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

CE-MS-based metabolomics reveals the metabolic profile of maitake mushroom (Grifola frondosa) strains with different cultivation characteristics.

Sat, 21/10/2017 - 12:38
Related Articles CE-MS-based metabolomics reveals the metabolic profile of maitake mushroom (Grifola frondosa) strains with different cultivation characteristics. Biosci Biotechnol Biochem. 2017 Oct 20;:1-9 Authors: Sato M, Miyagi A, Yoneyama S, Gisusi S, Tokuji Y, Kawai-Yamada M Abstract Maitake mushroom (Grifola frondosa [Dicks.] Gray) is generally cultured using the sawdust of broadleaf trees. The maitake strain Gf433 has high production efficiency, with high-quality of fruiting bodies even when 30% of the birch sawdust on the basal substrate is replaced with conifer sawdust. We performed metabolome analysis to investigate the effect of different cultivation components on the metabolism of Gf433 and Mori52 by performing CE-MS on their fruiting bodies in different cultivation conditions to quantify the levels of amino acids, organic acids, and phosphorylated organic acids. We found that amino acid and organic acid content in Gf433 were not affected by the kind of sawdust. However, Gf433 contained more organic acids and less amino acids than Mori52, and Gf433 also contained more chitin compared with Mori52. We believe that these differences in the metabolome contents of the two strains are related to the high production efficiency of Gf433. PMID: 29050513 [PubMed - as supplied by publisher]

A prospective study of serum metabolites and glioma risk.

Sat, 21/10/2017 - 12:38
Related Articles A prospective study of serum metabolites and glioma risk. Oncotarget. 2017 Sep 19;8(41):70366-70377 Authors: Huang J, Weinstein SJ, Kitahara CM, Karoly ED, Sampson JN, Albanes D Abstract Malignant glioma is one of the most lethal adult cancers, yet its etiology remains largely unknown. We conducted a prospective serum metabolomic analysis of glioma based on 64 cases and 64 matched controls selected from Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Median time from collection of baseline fasting serum to diagnosis was nine years (inter-decile range 3-20 years). LC/MS-MS identified 730 known metabolites, and conditional logistic regression models estimated odds ratios for one-standard deviation differences in log-metabolite signals. Forty-three metabolites were associated with glioma at P<0.05. 2-Oxoarginine, cysteine, alpha-ketoglutarate, chenodeoxycholate and argininate yielded the strongest metabolite signals and were inversely related to overall glioma risk (0.0065≤P<0.0083). Also, seven xanthine metabolites related to caffeine metabolism were higher in cases than in controls (0.017≤P<0.042). Findings were mostly similar in high-grade glioma cases, although prominent inversely associated metabolites included the secondary bile acids glycocholenate sulfate and 3β-hydroxy-5-cholenoic acid, xenobiotic methyl 4-hydroxybenzoate sulfate, sex steroid 5alpha-pregnan-3beta, 20beta-diol-monosulfate, and cofactor/vitamin oxalate (0.0091≤P<0.021). A serum metabolomic profile of glioma identified years in advance of clinical diagnoses is characterized by altered signals in arginine/proline, antioxidant, and coffee-related metabolites. The observed pattern provides new potential leads regarding the molecular basis relevant to etiologic or sub-clinical biomarkers for glioma. PMID: 29050286 [PubMed]

Lipid profiling of the therapeutic effects of berberine in patients with nonalcoholic fatty liver disease.

