68 results
Search Results
2. Metabolomic profiling of plasma from middle-aged and advanced-age male mice reveals the metabolic abnormalities of carnitine biosynthesis in metallothionein gene knockout mice
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Takashige Kawakami, Masao Sato, Shinya Suzuki, Asuka Yano, and Yoshito Kadota
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Male ,Aging ,medicine.medical_specialty ,TMLHE ,Mitochondrion ,medicine.disease_cause ,N6,N6,N6-trimethyl-L-lysine ,Bile Acids and Salts ,Mice ,Metabolomics ,Carnitine ,Internal medicine ,L-carnitine ,tmlhe gene ,medicine ,Animals ,Metallothionein ,metabolomic profiling ,Amino Acids ,Gene knockout ,Mice, Knockout ,Nucleotides ,Chemistry ,Fatty Acids ,Bilirubin ,Cell Biology ,Metabolic intermediate ,metallothionein ,Endocrinology ,Carnitine biosynthesis ,Carbohydrate Metabolism ,Oxidative stress ,Research Paper - Abstract
Metallothionein (MT) is a family of low molecular weight, cysteine-rich proteins that regulate zinc homeostasis and have potential protective effects against oxidative stress and toxic metals. MT1 and MT2 gene knockout (MTKO) mice show shorter lifespans than wild-type (WT) mice. In this study, we aimed to investigate how MT gene deficiency accelerates aging. We performed comparative metabolomic analyses of plasma between MTKO and WT male mice at middle age (50-week-old) and advanced age (100-week-old) using liquid chromatography with time-of-flight mass spectrometry (LC-TOF-MS). The concentration of N6,N6,N6-trimethyl-L-lysine (TML), which is a metabolic intermediate in carnitine biosynthesis, was consistently higher in the plasma of MTKO mice compared to that of WT mice at middle and advanced age. Quantitative reverse transcription PCR (RT-PCR) analysis revealed remarkably lower mRNA levels of Tmlhe, which encodes TML dioxygenase, in the liver and kidney of male MTKO mice compared to that of WT mice. L-carnitine is essential for β-oxidation of long-chain fatty acids in mitochondria, the activity of which is closely related to aging. Our results suggest that reduced carnitine biosynthesis capacity in MTKO mice compared to WT mice led to metabolic disorders of fatty acids in mitochondria in MTKO mice, which may have caused shortened lifespans.
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- 2021
3. The central role of the glutamate metabolism in long-term antiretroviral treated HIV-infected individuals with metabolic syndrome
- Author
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Gelpi, Marco, Mikaeloff, Flora, Knudsen, Andreas D., Benfeitas, Rui, Krishnan, Shuba, Akusjärvi, Sara Svenssson, Høgh, Julie, Murray, Daniel D., Ullum, Henrik, Neogi, Ujjwal, and Nielsen, Susanne D.
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Male ,Metabolic Syndrome ,Anti-HIV Agents ,antiretroviral therapy ,Glutamic Acid ,HIV Infections ,Middle Aged ,immune-phenotyping ,metabolomics ,metabolic syndrome ,Carbohydrate Metabolism ,Humans ,Female ,Amino Acids ,HIV-infection ,Research Paper - Abstract
Metabolic syndrome (MetS) is a significant factor for cardiometabolic comorbidities in people living with HIV (PLWH) and a barrier to healthy aging. The long-term consequences of HIV-infection and combination antiretroviral therapy (cART) in metabolic reprogramming are unknown. In this study, we investigated metabolic alterations in well-treated PLWH with MetS to identify potential mechanisms behind the MetS phenotype using advanced statistical and machine learning algorithms. We included 200 PLWH from the Copenhagen Comorbidity in HIV-infection (COCOMO) study. PLWH were grouped into PLWH with MetS (n= 100) defined according to the International Diabetes Federation (IDF) consensus worldwide definition of the MetS or without MetS (n= 100). The untargeted plasma metabolomics was performed using ultra-high-performance liquid chromatography/mass spectrometry (UHPLC/MS/MS) and immune-phenotyping of Glut1 (glucose transporter), xCT (glutamate/cysteine transporter) and MCT1 (pyruvate/lactate transporter) by flow cytometry. We applied several conventional approaches, machine learning algorithms, and linear classification models to identify the biologically relevant metabolites associated with MetS in PLWH. Of the 877 identified biochemicals, 9% (76/877) differed significantly between PLWH with and without MetS (false discovery rate
