PubMed

Depletion of Stercobilin in Fecal Matter from a Mouse Model of Autism Spectrum Disorders. Metabolomics. 2017 Nov;13(11): Authors: Sekera ER, Rudolph HL, Carro SD, Morales MJ, Bett GCL, Rasmusson RL, Wood TD Abstract Introduction: Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders lacking a clinical biomarker for diagnosis. Emerging evidence shows that intestinal microflora from ASD subjects can be distinguished from controls, suggesting metabolite differences due to the action of intestinal microbes may provide a means for identifying potential biomarkers for ASD. Objectives: The aim of this study was to determine if quantitative differences in levels of stercobilin and stercobilinogen, metabolites produced by biological action of intestinal microflora, exist in the fecal matter between an ASD mouse model population and controls. Methods: Pairs of fecal samples were collected from two mouse groups, an ASD model group with Timothy syndrome 2 (TS2-NEO) and a gender-matched control group. After centrifugation, supernatant was spiked with an (18)O-labeled stercobilin isotopomer and subjected to solid phase extraction for processing. Extracted samples were spotted on a stainless steel plate and subjected to matrix-assisted laser desorption and ionization mass spectrometry using dihydroxybenzoic acid as the matrix (n = 5). Peak areas for bilins and (18)O-stercobilin isotopomers were determined in each fecal sample. Results: A 40-45% depletion in stercobilin in TS2-NEO fecal samples compared with controls was observed with p < 0.05; a less dramatic depletion was observed for stercobilinogen. Conclusions: The results show that stercobilin depletion in feces is observed for an ASD mouse model vs. controls. This may help to explain recent observations of a less diverse microbiome in humans with ASD and may prove helpful in developing a clinical ASD biomarker. PMID: 29147105 [PubMed]

Disturbance in Plasma Metabolic Profile in Different Types of Human Cytomegalovirus-Induced Liver Injury in Infants. Sci Rep. 2017 Nov 16;7(1):15696 Authors: Li WW, Shan JJ, Lin LL, Xie T, He LL, Yang Y, Wang SC Abstract Human cytomegalovirus (HCMV) infection in infants is a global problem and the liver is a target organ of HCMV invasion. However, the mechanism by which HCMV causes different types of liver injury is unclear, and there are many difficulties in the differential diagnosis of HCMV infantile cholestatic hepatopathy (ICH) and extrahepatic biliary atresia (EHBA). We established a non-targeted gas chromatography-mass spectrometry metabolomics method in conjunction with orthogonal partial least squares-discriminate analysis based on 127 plasma samples from healthy controls, and patients with HCMV infantile hepatitis, HCMV ICH, and HCMV EHBA to explore the metabolite profile of different types of HCMV-induced liver injury. Twenty-nine metabolites related to multiple amino acid metabolism disorder, nitrogen metabolism and energy metabolism were identified. Carbamic acid, glutamate, L-aspartic acid, L-homoserine, and noradrenaline for HCMV ICH vs. HCMV EHBA were screened as potential biomarkers and showed excellent discriminant performance. These results not only revealed the potential pathogenesis of HCMV-induced liver injury, but also provided a feasible diagnostic tool for distinguishing EHBA from ICH. PMID: 29146975 [PubMed - in process]

Diacylglycerols as biomarkers of sustained immune activation in Proteinopathies associated with dementia. Clin Chim Acta. 2017 Nov 13;: Authors: Wood PL, Cebak JE, Woltjer RL Abstract Cognitive decline is a devastating clinical condition, heavily correlated with age progression. In the cases of Alzheimer's disease, Parkinson's disease, and Lewy body disease, the common neuropathologies are proteinopathies and neuroinflammation. Herein, we review current lipidomics findings and conclude that brain and circulating diacylglycerols represent biomarkers of this ongoing sustained immune response, presumably involving microglia. We further hypothesize that a logical next step will be to evaluate biomarkers of immune activation in a cohort of patients with Mild Cognitive Impairment (MCI) and subsequently attempt to provide therapeutic intervention with anti-inflammatory therapy in MCI patients with immune activation. Although this is an urgent and theoretically safe therapeutic trial, it will likely necessitate government support. PMID: 29146478 [PubMed - as supplied by publisher]

