PubMed

Related Articles Altered somatosensory cortex neuronal activity in a rat model of Parkinson's disease and levodopa-induced dyskinesias. Exp Neurol. 2017 Apr 23;: Authors: Alam M, Rumpel R, Jin X, von Wrangel C, Tschirner S, Krauss JK, Grothe C, Ratzka A, Schwabe K Abstract Several findings support the concept that sensorimotor integration is disturbed in Parkinson's disease (PD) and in levodopa-induced dyskinesias. In this study, we explored the neuronal firing activity of excitatory pyramidal cells and inhibitory interneurons in the forelimb region of the primary somatosensory cortex (S1FL-Ctx), along with its interaction with oscillatory activity of the primary motor cortex (MCtx) in 6-hydroxydopamine lesioned hemiparkinsonian (HP) and levodopa-primed dyskinetic (HP-LID) rats as compared to controls under urethane (1.4g/kg, i.p.) anesthesia. Further, gene expression patterns of distinct markers for inhibitory GABAergic neurons were analyzed in both cortical regions. While firing frequency and burst activity of S1FL-Ctx inhibitory interneurons were reduced in HP and HP-LID rats, measures of irregularity were enhanced in pyramidal cells. Further, enhanced coherence of distinct frequency bands of the theta/alpha, high-beta, and gamma frequency, together with enhanced synchronization of putative pyramidal cells and interneurons with MCtx oscillatory activity were observed. While GABA level was similar, gene expression levels of interneuron and GABAergic markers in S1FL-Ctx and MCtx of HP-LID rats differed to some extent. Our study shows that in a rat model of PD with dyskinesias, neuronal activity in putative interneurons was reduced, which was accompanied by high beta and gamma coherence between S1FL-Ctx and MCtx, together with changes in gene expression, indicating maladaptive neuroplasticity after long term levodopa treatment. PMID: 28445715 [PubMed - as supplied by publisher]

Related Articles Modular Design of Picroside-II Biosynthesis Deciphered through NGS Transcriptomes and Metabolic Intermediates Analysis in Naturally Variant Chemotypes of a Medicinal Herb, Picrorhiza kurroa. Front Plant Sci. 2017;8:564 Authors: Kumar V, Bansal A, Chauhan RS Abstract Picroside-II (P-II), an iridoid glycoside, is used as an active ingredient of various commercial herbal formulations available for the treatment of liver ailments. Despite this, the knowledge of P-II biosynthesis remains scarce owing to its negligence in Picrorhiza kurroa shoots which sets constant barrier for function validation experiments. In this study, we utilized natural variation for P-II content in stolon tissues of different P. kurroa accessions and deciphered its metabolic route by integrating metabolomics of intermediates with differential NGS transcriptomes. Upon navigating through high vs. low P-II content accessions (1.3-2.6%), we have established that P-II is biosynthesized via degradation of ferulic acid (FA) to produce vanillic acid (VA) which acts as its immediate biosynthetic precursor. Moreover, the FA treatment in vitro at 150 μM concentration provided further confirmation with 2-fold rise in VA content. Interestingly, the cross-talk between different compartments of P. kurroa, i.e., shoots and stolons, resolved spatial complexity of P-II biosynthesis and consequently speculated the burgeoning necessity to bridge gap between VA and P-II production in P. kurroa shoots. This work thus, offers a forward looking strategy to produce both P-I and P-II in shoot cultures, a step toward providing a sustainable production platform for these medicinal compounds via-à-vis relieving pressure from natural habitat of P. kurroa. PMID: 28443130 [PubMed - in process]

Related Articles The biomarker and causal roles of homoarginine in the development of cardiometabolic diseases: an observational and Mendelian randomization analysis. Sci Rep. 2017 Apr 25;7(1):1130 Authors: Seppälä I, Oksala N, Jula A, Kangas AJ, Soininen P, Hutri-Kähönen N, März W, Meinitzer A, Juonala M, Kähönen M, Raitakari OT, Lehtimäki T Abstract High L-homoarginine (hArg) levels are directly associated with several risk factors for cardiometabolic diseases whereas low levels predict increased mortality in prospective studies. The biomarker role of hArg in young adults remains unknown. To study the predictive value of hArg in the development of cardiometabolic risk factors and diseases, we utilized data on high-pressure liquid chromatography-measured hArg, cardiovascular risk factors, ultrasound markers of preclinical atherosclerosis and type 2 diabetes from the population-based Young Finns Study involving 2,106 young adults (54.6% females, aged 24-39). We used a Mendelian randomization approach involving tens to hundreds of thousands of individuals to test causal associations. In our 10-year follow-up analysis, hArg served as an independent predictor for future hyperglycaemia (OR 1.31, 95% CI 1.06-1.63) and abdominal obesity (OR 1.60, 95% 1.14-2.30) in men and type 2 diabetes in women (OR 1.55, 95% CI 1.02-2.41). The MR analysis revealed no evidence of causal associations between serum hArg and any of the studied cardiometabolic outcomes. In conclusion, lifetime exposure to higher levels of circulating hArg does not seem to alter cardiometabolic disease risk. Whether hArg could be used as a biomarker for identification of individuals at risk developing cardiometabolic abnormalities merits further investigation. PMID: 28442717 [PubMed - in process]