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- 2021
4. Metabolomic profiling identifies pathways associated with minimal residual disease in childhood acute lymphoblastic leukaemia
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Jacob J. Junco, Karen R. Rabin, Jeremy M. Schraw, Philip J. Lupo, Austin L. Brown, and Michael E. Scheurer
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Male ,0301 basic medicine ,Oncology ,Neoplasm, Residual ,Research paper ,Epidemiology ,Nicotinamide phosphoribosyltransferase ,lcsh:Medicine ,Disease ,NAMPT ,chemistry.chemical_compound ,0302 clinical medicine ,Immunophenotyping ,Amino Acids ,Child ,lcsh:R5-920 ,Hematology ,Acute lymphoblastic leukaemia ,General Medicine ,3. Good health ,medicine.anatomical_structure ,Child, Preschool ,030220 oncology & carcinogenesis ,Metabolome ,Carbohydrate Metabolism ,Female ,lcsh:Medicine (General) ,Metabolic Networks and Pathways ,medicine.medical_specialty ,General Biochemistry, Genetics and Molecular Biology ,Biological pathway ,03 medical and health sciences ,Cell Line, Tumor ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Metabolomics ,Cancer prevention ,business.industry ,Minimal residual disease ,lcsh:R ,Genetic Variation ,030104 developmental biology ,ROC Curve ,chemistry ,NAMPT inhibitors ,Bone marrow ,business - Abstract
Background: End-induction minimal residual disease (MRD) is the strongest predictor of relapse in paediatric acute lymphoblastic leukaemia (ALL), but an understanding of the biological pathways underlying early treatment response remains elusive. We hypothesized that metabolomic profiling of diagnostic bone marrow plasma could provide insights into the underlying biology of early treatment response and inform treatment strategies for high-risk patients. Methods: We performed global metabolomic profiling of samples from discovery (N = 93) and replication (N = 62) cohorts treated at Texas Children's Hospital. Next, we tested the cytotoxicity of drugs targeting central carbon metabolism in cell lines and patient-derived xenograft (PDX) cells. Findings: Metabolite set enrichment analysis identified altered central carbon and amino acid metabolism in MRD-positive patients from both cohorts at a 5% false discovery rate. Metabolites from these pathways were used as inputs for unsupervised hierarchical clustering. Two distinct clusters were identified, which were independently associated with MRD after adjustment for immunophenotype, cytogenetics, and NCI risk group. Three nicotinamide phosphoribosyltransferase (NAMPT) inhibitors, which reduce glycolytic/TCA cycle activities, demonstrated nanomolar-range cytotoxicity in B- and T-ALL cell lines and PDX cells. Interpretation: This study provides new insights into the role of central carbon metabolism in early treatment response and as a potential targetable pathway in high-risk disease. Funding: American Society of Hematology; Baylor College of Medicine Department of Paediatrics; Cancer Prevention and Research Institute of Texas; the Lynch family; St. Baldrick's Foundation with support from the Micaela's Army Foundation; United States National Institutes of Health. Keywords: Acute lymphoblastic leukaemia, Minimal residual disease, Epidemiology, NAMPT, NAMPT inhibitors
- Published
- 2019
5. CO2 Production by Extracts of Hymenolepis diminuta (Cestoda: Hymenolepididae) with Aspartate and α-Ketoglutarate as Substrates
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Hicks, Terrell C. and Ubelaker, John E.
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- 1973
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6. Evidence for Transaminase Activity in the Slime Mold, Dictyostelium discoideum Raper
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Krivanek, Jerome O. and Krivanek, Robin C.
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- 1965
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7. Chromatographic Analyses of Amino Acids in the Developing Slime Mold, Dictyostelium discoideum Raper
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Krivanek, Jerome O. and Krivanek, Robin C.