PHEOCHROMOCYTOMA: A GENETIC AND DIAGNOSTIC UPDATE. Endocr Pract. 2017 Nov 16;: Authors: Mercado-Asis LB, Wolf KI, Jochmanova I, Taïeb D Abstract OBJECTIVE: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors derived from adrenal or extra-adrenal locations, respectively. Upon suspicion of PPGL, specific metabolomic, molecular, biochemical, imaging, and histopathological studies are performed to prove, localize, treat, and monitor disease progression. Recently, improved diagnostic tools allow physicians to accurately diagnose PPGL, even in patients presenting with small (less than 1 cm) or biochemically silent tumors, which previously delayed proper detection and treatment. METHODS: This review outlines the most updated approach to PPGL patients, and presents a new diagnostic approach for physicians in order to increase earlier tumor identification and accurately assess metastatic behavior. CONCLUSION: We present the most recent advances in genetics, epigenetics, metabolomics, biochemical, and imaging diagnoses of this rare tumor in order to properly assess disease, decide treatment options, and manage follow-up. We also elaborate on new therapeutic perspectives in these very rare neoplastic entities. ABBREVIATIONS: 177Lu-DOTATATE = lutetium octreotate; ACO = aconitase; Ad = adenine; AD = autosomal dominant; ATRX = ATRX chromatin remodeler; ccRCC = clear cell renal cell carcinoma; c-MYC = MYC proto oncognene; CoA = coenzyme A; COMT = catechol-O-methyl transferase; CPE = carboxypeptidase E; CS = citrate synthase; CT = computed tomography; DH = pyruvate dehydrogenase; DOTATATE = DOTA-octreotate; EGLN1/2 = egl-9 family hypoxia inducible factor 1/2; EGLN2/PHD1 = egl-9 family hypoxia inducible factor 2; elF-4E = eukaryotic initiation factor 4E; EMT = epithelial-to-mesenchymal transition; EPAS1/HIF2A = endothelial PAS domain protein 2/hypoxia-inducible factor 2α; ERK = extracellular signal-regulated kinase; FH = fumarate hydroxylase; GSH = glutathione; H3F3A = histone 3.3 encoding gene; HIFs = Hypoxia-inducible factors; HIF-α = hypoxia-inducible factor alpha; HNPGLs = head and neck paragangliomas; HRAS = HRas protooncogene; IDH = isocitrate dehydrogenase; IGF-1R = growth factor 1 receptor; KIF1B = kinesin family member 1B; MAX = myc-associated factor X; MDH2 = malate dehydrogenase; MN = metanephrine; MRI = magnetic resonance imaging; mTORC1 = mammalian target of rapamycin complex 1; MTY = methoxytyramine; NAd = nicotinamide adenine dinucleotide; NETs = neuroendocrine tumors; NF1 = neurofibromin 1; NMN = normetanephrine; OPLS-DA = orthogonal partial least square discriminant analysis; PFS = progression free survival; PHD = prolyl hydroxylase domain protein; PPGLs = Pheochromocytoma and Paragangliomas; PRRT = peptide receptor radionuclide therapy; Pvhl = von Hippel-Lindau protein; Raptor = regulatory associated protein of mTOR; RAS = rat sarcoma oncogene; RET = rearranged during transfection proto-oncogene; ROS = reactive oxygen species; S6K = S6 kinase; SDH = succinate dehydrogenase; SDHA, -B, -C, -D, = succinate dehydrogenase subunits A, B, C, D; SDHAF2 = succinate dehydrogenase complex assembly factor 2; SDHB, C, D = succinate dehydrogenase subunits B, C, D; SDHx = succinate dehydrogenase subunits; SSTRs = somatostatin receptors; SUCLG = succinyl-CoA synthase; TERRA = Telomeric Repeat-containing RNA; TET = ten-eleven-translocation methylcytosine dioxygenase; TMEM127 = transmembrane protein 127; VEGF = vascular endothelial growth factor; VHL = von Hippel-Lindau; α-KGDH = alpha-ketoglutarate dehydrogenase. PMID: 29144820 [PubMed - as supplied by publisher]

