PubMed

Related Articles Effects of ADMA on gene expression and metabolism in serum-starved LoVo cells. Sci Rep. 2016 05 16;6:25892 Authors: Zheng N, Wang K, He J, Qiu Y, Xie G, Su M, Jia W, Li H Abstract Serum starvation is a typical way for inducing tumor cell apoptosis and stress. Asymmetric dimethylarginine (ADMA) is an endogenous metabolite. Our previous study reveals the plasma ADMA level is elevated in colon cancer patients, which can attenuate serum starvation-induced apoptosis in LoVo cells. In current study, we evaluated the effects of ADMA on gene expression and metabolism in serum-starved LoVo cells with gene microarray and metabolomic approaches. Our results indicated that 96 h serum starvation induced comprehensive alterations at transcriptional level, and most of them were restored by ADMA. The main signaling pathways induced by serum starvation included cancers-related pathways, pathways in cell death, apoptosis, and cell cycle etc. Meanwhile, the metabolomic data showed serum-starved cells were clearly separated with control cells, but not with ADMA-treated cells in PCA model. The identified differential metabolites indicated serum starvation significantly suppressed TCA cycle, altered glucose and fatty acids metabolism, as well as nucleic acids metabolism. However, very few differential metabolites were identified between ADMA and serum-starved cells. In summary, our current results indicated serum starvation profoundly altered the gene expression and metabolism of LoVo cells, whereas ADMA could restore most of the changes at transcriptional level, but not at metabolic level. PMID: 27180883 [PubMed - indexed for MEDLINE]

Related Articles Gut microbial metabolites in health and disease. Gut Microbes. 2016 05 03;7(3):187-8 Authors: Flint HJ PMID: 27115177 [PubMed - indexed for MEDLINE]

Altered metabolism distinguishes high-risk from stable carotid atherosclerotic plaques. Eur Heart J. 2018 Mar 19;: Authors: Tomas L, Edsfeldt A, Mollet IG, Perisic Matic L, Prehn C, Adamski J, Paulsson-Berne G, Hedin U, Nilsson J, Bengtsson E, Gonçalves I, Björkbacka H Abstract Aims: Identification and treatment of the rupture prone atherosclerotic plaque remains a challenge for reducing the burden of cardiovascular disease. The interconnection of metabolic and inflammatory processes in rupture prone plaques is poorly understood. Herein, we investigate associations between metabolite profiles, inflammatory mediators and vulnerability in carotid atherosclerotic plaques. Methods and results: We collected 159 carotid plaques from patients undergoing endarterectomy and measured 165 different metabolites in a targeted metabolomics approach. We identified a metabolite profile in carotid plaques that associated with histologically evaluated vulnerability and inflammatory mediators, as well as presence of symptoms in patients. The distinct metabolite profiles identified in high-risk and stable plaques were in line with different transcription levels of metabolic enzymes in the two groups, suggesting an altered metabolism in high-risk plaques. The altered metabolic signature in high-risk plaques was consistent with a change to increased glycolysis, elevated amino acid utilization and decreased fatty acid oxidation, similar to what is found in activated leucocytes and cancer cells. Conclusion: These results highlight a possible key role of cellular metabolism to support inflammation and a high-risk phenotype of atherosclerotic plaques. Targeting the metabolism of atherosclerotic plaques with novel metabolic radiotracers or inhibitors might therefore be valid future approaches to identify and treat the high-risk atherosclerotic plaque. PMID: 29562241 [PubMed - as supplied by publisher]

The Role of microRNAs in Alzheimer's Disease and Their Therapeutic Potentials. Genes (Basel). 2018 Mar 21;9(4): Authors: Miya Shaik M, Tamargo IA, Abubakar MB, Kamal MA, Greig NH, Gan SH Abstract MicroRNAs (miRNAs) are short, endogenous, non-coding RNAs that post-transcriptionally regulate gene expression by base pairing with mRNA targets. Altered miRNA expression profiles have been observed in several diseases, including neurodegeneration. Multiple studies have reported altered expressions of miRNAs in the brains of individuals with Alzheimer's disease (AD) as compared to those of healthy elderly adults. Some of the miRNAs found to be dysregulated in AD have been reported to correlate with neuropathological changes, including plaque and tangle accumulation, as well as altered expressions of species that are known to be involved in AD pathology. To examine the potentially pathogenic functions of several dysregulated miRNAs in AD, we review the current literature with a focus on the activities of ten miRNAs in biological pathways involved in AD pathogenesis. Comprehensive understandings of the expression profiles and activities of these miRNAs will illuminate their roles as potential therapeutic targets in AD brain and may lead to the discovery of breakthrough treatment strategies for AD. PMID: 29561798 [PubMed]