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- 1959
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8. Differences in gut microbiota composition in finishing Landrace pigs with low and high feed conversion ratios
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Kai Xing, Chuduan Wang, Hong Ao, Jianfeng Liu, Yuan Wang, Fengxia Zhang, Xitong Zhao, Ting Yang, Zhen Tan, and Shaokang Chen
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DNA, Bacterial ,0301 basic medicine ,Colon ,Swine ,030106 microbiology ,Ileum ,Gut microbiota ,Gut flora ,medicine.disease_cause ,digestive system ,Microbiology ,Feed conversion ratio ,Feces ,03 medical and health sciences ,Cecum ,RNA, Ribosomal, 16S ,Intestine, Small ,Microbial community ,Megasphaera ,medicine ,Prevotella ,Animals ,Food science ,Amino Acids ,Molecular Biology ,Original Paper ,Bacteria ,biology ,Feed conversion ratio (FCR) ,Campylobacter ,Discriminant Analysis ,Hindgut ,Biodiversity ,General Medicine ,biology.organism_classification ,Animal Feed ,Gastrointestinal Microbiome ,030104 developmental biology ,medicine.anatomical_structure ,Carbohydrate Metabolism ,Female ,Pigs ,Metagenomics ,Metabolic Networks and Pathways - Abstract
The goal of this study was to evaluate the microbial communities in the gut and feces from female finishing Landrace pigs with high and low feed conversion ratio (FCR) by 16S rRNA gene amplicon sequencing. Many potential biomarkers can distinguish between high and low FCR groups in the duodenum, ileum, cecum, colon, and rectum, according to linear discriminant analysis effect sizes. The relative abundance of microbes were tested by Mann–Whitney test between the high and low FCR groups in different organs: Campylobacter, Prevotella and Sphaerochaeta were different in the duodenum (P
- Published
- 2018
9. Down-regulation of the sucrose transporters HvSUT1 and HvSUT2 affects sucrose homeostasis along its delivery path in barley grains
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Diana Weier, Winfriede Weschke, Nese Sreenivasulu, Manuela Peukert, Marc Strickert, Hans-Henning Steinbiß, Andrea Matros, David Riewe, Volodymyr Radchuk, Ruslana Radchuk, and Hans Weber
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0106 biological sciences ,0301 basic medicine ,Sucrose ,Physiology ,Down-Regulation ,Plant Science ,Vacuole ,Carbohydrate metabolism ,01 natural sciences ,Endosperm ,Assimilate transport ,03 medical and health sciences ,chemistry.chemical_compound ,Cell Wall ,Gene Expression Regulation, Plant ,transcript profiling ,sucrose transporter ,Amino Acids ,Sugar ,starch synthesis ,Abscisic acid ,Plant Proteins ,chemistry.chemical_classification ,vacuole ,Membrane Transport Proteins ,food and beverages ,Biological Transport ,Hordeum ,Starch ,Plants, Genetically Modified ,Sucrose transport ,Research Papers ,Amino acid ,030104 developmental biology ,chemistry ,Biochemistry ,Seeds ,Carbohydrate Metabolism ,metabolite profiling ,Growth and Development ,010606 plant biology & botany - Abstract
RNAi-repression of vacuolar HvSUT2 in transgenic barley demonstrates its indispensable role for proper grain filling and for the control of sucrose homeostasis in concert with the plasma-membrane localised HvSUT1., Sucrose transport and partitioning are crucial for seed filling. While many plasma-membrane-localised sucrose transporters (SUT1 family members) have been analysed in seeds, the functions of vacuolar SUT2 members are still obscure. In barley grains, expression of HvSUT1 and HvSUT2 overlap temporally and spatially, suggesting concerted functions to regulate sucrose homeostasis. Using HvSUT2-RNAi plants, we found that grains were also deficient in HvSUT1 expression and seemingly sucrose-limited during mid-to-late grain filling. Transgenic endosperms accumulated less starch and dry weight, although overall sucrose and hexose contents were higher. Comprehensive transcript and metabolite profiling revealed that genes related to glycolysis, the tricarboxylic acid cycle, starch and amino acid synthesis, grain maturation, and abscisic acid signalling were down-regulated together with most glycolytic intermediates and amino acids. Sucrose was increased along the sucrose delivery route in the nucellar projection, the endosperm transfer cells, and the starchy endosperm, indicating that suppressed transporter activity diminished sucrose efflux from vacuoles, which generated sugar deficiency in the cytoplasm. Thus, endosperm vacuoles may buffer sucrose concentrations to regulate homeostasis at grain filling. Transcriptional changes revealed that limited endosperm sucrose initiated sugar starvation responses, such as sugar recycling from starch, hemicelluloses and celluloses together with vacuolar protein degradation, thereby supporting formation of nucleotide sugars. Barley endosperm cells can thus suppress certain pathways to retrieve resources to maintain essential cell functions.