Metabolic profiling of normal hepatocyte and hepatocellular carcinoma cells via (1) H nuclear magnetic resonance spectroscopy. Cell Biol Int. 2017 Nov 16;: Authors: Chen Y, Chen Z, Feng JH, Chen YB, Liao NS, Su Y, Zou CY Abstract Hepatocellular carcinoma (HCC) causes death mainly by disseminated metastasis progression from the organ being confined. Different metastatic stages are closely related to cellular metabolic profiles. Normal hepatocyte and HepG2 cell line from low metastatic HCC were studied by NMR-based metabolomic techniques. Multivariate and univariate statistical analyses were utilized to identify characteristic metabolites from cells and cultured media. Elevated levels of acetate, creatine, isoleucine, leucine, and phenylalanine were observed in HepG2 cells, suggesting more active in gathering nutrient components along with altered amino acid metabolisms and enhanced lipid metabolism. High glucose consumption was significantly different in low metastatic cells. A series of characteristic metabolites were identified and served as biomarkers. Relative metabolic pathway analysis shows that low metastatic HepG2 cell line exhibits active behaviors in metabolisms and biosynthesis of specific amino acids and energy metabolism. Moreover, characteristic metabolites-based classification models executed by support vector machines algorithm perform robustly to classify normal hepatocyte and HepG2 cell line. It is concluded that NMR-based metabolomic analyses of cell lines can provide a powerful approach to understand metastasis-related biological alterations. The present study also provides a basis for metabolic markers determination of hepatic carcinoma in the future clinical study. PMID: 29144590 [PubMed - as supplied by publisher]

A ubiquitin-dependent signalling axis specific for ALKBH-mediated DNA dealkylation repair. Nature. 2017 Nov 16;551(7680):389-393 Authors: Brickner JR, Soll JM, Lombardi PM, Vågbø CB, Mudge MC, Oyeniran C, Rabe R, Jackson J, Sullender ME, Blazosky E, Byrum AK, Zhao Y, Corbett MA, Gécz J, Field M, Vindigni A, Slupphaug G, Wolberger C, Mosammaparast N Abstract DNA repair is essential to prevent the cytotoxic or mutagenic effects of various types of DNA lesions, which are sensed by distinct pathways to recruit repair factors specific to the damage type. Although biochemical mechanisms for repairing several forms of genomic insults are well understood, the upstream signalling pathways that trigger repair are established for only certain types of damage, such as double-stranded breaks and interstrand crosslinks. Understanding the upstream signalling events that mediate recognition and repair of DNA alkylation damage is particularly important, since alkylation chemotherapy is one of the most widely used systemic modalities for cancer treatment and because environmental chemicals may trigger DNA alkylation. Here we demonstrate that human cells have a previously unrecognized signalling mechanism for sensing damage induced by alkylation. We find that the alkylation repair complex ASCC (activating signal cointegrator complex) relocalizes to distinct nuclear foci specifically upon exposure of cells to alkylating agents. These foci associate with alkylated nucleotides, and coincide spatially with elongating RNA polymerase II and splicing components. Proper recruitment of the repair complex requires recognition of K63-linked polyubiquitin by the CUE (coupling of ubiquitin conjugation to ER degradation) domain of the subunit ASCC2. Loss of this subunit impedes alkylation adduct repair kinetics and increases sensitivity to alkylating agents, but not other forms of DNA damage. We identify RING finger protein 113A (RNF113A) as the E3 ligase responsible for upstream ubiquitin signalling in the ASCC pathway. Cells from patients with X-linked trichothiodystrophy, which harbour a mutation in RNF113A, are defective in ASCC foci formation and are hypersensitive to alkylating agents. Together, our work reveals a previously unrecognized ubiquitin-dependent pathway induced specifically to repair alkylation damage, shedding light on the molecular mechanism of X-linked trichothiodystrophy. PMID: 29144457 [PubMed - in process]