Targeting human urinary metabolome by LC-MS/MS: a review. Bioanalysis. 2018 Mar 21;: Authors: Rodríguez-Morató J, Pozo ÓJ, Marcos J Abstract Urine is a biological matrix that contains hundreds of metabolic end products which constitute the urinary metabolome. The development and advances on LC-MS/MS have revolutionized the analytical study of biomolecules by enabling their accurate identification and quantification in an unprecedented manner. Nowadays, LC-MS/MS is helping to unveil the complexity of urine metabolome, and the results obtained have multiple biomedical applications. This review focuses on the targeted LC-MS/MS analysis of the urine metabolome. In the first part, we describe general considerations (from sample collection to quantitation) required for a proper targeted metabolic analysis. In the second part, we address the urinary analysis and recent applications of four relevant families: amino acids, catecholamines, lipids and steroids. PMID: 29561651 [PubMed - as supplied by publisher]

Microbiome-metabolome signatures in mice genetically prone to develop dementia, fed a normal or fatty diet. Sci Rep. 2018 Mar 20;8(1):4907 Authors: Sanguinetti E, Collado MC, Marrachelli VG, Monleon D, Selma-Royo M, Pardo-Tendero MM, Burchielli S, Iozzo P Abstract Cognitive decline, obesity and gut dysfunction or microbial dysbiosis occur in association. Our aim was to identify gut microbiota-metabolomics signatures preceding dementia in genetically prone (3xtg) mice, with and without superimposed high-fat diet. We examined the composition and diversity of their gut microbiota, and serum and faecal metabolites. 3xtg mice showed brain hypometabolism typical of pre-demented stage, and lacked the physiological bacterial diversity between caecum and colon seen in controls. Cluster analyses revealed distinct profiles of microbiota, and serum and fecal metabolome across groups. Elevation in Firmicutes-to-Bacteroidetes abundance, and exclusive presence of Turicibacteraceae, Christensenellaceae, Anaeroplasmataceae and Ruminococcaceae, and lack of Bifidobacteriaceae, were also observed. Metabolome analysis revealed a deficiency in unsaturated fatty acids and choline, and an overabundance in ketone bodies, lactate, amino acids, TMA and TMAO in 3xtg mice, with additive effects of high-fat diet. These metabolic alterations were correlated with high prevalence of Enterococcaceae, Staphylococcus, Roseburia, Coprobacillus and Dorea, and low prevalence of S24.7, rc4.4 and Bifidobacterium, which in turn related to cognitive impairment and cerebral hypometabolism. Our results indicate an effect of transgenic background on gut microbiome-metabolome, enhanced by high-fat diet. The resulting profiles may precede overt cognitive impairment, suggesting their predictive or risk-stratifying potential. PMID: 29559675 [PubMed - in process]

Vitamin D is crucial for maternal care and offspring social behaviour in rats. J Endocrinol. 2018 May;237(2):73-85 Authors: Yates NJ, Tesic D, Feindel KW, Smith JT, Clarke MW, Wale C, Crew RC, Wharfe MD, Whitehouse AJO, Wyrwoll CS Abstract Early life vitamin D plays a prominent role in neurodevelopment and subsequent brain function, including schizophrenic-like outcomes and increasing evidence for an association with autism spectrum disorder (ASD). Here, we investigate how early life vitamin D deficiency during rat pregnancy and lactation alters maternal care and influences neurodevelopment and affective, cognitive and social behaviours in male adult offspring. Sprague-Dawley rats were placed on either a vitamin D control (2195 IU/kg) or deficient diet (0 IU/kg) for five weeks before timed mating, and diet exposure was maintained until weaning of offspring on postnatal day (PND) 23. MRI scans were conducted to assess brain morphology, and plasma corticosterone levels and neural expression of genes associated with language, dopamine and glucocorticoid exposure were characterised at PND1, PND12 and 4 months of age. Compared to controls, vitamin D-deficient dams exhibited decreased licking and grooming of their pups but no differences in pup retrieval. Offspring neurodevelopmental markers were unaltered, but vitamin D-deficient pup ultrasonic vocalisations were atypical. As adults, males that had been exposed to vitamin D deficiency in early life exhibited decreased social behaviour, impaired learning and memory outcomes and increased grooming behaviour, but unaltered affective behaviours. Accompanying these behavioural changes was an increase in lateral ventricle volume, decreased cortical FOXP2 (a protein implicated in language and communication) and altered neural expression of genes involved in dopamine and glucocorticoid-related pathways. These data highlight that early life levels of vitamin D are an important consideration for maternal behavioural adaptations as well as offspring neuropsychiatry. PMID: 29559544 [PubMed - in process]