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- 2017
10. Altered gut bacterial and metabolic signatures and their interaction in gestational diabetes mellitus
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Hongli Liu, Shuai Huang, Yifan Li, Chiying Cao, Hongbo Qi, Peng Zheng, Philip N. Baker, Chao Tong, Lan Zhang, and Xing Wang
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Adult ,Blood Glucose ,0301 basic medicine ,Microbiology (medical) ,endocrine system diseases ,diagnosis ,Firmicutes ,gut microbiome ,Physiology ,Microbiology ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Enterobacteriaceae ,Pregnancy ,RNA, Ribosomal, 16S ,medicine ,Metabolome ,Humans ,metabolic pathways ,Amino Acids ,lcsh:RC799-869 ,Feces ,biology ,Lachnospiraceae ,Gastroenterology ,nutritional and metabolic diseases ,medicine.disease ,biology.organism_classification ,gestational diabetes mellitus ,female genital diseases and pregnancy complications ,Gastrointestinal Microbiome ,Gestational diabetes ,Diabetes, Gestational ,Metabolic pathway ,030104 developmental biology ,Infectious Diseases ,Carbohydrate Metabolism ,Dysbiosis ,Female ,metabolome ,lcsh:Diseases of the digestive system. Gastroenterology ,030211 gastroenterology & hepatology ,Research Article ,Research Paper ,Ruminococcaceae - Abstract
Emerging evidence indicates that the gut microbiome can modulate metabolic homeostasis, and thus may influence the development of gestational diabetes mellitus (GDM). However, whether and how the gut microbiome and its correlated metabolites change in GDM is uncertain. Herein we compare the gut microbial compositions, and fecal and urine metabolomes, of 59 patients with GDM versus 48 pregnant healthy controls (HCs). We showed that the microbial and metabolic signatures of GDM patients were significantly different from those of HCs. Compared to HCs, the GDM subjects were characterized by enriched bacterial operational taxonomic units (OTUs) of the family Lachnospiraceae, and depleted OTUs of the families Enterobacteriaceae and Ruminococcaceae. Some altered gut microbes were significantly correlated with glucose values and fetal ultrasonography indexes. Moreover, we identified four fecal and 15 urine metabolites that discriminate GDM from HC. These differential metabolites are mainly involved in carbohydrate and amino acid metabolism. Significantly, co-occurrence network analysis revealed that Lachnospiraceae and Enterobacteriaceae bacterial OTUs formed strong co-occurring relationships with metabolites involved in carbohydrate and amino acid metabolism, suggesting that disturbed gut microbiome may mediate GDM. Furthermore, we identified a novel combinatorial marker panel that could distinguish GDM from HC subjects with high accuracy. Together our findings demonstrate that altered microbial composition and metabolic function may be relevant to the pathogenesis and pathophysiology of GDM.