NMR-Based Identification of Metabolites in Polar and Non-Polar Extracts of Avian Liver. Metabolites. 2017 Nov 16;7(4): Authors: Fathi F, Brun A, Rott KH, Falco Cobra P, Tonelli M, Eghbalnia HR, Caviedes-Vidal E, Karasov WH, Markley JL Abstract Metabolites present in liver provide important clues regarding the physiological state of an organism. The aim of this work was to evaluate a protocol for high-throughput NMR-based analysis of polar and non-polar metabolites from a small quantity of liver tissue. We extracted the tissue with a methanol/chloroform/water mixture and isolated the polar metabolites from the methanol/water layer and the non-polar metabolites from the chloroform layer. Following drying, we re-solubilized the fractions for analysis with a 600 MHz NMR spectrometer equipped with a 1.7 mm cryogenic probe. In order to evaluate the feasibility of this protocol for metabolomics studies, we analyzed the metabolic profile of livers from house sparrow (Passer domesticus) nestlings raised on two different diets: livers from 10 nestlings raised on a high protein diet (HP) for 4 d and livers from 12 nestlings raised on the HP diet for 3 d and then switched to a high carbohydrate diet (HC) for 1 d. The protocol enabled the detection of 52 polar and nine non-polar metabolites in ¹H NMR spectra of the extracts. We analyzed the lipophilic metabolites by one-way ANOVA to assess statistically significant concentration differences between the two groups. The results of our studies demonstrate that the protocol described here can be exploited for high-throughput screening of small quantities of liver tissue (approx. 100 mg wet mass) obtainable from small animals. PMID: 29144418 [PubMed]

Monitoring for Response to Antineoplastic Drugs: The Potential of a Metabolomic Approach. Metabolites. 2017 Nov 16;7(4): Authors: Rattner J, Bathe OF Abstract For most cancers, chemotherapeutic options are rapidly expanding, providing the oncologist with substantial choices. Therefore, there is a growing need to select the best systemic therapy, for any individual, that effectively halts tumor progression with minimal toxicity. Having the capability to predict benefit and to anticipate toxicity would be ideal, but remains elusive at this time. An alternative approach is an adaptive approach that involves close observation for treatment response and emergence of resistance. Currently, response to systemic therapy is estimated using radiographic tests. Unfortunately, radiographic estimates of response are imperfect and radiographic signs of response can be delayed. This is particularly problematic for targeted agents, as tumor shrinkage is often not apparent with these drugs. As a result, patients are exposed to prolonged courses of toxic drugs that may ultimately be found to be ineffective. A biomarker-based adaptive strategy that involves the serial analysis of the metabolome is attractive. The metabolome changes rapidly with changes in physiology. Changes in the circulating metabolome associated with various antineoplastic agents have been described, but further work will be required to understand what changes signify clinical benefit. We present an investigative approach for the discovery and validation of metabolomic response biomarkers, which consists of serial analysis of the metabolome and linkage of changes in the metabolome to measurable therapeutic benefit. Potential pitfalls in the development of metabolomic biomarkers of response and loss of response are reviewed. PMID: 29144383 [PubMed]

Salt-responsive gut commensal modulates TH17 axis and disease. Nature. 2017 Nov 15;: Authors: Wilck N, Matus MG, Kearney SM, Olesen SW, Forslund K, Bartolomaeus H, Haase S, Mähler A, Balogh A, Markó L, Vvedenskaya O, Kleiner FH, Tsvetkov D, Klug L, Costea PI, Sunagawa S, Maier L, Rakova N, Schatz V, Neubert P, Frätzer C, Krannich A, Gollasch M, Grohme DA, Côrte-Real BF, Gerlach RG, Basic M, Typas A, Wu C, Titze JM, Jantsch J, Boschmann M, Dechend R, Kleinewietfeld M, Kempa S, Bork P, Linker RA, Alm EJ, Müller DN Abstract A Western lifestyle with high salt consumption can lead to hypertension and cardiovascular disease. High salt may additionally drive autoimmunity by inducing T helper 17 (TH17) cells, which can also contribute to hypertension. Induction of TH17 cells depends on gut microbiota; however, the effect of salt on the gut microbiome is unknown. Here we show that high salt intake affects the gut microbiome in mice, particularly by depleting Lactobacillus murinus. Consequently, treatment of mice with L. murinus prevented salt-induced aggravation of actively induced experimental autoimmune encephalomyelitis and salt-sensitive hypertension by modulating TH17 cells. In line with these findings, a moderate high-salt challenge in a pilot study in humans reduced intestinal survival of Lactobacillus spp., increased TH17 cells and increased blood pressure. Our results connect high salt intake to the gut-immune axis and highlight the gut microbiome as a potential therapeutic target to counteract salt-sensitive conditions. PMID: 29143823 [PubMed - as supplied by publisher]

