. We have assessed the algal community composition of green and red snow including their associated microbiota, i.e., bacteria and archaea, their metabolic profiles (targeted and non-targeted metabolites) on the bulk and single-cell level, and assessed the feedbacks between the algae and their physico-chemical environment including liquid water content, pH, albedo, and nutrient availability. We demonstrate that green and red snow clearly vary in their physico-chemical environment, their microbial community composition and their metabolic profiles. For the algae this likely reflects both different stages of their life cycles and their adaptation strategies. Green snow represents a wet, carbon and nutrient rich environment and is dominated by the algae Microglena sp. with a metabolic profile that is characterized by key metabolites involved in growth and proliferation. In contrast, the dry and nutrient poor red snow habitat is colonized by various Chloromonas species with a high abundance of storage and reserve metabolites likely to face upcoming severe conditions. Combining a multitude of techniques we demonstrate the power of such complementary approaches in elucidating the function and ecology of extremophiles such as green and red snow algal blooms, which play crucial roles in glacial ecosystems. PMID: 26635781 [PubMed - as supplied by publisher]

Metabolome-Wide Analysis of Stable Isotope Labeling-Is It Worth the Effort? Front Physiol. 2015;6:344 Authors: Weindl D, Wegner A, Hiller K PMID: 26635630 [PubMed - as supplied by publisher]

Metabolomic profiles delineate mycolactone signature in Buruli ulcer disease. Sci Rep. 2015;5:17693 Authors: Niang F, Sarfo FS, Frimpong M, Guenin-Macé L, Wansbrough-Jones M, Stinear T, Phillips RO, Demangel C Abstract Infection of human skin with Mycobacterium ulcerans, the causative agent of Buruli ulcer, is associated with the systemic diffusion of a bacterial macrolide named mycolactone. Patients with progressive disease show alterations in their serum proteome, likely reflecting the inhibition of secreted protein production by mycolactone at the cellular level. Here, we used semi-quantitative metabolomics to characterize metabolic perturbations in serum samples of infected individuals, and human cells exposed to mycolactone. Among the 430 metabolites profiled across 20 patients and 20 healthy endemic controls, there were significant differences in the serum levels of hexoses, steroid hormones, acylcarnitines, purine, heme, bile acids, riboflavin and lysolipids. In parallel, analysis of 292 metabolites in human T cells treated or not with mycolactone showed alterations in hexoses, lysolipids and purine catabolites. Together, these data demonstrate that M. ulcerans infection causes systemic perturbations in the serum metabolome that can be ascribed to mycolactone. Of particular importance to Buruli ulcer pathogenesis is that changes in blood sugar homeostasis in infected patients are mirrored by alterations in hexose metabolism in mycolactone-exposed cells. PMID: 26634444 [PubMed - in process]

Metabolic markers in blood can separate prostate cancer from benign prostatic hyperplasia. Br J Cancer. 2015 Dec 3; Authors: Giskeødegård GF, Hansen AF, Bertilsson H, Gonzalez SV, Kristiansen KA, Bruheim P, Mjøs SA, Angelsen A, Bathen TF, Tessem MB Abstract BACKGROUND: An individualised risk-stratified screening for prostate cancer (PCa) would select the patients who will benefit from further investigations as well as therapy. Current detection methods suffer from low sensitivity and specificity, especially for separating PCa from benign prostatic conditions. We have investigated the use of metabolomics analyses of blood samples for separating PCa patients and controls with benign prostatic hyperplasia (BPH). METHODS: Blood plasma and serum samples from 29 PCa patient and 21 controls with BPH were analysed by metabolomics analysis using magnetic resonance spectroscopy, mass spectrometry and gas chromatography. Differences in blood metabolic patterns were examined by multivariate and univariate statistics. RESULTS: By combining results from different methodological platforms, PCa patients and controls were separated with a sensitivity and specificity of 81.5% and 75.2%, respectively. CONCLUSIONS: The combined analysis of serum and plasma samples by different metabolomics measurement techniques gave successful discrimination of PCa and controls, and provided metabolic markers and insight into the processes characteristic of PCa. Our results suggest changes in fatty acid (acylcarnitines), choline (glycerophospholipids) and amino acid metabolism (arginine) as markers for PCa compared with BPH.British Journal of Cancer advance online publication 3 December 2015. doi:10.1038/bjc.2015.411 www.bjcancer.com. PMID: 26633561 [PubMed - as supplied by publisher]