Sat, 21/10/2017 - 12:38
Related Articles Lipid profiling of the therapeutic effects of berberine in patients with nonalcoholic fatty liver disease. J Transl Med. 2016 Sep 15;14:266 Authors: Chang X, Wang Z, Zhang J, Yan H, Bian H, Xia M, Lin H, Jiang J, Gao X Abstract BACKGROUND: We recently demonstrated a positive effect of berberine on nonalcoholic fatty liver disease patients after 16 weeks of treatment by comparing mere lifestyle intervention in type 2 diabetes patients with berberine treatment, which decreased the content of hepatic fat. However, the potential mechanisms of the clinical effects are unclear. We used a lipidomic approach to characterize the state of lipid metabolism as reflected in the circulation of subjects with nonalcoholic fatty liver disease (NAFLD) before and after berberine treatment. METHODS: Liquid chromatography-mass spectrometry evaluated the various lipid metabolites in serum samples obtained from the participants (41 patients in the berberine group and 39 patients in the mere lifestyle intervention group) before and after treatment. RESULTS: A total of 256 serum lipid molecular species were identified and quantified. Both treatments regulated various types of lipids in metabolic pathways, such as free fatty acids, phosphoglycerides and glycerides, in metabolic pathways, but berberine induced a substantially greater change in serum lipid species compared with mere lifestyle intervention after treatment. Berberine also caused obvious differences on ceramides. Berberine treatment markedly decreased serum levels of ceramide and ceramide-1-phosphate. CONCLUSIONS: Berberine altered circulating ceramides, which may underlie the improvement in fatty liver disease. ClinicalTrials.gov NCT00633282, Registered March 3, 2008. PMID: 27629750 [PubMed - indexed for MEDLINE]

Synergistic Cysteamine Delivery Nanowafer as an Efficacious Treatment Modality for Corneal Cystinosis.

Sat, 21/10/2017 - 12:38
Related Articles Synergistic Cysteamine Delivery Nanowafer as an Efficacious Treatment Modality for Corneal Cystinosis. Mol Pharm. 2016 Oct 03;13(10):3468-3477 Authors: Marcano DC, Shin CS, Lee B, Isenhart LC, Liu X, Li F, Jester JV, Pflugfelder SC, Simpson J, Acharya G Abstract A synergy between the polymer biomaterial and drug plays an important role in enhancing the therapeutic efficacy, improving the drug stability, and minimizing the local immune responses in the development of drug delivery systems. Particularly, in the case of ocular drug delivery, the need for the development of synergistic drug delivery system becomes more pronounced because of the wet ocular mucosal surface and highly innervated cornea, which elicit a strong inflammatory response to the instilled drug formulations. This article presents the development of a synergistic cysteamine delivery nanowafer to treat corneal cystinosis. Corneal cystinosis is a rare metabolic disease that causes the accumulation of cystine crystals in the cornea resulting in corneal opacity and loss of vision. It is treated with topical cysteamine (Cys) eye drops that need to be instilled 6-12 times a day throughout the patient's life, which causes side effects such as eye pain, redness, and ocular inflammation. As a result, compliance and treatment outcomes are severely compromised. To surmount these issues, we have developed a clinically translatable Cys nanowafer (Cys-NW) that can be simply applied on the eye with a fingertip. During the course of the drug release, Cys-NW slowly dissolves and fades away. The in vivo studies in cystinosin knockout mice demonstrated twice the therapeutic efficacy of Cys-NW containing 10 μg of Cys administered once a day, compared to 44 μg of Cys as topical eye drops administered twice a day. Furthermore, Cys-NW stabilizes Cys for up to four months at room temperature compared to topical Cys eye drops that need to be frozen or refrigerated and still remain active for only 1 week. The Cys-NW, because of its enhanced therapeutic efficacy, safety profile, and extended drug stability at room temperature, can be rapidly translated to the clinic for human trials. PMID: 27571217 [PubMed - indexed for MEDLINE]

metabolomics; +22 new citations

Fri, 20/10/2017 - 15:09
22 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2017/10/20PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

metabolomics; +22 new citations

Fri, 20/10/2017 - 12:02
22 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2017/10/20PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

metabolomics; +27 new citations

Thu, 19/10/2017 - 14:41
27 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2017/10/19PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

metabolomics; +42 new citations

Tue, 17/10/2017 - 13:47
42 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2017/10/17PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

A Metabolomic Signature of Acute Caloric Restriction.