Metformin Potentiates the Benefits of Dietary Restraint: A Metabolomic Study. Int J Mol Sci. 2017 Oct 28;18(11): Authors: Riera-Borrull M, García-Heredia A, Fernández-Arroyo S, Hernández-Aguilera A, Cabré N, Cuyàs E, Luciano-Mateo F, Camps J, Menendez JA, Joven J Abstract Prevention of the metabolic consequences of a chronic energy-dense/high-fat diet (HFD) represents a public health priority. Metformin is a strong candidate to be incorporated in alternative therapeutic approaches. We used a targeted metabolomic approach to assess changes related to the multi-faceted metabolic disturbances provoked by HFD. We evaluated the protective effects of metformin and explored how pro-inflammatory and metabolic changes respond when mice rendered obese, glucose-intolerant and hyperlipidemic were switched to diet reversal with or without metformin. Mice treated with metformin and diet-reversal showed a dramatically improved protection against HFD-induced hepatic steatosis, a beneficial effect that was accompanied by a lowering of liver-infiltrating pro-inflammatory macrophages and lower release of pro-inflammatory cytokines. Metformin combined with diet reversal promoted effective weight loss along with better glucose control, lowered levels of circulating cholesterol and triglycerides, and reduced adipose tissue content. Our findings underscored the ability of metformin to target the contribution of branched chain amino acids to adipose tissue metabolism while suppressing mitochondrial-dependent biosynthesis in hepatic tissue. The relationship between adipose tissue and liver might provide clinical potential for combining metformin and dietary modifications to protect against the metabolic damage occurring upon excessive dietary fat intake. PMID: 29143783 [PubMed - in process]

Is food intolerance a factor underlying chronic immune thrombocytopenia (ITP)? Br J Haematol. 2017 Nov 16;: Authors: Batty CA, Hunter JO, Woolner J, Baglin T, Turner C PMID: 29143303 [PubMed - as supplied by publisher]

Myo-inositol concentration in MR spectroscopy for differentiating high grade glioma from primary central nervous system lymphoma. J Neurooncol. 2017 Nov 15;: Authors: Nagashima H, Sasayama T, Tanaka K, Kyotani K, Sato N, Maeyama M, Kohta M, Sakata J, Yamamoto Y, Hosoda K, Itoh T, Sasaki R, Kohmura E Abstract It is sometimes difficult to distinguish gliomas from other tumors on routine imaging. In this study, we assessed whether 3-T magnetic resonance spectroscopy (MRS) with LCModel software might be useful for discriminating glioma from other brain tumors, such as primary central nervous system lymphomas (PCNSLs) and metastatic tumors. A total of 104 cases of brain tumor (66 gliomas, 20 PCNSLs, 6 metastatic tumors, 12 other tumors) were preoperatively investigated with short echo time (35 ms) single-voxel 3-T MRS. LCModel software was used to evaluate differences in the absolute concentrations of choline, N-acetylaspartate, N-acetylaspartylglutamate, glutamate + glutamine, myo-inositol (mIns), and lipid. mIns levels were significantly increased in high-grade glioma (HGG) compared with PCNSL (p < 0.001). In multivariate logistic regression analysis, mIns was the best marker for differentiating HGG from PCNSL (p < 0.0001, odds ratio 1.9927, 95% confidence interval 1.3628-3.2637). Conventional MRS detection of mIns resulted in a high diagnostic accuracy (sensitivity, 64%; specificity, 90%; area under the receiver operator curve, 0.80) for HGG. The expression of inositol 3-phosphate synthase (ISYNA1) was significantly higher in gliomas than in PCNSLs (p < 0.05), suggesting that the increased level of mIns in glioma is due to high expression of ISYNA1, the rate-limiting enzyme in the mIns-producing pathway. In conclusion, noninvasive analysis of mIns using single-voxel MRS may be useful in distinguishing gliomas from other brain tumors, particularly PCNSLs. PMID: 29143277 [PubMed - as supplied by publisher]

