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

Epidemiology of Brain Tumors.

Sat, 04/08/2018 - 12:43
Related Articles Epidemiology of Brain Tumors. Neurol Clin. 2018 Aug;36(3):395-419 Authors: Barnholtz-Sloan JS, Ostrom QT, Cote D Abstract Incidence, prevalence, and survival for brain tumors varies by histologic type, age at diagnosis, sex, and race/ethnicity. Significant progress has been made in identifying potential risk factors for brain tumors, although more research is warranted. The strongest risk factors that have been identified thus far include allergies/atopic disease, ionizing radiation, and heritable genetic factors. Further analysis of large, multicenter, epidemiologic studies, as well as well annotated omic datasets (including genomic, epigenomic, transcriptomic, proteomic, or metabolomics data) can potentially lead to further understanding of the relationship between gene and environment in the process of brain tumor development. PMID: 30072062 [PubMed - in process]

High-resolution magnetic resonance spectroscopy using a solid-state spin sensor.

Sat, 04/08/2018 - 12:43
Related Articles High-resolution magnetic resonance spectroscopy using a solid-state spin sensor. Nature. 2018 03 14;555(7696):351-354 Authors: Glenn DR, Bucher DB, Lee J, Lukin MD, Park H, Walsworth RL Abstract Quantum systems that consist of solid-state electronic spins can be sensitive detectors of nuclear magnetic resonance (NMR) signals, particularly from very small samples. For example, nitrogen-vacancy centres in diamond have been used to record NMR signals from nanometre-scale samples, with sensitivity sufficient to detect the magnetic field produced by a single protein. However, the best reported spectral resolution for NMR of molecules using nitrogen-vacancy centres is about 100 hertz. This is insufficient to resolve the key spectral identifiers of molecular structure that are critical to NMR applications in chemistry, structural biology and materials research, such as scalar couplings (which require a resolution of less than ten hertz) and small chemical shifts (which require a resolution of around one part per million of the nuclear Larmor frequency). Conventional, inductively detected NMR can provide the necessary high spectral resolution, but its limited sensitivity typically requires millimetre-scale samples, precluding applications that involve smaller samples, such as picolitre-volume chemical analysis or correlated optical and NMR microscopy. Here we demonstrate a measurement technique that uses a solid-state spin sensor (a magnetometer) consisting of an ensemble of nitrogen-vacancy centres in combination with a narrowband synchronized readout protocol to obtain NMR spectral resolution of about one hertz. We use this technique to observe NMR scalar couplings in a micrometre-scale sample volume of approximately ten picolitres. We also use the ensemble of nitrogen-vacancy centres to apply NMR to thermally polarized nuclear spins and resolve chemical-shift spectra from small molecules. Our technique enables analytical NMR spectroscopy at the scale of single cells. PMID: 29542693 [PubMed - indexed for MEDLINE]

High-Resolution Lipidomics of the Early Life Stages of the Red Seaweed Porphyra dioica.

Sat, 04/08/2018 - 12:43
Related Articles High-Resolution Lipidomics of the Early Life Stages of the Red Seaweed Porphyra dioica. Molecules. 2018 Jan 17;23(1): Authors: da Costa E, Azevedo V, Melo T, Rego AM, V Evtuguin D, Domingues P, Calado R, Pereira R, Abreu MH, Domingues MR Abstract Porphyra dioica is a commercial seaweed consumed all over the world, mostly in the shape of nori sheets used for "sushi" preparation. It is a well-known part of the Asian diet with health benefits, which have been associated, among others, to the high levels of n-3 and n-6 fatty acids in this red alga. However, other highly valued lipids of Porphyra are polar lipids that remain largely undescribed and can have both nutritional value and bioactivity, thus could contribute to the valorization of this seaweed. In this context, the present work aims to identify the lipidome of two life cycle stages of the Atlantic species Porphyra dioica: the early life stage conchocelis produced in an indoor-nursery, and young blades produced outdoors using an integrated multitrophic aquaculture (IMTA) framework. Both the blades (gametophyte) and conchocelis (sporophyte) are commercialized in the food and cosmetics sectors. Liquid chromatography coupled to Q-Exactive high resolution-mass spectrometry (MS) platform was used to gain insight into the lipidome of these species. Our results allowed the identification of 110 and 100 lipid molecular species in the lipidome of the blade and conchocelis, respectively. These lipid molecular species were distributed as follows (blade/conchocelis): 14/15 glycolipids (GLs), 93/79 phospholipids (PLs), and 3/6 betaine lipids. Both life stages displayed a similar profile of GLs and comprised 20:4(n-6) and 20:5(n-3) fatty acids that contribute to n-3 and n-6 fatty acid pool recorded and rank among the molecular species with higher potential bioactivity. PLs' profile was different between the two life stages surveyed, mainly due to the number and relative abundance of molecular species. This finding suggests that differences between both life stages were more likely related with shifts in the lipids of extraplastidial membranes rather than in plastidial membranes. PLs contained n-6 and n-3 precursors and in both life stages of Porphyra dioica the n-6/n-3 ratio recorded was less than 2, highlighting the potential benefits of using these life stages in human diet to prevent chronic diseases. Atherogenic and thrombogenic indexes of blades (0.85 and 0.49, respectively) and conchocelis (0.34 and 0.30, respectively) are much lower than those reported for other Rhodophyta, which highlights their potential application as food or as functional ingredients. Overall, MS-based platforms represent a powerful tool to characterize lipid metabolism and target lipids along different life stages of algal species displaying complex life cycles (such as Porphyra dioica), contributing to their biotechnological application. PMID: 29342096 [PubMed - indexed for MEDLINE]