Related Articles N-Methyl-d-Aspartate (NMDA) Receptor Blockade Prevents Neuronal Death Induced by Zika Virus Infection. MBio. 2017 Apr 25;8(2): Authors: Costa VV, Del Sarto JL, Rocha RF, Silva FR, Doria JG, Olmo IG, Marques RE, Queiroz-Junior CM, Foureaux G, Araújo JMS, Cramer A, Real ALCV, Ribeiro LS, Sardi SI, Ferreira AJ, Machado FS, de Oliveira AC, Teixeira AL, Nakaya HI, Souza DG, Ribeiro FM, Teixeira MM Abstract Zika virus (ZIKV) infection is a global health emergency that causes significant neurodegeneration. Neurodegenerative processes may be exacerbated by N-methyl-d-aspartate receptor (NMDAR)-dependent neuronal excitoxicity. Here, we have exploited the hypothesis that ZIKV-induced neurodegeneration can be rescued by blocking NMDA overstimulation with memantine. Our results show that ZIKV actively replicates in primary neurons and that virus replication is directly associated with massive neuronal cell death. Interestingly, treatment with memantine or other NMDAR blockers, including dizocilpine (MK-801), agmatine sulfate, or ifenprodil, prevents neuronal death without interfering with the ability of ZIKV to replicate in these cells. Moreover, in vivo experiments demonstrate that therapeutic memantine treatment prevents the increase of intraocular pressure (IOP) induced by infection and massively reduces neurodegeneration and microgliosis in the brain of infected mice. Our results indicate that the blockade of NMDARs by memantine provides potent neuroprotective effects against ZIKV-induced neuronal damage, suggesting it could be a viable treatment for patients at risk for ZIKV infection-induced neurodegeneration.IMPORTANCE Zika virus (ZIKV) infection is a global health emergency associated with serious neurological complications, including microcephaly and Guillain-Barré syndrome. Infection of experimental animals with ZIKV causes significant neuronal damage and microgliosis. Treatment with drugs that block NMDARs prevented neuronal damage both in vitro and in vivo These results suggest that overactivation of NMDARs contributes significantly to the neuronal damage induced by ZIKV infection, and this is amenable to inhibition by drug treatment. PMID: 28442607 [PubMed - in process]

Related Articles Impact of 27-hydroxylase (CYP27A1) and 27-hydroxycholesterol in breast cancer. Endocr Relat Cancer. 2017 Apr 25;: Authors: Kimbung S, Chang C, Bendahl PO, Dubois L, Thompson WJ, McDonnell DP, Borgquist S Abstract The impact of systemic 27-hydroxycholesterol (27HC) and intra-tumoral CYP27A1 expression on pathobiology and clinical response to statins in breast cancer needs clarification. 27HC is an oxysterol produced from cholesterol by the monooxygenase CYP27A1, which regulates intracellular cholesterol homeostasis. 27HC also acts as an endogenous selective estrogen receptor (ER) modulator capable of increasing breast cancer growth and metastasis. 27HC levels can be modulated by statins or direct inhibition of CYP27A1, thereby attenuating its pro-tumorigenic activities. Herein, the effect of statins on serum 27HC and tumor-specific CYP27A1 expression was evaluated in 42 breast cancer patients treated with atorvastatin within a phase II clinical trial. Further, the associations between CYP27A1 expression with other primary tumor pathological features and clinical outcomes were studied in two additional independent cohorts. Statin treatment effectively decreased serum 27HC and deregulated CYP27A1 expression in tumors. However, these changes were not associated with anti-proliferative responses to statin treatment. CYP27A1 was heterogeneously expressed among primary tumors, with high expression significantly associated with high tumor grade, ER negativity and basal-like subtype. High CYP27A1 expression was independently prognostic for longer recurrence-free and overall survival. Importantly, the beneficial effect of high CYP27A1 in ER positive breast cancer seemed limited to women ≤50 years. These results establish a link between CYP27A1 and breast cancer pathobiology and prognosis and propose that the efficacy of statins in reducing serum lipids does not directly translate to anti-proliferative effects in tumors. Changes in other undetermined serum or tumor factors suggestively mediate the anti-proliferative effects of statins in breast cancer. PMID: 28442559 [PubMed - as supplied by publisher]