Sun, 15/10/2017 - 22:00
A Metabolomic Signature of Acute Caloric Restriction. J Clin Endocrinol Metab. 2017 Sep 28;: Authors: Collet TH, Sonoyama T, Henning E, Keogh JM, Ingram B, Kelway S, Guo L, Farooqi IS Abstract Context: The experimental paradigm of acute caloric restriction followed by refeeding can be used to study the homeostatic mechanisms that regulate energy homeostasis, which are relevant to understanding the adaptive response to weight loss. Objective: Metabolomics, the measurement of hundreds of small molecule metabolites, their precursors, derivatives, and degradation products, has emerged as a useful tool for the study of physiology and disease and was used here to study the metabolic response to acute caloric restriction. Participants, Design and Setting: We used four ultra high performance liquid chromatography-tandem mass spectrometry methods to characterize changes in carbohydrates, lipids, amino acids and steroids in eight normal weight men at baseline, after 48 hours of caloric restriction (CR; 10% of energy requirements) and after 48 hours of ad libitum refeeding in a tightly-controlled environment. Results: We identified a distinct metabolomic signature associated with acute CR characterized by the expected switch from carbohydrate to fat utilization with increased lipolysis and beta-fatty acid oxidation. We found an increase in omega-fatty acid oxidation and levels of endocannabinoids which are known to promote food intake. These changes were reversed with refeeding. Several plasmalogen phosphatidylethanolamines (endogenous anti-oxidants) significantly decreased with CR (all p≤0.0007). Additionally, acute CR was associated with an increase in the branched chain amino acids (all p≤1.4x10-7) and dehydroepiandrosterone sulfate (p=0.0006). Conclusions: We identified a distinct metabolomic signature associated with acute CR. Further studies are needed to characterise the mechanisms that mediate these changes and their potential contribution to the adaptive response to dietary restriction. PMID: 29029202 [PubMed - as supplied by publisher]

Metabolomics of Small Numbers of Cells: Metabolomic Profiling of 100, 1000 and 10000 Human Breast Cancer Cells.

Sun, 15/10/2017 - 22:00
Metabolomics of Small Numbers of Cells: Metabolomic Profiling of 100, 1000 and 10000 Human Breast Cancer Cells. Anal Chem. 2017 Oct 13;: Authors: Luo X, Li L Abstract In cellular metabolomics, it is desirable to carry out metabolomic profiling using a small number of cells in order to save time and cost. In some applications (e.g., working with circulating tumor cells in blood), only a limited number of cells are available for analysis. In this report, we describe a method based on high-performance chemical isotope labeling (CIL) nanoflow liquid chromatography mass spectrometry (nanoLC-MS) for high-coverage metabolomic analysis of small numbers of cells (i.e., ≤10000 cells). As an example, (12)C-/(13)C-dansyl labeling of the metabolites in lysates of 100, 1000 and 10000 MCF-7 breast cancer cells was carried out using a new labeling protocol tailored to handle small amounts of metabolites. Chemical-vapor-assisted ionization in a captivespray interface was optimized for improving metabolite ionization and increasing robustness of nanoLC-MS. Compared to microflow LC-MS, the nanoflow system provided much improved metabolite detectability with a significantly reduced sample amount required for analysis. Experimental duplicate analyses of biological triplicates resulted in the detection of 1620±148, 2091±89 and 2402±80 (n=6) peak pairs or metabolites in the amine/phenol submetabolome from the (12)C-/(13)C-dansyl labeled lysates of 100, 1000, and 10000 cells, respectively. About 63-69% of these peak pairs could be either identified using dansyl labeled standard library or mass-matched to chemical structures in human metabolome databases. We envisage the routine applications of this method for high-coverage quantitative cellular metabolomics using a starting material of 10000 cells. Even for analyzing 100 or 1000 cells, although the metabolomic coverage is reduced from the maximal coverage, this method can still detect thousands of metabolites, allowing the analysis of a large fraction of the metabolome and focused analysis of the detectable metabolites. PMID: 29028307 [PubMed - as supplied by publisher]

Chemotaxonomic Classification Applied to the Identification of Two Closely-Related Citrus TCMs Using UPLC-Q-TOF-MS-Based Metabolomics.