Chemical Analysis and Evaluation of Antioxidant, Antimicrobial, and Photoprotective Activities of Schinopsis brasiliensis Engl. (Anacardiaceae).

Sat, 04/08/2018 - 12:43
Related Articles Chemical Analysis and Evaluation of Antioxidant, Antimicrobial, and Photoprotective Activities of Schinopsis brasiliensis Engl. (Anacardiaceae). ScientificWorldJournal. 2017;2017:1713921 Authors: de Lima-Saraiva SRG, Oliveira FGDS, Junior RGO, Araújo CS, de Oliveira AP, Pacheco AGM, Rolim LA, de Amorim ELC, César FCS, Almeida JRGDS Abstract Schinopsis brasiliensis Engl. is a native plant of Caatinga which has high concentrations of compounds capable of absorbing ultraviolet light, suggesting its potential application for the development of sunscreen preparations. After its identification and collection, this vegetable drug was submitted to a physicochemical analysis through the preparation of ethanolic extract. The phytochemical screening and analysis of extracts were carried out by high-performance liquid chromatography (HPLC) evaluation. The antioxidant activity of the extract was evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) method and β-carotene bleaching test. Inhibitory hemolytic activity and morphological deformation of erythrocytes induced by H2O2 were also demonstrated and the antimicrobial activity was analyzed by the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) method. For the in vitro determination of the sun protection factor (SPF), the spectrophotometric method was used. From the analyses carried out with this species, this plant showed significant results for the antioxidant and antimicrobial activities, as well as sunscreen action. Important flavonoids were identified. These data are an important step for the development of new photoprotective cosmetic with Caatinga species, revealing importance and representing another incentive for the preservation of the species involved and analyzed in the study. PMID: 29124118 [PubMed - indexed for MEDLINE]

Cold acclimation increases cold tolerance independently of diapause programing in the bean bug, Riptortus pedestris.

Sat, 04/08/2018 - 12:43
Related Articles Cold acclimation increases cold tolerance independently of diapause programing in the bean bug, Riptortus pedestris. Bull Entomol Res. 2018 Aug;108(4):487-493 Authors: Rozsypal J, Moos M, Goto SG Abstract The bean bug (Riptortus pedestris) is a pest of soybeans and other legumes in Japan and other Asian countries. It enters a facultative adult diapause on exposure to short days. While photoperiodism and diapause are well understood in R. pedestris, knowledge of cold tolerance is very limited, as is information on the effect of diapause on cold tolerance. We examined the effect of photoperiod, cold acclimation, and feeding status on cold tolerance in R. pedestris. We found that cold acclimation significantly increased survival at -10°C in both long- and short-day adult R. pedestris. Since the difference in cold survival between long- and short-day cold-acclimated groups was only marginal, we conclude that entering diapause is not crucial for R. pedestris to successfully pass through cold acclimation and become cold tolerant. We observed similar effects in 5th instar nymphs, with both long- and short-day cold-acclimated groups surviving longer cold exposures compared with non-acclimated groups. Starvation, which was tested only in adult bugs, had only a negligible and negative impact on cold survival. Although cold tolerance significantly increased with cold acclimation in adult bugs, supercooling capacity unexpectedly decreased. Our results suggest that changes in supercooling capacity as well as in water content are unrelated to cold tolerance in R. pedestris. An analysis of metabolites revealed differences between the treatments, and while several metabolites markedly increased with cold acclimation, their concentrations were too low to have a significant effect on cold tolerance. PMID: 29037264 [PubMed - indexed for MEDLINE]

Parental high dietary arachidonic acid levels modulated the hepatic transcriptome of adult zebrafish (Danio rerio) progeny.