Related Articles Breach of autoreactive B cell tolerance by post-translationally modified proteins. Ann Rheum Dis. 2017 Apr 25;: Authors: Dekkers JS, Verheul MK, Stoop JN, Liu B, Ioan-Facsinay A, van Veelen PA, de Ru AH, Janssen GMC, Hegen M, Rapecki S, Huizinga TWJ, Trouw LA, Toes REM Abstract OBJECTIVES: Over 50% of patients with rheumatoid arthritis (RA) harbour a variety of anti-modified protein antibodies (AMPA) against different post-translationally modified (PTM) proteins, including anti-carbamylated protein (anti-CarP) antibodies. At present, it is unknown how AMPA are generated and how autoreactive B cell responses against PTM proteins are induced. Here we studied whether PTM foreign antigens can breach B cell tolerance towards PTM self-proteins. METHODS: Serum reactivity towards five carbamylated proteins was determined for 160 patients with RA and 40 healthy individuals. Antibody cross-reactivity was studied by inhibition experiments. Mass spectrometry was performed to identify carbamylated self-proteins in human rheumatic joint tissue. Mice were immunised with carbamylated or non-modified (auto)antigens and analysed for autoantibody responses. RESULTS: We show that anti-CarP antibodies in RA are highly cross-reactive towards multiple carbamylated proteins, including modified self-proteins and modified non-self-proteins. Studies in mice show that anti-CarP antibody responses recognising carbamylated self-proteins are induced by immunisation with carbamylated self-proteins and by immunisation with carbamylated proteins of non-self-origin. Similar to the data observed with sera from patients with RA, the murine anti-CarP antibody response was, both at the monoclonal level and the polyclonal level, highly cross-reactive towards multiple carbamylated proteins, including carbamylated self-proteins. CONCLUSIONS: Self-reactive AMPA responses can be induced by exposure to foreign proteins containing PTM. These data show how autoreactive B cell responses against PTM self-proteins can be induced by exposure to PTM foreign proteins and provide new insights on the breach of autoreactive B cell tolerance. PMID: 28442530 [PubMed - as supplied by publisher]

Related Articles Arginine deiminase pathway provides ATP and boosts growth of the gas-fermenting acetogen Clostridium autoethanogenum. Metab Eng. 2017 Apr 22;: Authors: Valgepea K, Loi KQ, Behrendorff JB, Lemgruber RSP, Plan M, Hodson MP, Köpke M, Nielsen LK, Marcellin E Abstract Acetogens are attractive organisms for the production of chemicals and fuels from inexpensive and non-food feedstocks such as syngas (CO, CO2 and H2). Expanding their product spectrum beyond native compounds is dictated by energetics, particularly ATP availability. Acetogens have evolved sophisticated strategies to conserve energy from reduction potential differences between major redox couples, however, this coupling is sensitive to small changes in thermodynamic equilibria. To accelerate the development of strains for energy-intensive products from gases, we used a genome-scale metabolic model (GEM) to explore alternative ATP-generating pathways in the gas-fermenting acetogen Clostridium autoethanogenum. Shadow price analysis revealed a preference of C. autoethanogenum for nine amino acids. This prediction was experimentally confirmed under heterotrophic conditions. Subsequent in silico simulations identified arginine (ARG) as a key enhancer for growth. Predictions were experimentally validated, and faster growth was measured in media containing ARG (tD~4h) compared to growth on yeast extract (tD~9h). The growth-boosting effect of ARG was confirmed during autotrophic growth. Metabolic modelling and experiments showed that acetate production is nearly abolished and fast growth is realised by a three-fold increase in ATP production through the arginine deiminase (ADI) pathway. The involvement of the ADI pathway was confirmed by metabolomics and RNA-sequencing which revealed a ~500-fold up-regulation of the ADI pathway with an unexpected down-regulation of the Wood-Ljungdahl pathway. The data presented here offer a potential route for supplying cells with ATP, while demonstrating the usefulness of metabolic modelling for the discovery of native pathways for stimulating growth or enhancing energy availability. PMID: 28442386 [PubMed - as supplied by publisher]