Sun, 15/10/2017 - 22:00
Chemotaxonomic Classification Applied to the Identification of Two Closely-Related Citrus TCMs Using UPLC-Q-TOF-MS-Based Metabolomics. Molecules. 2017 Oct 13;22(10): Authors: Zhao SY, Liu ZL, Shu YS, Wang ML, He D, Song ZQ, Zeng HL, Ning ZC, Lu C, Lu AP, Liu YY Abstract This manuscript elaborates on the establishment of a chemotaxonomic classification strategy for closely-related Citrus fruits in Traditional Chinese Medicines (TCMs). UPLC-Q-TOF-MS-based metabolomics was applied to depict the variable chemotaxonomic markers and elucidate the metabolic mechanism of Citrus TCMs from different species and at different ripening stages. Metabolomics can capture a comprehensive analysis of small molecule metabolites and can provide a powerful approach to establish metabolic profiling, creating a bridge between genotype and phenotype. To further investigate the different metabolites in four closely-related Citrus TCMs, non-targeted metabolite profiling analysis was employed as an efficient technique to profile the primary and secondary metabolites. The results presented in this manuscript indicate that primary metabolites enable the discrimination of species, whereas secondary metabolites are associated with species and the ripening process. In addition, analysis of the biosynthetic pathway highlighted that the syntheses of flavone and flavone glycosides are deeply affected in Citrus ripening stages. Ultimately, this work might provide a feasible strategy for the authentication of Citrus fruits from different species and ripening stages and facilitate a better understanding of their different medicinal uses. PMID: 29027971 [PubMed - in process]

Peroxisomal 2-Hydroxyacyl-CoA Lyase Is Involved in Endogenous Biosynthesis of Heptadecanoic Acid.

Sun, 15/10/2017 - 22:00
Peroxisomal 2-Hydroxyacyl-CoA Lyase Is Involved in Endogenous Biosynthesis of Heptadecanoic Acid. Molecules. 2017 Oct 13;22(10): Authors: Jenkins B, Schryver E, Veldhoven PPV, Koulman A Abstract Circulating heptadecanoic acid (C17:0) is reported to be a pathology risk/prognosis biomarker and a dietary biomarker. This pathology relationship has been shown to be reliably predictive even when independent of dietary contributions, suggesting that the endogenous biosynthesis of C17:0 is related to the pathological aetiology. Little is known about C17:0 biosynthesis, which tissues contribute to the circulating levels, and how C17:0 is related to pathology. Hacl1+/- mice were mated to obtain Hacl1-/- and Hacl1+/+ control mice. At 14 weeks, they were anesthetized for tissue collection and fatty acid analysis. Compared to Hacl1+/+, C15:0 was not significantly affected in any Hacl1-/- tissues. However, the Hacl1-/- plasma and liver C17:0 levels were significantly lower: ~26% and ~22%, respectively. No significant differences were seen in the different adipose tissues. To conclude, Hacl1 plays a significant role in the liver and plasma levels of C17:0, providing evidence it can be endogenously biosynthesized via alpha-oxidation. The strong inverse association of C17:0 with pathology raises the question whether there is a direct link between α-oxidation and these diseases. Currently, there is no clear evidence, warranting further research into the role of α-oxidation in relation to metabolic diseases. PMID: 29027957 [PubMed - in process]

Immunogenic stress and death of cancer cells: Contribution of antigenicity vs adjuvanticity to immunosurveillance.