Fri, 03/08/2018 - 12:19
Parental high dietary arachidonic acid levels modulated the hepatic transcriptome of adult zebrafish (Danio rerio) progeny. PLoS One. 2018;13(8):e0201278 Authors: Adam AC, Skjærven KH, Whatmore P, Moren M, Lie KK Abstract Disproportionate high intake of n-6 polyunsaturated fatty acids (PUFAs) in the diet is considered as a major human health concern. The present study examines changes in the hepatic gene expression pattern of adult male zebrafish progeny associated with high levels of the n-6 PUFA arachidonic acid (ARA) in the parental diet. The parental generation (F0) was fed a diet which was either low (control) or high in ARA (high ARA). Progenies of both groups (F1) were given the control diet. No differences in body weight were found between the diet groups within adult stages of either F0 or F1 generation. Few differentially expressed genes were observed between the two dietary groups in the F0 in contrast to the F1 generation. Several links were found between the previous metabolic analysis of the parental fish and the gene expression analysis in their adult progeny. Main gene expression differences in the progeny were observed related to lipid and retinoid metabolism by PPARα/RXRα playing a central role in mediating changes to lipid and long-chain fatty acid metabolism. The enrichment of genes involved in β-oxidation observed in the progeny, corresponded to the increase in peroxisomal β-oxidative degradation of long-chain fatty acids in the parental fish metabolomics data. Similar links between the F0 and F1 generation were identified for the methionine cycle and transsulfuration pathway in the high ARA group. In addition, estrogen signalling was found to be affected by parental high dietary ARA levels, where gene expression was opposite directed in F1 compared to F0. This study shows that the dietary n-3/n-6 PUFA ratio can alter gene expression patterns in the adult progeny. Whether the effect is mediated by permanent epigenetic mechanisms regulating gene expression in developing gametes needs to be further investigated. PMID: 30070994 [PubMed - in process]

[Current challenges of nutrition applied research: ¿person or population?]

Fri, 03/08/2018 - 12:19
Related Articles [Current challenges of nutrition applied research: ¿person or population?] Nutr Hosp. 2018 Jun 12;35(Spec No4):39-43 Authors: Gil Hernández Á Abstract During the last half of the 20th century, Nutrition has evolved in a quick way based on the knowledge of both basic sciences as Biochemistry and Physiology and applied sciences as Epidemiology and Public Health. In that period the nutritional requirements for different population groups grouped by sex, age and physiological conditions have been established. However, in spite of the enormous knowledge in food and nutritional sciences, malnutrition by nutrient deficiencies (protein-energy undernutrition and micronutrient deficiencies) and by excess of nutrient intake (overweight and obesity) continues being a critical burden and challenge for numerous countries. In September 2015, the General Assembly of the United Nations established the "Sustainable Development Goals" with the aim of "to warrant a healthy life and promote the welfare for all in all ages", and defined a number of targets to reach maternal, infant and childhood nutrition, as well as to prevent non-communicable chronic diseases. Even though there are food intake guidelines and general recommendations for population nutrient intakes, individuals respond differently to lifestyle interventions depending on their genetic variants, which in turn influence the absorption and metabolism of nutrients. Indeed, the response of an individual to food intake and nutrients is the result of the interaction of a number of metabolic, genetic, environmental and social factors. Nutritional genomics is the science trying to facilitate an explanation at molecular levels of how nutrients and other bioactive food components interact with the genes of an individual and their effects on health. The new "omics" science tools (genomics, epigenomics, transcriptomics, proteomics and metabolomics) applied to nutrition is currently allowing the development of nutritional genomics. While "personalized nutrition" refers to the adaptation of the diet to individual needs and preferences, "precision nutrition" predicts whether an individual is responding or not to specific nutrients and food and dietary patterns in such a way they can contribute to the prevention of disease based on the genetic information and phenotype of that particular individual. One of the biggest challenges of nutrition today is to make possible precision nutrition in order to contribute to the improvement of the population and decrease the burden of non-communicable chronic diseases. PMID: 30070120 [PubMed - in process]

[The role of omics in precision nutrition: strengths and weaknesses].