Related Articles Altered glucose metabolism and hypoxic response in alloxan-induced diabetic atherosclerosis in rabbits. PLoS One. 2017;12(4):e0175976 Authors: Matsuura Y, Yamashita A, Zhao Y, Iwakiri T, Yamasaki K, Sugita C, Koshimoto C, Kitamura K, Kawai K, Tamaki N, Zhao S, Kuge Y, Asada Y Abstract Diabetes mellitus accelerates atherosclerosis that causes most cardiovascular events. Several metabolic pathways are considered to contribute to the development of atherosclerosis, but comprehensive metabolic alterations to atherosclerotic arterial cells remain unknown. The present study investigated metabolic changes and their relationship to vascular histopathological changes in the atherosclerotic arteries of rabbits with alloxan-induced diabetes. Diabetic atherosclerosis was induced in rabbit ilio-femoral arteries by injecting alloxan (100 mg/kg), injuring the arteries using a balloon, and feeding with a 0.5% cholesterol diet. We histologically assessed the atherosclerotic lesion development, cellular content, pimonidazole positive-hypoxic area, the nuclear localization of hypoxia-inducible factor-1α, and apoptosis. We evaluated comprehensive arterial metabolism by performing metabolomic analyses using capillary electrophoresis-time of flight mass spectrometry. We evaluated glucose uptake and its relationship to vascular hypoxia using 18F-fluorodeoxyglucose and pimonidazole. Plaque burden, macrophage content, and hypoxic areas were more prevalent in arteries with diabetic, than non-diabetic atherosclerosis. Metabolomic analyses highlighted 12 metabolites that were significantly altered between diabetic and non-diabetic atherosclerosis. A half of them were associated with glycolysis metabolites, and their levels were decreased in diabetic atherosclerosis. The uptake of glucose evaluated as 18F-fluorodeoxyglucose in atherosclerotic lesions increased according to increased macrophage content or hypoxic areas in non-diabetic, but not diabetic rabbits. Despite profound hypoxic areas, the nuclear localization of hypoxia-inducible factor-1α decreased and the number of apoptotic cells increased in diabetic atherosclerotic lesions. Altered glycolysis metabolism and an impaired response to hypoxia in atherosclerotic lesions under conditions of insulin-dependent diabetes might be involved in the development of diabetic atherosclerosis. PMID: 28410399 [PubMed - indexed for MEDLINE]

Related Articles Systems Toxicology: Real World Applications and Opportunities. Chem Res Toxicol. 2017 Apr 17;30(4):870-882 Authors: Hartung T, FitzGerald RE, Jennings P, Mirams GR, Peitsch MC, Rostami-Hodjegan A, Shah I, Wilks MF, Sturla SJ Abstract Systems Toxicology aims to change the basis of how adverse biological effects of xenobiotics are characterized from empirical end points to describing modes of action as adverse outcome pathways and perturbed networks. Toward this aim, Systems Toxicology entails the integration of in vitro and in vivo toxicity data with computational modeling. This evolving approach depends critically on data reliability and relevance, which in turn depends on the quality of experimental models and bioanalysis techniques used to generate toxicological data. Systems Toxicology involves the use of large-scale data streams ("big data"), such as those derived from omics measurements that require computational means for obtaining informative results. Thus, integrative analysis of multiple molecular measurements, particularly acquired by omics strategies, is a key approach in Systems Toxicology. In recent years, there have been significant advances centered on in vitro test systems and bioanalytical strategies, yet a frontier challenge concerns linking observed network perturbations to phenotypes, which will require understanding pathways and networks that give rise to adverse responses. This summary perspective from a 2016 Systems Toxicology meeting, an international conference held in the Alps of Switzerland, describes the limitations and opportunities of selected emerging applications in this rapidly advancing field. Systems Toxicology aims to change the basis of how adverse biological effects of xenobiotics are characterized, from empirical end points to pathways of toxicity. This requires the integration of in vitro and in vivo data with computational modeling. Test systems and bioanalytical technologies have made significant advances, but ensuring data reliability and relevance is an ongoing concern. The major challenge facing the new pathway approach is determining how to link observed network perturbations to phenotypic toxicity. PMID: 28362102 [PubMed - indexed for MEDLINE]