Profiling of Plasma Metabolites Suggests Altered Mitochondrial Fuel Usage and Remodeling of Sphingolipid Metabolism in Individuals With Type 2 Diabetes and Kidney Disease. Kidney Int Rep. 2017 May;2(3):470-480 Authors: Liu JJ, Ghosh S, Kovalik JP, Ching J, Choi HW, Tavintharan S, Ong CN, Sum CF, Summers SA, Tai ES, Lim SC Abstract Introduction: Pathophysiology of diabetic kidney disease (DKD) is incompletely understood. We aim to elucidate metabolic abnormalities associated with DKD in type 2 diabetes mellitus (T2DM) by targeted plasma metabolomics. Methods: A total of 126 T2DM participants with early DKD (urinary albumin-to-creatinine ratio [ACR] 30-299 mg/g and eGFR ≥ 60 ml/min/1.73 m(2)), 154 overt DKD (ACR ≥ 300 mg/g or eGFR < 60 ml/min/1.73 m(2)), and 129 non-DKD T2DM controls (ACR < 30 mg/g and eGFR ≥ 60 ml/min/1.73 m(2)) were included in discovery study. Findings were subsequently validated in 149 T2DM with macroalbuminuria (ACR ≥ 300 mg/g) and 149 matched non-DKD T2DM controls. Plasma amino acid, acylcarnitine, Krebs cycle organic acid, and sphingolipids/ceramide levels were quantified by liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry. Results: Of 123 metabolites included in the data analysis, 24 differed significantly between DKD and controls in the same direction in both discovery and validation subpopulations. A number of short acylcarnitines including their dicarboxylic derivatives (C2-C6) were elevated in DKD, suggesting abnormalities in fatty acids and amino acids metabolic pathways. Five phosphatidylcholines were lower whereas 4 metabolites in the sphingomyelin-ceramide subfamily were higher in DKD. Principal component regression revealed that long-chain ceramides were independently associated with ACR but not eGFR. Conversely, essential amino acids catabolism and short dicarboxylacylcarnitine accumulation were associated with eGFR but not ACR. Discussion: DKD is associated with altered fuel substrate use and remodeling of sphingolipid metabolism in T2DM with DKD. Associations of albuminuria and impaired filtration function with distinct metabolomic signatures suggest different pathophysiology underlying these 2 manifestations of DKD. PMID: 29142974 [PubMed]

Urine metabolomics as a predictor of patient tolerance and response to adjuvant chemotherapy in colorectal cancer. Mol Clin Oncol. 2017 Nov;7(5):767-770 Authors: Dykstra MA, Switzer N, Eisner R, Tso V, Foshaug R, Ismond K, Fedorak R, Wang H Abstract Colorectal cancer is the third leading cause of cancer-associated mortality in the western world. The ability to predict a patient's response to chemotherapy may be of great value for clinicians and patients when planning cancer treatment. The aim of the current study was to develop a urine metabolomics-based biomarker panel to predict adverse events and response to chemotherapy in patients with colorectal cancer. A retrospective chart review of patients diagnosed with stage III or IV colorectal cancer between 2008 and 2012 was performed. The exclusion criteria included chemotherapy for palliation and patients living outside of Alberta. Data was collected concerning the chemotherapy regimen, adverse events associated with chemotherapy, disease progression and recurrence and 5-year survival. Adverse events were subdivided as follows: Delays in treatment, dose reductions, hospitalizations and chemotherapy regime changes. Patients provided urine samples for analysis prior to any intervention. Nuclear magnetic resonance (NMR) spectra of urine samples were acquired. The 1H NMR spectrum of each urine sample was analyzed using Chenomx NMRSuite v7.0. Using machine learning, predictors were generated and evaluated using 10-fold cross-validation. Urine spectra were obtained for 62 patients. The best predictors resulted in area under the receiver operating characteristic curve values of: 0.542 for chemotherapy dose reduction, 0.612 for 5-year survival, 0.650 for cancer recurrence and 0.750 for treatment delay. Therefore, predictors were developed for response to and adverse events from chemotherapy for patients with colorectal cancer patients. The predictor for treatment delay has the most promise, and further studies will aid its refinement and improvement of its accuracy. PMID: 29142749 [PubMed]