Biosynthesis of D-series resolvins in skin provides insights into their role in tissue repair. J Invest Dermatol. 2018 Mar 17;: Authors: Hellmann J, Sansbury BE, Wong B, Li X, Singh M, Nuutila K, Chiang N, Eriksson E, Serhan CN, Spite M Abstract Cutaneous injury causes underlying tissue damage that must be quickly repaired to minimize exposure to pathogens and to restore barrier function. While the role of growth factors in tissue repair is established, the role of lipid mediators in skin repair has not been extensively investigated. Using a mass spectrometry-based lipid mediator metabolomics approach, we identified D-series resolvins and related pro-resolving lipid mediators during skin injury in mice and pigs. Differentiation of human epidermal keratinocytes increased expression of 15-lipoxygenase and stereospecific production of 17S-hydroxydocosahexaenoic acid, the common upstream biosynthetic marker and precursor of D-series resolvins. In human and pig skin, specific receptors for D-series resolvins were expressed in the epidermal layer and mice deficient in RvD1 receptor Alx/Fpr2 showed an endogenous defect in re-epithelialization. Topical application of D-series resolvins expedited re-epithelialization during skin injury and they enhanced migration of human epidermal keratinocytes in a receptor-dependent manner. The enhancement of re-epithelialization by RvD2 was lost in mice genetically-deficient in its receptor and migration of keratinocytes stimulated with RvD2 was associated with activation of the PI3K-AKT-mTOR-S6 pathway, blockade of which prevented its pro-migratory actions. Collectively, these results demonstrate that resolvins have direct roles in the tissue repair program. PMID: 29559341 [PubMed - as supplied by publisher]

Amino acid levels in nascent metabolic syndrome: A contributor to the pro-inflammatory burden. J Diabetes Complications. 2018 Mar 09;: Authors: Reddy P, Leong J, Jialal I Abstract AIMS: Metabolic Syndrome (MetS) is a cluster of cardio-metabolic risk factors characterized by low-grade inflammation which confers an increased risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Prior studies have linked elevated branched chain amino acids (BCAA) and aromatic amino acids (AAA) with T2DM and CVD. Due to the paucity of data in MetS, the aim of this study was to investigate the status of amino acids as early biomarkers of nascent MetS patients without T2DM and CVD or smoking. RESEARCH DESIGN AND METHODS: Healthy controls (n = 20) and MetS (n = 29) patients were recruited for the study. MetS was defined by criteria of National Cholesterol Education Program Adult Treatment Panel III of having at least 3 risk factors. Urinary amino acids were quantified by gas chromatography time-of-flight mass spectrometry at the Western NIH Metabolomics Center as expressed to urinary creatinine. RESULTS: Tyrosine and Isoleucine levels were significantly elevated in MetS patients. Isoleucine positively correlated with salient cardio-metabolic features and inflammatory biomarkers. Lysine and Methionine levels were decreased in MetS patients. Lysine correlated negatively with cardio-metabolic features and inflammatory bimarkers. Methionine also correlated negatively with blood pressure and certain inflammatory biomarkers. CONCLUSION: Our novel results suggest that with regards to the cardio-metabolic risk factors and pro-inflammatory features of MetS, isoleucine (BCAA) demonstrated a positive correlation while lysine demonstrated a negative correlation. Thus, increased levels of isoleucine and decreased levels of lysine could be potential early biomarkers of MetS. PMID: 29559272 [PubMed - as supplied by publisher]