Fri, 03/08/2018 - 12:19
Related Articles [The role of omics in precision nutrition: strengths and weaknesses]. Nutr Hosp. 2018 Jun 12;35(Spec No4):10-18 Authors: Corella D, Ordovás JM Abstract Precision medicine has taken huge strides forward in recent years. Although there is still no generally accepted single definition, it basically considers the particular characteristics of each person as relevant in order to better adapt therapeutic or preventive measures in a more personalized fashion. Likewise, the concept of precision nutrition has gathered strength, in which the aim is to provide the best dietary recommendations to prevent or treat a disease in accordance with the characteristics of the individual in question. Of special importance among these characteristics are those based on omics. Initially genomics, and now epigenomics, metabolomics, proteomics and transcriptomics are providing us with new information on the different responses to the diet based on genotype, on new early biomarkers of disease, on dietary intake, or on the regulatory effects of diet. However, precision nutrition can go further still to include much more holistic aspects, not focusing on the disease, but on wellbeing and other indicators of positive health. Hence, other omics have been added to those mentioned above that provide us with a more multidimensional analysis. Gastronomy also plays an important role in precision nutrition. Although we are still at the preliminary validation stage of precision nutrition, this field presents huge potential for development. In this context, we shall review the role of omics in precision nutrition as well as their main strengths and weaknesses. PMID: 30070116 [PubMed - in process]

NMR metabolomics study of follicular fluid in women with cancer resorting to fertility preservation.

Fri, 03/08/2018 - 12:19
Related Articles NMR metabolomics study of follicular fluid in women with cancer resorting to fertility preservation. J Assist Reprod Genet. 2018 Aug 01;: Authors: Castiglione Morelli MA, Iuliano A, Schettini SCA, Petruzzi D, Ferri A, Colucci P, Viggiani L, Cuviello F, Ostuni A Abstract PURPOSE: The purpose of this study was to evaluate the possible application of metabolomics to identify follicular fluid changes in cancer patients undergoing fertility preservation. Although metabolomics have been applied already in cancer studies, this is the first application on follicular fluid of cancer patients. METHODS: We selected for the study ten patients with breast cancer and lymphoma who resorted to oocyte cryopreservation to preserve fertility and ten healthy women undergoing in vitro fertilization treatments. Follicular fluid was collected at the time of oocytes retrieval. Metabolomic analysis of follicular fluids was performed by 1H-nuclear magnetic resonance (NMR) spectroscopy in combination with multivariate analysis to interpret the spectral data. Univariate statistical analysis was applied to find correlations between patients' features and metabolites identified by NMR. RESULTS: Partial least squares discriminant analysis allowed to discriminate samples from cancer patients and healthy controls. Univariate statistical analysis found significant correlations between patients' features and metabolites identified by NMR. This finding allowed to identify biomarkers to differentiate both healthy controls from cancer patients and the two different classes of oncological patients. CONCLUSION: The follicular fluids of cancer patients display significant metabolic alterations in comparison to healthy subjects. NMR-based metabolomics could be a valid prognostic tool for identifying and selecting the best cryopreserved oocytes and improving the outcome prediction in cancer women undergoing in vitro fertilization. PMID: 30069850 [PubMed - as supplied by publisher]

Chronic Dysregulation of Cortical and Subcortical Metabolism After Experimental Traumatic Brain Injury.

Fri, 03/08/2018 - 12:19
Related Articles Chronic Dysregulation of Cortical and Subcortical Metabolism After Experimental Traumatic Brain Injury. Mol Neurobiol. 2018 Aug 01;: Authors: McGuire JL, DePasquale EAK, Watanabe M, Anwar F, Ngwenya LB, Atluri G, Romick-Rosendale LE, McCullumsmith RE, Evanson NK Abstract Traumatic brain injury (TBI) is a leading cause of death and long-term disability worldwide. Although chronic disability is common after TBI, effective treatments remain elusive and chronic TBI pathophysiology is not well understood. Early after TBI, brain metabolism is disrupted due to unregulated ion release, mitochondrial damage, and interruption of molecular trafficking. This metabolic disruption causes at least part of the TBI pathology. However, it is not clear how persistent or pervasive metabolic injury is at later stages of injury. Using untargeted 1H-NMR metabolomics, we examined ex vivo hippocampus, striatum, thalamus, frontal cortex, and brainstem tissue in a rat lateral fluid percussion model of chronic brain injury. We found altered tissue concentrations of metabolites in the hippocampus and thalamus consistent with dysregulation of energy metabolism and excitatory neurotransmission. Furthermore, differential correlation analysis provided additional evidence of metabolic dysregulation, most notably in brainstem and frontal cortex, suggesting that metabolic consequences of injury are persistent and widespread. Interestingly, the patterns of network changes were region-specific. The individual metabolic signatures after injury in different structures of the brain at rest may reflect different compensatory mechanisms engaged to meet variable metabolic demands across brain regions. PMID: 30069831 [PubMed - as supplied by publisher]

Nanoformulated Antiretroviral Therapy Attenuates Brain Metabolic Oxidative Stress.