A mass spectrometric insight into the origins of benign gynecological disorders. Mass Spectrom Rev. 2015 Dec 3; Authors: Yang H, Lau WB, Lau B, Xuan Y, Zhou S, Zhao L, Luo Z, Lin Q, Ren N, Zhao X, Wei Y Abstract Applications of mass spectrometry (MS) are rapidly expanding and encompass molecular and cellular biology. MS aids in the analysis of in vivo global molecular alterations, identifying potential biomarkers which may improve diagnosis and treatment of various pathologies. MS has added new dimensionality to medical research. Pioneering gynecologists now study molecular mechanisms underlying female reproductive pathology with MS-based tools. Although benign gynecologic disorders including endometriosis, adenomyosis, leiomyoma, and polycystic ovarian syndrome (PCOS) carry low mortality rates, they cause significant physical, mental, and social detriments. Additionally, some benign disorders are unfortunately associated with malignancies. MS-based technology can detect malignant changes in formerly benign proteomes and metabolomes with distinct advantages of speed, sensitivity, and specificity. We present the use of MS in proteomics and metabolomics, and summarize the current understanding of the molecular pathways concerning female reproductive anatomy. Highlight discoveries of novel protein and metabolite biomarkers via MS-based technology, we underscore the clinical application of these techniques in the diagnosis and management of benign gynecological disorders. © 2015 Wiley Periodicals, Inc. Mass Spec Rev 9999: XX-XX, 2015. PMID: 26633258 [PubMed - as supplied by publisher]

Targeted Metabolomics Approach to Detect the Misuse of Steroidal Aromatase Inhibitors in Equine Sports by Biomarkers Profiling. Anal Chem. 2015 Dec 3; Authors: Chan GH, Ho EN, Leung DK, Wong KS, Wan TS Abstract The use of anabolic androgenic steroids (AAS) is prohibited in both human and equine sports. Conventional approach in doping control testing for AAS (as well as other prohibited substances) is accomplished by the direct detection of target AAS or their characteristic metabolites in biological samples using hyphenated techniques such as gas-chromatography or liquid-chromatography coupled with mass-spectrometry. Such approach, however, falls short when dealing with unknown designer steroids where reference materials and their pharmacokinetics are not available. In addition, AASs with fast elimination times renders the direct detection approach ineffective as the detection window is short. Targeted metabolomics approach is a plausible alternative to the conventional direct detection approach for controlling the misuse of AAS in sports. Since the administration of AAS of the same class may trigger similar physiological responses or effects in the body, it may be possible to detect such administrations by monitoring changes in the endogenous steroidal expression profile. This study attempts to evaluate the viability of using the targeted metabolomic approach to detect the administration of steroidal aromatase inhibitors, namely androst-4-ene-3,6,17-trione (6-OXO) and androsta-1,4,6-triene-3,17-dione (ATD), in horses. Total (free and conjugated) urinary concentrations of 31 endogenous steroids were determined by gas chromatography-tandem mass spectrometry (GC-MS/MS) for a group of 2 resting and 2 in-training thoroughbred geldings having been treated with either 6-OXO or ATD. Similar data were also obtained from a control (untreated) group of in-training thoroughbred geldings (n = 28). Statistical processing and chemometric procedures using principle component analysis (PCA) and orthogonal projection of latent structures-discriminant analysis (OPLS-DA) have highlighted 7 potential biomarkers that could be used to differentiate urine samples obtained from the control and the treated groups. Based on this targeted metabolomic approach, the administration of 6-OXO and ATD could be detected much longer as compared with the conventional direct detection approach. PMID: 26632865 [PubMed - as supplied by publisher]