Related Articles Experimental and Human Evidence for Lipocalin-2 (Neutrophil Gelatinase-Associated Lipocalin [NGAL]) in the Development of Cardiac Hypertrophy and heart failure. J Am Heart Assoc. 2017 Jun 14;6(6): Authors: Marques FZ, Prestes PR, Byars SG, Ritchie SC, Würtz P, Patel SK, Booth SA, Rana I, Minoda Y, Berzins SP, Curl CL, Bell JR, Wai B, Srivastava PM, Kangas AJ, Soininen P, Ruohonen S, Kähönen M, Lehtimäki T, Raitoharju E, Havulinna A, Perola M, Raitakari O, Salomaa V, Ala-Korpela M, Kettunen J, McGlynn M, Kelly J, Wlodek ME, Lewandowski PA, Delbridge LM, Burrell LM, Inouye M, Harrap SB, Charchar FJ Abstract BACKGROUND: Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin-2 (LCN2/NGAL), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants. METHODS AND RESULTS: We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and Lcn2-knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating Lcn2 was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. Lcn2 expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas Lcn2-knockout mice had smaller hearts. In cultured cardiomyocytes, Lcn2 activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS, LCN2 expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single-nucleotide polymorphism, rs13297295, located near LCN2 defined a significant cis-eQTL for LCN2 expression. CONCLUSIONS: Direct effects of LCN2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN2 in the ontogeny of cardiac hypertrophy and heart failure. PMID: 28615213 [PubMed - indexed for MEDLINE]

What's in Metabolomics for Alcoholic Liver Disease? J Gastrointestin Liver Dis. 2018 Mar;27(1):51-58 Authors: Suciu AM, Crisan DA, Procopet BD, Radu CI, Socaciu C, Tantau MV, Stefanescu HO, Grigorescu M Abstract BACKGROUND AND AIMS: Current management of alcoholic liver disease (ALD), especially for alcoholic hepatitis (AH) is still driven by liver biopsy. Therefore, the identification of novel and accurate noninvasive biomarkers for the diagnosis and assessment of severity is important. Metabolomics, because it unravels changes closest to the phenotype, may represent the key for novel biomarkers. The aim of this study was to identify and characterize potential metabolomic biomarkers for diagnosis, staging and severity assessment of ALD. METHODS: 30 consecutive ALD patients and 10 healthy controls were included in this proof-of-concept cross-sectional study. Baseline assessment consisted in evaluation of Maddrey's Discriminant Function, Model for End-Stage Liver Disease (MELD) and ABIC scores as well as ASH-Test (Fibromax) as a surrogate for the confirmatory diagnosis of AH in suggestive clinical and biologic settings. Additionally, SOP metabolomics and lipidomics were performed from serum samples by liquid chromatography mass-spectrometry analysis. RESULTS: From the 127 and 135 serum/urine candidate metabolites initially identified, only 11/5 metabolites were characteristic for ALD patients. None of them correlated with alcohol intake, and only 5/1 metabolites could differentiate cirrhotic from non-cirrhotic patients. Of those, N-Lauroglycine (NLG) was the best for identifying cirrhosis (100% sensitivity and 90% negative predictive value, NPV) and decatrienoic acid (DTEA) was the best for assessing disease severity (evaluated by ABIC score) with 100% sensitivity and 100% NPV. CONCLUSION: Due to their high NPV, NLG and DTEA could be used in conjunction in ALD patients to exclude cirrhosis or a severe disease. If further validated, they could become biomarkers for better management and risk assessment in ALD. PMID: 29557415 [PubMed - in process]