Fri, 03/08/2018 - 12:19
Related Articles Nanoformulated Antiretroviral Therapy Attenuates Brain Metabolic Oxidative Stress. Mol Neurobiol. 2018 Aug 01;: Authors: Montenegro-Burke JR, Woldstad CJ, Fang M, Bade AN, McMillan J, Edagwa B, Boska MD, Gendelman HE, Siuzdak G Abstract Antiretroviral therapy (ART) restricts human immunodeficiency virus type one (HIV-1) replication and by so doing, improves the quality and longevity of life for infected people. Nonetheless, treatment can also lead to adverse clinical outcomes such as drug resistance and systemic adverse events. Both could be affected by long-acting slow effective release ART. Indeed, maintenance of sustained plasma drug levels, for weeks or months, after a single high-level dosing, could improve regimen adherence but, at the same time, affect systemic toxicities. Of these, the most troubling are those that affect the central nervous system (CNS). To address this, dolutegravir (Tivicay, DTG), a potent and durable HIV integrase inhibitor used effectively in combination ART was tested. Rodents were administered parenteral 45-mg/kg doses. DTG-associated changes in CNS homeostasis were assessed by measuring brain metabolic activities. After antiretroviral treatment, brain subregions were dissected and screened by mass spectrometry-based metabolomics. Metabolic drug-related dysregulation of energy and oxidative stress were readily observed within the cerebellum and frontal cortex following native drug administrations. Each was associated with alterations in neural homeostasis and depleted canonical oxidation protection pools that included glutathione and ascorbic acid. Surprisingly, the oxidative stress-related metabolites were completely attenuated when DTG was administered as nanoformulations. These data demonstrate the importance of formulation design in control of DTG or perhaps other antiretroviral drug-associated CNS events. PMID: 30069830 [PubMed - as supplied by publisher]

Chronic refined low-fat diet consumption reduces cholecystokinin satiation in rats.

Fri, 03/08/2018 - 12:19
Related Articles Chronic refined low-fat diet consumption reduces cholecystokinin satiation in rats. Eur J Nutr. 2018 Aug 01;: Authors: Guerville M, Hamilton MK, Ronveaux CC, Ellero-Simatos S, Raybould HE, Boudry G Abstract PURPOSE: Reduced ability of cholecystokinin (CCK) to induce satiation contributes to hyperphagia and weight gain in high-fat/high-sucrose (HF/HS) diet-induced obesity, and has been linked to altered gut microbiota. Rodent models of obesity use chow or low-fat (LF) diets as control diets; the latter has been shown to alter gut microbiota and metabolome. We aimed to determine whether LF-diet consumption impacts CCK satiation in rats and if so, whether this is prevented by addition of inulin to LF diet. METHODS: Rats (n = 40) were fed, for 8 weeks, a chow diet (chow) or low-fat (10%) or high-fat/high-sucrose (45 and 17%, respectively) refined diets with either 10% cellulose (LF and HF/HS) or 10% inulin (LF-I and HF/HS-I). Caecal metabolome was assessed by 1H-NMR-based metabolomics. CCK satiation was evaluated by measuring the suppression of food intake after intraperitoneal CCK injection (1 or 3 µg/kg). RESULTS: LF-diet consumption altered the caecal metabolome, reduced caecal weight, and increased IAP activity, compared to chow. CCK-induced inhibition of food intake was abolished in LF diet-fed rats compared to chow-fed rats, while HF/HS diet-fed rats responded only to the highest CCK dose. Inulin substitution ameliorated caecal atrophy, reduced IAP activity, and modulated caecal metabolome, but did not improve CCK-induced satiety in either LF- or HF/HS-fed rats. CONCLUSIONS: CCK signaling is impaired by LF-diet consumption, highlighting that caution must be taken when using LF diet until a more suitable refined control diet is identified. PMID: 30069617 [PubMed - as supplied by publisher]

The Metabolomic Bioenergetic Signature of Opa1-Disrupted Mouse Embryonic Fibroblasts Highlights Aspartate Deficiency.