Using an NMR metabolomics approach to investigate the pathogenicity of amyloid-beta and alpha-synuclein. Metabolomics. 2017;13(12):151 Authors: Phelan MM, Caamaño-Gutiérrez E, Gant MS, Grosman RX, Madine J Abstract Introduction: The pathogenicity at differing points along the aggregation pathway of many fibril-forming proteins associated with neurodegenerative diseases is unclear. Understanding the effect of different aggregation states of these proteins on cellular processes is essential to enhance understanding of diseases and provide future options for diagnosis and therapeutic intervention. Objectives: To establish a robust method to probe the metabolic changes of neuronal cells and use it to monitor cellular response to challenge with three amyloidogenic proteins associated with neurodegenerative diseases in different aggregation states. Method: Neuroblastoma SH-SY5Y cells were employed to design a robust routine system to perform a statistically rigorous NMR metabolomics study into cellular effects of sub-toxic levels of alpha-synuclein, amyloid-beta 40 and amyloid-beta 42 in monomeric, oligomeric and fibrillar conformations. Results: This investigation developed a rigorous model to monitor intracellular metabolic profiles of neuronal cells through combination of existing methods. This model revealed eight key metabolites that are altered when neuroblastoma cells are challenged with proteins in different aggregation states. Metabolic pathways associated with lipid metabolism, neurotransmission and adaptation to oxidative stress and inflammation are the predominant contributors to the cellular variance and intracellular metabolite levels. The observed metabolite changes for monomer and oligomer challenge may represent cellular effort to counteract the pathogenicity of the challenge, whereas fibrillar challenge is indicative of system shutdown. This implies that although markers of stress are more prevalent under oligomeric challenge the fibrillar response suggests a more toxic environment. Conclusion: This approach is applicable to any cell type that can be cultured in a laboratory (primary or cell line) as a method of investigating how protein challenge affects signalling pathways, providing additional understanding as to the role of protein aggregation in neurodegenerative disease initiation and progression. PMID: 29142509 [PubMed]

Amyloid β42 peptide is toxic to non-neural cells in Drosophila yielding a characteristic metabolite profile and the effect can be suppressed by PI3K. Biol Open. 2017 Nov 15;6(11):1664-1671 Authors: Arnés M, Casas-Tintó S, Malmendal A, Ferrús A Abstract The human Aβ42 peptide is associated with Alzheimer's disease through its deleterious effects in neurons. Expressing the human peptide in adult Drosophila in a tissue- and time-controlled manner, we show that Aβ42 is also toxic in non-neural cells, neurosecretory and epithelial cell types in particular. This form of toxicity includes the aberrant signaling by Wingless morphogen leading to the eventual activation of Caspase 3. Preventing Caspase 3 activation by means of p53 keeps epithelial cells from elimination but maintains the Aβ42 toxicity yielding more severe deleterious effects to the organism. Metabolic profiling by nuclear magnetic resonance (NMR) of adult flies at selected ages post Aβ42 expression onset reveals characteristic changes in metabolites as early markers of the pathological process. All morphological and most metabolic features of Aβ42 toxicity can be suppressed by the joint overexpression of PI3K. PMID: 29141953 [PubMed]

A role for bacterial urease in gut dysbiosis and Crohn's disease. Sci Transl Med. 2017 Nov 15;9(416): Authors: Ni J, Shen TD, Chen EZ, Bittinger K, Bailey A, Roggiani M, Sirota-Madi A, Friedman ES, Chau L, Lin A, Nissim I, Scott J, Lauder A, Hoffmann C, Rivas G, Albenberg L, Baldassano RN, Braun J, Xavier RJ, Clish CB, Yudkoff M, Li H, Goulian M, Bushman FD, Lewis JD, Wu GD Abstract Gut dysbiosis during inflammatory bowel disease involves alterations in the gut microbiota associated with inflammation of the host gut. We used a combination of shotgun metagenomic sequencing and metabolomics to analyze fecal samples from pediatric patients with Crohn's disease and found an association between disease severity, gut dysbiosis, and bacterial production of free amino acids. Nitrogen flux studies using (15)N in mice showed that activity of bacterial urease, an enzyme that releases ammonia by hydrolysis of host urea, led to the transfer of murine host-derived nitrogen to the gut microbiota where it was used for amino acid synthesis. Inoculation of a conventional murine host (pretreated with antibiotics and polyethylene glycol) with commensal Escherichia coli engineered to express urease led to dysbiosis of the gut microbiota, resulting in a predominance of Proteobacteria species. This was associated with a worsening of immune-mediated colitis in these animals. A potential role for altered urease expression and nitrogen flux in the development of gut dysbiosis suggests that bacterial urease may be a potential therapeutic target for inflammatory bowel diseases. PMID: 29141885 [PubMed - in process]