Effect of a traditional Chinese medicine prescription Quzhuotongbi decoction on hyperuricemia model rats studied by using serum metabolomics based on gas chromatography-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2015 Nov 21; Authors: Chen J, Zhou J, Wei S, Xie Z, Wen C, Xu G Abstract Morbidity of hyperuricemia has constantly increased in population in decades, and hyperuricemia has proved to be an important risk factor for gout, cardiovascular diseases and others. Many urate-lowering drugs have unfavorable side effects and drug interactions. Quzhuotongbi decoction (QZTBD) is an empirical traditional Chinese medicine prescription for clinical therapy of hyperuricemia without serious adverse effects. In the study, we investigated the effects of QZTBD on urate and other metabolites in the sera of hyperuricemia model rats. Hyperuricemia model was established by orally administering yeast extract paste, and allopurinol served as a positive control drug. Serum metabolomics was performed by using a gas chromatography-mass spectrometry (GC-MS) method. Student's t-test and the principal component analysis (PCA) were employed to find the metabolic perturbations in hyperuricemia model rats. The levels of urate, lactate, pyruvate and ornithine were significantly increased, and xanthine, glyconic acids (ribonate, galactonate), amino acids (aspartate, proline, glutamine, serine, pyroglutamate, glutamate) and glucose were down-regulated greatly in the model rats. It demonstrated that nucleotide metabolism, amino acid metabolism and glycolytic pathway were disturbed by yeast administration. An orthogonal signal correction-partial least-squares discriminant analysis (OSC-PLS DA) was performed to assess the effects of yeast administering and drug treatment. 11 significantly distinctive metabolites among four groups were defined according to the variable importance for project values (VIP>1) and univariate ANOVA (p value<0.05). As compared to the model rats, the serum uric acid levels were lowered markedly under the treatment of allopurinol or QZTBD. Aspartate and glutamine involved in purine metabolism, were raised to normal level as well. The different influences on xanthine, glutamate pyroglutamate and galactonate suggested there were different mechanisms of two drugs in urate-lowering therapy. Our finding proved that QZTBD can efficiently lower the level of serum uric acid in a different way from allopurinol, which suggested that QZTBD based on the theory of TCM could be an effective therapeutic option for hyperuricemia. PMID: 26632444 [PubMed - as supplied by publisher]

Characterization of the multiple components of Acanthopanax Senticosus stem by ultra high performance liquid chromatography with quadrupole time-of-flight tandem mass spectrometry. J Sep Sci. 2015 Dec 3; Authors: Sun H, Liu J, Zhang A, Zhang Y, Meng X, Han Y, Zhang Y, Wang X Abstract Acanthopanax Senticosus Harms. has been used widely in traditional Chinese medicine for the treatment of chronic bronchitis, neurasthenia, hypertension, and ischemic heart disease. However, the in vivo constituents of the stem of Acanthopanax Senticosus remain unknown. In this paper, ultra high performance liquid chromatography with electrospray ionization quadrupole time-of-flight mass spectrometry and the MarkerLynx(TM) software combined with multiple data processing approach were used to study the constituents in vitro and in vivo. The aqueous extract from the Acanthopanax Senticosus stem and the compositions in rat serum after intragastric administration were completely analyzed. Consequently, 115 compounds in the aqueous extract from Acanthopanax Senticosus stem and 41 compounds absorbed into blood were characterized. Of the 115 compounds in vitro, 54 were reported for first time, including sinapyl alcohol, sinapyl alcohol diglucoside, 1-O-sinapoyl-β-d-glucose, etc. In the 41 compounds in vivo, 7 were prototype components and 34 were metabolites which were from 21 components of aqueous extract from Acanthopanax Senticosus stem as well as the metabolic pathways of the metabolites were also elucidated for first time. The results narrowed the range of screening the active components and provided a basis for the study of action mechanism and pharmacology. This article is protected by copyright. All rights reserved. PMID: 26632031 [PubMed - as supplied by publisher]