Fri, 03/08/2018 - 12:19
Related Articles The Metabolomic Bioenergetic Signature of Opa1-Disrupted Mouse Embryonic Fibroblasts Highlights Aspartate Deficiency. Sci Rep. 2018 Aug 01;8(1):11528 Authors: Bocca C, Kane MS, Veyrat-Durebex C, Chupin S, Alban J, Kouassi Nzoughet J, Le Mao M, Chao de la Barca JM, Amati-Bonneau P, Bonneau D, Procaccio V, Lenaers G, Simard G, Chevrollier A, Reynier P Abstract OPA1 (Optic Atrophy 1) is a multi-isoform dynamin GTPase involved in the regulation of mitochondrial fusion and organization of the cristae structure of the mitochondrial inner membrane. Pathogenic OPA1 variants lead to a large spectrum of disorders associated with visual impairment due to optic nerve neuropathy. The aim of this study was to investigate the metabolomic consequences of complete OPA1 disruption in Opa1-/- mouse embryonic fibroblasts (MEFs) compared to their Opa1+/+ counterparts. Our non-targeted metabolomics approach revealed significant modifications of the concentration of several mitochondrial substrates, i.e. a decrease of aspartate, glutamate and α-ketoglutaric acid, and an increase of asparagine, glutamine and adenosine-5'-monophosphate, all related to aspartate metabolism. The signature further highlighted the altered metabolism of nucleotides and NAD together with deficient mitochondrial bioenergetics, reflected by the decrease of creatine/creatine phosphate and pantothenic acid, and the increase in pyruvate and glutathione. Interestingly, we recently reported significant variations of five of these molecules, including aspartate and glutamate, in the plasma of individuals carrying pathogenic OPA1 variants. Our findings show that the disruption of OPA1 leads to a remodelling of bioenergetic pathways with the central role being played by aspartate and related metabolites. PMID: 30068998 [PubMed - in process]

Celastrol Suppresses Tryptophan Catabolism in Human Colon Cancer Cells as Revealed by Metabolic Profiling and Targeted Metabolite Analysis.

Fri, 03/08/2018 - 12:19
Related Articles Celastrol Suppresses Tryptophan Catabolism in Human Colon Cancer Cells as Revealed by Metabolic Profiling and Targeted Metabolite Analysis. Biol Pharm Bull. 2018;41(8):1243-1250 Authors: Qi Y, Wang R, Zhao L, Lv L, Zhou F, Zhang T, Lu F, Yan H, Duan G Abstract Celastrol is well known for its anti-cancer effects, yet its specific mechanisms against colon cancer are still not fully elucidated. In this study, cytotoxic effect of celastrol against HCT116 colon cancer cells was investigated based on cell viability assay and flow cytometry assay, and the possible mechanism was explored using a strategy combining metabolic profiling and targeted metabolite analysis based on ultra performance liquid chromatography (UPLC)/MS. Celastrol was found to inhibit the growth of colon cancer cells and induce apoptosis. Metabolomics analysis revealed characteristic changes in metabolic profiles of the colon cancer cells, revealing altered levels of amino acids, carnitine, and lipid markers. Most interestingly, with the assistance of targeted metabolite analysis, tryptophan (Trp) level was significantly increased whereas kynurenine (Kyn) level was decreased in colon cancer cells after celastrol treatment, together with markedly declined Kyn/Trp ratios. Western blot analysis revealed that expression of indoleamine 2,3-dioxygenase (IDO), the enzyme catalyzing Trp to generate Kyn, was dramatically inhibited in colon cancer cells after celastrol treatment, with a dose-dependent manner. These results suggest that suppression of IDO expression and tryptophan catabolism may be part of the mechanisms of celastrol in its cytotoxic effect against HCT116 colon cancer cells. This study provided scientific basis for further development of celastrol on treating colon cancer. PMID: 30068874 [PubMed - in process]

Identification of Metabolites Associated with Onset of CAD in Diabetic Patients Using CE-MS Analysis: A Pilot Study.

Fri, 03/08/2018 - 12:19
Related Articles Identification of Metabolites Associated with Onset of CAD in Diabetic Patients Using CE-MS Analysis: A Pilot Study. J Atheroscler Thromb. 2018 Aug 01;: Authors: Omori K, Katakami N, Yamamoto Y, Ninomiya H, Takahara M, Matsuoka TA, Bamba T, Fukusaki E, Shimomura I Abstract AIM: Coronary artery disease (CAD) is the result of a complex metabolic disorder caused by various environmental and genetic factors. Metabolomics is a potential tool for identifying biomarkers for better risk classification and for understanding the pathophysiological mechanisms of CAD. With this background, we performed a pilot study to identify metabolites associated with the future onset of CAD in patients with type 2 diabetes. METHODS: Sixteen subjects who suffered from CAD event during the observation period and 39 non-CAD subjects who were matched to the CAD subjects for Framingham Coronary Heart Disease Risk Score, diabetes duration, and HbA1c were selected. Capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) was used to perform non-targeted metabolome analysis of serum samples collected in 2005. RESULTS: A total of 104 metabolites were identified. Unsupervised principal component analysis (PCA) did not to reveal two distinct clusters of individuals. However, a significant association with CAD was found for 7 metabolites (pelargonic acid, glucosamine:galactosamine, thymine, 3-hydroxybutyric acid, creatine, 2-aminoisobutyric acid, hypoxanthine) and the levels of all these metabolites were significantly lower in the CAD group compared with the non-CAD group. CONCLUSIONS: We identified 7 metabolites related to long-term future onset of CAD in Japanese patients with diabetes. Further studies with large sample size would be necessary to confirm our findings, and future studies using in vivo or in vitro models would be necessary to elucidate whether direct relationships exist between the detected metabolites and CAD pathophysiology. PMID: 30068816 [PubMed - as supplied by publisher]