Sun, 15/10/2017 - 22:00
Related Articles Immunogenic stress and death of cancer cells: Contribution of antigenicity vs adjuvanticity to immunosurveillance. Immunol Rev. 2017 Nov;280(1):165-174 Authors: Bloy N, Garcia P, Laumont CM, Pitt JM, Sistigu A, Stoll G, Yamazaki T, Bonneil E, Buqué A, Humeau J, Drijfhout JW, Meurice G, Walter S, Fritsche J, Weinschenk T, Rammensee HG, Melief C, Thibault P, Perreault C, Pol J, Zitvogel L, Senovilla L, Kroemer G Abstract Cancer cells are subjected to constant selection by the immune system, meaning that tumors that become clinically manifest have managed to subvert or hide from immunosurveillance. Immune control can be facilitated by induction of autophagy, as well as by polyploidization of cancer cells. While autophagy causes the release of ATP, a chemotactic signal for myeloid cells, polyploidization can trigger endoplasmic reticulum stress with consequent exposure of the "eat-me" signal calreticulin on the cell surface, thereby facilitating the transfer of tumor antigens into dendritic cells. Hence, both autophagy and polyploidization cause the emission of adjuvant signals that ultimately elicit immune control by CD8(+) T lymphocytes. We investigated the possibility that autophagy and polyploidization might also affect the antigenicity of cancer cells by altering the immunopeptidome. Mass spectrometry led to the identification of peptides that were presented on major histocompatibility complex (MHC) class I molecules in an autophagy-dependent fashion or that were specifically exposed on the surface of polyploid cells, yet lost upon passage of such cells through immunocompetent (but not immunodeficient) mice. However, the preferential recognition of autophagy-competent and polyploid cells by the innate and cellular immune systems did not correlate with the preferential recognition of such peptides in vivo. Moreover, vaccination with such peptides was unable to elicit tumor growth-inhibitory responses in vivo. We conclude that autophagy and polyploidy increase the immunogenicity of cancer cells mostly by affecting their adjuvanticity rather than their antigenicity. PMID: 29027230 [PubMed - in process]

Extracellular nucleosides and nucleotides as immunomodulators.

Sun, 15/10/2017 - 22:00
Related Articles Extracellular nucleosides and nucleotides as immunomodulators. Immunol Rev. 2017 Nov;280(1):83-92 Authors: Kepp O, Loos F, Liu P, Kroemer G Abstract Some anticancer agents induce immunogenic cell death that is accompanied by the emission of danger signals into the tumor microenvironment, thus attracting and activating innate immune effectors and finally inducing anticancer immunity. The release of extracellular nucleosides such as adenosine triphosphate (ATP) from the tumor in response to anticancer therapy plays a pivotal role in the attraction of antigen presenting cells and the activation of inflammasome-mediated proinflammatory cascades. In contrast, the ectonucleotidase-catalyzed phosphohydrolysis of nucleotides to nucleosides reduces the extracellular availability of nucleotides, hence limiting the recruitment and activation of antigen-presenting cells. In addition, the (over-)production of nucleosides including adenosine by ectonucleotidases located on cancer cells and regulatory T cells can induce immunosuppression, as adenosine directly inhibits the proliferation and activation of effector T cells. Here, we discuss the importance of death metabolites for immunomodulation in general, and the role of the purine nucleotide ATP and its derivative adenosine in particular. In addition, we provide an overview on therapeutic interventions that reinstate tumor immunogenicity in conditions where nucleotide-dependent immunostimulation is obstructed. PMID: 29027229 [PubMed - in process]

Death, danger & immunity: Fundamental mechanisms linking pathogenic or iatrogenic cell death events to immune responses.

Sun, 15/10/2017 - 22:00
Related Articles Death, danger & immunity: Fundamental mechanisms linking pathogenic or iatrogenic cell death events to immune responses. Immunol Rev. 2017 Nov;280(1):5-7 Authors: Kroemer G PMID: 29027215 [PubMed - in process]

Metabolic Responses of Eisenia Fetida to Individual Pb and Cd Contamination in Two Types of Soils.