Related Articles Urine metabolic profiling for the pathogenesis research of erosive oral lichen planus. Arch Oral Biol. 2017 Jan;73:206-213 Authors: Li XZ, Yang XY, Wang Y, Zhang SN, Zou W, Wang Y, Li XN, Wang LS, Zhang ZG, Xie LZ Abstract OBJECTIVE: Oral lichen planus (OLP) is a relatively common chronic immune-pathological and inflammatory disease and potentially oral precancerous lesion. Erosive OLP patients show the higher rate of malignant transformation than patients with non-erosive OLP. Identifying the potential biomarkers related to erosive OLP may help to understand the pathogenesis of the diseases. METHODS: Metabolic profiles were compared in control and patient subjects with erosive OLP by using ultra-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-QTOF-MS) coupled with pattern recognition methods An integrative analysis was used to identify the perturbed metabolic pathways and pathological processes that may be associated with the disease. RESULTS: In total, 12 modulated metabolites were identified and considered as the potential biomarkers of erosive OLP. Multiple metabolic pathways and pathological processes were involved in erosive OLP. CONCLUSION: The dysregulations of these metabolites could be used to explain the pathogenesis of the disease, which could also be the potential therapeutic targets for the disease. PMID: 27771589 [PubMed - indexed for MEDLINE]

Related Articles Effects of Different Salt Treatments on the Fermentation Metabolites and Bacterial Profiles of Kimchi. J Food Sci. 2017 Apr 25;: Authors: Kim DW, Kim BM, Lee HJ, Jang GJ, Song SH, Lee JI, Lee SB, Shim JM, Lee KW, Kim JH, Ham KS, Chen F, Kim HJ Abstract The effects of purified salt (PS) and mineral-rich sea salt (MRS), both with different mineral profiles, on kimchi fermentation were studied using a culture-dependent 16S rRNA sequencing technique and mass-based metabolomic analysis. The different mineral profiles in the fermentation medium caused changes in the bacterial profiles of the 2 kimchi products. An increase of Leuconostoc species in MRS-kimchi decreased the Lactobacillus/Leuconostoc ratio, which led to changes in metabolites (including sugars, amino acids, organic acids, lipids, sulfur compounds, and terpenoids) associated with kimchi quality. Although further studies on the relationship between these salt types and kimchi fermentation are needed, these results suggested that the MRS treatment had positively affected the changes of the kimchi mineral contents, bacterial growth, and metabolite profiles, which are linked to kimchi quality. PMID: 28440871 [PubMed - as supplied by publisher]

Related Articles Comparative genomics and metabolomics analyses of the adaptation mechanism in Ketogulonicigenium vulgare-Bacillus thuringiensis consortium. Sci Rep. 2017 Apr 25;7:46759 Authors: Jia N, Ding MZ, Zou Y, Gao F, Yuan YJ Abstract Adaptive evolution by serial subcultivation of co-cultured Bacillus thuringiensis and Ketogulonicigenium vulgare significantly enhanced the productivity of 2-keto-L-gulonic acid in two-step vitamin C production. The adaptation mechanism in K. vulgare-B. thuringiensis consortium was investigated in this study based on comparative genomics and metabolomics studies. It was found that the growth, anti-oxidation, transcription and regulation were significantly enhanced in the adapted consortium. The mutation of the genes, which encode amidohydrolase in adapted K. vulgare (K150) and amino acid permease in adapted B. thuringiensis (B150), resulted in the increase of some amino acids levels in each species, and further enhanced the metabolic exchange and growth ability of the two species. Besides, the mutation of the gene encoding spore germination protein enhanced the metabolic levels of tricarboxylic acid cycle, and decreased the sporulation in B150, which induced its growth. The mutation of the genes, which encode NADPH nitroreductase in K150 and NADPH-dependent FMN reductase in B150, may enhance the ability of anti-oxidation. Overall, the long-term adaptation of K. vulgare and B. thuringiensis influenced the global regulation and made them more inseparable in metabolite exchange. Our work will provide ideas for the molecular design and optimization in microbial consortium. PMID: 28440340 [PubMed - in process]

Related Articles SYSTEMS METABOLOMICS FOR PREDICTION OF METABOLIC SYNDROME. J Proteome Res. 2017 Apr 25;: Authors: Pujos-Guillot E, Brandolini M, Pétéra M, Grissa D, Joly C, Lyan B, Herquelot E, Czernichow S, Zins M, Goldberg M, Comte B Abstract The evolution of human health is a continuum of transitions, involving multifaceted processes at multiple levels and there is an urgent need for integrative biomarkers that can characterize and predict progression towards disease development. The objective of this work was to perform a systems metabolomics approach to predict metabolic syndrome (MetS) development. A case-control design was used within the French occupational GAZEL cohort (n=112 males: discovery study; n=94: replication/validation study). Our integrative strategy was to combine untargeted metabolomics with clinical, sociodemographic and food habit parameters to describe early phenotypes and build multidimensional predictive models. Different models were built from the discriminant variables and prediction performances were optimized either when reducing the number of metabolites used, or when keeping the associated signature. We illustrated that a selected reduced metabolic profile was able to reveal subtle phenotypic differences five years before MetS occurrence. Moreover, resulting metabolomic markers, when combined with clinical characteristics, allowed improving the disease development prediction. The validation study showed that this predictive performance was specific of the MetS component. This work also demonstrates the interest of such an approach to discover sub-phenotypes that will need further characterization to be able to shift to molecular reclassification and targeting of MetS. PMID: 28440083 [PubMed - as supplied by publisher]