Application of "Omics" and Systems Biology to Sarcoidosis Research.

Fri, 03/08/2018 - 12:19
Related Articles Application of "Omics" and Systems Biology to Sarcoidosis Research. Ann Am Thorac Soc. 2017 Dec;14(Supplement_6):S445-S451 Authors: Crouser ED, Fingerlin TE, Yang IV, Maier LA, Nana-Sinkam P, Collman RG, Kaminski N Abstract Sarcoidosis is a complex, polygenic disease of unknown cause with diverse clinical phenotypes, ranging from self-limited, asymptomatic disease to life-altering symptoms and early disease-related mortality. It is unlikely that a single common environmental exposure (e.g., infection, antigen) entirely explains the disease, and numerous genetic mutations are associated with the disease. As such, it is reasonable to assume, as with other phenotypically diverse diseases, that distinct genetic mechanisms and related biological biomarkers will serve to further define sarcoidosis subphenotypes, mechanisms, and possibly etiology, thus guiding personalized care. The fields of "omics" and systems biology research are widely applied to understand polygenic and phenotypically diverse diseases, such as sarcoidosis. "Omics" refers to technologies that allow comprehensive profiling of sets of molecules in an organism. Systems biology applies advanced computational approaches to make sense of the enormous data sets that are typically generated from "omics" platforms. The primary objectives of this article are to review the available "omics" tools, assess the current status of "omics" and systems biology research in the field of sarcoidosis, and consider how this technology could be applied to advance our understanding of the mechanistic underpinnings of disease and to develop novel treatments. PMID: 29053026 [PubMed - indexed for MEDLINE]

The General Explanation Method Using NMR Enables Identification of Metabolite Profiles Specific for Normal and Tumor Cell Lines.

Thu, 02/08/2018 - 14:58
The General Explanation Method Using NMR Enables Identification of Metabolite Profiles Specific for Normal and Tumor Cell Lines. Chembiochem. 2018 Aug 01;: Authors: Pečnik K, Todorović V, Bošnjak M, Čemažar M, Kononenko I, Serša G, Plavec J Abstract Machine learning models in metabolomics, despite their great prediction accuracy, are still not widely adopted due to lack of efficient explanation of their predictions. In this study we propose using the general explanation method to explain machine learning model's predictions in order to gain detailed insights into metabolic differences between biological systems. The method was tested on a dataset of 1H NMR spectra acquired on normal lung and mesothelial cell lines and their tumor counterparts. Initially, the random forests and artificial neural network models were applied to the dataset and achieved excellent prediction accuracy. The models' predictions were explained with the general explanation method which enabled identification of discriminating metabolic concentration differences between individual cell lines and enabled the construction of their specific metabolic concentration profiles. This intuitive and robust method holds great promises for in-depth understanding of the mechanisms that underline phenotypes as well as biomarker discovery in complex diseases. PMID: 30067305 [PubMed - as supplied by publisher]

Interactomics and tick vaccine development: New directions for the control of tick-borne diseases.