Serum metabolomic profile of incident diabetes. Diabetologia. 2018 Mar 20;: Authors: Rebholz CM, Yu B, Zheng Z, Chang P, Tin A, Köttgen A, Wagenknecht LE, Coresh J, Boerwinkle E, Selvin E Abstract AIMS/HYPOTHESIS: Metabolomic profiling offers the potential to reveal metabolic pathways relevant to the pathophysiology of diabetes and improve diabetes risk prediction. METHODS: We prospectively analysed known metabolites using an untargeted approach in serum specimens from baseline (1987-1989) and incident diabetes through to 31 December 2015 in a subset of 2939 Atherosclerosis Risk in Communities (ARIC) study participants with metabolomics data and without prevalent diabetes. RESULTS: Among the 245 named compounds identified, seven metabolites were significantly associated with incident diabetes after Bonferroni correction and covariate adjustment; these included a food additive (erythritol) and compounds involved in amino acid metabolism [isoleucine, leucine, valine, asparagine, 3-(4-hydoxyphenyl)lactate] and glucose metabolism (trehalose). Higher levels of metabolites were associated with increased risk of incident diabetes (HR per 1 SD increase in isoleucine 2.96, 95% CI 2.02, 4.35, p = 3.18 × 10-8; HR per 1 SD increase in trehalose 1.16, 95% CI 1.09, 1.25, p = 1.87 × 10-5), with the exception of asparagine, which was associated with a lower risk of diabetes (HR per 1 SD increase in asparagine 0.78, 95% CI 0.71, 0.85, p = 4.19 × 10-8). The seven metabolites modestly improved prediction of incident diabetes beyond fasting glucose and established risk factors (C statistics 0.744 vs 0.735, p = 0.001 for the difference in C statistics). CONCLUSIONS/INTERPRETATION: Branched chain amino acids may play a role in diabetes development. Our study is the first to report asparagine as a protective biomarker of diabetes risk. The serum metabolome reflects known and novel metabolic disturbances that improve prediction of diabetes. PMID: 29556673 [PubMed - as supplied by publisher]

Metabolomics and Agriculture: What Can Be Done? mSystems. 2018 Mar-Apr;3(2): Authors: do Prado RM, Porto C, Nunes E, de Aguiar CL, Pilau EJ Abstract The importance of Brazil as a producer and exporter of food and feed will continuously increase. Despite the recent economic and political problems in Brazil, the scientific field is expanding. Cutting-edge technology has only recently become available in the country, and we can now also join efforts with the global community to tackle global challenges. Using metabolomics based on mass spectrometry approaches to understand system-wide metabolism and metabolic pathways can have a significant impact in the society. With the recent development of a platform for organization and sharing of tandem mass spectrometry data, the global community can now work with complex biological samples. In this Perspective, we aim to describe how challenges and problems in global and local agriculture can be addressed using metabolomics based on mass spectrometry strategies. PMID: 29556551 [PubMed]

Ecosystem Microbiology of Coral Reefs: Linking Genomic, Metabolomic, and Biogeochemical Dynamics from Animal Symbioses to Reefscape Processes. mSystems. 2018 Mar-Apr;3(2): Authors: Wegley Kelly L, Haas AF, Nelson CE Abstract Over the past 2 decades, molecular techniques have established the critical role of both free-living and host-associated microbial partnerships in the environment. Advancing research to link microbial community dynamics simultaneously to host physiology and ecosystem biogeochemistry is required to broaden our understanding of the ecological roles of environmental microbes. Studies on coral reefs are actively integrating these data streams at multiple levels, from the symbiotic habitat of the coral holobiont to microbially mediated interactions between corals and algae to the effects of these interactions on the microbial community structure, metabolism, and organic geochemistry of the reef ecosystem. Coral reefs endure multiple anthropogenic impacts, including pollution, overfishing, and global change. In this context, we must develop ecosystem microbiology with an eye to providing managers with microbial indicators of reef ecosystem processes, coral health, and resilience to both local and global stressors. PMID: 29556542 [PubMed]

A case study of primary malignancy of buccal mucosa using proton HR-MAS NMR spectroscopy on tissue specimens. J Oral Biol Craniofac Res. 2018 Jan-Apr;8(1):68-72 Authors: Khanna R, Kumar K, Roy R Abstract The diagnosis and confirmation of oral SCC (squamous cell carcinoma) is still dependent on histopathology report in spite of development of radiological investigations. It is, thus important to understand the underlying molecular mechanisms and how the alterations in metabolic pathways effect the tumor development and progression. The simultaneous and comprehensive information about the presence and absence of small molecule metabolites and their relative concentrations has been provided by 1H HR-MAS NMR spectroscopy on tissue specimens. In this paper a unique case study was presented in order to correlate histological and NMR spectroscopic findings. The patient's initially lesion was found to be non-malignant in nature based on histological findings but its periodic localized recurrence even after laser ablation prompted us to perform HR-MAS based analysis and its role in identifying the metabolic alterations in known pathways occurring during its progressions. Thus it was confirmed after analysis that HR-MAS NMR can also be used as an analytical tool which is reliable in order to distinguish between malignant and non-malignant tissues, in combination with histopathology. PMID: 29556467 [PubMed]