Sun, 15/10/2017 - 22:00
Related Articles Metabolic Responses of Eisenia Fetida to Individual Pb and Cd Contamination in Two Types of Soils. Sci Rep. 2017 Oct 12;7(1):13110 Authors: Tang R, Ding C, Ma Y, Wang J, Zhang T, Wang X Abstract To characterize the potential toxicity of low Pb- and Cd-contaminated arable soils, earthworms were exposed to Pb contaminated ferrosol, cambosol or Cd contaminated ferrosol for two weeks. Polar metabolites of earthworms were detected by nuclear magnetic resonance. Data were then analyzed with principal component analysis followed by orthogonal signal correction-partial least squares-discriminant analysis and univariate analysis to determine possible mechanisms for the changes in metabolites. The survival rates, metal concentrations and bioaccumulation factor (BAF) of the earthworms were also measured and calculated as auxiliary data. The results showed that the metabolite profiles were highly similar in Pb-contaminated ferrosol and cambosol (R(2) = 0.76, p < 0.0001), which can be attributed to similar response mechanisms. However, there was a more intense response in ferrosol likely due to higher Pb concentrations in earthworms. Metabolic pathways and BAFs exhibited apparent distinctions between Pb- and Cd-contaminated ferrosol, likely because they bind to different bio-ligands. The affected metabolic pathways were involved in alanine-aspartate-glutamate, purine, glutathione, valine-leucine-isoleucine biosynthesis and degradation and nicotinate and nicotinamide metabolism. Regarding the bioavailability in earthworms, Pb availability was higher for ferrosol than for cambosol. We confirmed that the potential toxicity of low Pb/Cd-contaminated soils can be characterized using earthworm metabolomics. PMID: 29026156 [PubMed - in process]

Effect of masticatory stimulation on the quantity and quality of saliva and the salivary metabolomic profile.

Sun, 15/10/2017 - 22:00
Related Articles Effect of masticatory stimulation on the quantity and quality of saliva and the salivary metabolomic profile. PLoS One. 2017;12(8):e0183109 Authors: Okuma N, Saita M, Hoshi N, Soga T, Tomita M, Sugimoto M, Kimoto K Abstract BACKGROUND: This study characterized the changes in quality and quantity of saliva, and changes in the salivary metabolomic profile, to understand the effects of masticatory stimulation. METHODS: Stimulated and unstimulated saliva samples were collected from 55 subjects and salivary hydrophilic metabolites were comprehensively quantified using capillary electrophoresis-time-of-flight mass spectrometry. RESULTS: In total, 137 metabolites were identified and quantified. The concentrations of 44 metabolites in stimulated saliva were significantly higher than those in unstimulated saliva. Pathway analysis identified the upregulation of the urea cycle and synthesis and degradation pathways of glycine, serine, cysteine and threonine in stimulated saliva. A principal component analysis revealed that the effect of masticatory stimulation on salivary metabolomic profiles was less dependent on sample population sex, age, and smoking. The concentrations of only 1 metabolite in unstimulated saliva, and of 3 metabolites stimulated saliva, showed significant correlation with salivary secretion volume, indicating that the salivary metabolomic profile and salivary secretion volume were independent factors. CONCLUSIONS: Masticatory stimulation affected not only salivary secretion volume, but also metabolite concentration patterns. A low correlation between the secretion volume and these patterns supports the conclusion that the salivary metabolomic profile may be a new indicator to characterize masticatory stimulation. PMID: 28813487 [PubMed - indexed for MEDLINE]

CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells.