Related Articles Global and Targeted Metabolomics of Synovial Fluid Discovers Special Osteoarthritis Metabolites. J Orthop Res. 2017 Apr 25;: Authors: Zheng K, Ni S, Chen H, Lou S, Hu M, Sun L, Yang X Abstract PURPOSE: To identify special metabolites in synovial fluid of osteoarthritis (OA) via a metabolomics approach. METHOD: Synovial fluid of 35 participants (25 OA patients and 10 controls) was detected by GC-TOF/MS and multivariate data analysis was applied to analyze correlation among the observations. Different metabolites were screened by VIP value (VIP > 1), student t test (p < 0.05), and fold change (fold > 1.5), and verified with the standard metabolites in the synovial fluid of 24 OA patients and 11 controls by LC/MS. The classification performance of different metabolites was analyzed by receiver operating characteristic (ROC) analysis. RESULTS: The results showed that 6 different metabolites (glutamine, 1,5-anhydroglucitol, gluconic lactone, tyramine, threonine, and 8-aminocaprylic acid) were strongly associated with OA in global metabolomics. Verified results of the first 3 metabolites were the same as the identified results using targeted metabolomics. ROC curve analysis demonstrated that their concentrations in synovial fluid were strongly correlated to OA. In addition, the concentrations of gluconic lactone were significantly different between OA and RA. CONCLUSION: Metabolites with altered levels may be contributors to OA pathogenesis and can be used as potential diagnosis criteria for OA. Gluconic lactone may prove to be a novel criterion for differential diagnosis of OA from RA. This article is protected by copyright. All rights reserved. PMID: 28439964 [PubMed - as supplied by publisher]

Related Articles Genetic variants of Helicobacter pylori type IV secretion system components CagL and CagI and their association with clinical outcomes. Gut Pathog. 2017;9:21 Authors: Ogawa H, Iwamoto A, Tanahashi T, Okada R, Yamamoto K, Nishiumi S, Yoshida M, Azuma T Abstract BACKGROUND: Helicobacter pylori infection is associated with risk for chronic gastritis (CG), gastric ulcer (GU), duodenal ulcer (DU), and gastric cancer (GC). The H. pylori Cag type IV secretion system (TFSS) translocates the virulence factor cytotoxin-associated gene A protein into host cells and plays an important role in initiating gastric carcinogenesis. The CagL and CagI proteins are components of the TFSS. The Arg-Gly-Asp (RGD) motif of CagL, and the six most distal C-terminal amino acids (Ser-Lys-Ile-Ile-Val-Lys, and Ser-Lys-Val-Ile-Val-Lys) of CagL and CagI are essential for TFSS adhesion to host cells. Additionally, the CagL variant Tyr58Glu59 was previously shown to be associated with GC patients. RESULTS: We isolated 43 H. pylori isolates from 17 CG, 8 GU, 8 DU, and 10 GC patients in Southeast Asia. Total DNAs were extracted and sequenced with MiSeq. H. pylori strain ATCC 26695, which was isolated from CG patients, was used as a reference. We examined the full sequences of H. pylori cagL and cagI using whole-genome sequencing (WGS), and analyzed whether single nucleotide variants and amino acid changes (AACs) correlated with adverse clinical outcomes. Three isolates were excluded from the analysis due to cagPAI rearrangements. CagL RGD motifs were conserved in 39 isolates (97.5%). CagL-Glu59 and Ile234 in the C-terminal motif were more common in 10 H. pylori isolates from GC patients (p < 0.001 and p < 0.05, respectively). When 5 Vietnamese isolates from GC patients were excluded, CagL-Glu59 still remains significant (p < 0.05), but not Ile234. CagL-Tyr58 was seen in only one isolate. The CagI C-terminal motif was completely conserved across all 40 isolates, and there were no significant AACs in CagI. CONCLUSIONS: Using WGS, we analyzed genetic variants in clinical H. pylori isolates and identified putative novel and candidate variants in uncharacterized CagL and CagI sequences that are related to gastric carcinogenesis. In particular, CagL-Glu59 has the possible association with GC. PMID: 28439300 [PubMed - in process]