Urinary Metabolites Associated with Blood Pressure on a Low- or High-Sodium Diet. Theranostics. 2018;8(6):1468-1480 Authors: Cheng Y, Song H, Pan X, Xue H, Wan Y, Wang T, Tian Z, Hou E, Lanza IR, Liu P, Liu Y, Laud PW, Usa K, He Y, Liang M Abstract Dietary salt intake has significant effects on arterial blood pressure and the development of hypertension. Mechanisms underlying salt-dependent changes in blood pressure remain poorly understood, and it is difficult to assess blood pressure salt-sensitivity clinically. Methods: We examined urinary levels of metabolites in 103 participants of the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial after nearly 30 days on a defined diet containing high sodium (targeting 150 mmol sodium intake per day) or low sodium (50 mmol per day). Targeted chromatography/mass spectrometry analysis was performed in 24 h urine samples for 47 amino metabolites and 10 metabolites related to the tricarboxylic acid cycle. The effect of an identified metabolite on blood pressure was examined in Dahl salt-sensitive rats. Results: Urinary metabolite levels improved the prediction of classification of blood pressure salt-sensitivity based on race, age and sex. Random forest and generalized linear mixed model analyses identified significant (false discovery rate <0.05) associations of 24 h excretions of β-aminoisobutyric acid, cystine, citrulline, homocysteine and lysine with systolic blood pressure and cystine with diastolic blood pressure. The differences in homocysteine levels between low- and high-sodium intakes were significantly associated with the differences in diastolic blood pressure. These associations were significant with or without considering demographic factors. Treatment with β-aminoisobutyric acid significantly attenuated high-salt-induced hypertension in Dahl salt-sensitive rats. Conclusion: These findings support the presence of new mechanisms of blood pressure regulation involving metabolic intermediaries, which could be developed as markers or therapeutic targets for salt-sensitive hypertension. PMID: 29556335 [PubMed - in process]

Circadian Rhythms and Redox State in Plants: Till Stress Do Us Part. Front Plant Sci. 2018;9:247 Authors: Guadagno CR, Ewers BE, Weinig C Abstract A growing body of evidence demonstrates a significant relationship between cellular redox state and circadian rhythms. Each day these two vital components of plant biology influence one another, dictating the pace for metabolism and physiology. Diverse environmental stressors can disrupt this condition and, although plant scientists have made significant progress in re-constructing functional networks of plant stress responses, stress impacts on the clock-redox crosstalk is poorly understood. Inter-connected phenomena such as redox state and metabolism, internal and external environments, cellular homeostasis and rhythms can impede predictive understanding of coordinated regulation of plant stress response. The integration of circadian clock effects into predictive network models is likely to increase final yield and better predict plant responses to stress. To achieve such integrated understanding, it is necessary to consider the internal clock not only as a gatekeeper of environmental responses but also as a target of stress syndromes. Using chlorophyll fluorescence as a reliable and high-throughput probe of stress coupled to functional genomics and metabolomics will provide insights on the crosstalk across a wide range of stress severity and duration, including potential insights into oxidative stress response and signaling. We suggest the efficiency of photosystem II in light conditions (Fv'/Fm') to be the most dynamic of the fluorescence variables and therefore the most reliable parameter to follow the stress response from early sensing to mortality. PMID: 29556244 [PubMed]