Early career researchers want Open Science. Genome Biol. 2017 Nov 15;18(1):221 Authors: Farnham A, Kurz C, Öztürk MA, Solbiati M, Myllyntaus O, Meekes J, Pham TM, Paz C, Langiewicz M, Andrews S, Kanninen L, Agbemabiese C, Guler AT, Durieux J, Jasim S, Viessmann O, Frattini S, Yembergenova D, Benito CM, Porte M, Grangeray-Vilmint A, Curiel RP, Rehncrona C, Malas T, Esposito F, Hettne K Abstract Open Science is encouraged by the European Union and many other political and scientific institutions. However, scientific practice is proving slow to change. We propose, as early career researchers, that it is our task to change scientific research into open scientific research and commit to Open Science principles. PMID: 29141654 [PubMed - in process]

Recent Advances and Challenges in Steroid Metabolomics for Biomarker Discovery. Curr Med Chem. 2017 Nov 13;: Authors: Kotlowska A, Szefer P Abstract Steroid hormones belong to a group of low-molecular-weight compounds which are responsible for maintenance of various body functions, thus, their accurate assessment is crucial for evaluation of biosynthetic defects. The development of reliable methods allowing disease diagnosis is essential to improve early detection of various disorders connected with altered steroidogenesis. Currently, the field of metabolomics offers several improvements in terms of sensitivity and specificity of the diagnostic methods when opposed to classical diagnostic approaches. The combination of hyphenated techniques and pattern recognition methods allows to carry out a comprehensive assessment of the slightest alterations in steroid metabolic pathways. Moreover, metabolomics can also provide insights concerning personalized treatment of endocrine disorders in terms of supplying information about the response of the patient to treatment. In spite of several advantages, steroid metabolomics still faces some challenges which affect its availability and potential as a more widespread tool for biomarker discovery. This review will present the strengths, challenges and recent developments in steroid based metabolomics taking into consideration its potential in the area of clinical biomarkers discovery. PMID: 29141530 [PubMed - as supplied by publisher]

HMDB 4.0: the human metabolome database for 2018. Nucleic Acids Res. 2017 Nov 11;: Authors: Wishart DS, Feunang YD, Marcu A, Guo AC, Liang K, Vázquez-Fresno R, Sajed T, Johnson D, Li C, Karu N, Sayeeda Z, Lo E, Assempour N, Berjanskii M, Singhal S, Arndt D, Liang Y, Badran H, Grant J, Serra-Cayuela A, Liu Y, Mandal R, Neveu V, Pon A, Knox C, Wilson M, Manach C, Scalbert A Abstract The Human Metabolome Database or HMDB (www.hmdb.ca) is a web-enabled metabolomic database containing comprehensive information about human metabolites along with their biological roles, physiological concentrations, disease associations, chemical reactions, metabolic pathways, and reference spectra. First described in 2007, the HMDB is now considered the standard metabolomic resource for human metabolic studies. Over the past decade the HMDB has continued to grow and evolve in response to emerging needs for metabolomics researchers and continuing changes in web standards. This year's update, HMDB 4.0, represents the most significant upgrade to the database in its history. For instance, the number of fully annotated metabolites has increased by nearly threefold, the number of experimental spectra has grown by almost fourfold and the number of illustrated metabolic pathways has grown by a factor of almost 60. Significant improvements have also been made to the HMDB's chemical taxonomy, chemical ontology, spectral viewing, and spectral/text searching tools. A great deal of brand new data has also been added to HMDB 4.0. This includes large quantities of predicted MS/MS and GC-MS reference spectral data as well as predicted (physiologically feasible) metabolite structures to facilitate novel metabolite identification. Additional information on metabolite-SNP interactions and the influence of drugs on metabolite levels (pharmacometabolomics) has also been added. Many other important improvements in the content, the interface, and the performance of the HMDB website have been made and these should greatly enhance its ease of use and its potential applications in nutrition, biochemistry, clinical chemistry, clinical genetics, medicine, and metabolomics science. PMID: 29140435 [PubMed - as supplied by publisher]