Related Articles Intriguing Interaction of Bacteriophage-Host Association: An Understanding in the Era of Omics. Front Microbiol. 2017;8:559 Authors: Parmar KM, Gaikwad SL, Dhakephalkar PK, Kothari R, Singh RP Abstract Innovations in next-generation sequencing technology have introduced new avenues in microbial studies through "omics" approaches. This technology has considerably augmented the knowledge of the microbial world without isolation prior to their identification. With an enormous volume of bacterial "omics" data, considerable attempts have been recently invested to improve an insight into virosphere. The interplay between bacteriophages and their host has created a significant influence on the biogeochemical cycles, microbial diversity, and bacterial population regulation. This review highlights various concepts such as genomics, transcriptomics, proteomics, and metabolomics to infer the phylogenetic affiliation and function of bacteriophages and their impact on diverse microbial communities. Omics technologies illuminate the role of bacteriophage in an environment, the influences of phage proteins on the bacterial host and provide information about the genes important for interaction with bacteria. These investigations will reveal some of bio-molecules and biomarkers of the novel phage which demand to be unveiled. PMID: 28439260 [PubMed - in process]

Related Articles Integrating cell biology and proteomic approaches in plants. J Proteomics. 2017 Apr 21;: Authors: Takáč T, Šamajová O, Šamaj J Abstract Significant improvements of protein extraction, separation, mass spectrometry and bioinformatics nurtured advancements of proteomics during the past years. The usefulness of proteomics in the investigation of biological problems can be enhanced by integration with other experimental methods from cell biology, genetics, biochemistry, pharmacology, molecular biology and other omics approaches including transcriptomics and metabolomics. This review aims to summarize current trends integrating cell biology and proteomics in plant science. Cell biology approaches are most frequently used in proteomic studies investigating subcellular and developmental proteomes, however, they were also employed in proteomic studies exploring abiotic and biotic stress responses, vesicular transport, cytoskeleton and protein posttranslational modifications. They are used either for detailed cellular or ultrastructural characterization of the object subjected to proteomic study, for validation of proteomic results, or they might be used to expand proteomic data. In this respect, a broad spectrum of methods is employed to support proteomic studies including ultrastructural electron microscopy studies, histochemical staining, immunochemical localization, in vivo imaging of fluorescently tagged proteins and visualization of protein-protein interactions. Thus, cell biological observations on fixed or living cell compartments, cells, tissues and organs are feasible, and in some cases fundamental for the validation and complementation of proteomic data. SIGNIFICANCE: Validation of proteomic data by independent experimental methods requires development of new complementary approaches. Benefits of cell biology methods and techniques are not sufficiently highlighted in current proteomic studies. This encouraged us to review most popular cell biology methods used in proteomic studies and to evaluate their relevance and potential for proteomic data validation and enrichment of purely proteomic analyses. We also provide examples of representative studies combining proteomic and cell biology methods for various purposes. Integrating cell biology approaches with proteomic ones allow validation and better interpretation of proteomic data. Moreover, cell biology methods remarkably extend the knowledge provided by proteomic studies and might be fundamental for the functional complementation of proteomic data. This review article summarizes current literature linking proteomics with cell biology. PMID: 28438675 [PubMed - as supplied by publisher]

Related Articles Identification of a plasma metabolomic signature of thrombotic myocardial infarction that is distinct from non-thrombotic myocardial infarction and stable coronary artery disease. PLoS One. 2017;12(4):e0175591 Authors: DeFilippis AP, Trainor PJ, Hill BG, Amraotkar AR, Rai SN, Hirsch GA, Rouchka EC, Bhatnagar A Abstract AIMS: Current non-invasive diagnostics for acute myocardial infarction (MI) identify myocardial necrosis rather than the primary cause and therapeutic target-plaque disruption and resultant thrombosis. The aim of this study was to identify changes specific to plaque disruption and pathological thrombosis that are distinct from acute myocardial necrosis. METHODS AND RESULTS: We quantified 1,032 plasma metabolites by mass spectrometry in 11 thrombotic MI, 12 non-thrombotic MI, and 15 stable coronary artery disease (CAD) subjects at two acute phase (time of catheterization [T0], six hours [T6]) and one quiescent (>3 months follow-up) time points. A statistical classifier was constructed utilizing baseline (T0) abundances of a parsimonious set of 17 qualifying metabolites. Qualifying metabolites were those that demonstrated a significant change between the quiescent phase and the acute phase and that were distinct from any change seen in non-thrombotic MI or stable CAD subjects. Classifier performance as estimated by 10-fold cross-validation was suggestive of high sensitivity and specificity for differentiating thrombotic from non-thrombotic MI and stable CAD subjects at presentation. Nineteen metabolites demonstrated an intra-subject change from time of acute thrombotic MI presentation to the quiescent state that was distinct from any change measured in both the non-thrombotic MI and stable CAD subjects undergoing cardiac catheterization over the same time course (false discovery rate <5%). CONCLUSIONS: We have identified a candidate metabolic signature that differentiates acute thrombotic MI from quiescent state after MI, from acute non-thrombotic MI, and from stable CAD. Further validation of these metabolites is warranted given their potential as diagnostic biomarkers and novel therapeutic targets for the prevention or treatment of acute MI. PMID: 28414761 [PubMed - indexed for MEDLINE]