Thu, 02/08/2018 - 14:58
Interactomics and tick vaccine development: New directions for the control of tick-borne diseases. Expert Rev Proteomics. 2018 Aug 01;: Authors: Artigas-Jerónimo S, de la Fuente J, Villar M Abstract INTRODUCTION: Ticks are obligate hematophagous arthropod ectoparasites that transmit pathogens responsible for a growing number of tick-borne diseases (TBDs) throughout the world. Vaccines have been shown to be the most efficient, cost-effective and environmentally friendly approach for the control of ticks and the prevention of TBDs. Although at its infancy, interactomics have shown the possibilities that the knowledge of the interactome offers in understanding tick biology and the molecular mechanisms involved in pathogen infection and transmission. Furthermore, interactomics has provided information for the identification of candidate vaccine protective antigens. Areas covered: In this special report we review the different approaches used for the study of protein-protein physical and functional interactions, and summarize the application of interactomics to the characterization of tick biology and tick-host-pathogen interactions, and the possibilities that offers to vaccine development for the control of ticks and TBDs. Expert commentary: The combination of interacting proteins in antigen formulations may increase vaccine efficacy. In the near future, the combination of interactomics with other omics approaches such as transcriptomics, proteomics, metabolomics and regulomics together with intelligent Big Data analytic techniques will improve the high throughput discovery and characterization of vaccine protective antigens for the prevention and control of TBDs. PMID: 30067120 [PubMed - as supplied by publisher]

Mendelian randomisation analysis of clustered causal effects of body mass on cardiometabolic biomarkers.

Thu, 02/08/2018 - 14:58
Mendelian randomisation analysis of clustered causal effects of body mass on cardiometabolic biomarkers. BMC Bioinformatics. 2018 Jul 09;19(Suppl 7):195 Authors: Conde S, Xu X, Guo H, Perola M, Fazia T, Bernardinelli L, Berzuini C Abstract BACKGROUND: Recent advances in data analysis methods based on principles of Mendelian Randomisation, such as Egger regression and the weighted median estimator, add to the researcher's ability to infer cause-effect links from observational data. Now is the time to gauge the potential of these methods within specific areas of biomedical research. In this paper, we choose a study in metabolomics as an illustrative testbed. We apply Mendelian Randomisation methods in the analysis of data from the DILGOM (Dietary, Lifestyle and Genetic determinants of Obesity and Metabolic syndrome) study, in the context of an effort to identify molecular pathways of cardiovascular disease. In particular, our illustrative analysis addresses the question whether body mass, as measured by body mass index (BMI), exerts a causal effect on the concentrations of a collection of 137 cardiometabolic markers with different degrees of atherogenic power, such as the (highly atherogenic) lipoprotein metabolites with very low density (VLDLs) and the (protective) high density lipoprotein metabolites. RESULTS: We found strongest evidence of a positive BMI effect (that is, evidence that an increase in BMI causes an increase in the metabolite concentration) on those metabolites known to represent strong risk factors for coronary artery disease, such as the VLDLs, and evidence of a negative effect on protective biomarkers. CONCLUSIONS: The methods discussed represent a useful scientific tool, although they assume the validity of conditions that are (at best) only partially verifiable. This paper provides a rigorous account of such conditions. The results of our analysis provide a proof-of-concept illustration of the potential usefulness of Mendelian Randomisation in genomic biobank studies aiming to dissect the molecular causes of disease, and to identify candidate pharmacological targets. PMID: 30066639 [PubMed - in process]

Genome-wide researches and applications on Dendrobium.

Thu, 02/08/2018 - 14:58
Related Articles Genome-wide researches and applications on Dendrobium. Planta. 2018 Jul 31;: Authors: Zheng SG, Hu YD, Zhao RX, Yan S, Zhang XQ, Zhao TM, Chun Z Abstract MAIN CONCLUSION: This review summarizes current knowledge of chromosome characterization, genetic mapping, genomic sequencing, quality formation, floral transition, propagation, and identification in Dendrobium. The widely distributed Dendrobium has been studied for a long history, due to its important economic values in both medicine and ornamental. In recent years, some species of Dendrobium and other orchids had been reported on genomic sequences, using the next-generation sequencing technology. And the chloroplast genomes of many Dendrobium species were also revealed. The chromosomes of most Dendrobium species belong to mini-chromosomes, and showed 2n = 38. Only a few of genetic studies were reported in Dendrobium. After revealing of genomic sequences, the techniques of transcriptomics, proteomics and metabolomics could be employed on Dendrobium easily. Some other molecular biological techniques, such as gene cloning, gene editing, genetic transformation and molecular marker developing, had also been applied on the basic research of Dendrobium, successively. As medicinal plants, insights into the biosynthesis of some medicinal components were the most important. As ornamental plants, regulation of flower related characteristics was the most important. More, knowledge of growth and development, environmental interaction, evolutionary analysis, breeding of new cultivars, propagation, and identification of species and herbs were also required for commercial usage. All of these studies were improved using genomic sequences and related technologies. To answer some key scientific issues in Dendrobium, quality formation, flowering, self-incompatibility and seed germination would be the focus of future research. And genome related technologies and studies would be helpful. PMID: 30066218 [PubMed - as supplied by publisher]

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