Sun, 15/10/2017 - 22:00
Related Articles CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells. Nature. 2017 06 01;546(7656):168-172 Authors: Kim J, Hu Z, Cai L, Li K, Choi E, Faubert B, Bezwada D, Rodriguez-Canales J, Villalobos P, Lin YF, Ni M, Huffman KE, Girard L, Byers LA, Unsal-Kacmaz K, Peña CG, Heymach JV, Wauters E, Vansteenkiste J, Castrillon DH, Chen BPC, Wistuba I, Lambrechts D, Xu J, Minna JD, DeBerardinis RJ Abstract Metabolic reprogramming by oncogenic signals promotes cancer initiation and progression. The oncogene KRAS and tumour suppressor STK11, which encodes the kinase LKB1, regulate metabolism and are frequently mutated in non-small-cell lung cancer (NSCLC). Concurrent occurrence of oncogenic KRAS and loss of LKB1 (KL) in cells specifies aggressive oncological behaviour. Here we show that human KL cells and tumours share metabolomic signatures of perturbed nitrogen handling. KL cells express the urea cycle enzyme carbamoyl phosphate synthetase-1 (CPS1), which produces carbamoyl phosphate in the mitochondria from ammonia and bicarbonate, initiating nitrogen disposal. Transcription of CPS1 is suppressed by LKB1 through AMPK, and CPS1 expression correlates inversely with LKB1 in human NSCLC. Silencing CPS1 in KL cells induces cell death and reduces tumour growth. Notably, cell death results from pyrimidine depletion rather than ammonia toxicity, as CPS1 enables an unconventional pathway of nitrogen flow from ammonia into pyrimidines. CPS1 loss reduces the pyrimidine to purine ratio, compromises S-phase progression and induces DNA-polymerase stalling and DNA damage. Exogenous pyrimidines reverse DNA damage and rescue growth. The data indicate that the KL oncological genotype imposes a metabolic vulnerability related to a dependence on a cross-compartmental pathway of pyrimidine metabolism in an aggressive subset of NSCLC. PMID: 28538732 [PubMed - indexed for MEDLINE]

Venomics analyses of the skin secretion of Dermatonotus muelleri: Preliminary proteomic and metabolomic profiling.

Sun, 15/10/2017 - 22:00
Related Articles Venomics analyses of the skin secretion of Dermatonotus muelleri: Preliminary proteomic and metabolomic profiling. Toxicon. 2017 May;130:127-135 Authors: Cavalcante ID, Antoniazzi MM, Jared C, Pires OR, Sciani JM, Pimenta DC Abstract Dermatonotus muelleri is the sole species of the Dermatonotus genus and inhabits Argentina, Bolivia, Brazil and Paraguay. This animal exhibits an explosive reproductive behavior during the Southern spring months, which lasts only for five days. Moreover, this animal displays specific adaptations to the habitat resulting in the energy conservation needed during either the intense reproduction period or times of estivation. During dry seasons and/or food shortages D. muelleri can survive because its food specialization and ability to dig an underground chamber for protection. Few literature is available on this amphibian and no biochemical characterization has ever been performed on the animal's skin secretion. This work, on the other hand, presents for the first time a venomic analysis of the major components present in the skin secretion of this microhylid. The crude skin secretion was obtained my mechanical stimulation and was analyzed according to one major criterion: >10 kDa or <10 kDa. The high molecular mass fraction was subjected to typical gel-based proteomic processing whereas the low molecular mass fraction was analyzed by liquid chromatography, mass spectrometry and nuclear magnetic resonance (NMR), yielding an overall 'venomics' approach. No classical/evident toxin was detected, but peptidases (metallo and serino) and structural proteins could be identified. In the low molecular mass fraction no peptides were detected, as well as no typical alkaloid or steroid. On the other hand, the amino acid tryptophan could be identified and a typical sugar spectrum was obtained in the NMR analyses. Altogether these findings point out to the fact that D. muelleri skin secretion is unique and the molecular arsenal present herein is yet to be explored; therefore, this venomics study is only the beginning. PMID: 28249803 [PubMed - indexed for MEDLINE]

metabolomics; +20 new citations

Fri, 13/10/2017 - 15:01
20 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2017/10/13PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

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