Related Articles Metabolic changes and inflammation in cultured astrocytes from the 5xFAD mouse model of Alzheimer's disease: Alleviation by pantethine. PLoS One. 2017;12(4):e0175369 Authors: van Gijsel-Bonnello M, Baranger K, Benech P, Rivera S, Khrestchatisky M, de Reggi M, Gharib B Abstract Astrocytes play critical roles in central nervous system homeostasis and support of neuronal function. A better knowledge of their response may both help understand the pathophysiology of Alzheimer's disease (AD) and implement new therapeutic strategies. We used the 5xFAD transgenic mouse model of AD (Tg thereafter) to generate astrocyte cultures and investigate the impact of the genotype on metabolic changes and astrocytes activation. Metabolomic analysis showed that Tg astrocytes exhibited changes in the glycolytic pathway and tricarboxylic acid (TCA) cycle, compared to wild type (WT) cells. Tg astrocytes displayed also a prominent basal inflammatory status, with accentuated reactivity and increased expression of the inflammatory cytokine interleukin-1 beta (IL-1β). Compensatory mechanisms were activated in Tg astrocytes, including: i) the hexose monophosphate shunt with the consequent production of reducing species; ii) the induction of hypoxia inducible factor-1 alpha (HIF-1α), known to protect against amyloid-β (Aβ) toxicity. Such events were associated with the expression by Tg astrocytes of human isoforms of both amyloid precursor protein (APP) and presenilin-1 (PS1). Similar metabolic and inflammatory changes were induced in WT astrocytes by exogenous Aβ peptide. Pantethine, the vitamin B5 precursor, known to be neuroprotective and anti-inflammatory, alleviated the pathological pattern in Tg astrocytes as well as WT astrocytes treated with Aß. In conclusion, our data enlighten the dual pathogenic/protective role of astrocytes in AD pathology and the potential protective role of pantethine. PMID: 28410378 [PubMed - indexed for MEDLINE]

Nontargeted metabolomics approach for the differentiation of cultivation ages of mountain cultivated ginseng leaves using UHPLC/QTOF-MS. J Pharm Biomed Anal. 2017 Apr 13;141:108-122 Authors: Chang X, Zhang J, Li D, Zhou D, Zhang Y, Wang J, Hu B, Ju A, Ye Z Abstract The adulteration or falsification of the cultivation age of mountain cultivated ginseng (MCG) has been a serious problem in the commercial MCG market. To develop an efficient discrimination tool for the cultivation age and to explore potential age-dependent markers, an optimized ultra high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UHPLC/QTOF-MS)-based metabolomics approach was applied in the global metabolite profiling of 156 MCG leaf (MGL) samples aged from 6 to 18 years. Multivariate statistical methods such as principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were used to compare the derived patterns between MGL samples of different cultivation ages. The present study demonstrated that 6-18-year-old MGL samples can be successfully discriminated using two simple successive steps, together with four PLS-DA discrimination models. Furthermore, 39 robust age-dependent markers enabling differentiation among the 6-18-year-old MGL samples were discovered. The results were validated by a permutation test and an external test set to verify the predictability and reliability of the established discrimination models. More importantly, without destroying the MCG roots, the proposed approach could also be applied to discriminate MCG root ages indirectly, using a minimum amount of homophyletic MGL samples combined with the established four PLS-DA models and identified markers. Additionally, to the best of our knowledge, this is the first study in which 6-18-year-old MCG root ages have been nondestructively differentiated by analyzing homophyletic MGL samples using UHPLC/QTOF-MS analysis and two simple successive steps together with four PLS-DA models. The method developed in this study can be used as a standard protocol for discriminating and predicting MGL ages directly and homophyletic MCG root ages indirectly. PMID: 28437718 [PubMed - as supplied by publisher]