Promising Metabolite Profiles in the Plasma and CSF of Early Clinical Parkinson's Disease. Front Aging Neurosci. 2018;10:51 Authors: Stoessel D, Schulte C, Teixeira Dos Santos MC, Scheller D, Rebollo-Mesa I, Deuschle C, Walther D, Schauer N, Berg D, Nogueira da Costa A, Maetzler W Abstract Parkinson's disease (PD) shows high heterogeneity with regard to the underlying molecular pathogenesis involving multiple pathways and mechanisms. Diagnosis is still challenging and rests entirely on clinical features. Thus, there is an urgent need for robust diagnostic biofluid markers. Untargeted metabolomics allows establishing low-molecular compound biomarkers in a wide range of complex diseases by the measurement of various molecular classes in biofluids such as blood plasma, serum, and cerebrospinal fluid (CSF). Here, we applied untargeted high-resolution mass spectrometry to determine plasma and CSF metabolite profiles. We semiquantitatively determined small-molecule levels (≤1.5 kDa) in the plasma and CSF from early PD patients (disease duration 0-4 years; n = 80 and 40, respectively), and sex- and age-matched controls (n = 76 and 38, respectively). We performed statistical analyses utilizing partial least square and random forest analysis with a 70/30 training and testing split approach, leading to the identification of 20 promising plasma and 14 CSF metabolites. These metabolites differentiated the test set with an AUC of 0.8 (plasma) and 0.9 (CSF). Characteristics of the metabolites indicate perturbations in the glycerophospholipid, sphingolipid, and amino acid metabolism in PD, which underscores the high power of metabolomic approaches. Further studies will enable to develop a potential metabolite-based biomarker panel specific for PD. PMID: 29556190 [PubMed]

A novel ASXL1-OGT axis plays roles in H3K4 methylation and tumor suppression in myeloid malignancies. Leukemia. 2018 Mar 03;: Authors: Inoue D, Fujino T, Sheridan P, Zhang YZ, Nagase R, Horikawa S, Li Z, Matsui H, Kanai A, Saika M, Yamaguchi R, Kozuka-Hata H, Kawabata KC, Yokoyama A, Goyama S, Inaba T, Imoto S, Miyano S, Xu M, Yang FC, Oyama M, Kitamura T Abstract ASXL1 plays key roles in epigenetic regulation of gene expression through methylation of histone H3K27, and disruption of ASXL1 drives myeloid malignancies, at least in part, via derepression of posterior HOXA loci. However, little is known about the identity of proteins that interact with ASXL1 and about the functions of ASXL1 in modulation of the active histone mark, such as H3K4 methylation. In this study, we demonstrate that ASXL1 is a part of a protein complex containing HCFC1 and OGT; OGT directly stabilizes ASXL1 by O-GlcNAcylation. Disruption of this novel axis inhibited myeloid differentiation and H3K4 methylation as well as H2B glycosylation and impaired transcription of genes involved in myeloid differentiation, splicing, and ribosomal functions; this has implications for myelodysplastic syndrome (MDS) pathogenesis, as each of these processes are perturbed in the disease. This axis is responsible for tumor suppression in the myeloid compartment, as reactivation of OGT induced myeloid differentiation and reduced leukemogenecity both in vivo and in vitro. Our data also suggest that MLL5, a known HCFC1/OGT-interacting protein, is responsible for gene activation by the ASXL1-OGT axis. These data shed light on the novel roles of the ASXL1-OGT axis in H3K4 methylation and activation of transcription. PMID: 29556021 [PubMed - as supplied by publisher]

Dynamic metabolic patterns tracking neurodegeneration and gliosis following 26S proteasome dysfunction in mouse forebrain neurons. Sci Rep. 2018 Mar 19;8(1):4833 Authors: Geiszler PC, Ugun-Klusek A, Lawler K, Pardon MC, Yuchun D, Bai L, Daykin CA, Auer DP, Bedford L Abstract Metabolite profiling is an important tool that may better capture the multiple features of neurodegeneration. With the considerable parallels between mouse and human metabolism, the use of metabolomics in mouse models with neurodegenerative pathology provides mechanistic insight and ready translation into aspects of human disease. Using 400 MHz nuclear magnetic resonance spectroscopy we have carried out a temporal region-specific investigation of the metabolome of neuron-specific 26S proteasome knockout mice characterised by progressive neurodegeneration and Lewy-like inclusion formation in the forebrain. An early significant decrease in N-acetyl aspartate revealed evidence of neuronal dysfunction before cell death that may be associated with changes in brain neuroenergetics, underpinning the use of this metabolite to track neuronal health. Importantly, we show early and extensive activation of astrocytes and microglia in response to targeted neuronal dysfunction in this context, but only late changes in myo-inositol; the best established glial cell marker in magnetic resonance spectroscopy studies, supporting recent evidence that additional early neuroinflammatory markers are needed. Our results extend the limited understanding of metabolite changes associated with gliosis and provide evidence that changes in glutamate homeostasis and lactate may correlate with astrocyte activation and have biomarker potential for tracking neuroinflammation. PMID: 29555943 [PubMed - in process]