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- 2020
11. Low vapour pressure deficit affects nitrogen nutrition and foliar metabolites in silver birch
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Sari Kontunen-Soppela, Elina Oksanen, Sarita Keski-Saari, Jenna Lihavainen, Markku Keinänen, and Viivi Ahonen
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0106 biological sciences ,0301 basic medicine ,Stomatal conductance ,Nitrogen ,Physiology ,Vapour Pressure Deficit ,carbohydrates ,chemistry.chemical_element ,Plant Science ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Nutrient ,pendula ,Air humidity ,VPD ,mineral nutrients ,Raffinose ,Betula ,Transpiration ,amino acids ,starch ,fungi ,food and beverages ,Humidity ,Plant Transpiration ,Starch production ,Plant Leaves ,030104 developmental biology ,chemistry ,Agronomy ,Chlorophyll ,flavonoids ,Plant Stomata ,metabolite profiling ,Carbohydrate Metabolism ,Research Paper ,010606 plant biology & botany - Abstract
Highlight Changing leaf to air vapour pressure deficit (VPD) modifies primary metabolism of plants as demonstrated by excess starch synthesis and reduced amino acid, chlorophyll, and nitrogen concentrations in leaves under low VPD., Air humidity indicated as vapour pressure deficit (VPD) is directly related to transpiration and stomatal function of plants. We studied the effects of VPD and nitrogen (N) supply on leaf metabolites, plant growth, and mineral nutrition with young micropropagated silver birches (Betula pendula Roth.) in a growth chamber experiment. Plants that were grown under low VPD for 26 d had higher biomass, larger stem diameter, more leaves, fewer fallen leaves, and larger total leaf area than plants that were grown under high VPD. Initially, low VPD increased height growth rate and stomatal conductance; however, the effect was transient and the differences between low and high VPD plants became smaller with time. Metabolic adjustment to low VPD reflected N deficiency. The concentrations of N, iron, chlorophyll, amino acids, and soluble carbohydrates were lower and the levels of starch, quercetin glycosides, and raffinose were higher in the leaves that had developed under low VPD compared with high VPD. Additional N supply did not fully overcome the negative effect of low VPD on nutrient status but it diminished the effects of low VPD on leaf metabolism. Thus, with high N supply, the glutamine to glutamate ratio and starch production under low VPD became comparable with the levels under high VPD. The present study demonstrates that low VPD affects carbon and nutrient homeostasis and modifies N allocation of plants.
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- 2016
12. Proteomic analysis reveals dynamic regulation of fruit development and sugar and acid accumulation in apple
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Sheng Zhang, Mingjun Li, Fengwang Ma, Dongxia Li, Fengjuan Feng, and Lailiang Cheng
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0106 biological sciences ,0301 basic medicine ,Proteomics ,Sucrose ,Physiology ,Malates ,apple ,Plant Science ,Tandem mass tag ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Botany ,Metabolomics ,Glycolysis ,Amino Acids ,Bisphosphoglycerate mutase ,ComputingMilieux_MISCELLANEOUS ,Plant Proteins ,organic acid ,biology ,fungi ,food and beverages ,Fructose ,Metabolism ,biochemical phenomena, metabolism, and nutrition ,functional annotation ,equipment and supplies ,Amino acid ,030104 developmental biology ,ComputingMethodologies_PATTERNRECOGNITION ,chemistry ,Biochemistry ,sugar ,Fruit ,Malus ,biology.protein ,bacteria ,Carbohydrate Metabolism ,fruit development ,Flux (metabolism) ,tandem mass tag ,Metabolic Networks and Pathways ,010606 plant biology & botany ,Research Paper - Abstract
Highlight Proteomic analysis of apple fruit development provided a comprehensive view of the major processes and pathways underlying apple fruit development and key fruit quality traits., Understanding the fruit developmental process is critical for fruit quality improvement. Here, we report a comprehensive proteomic analysis of apple fruit development over five growth stages, from young fruit to maturity, coupled with metabolomic profiling. A tandem mass tag (TMT)-based comparative proteomics approach led to the identification and quantification of 7098 and 6247 proteins, respectively. This large-scale proteomic dataset presents a global view of the critical pathways involved in fruit development and metabolism. When linked with metabolomics data, these results provide new insights into the modulation of fruit development, the metabolism and storage of sugars and organic acids (mainly malate), and events within the energy-related pathways for respiration and glycolysis. We suggest that the key steps identified here (e.g. those involving the FK2, TST, EDR6, SPS, mtME and mtMDH switches), can be further targeted to confirm their roles in accumulation and balance of fructose, sucrose and malate. Moreover, our findings imply that the primary reason for decreases in amino acid concentrations during fruit development is related to a reduction in substrate flux via glycolysis, which is mainly regulated by fructose-bisphosphate aldolase and bisphosphoglycerate mutase.
- Published
- 2016
13. The genome sequence of the highly acetic acid-tolerant zygosaccharomyces bailii-derived interspecies hybrid strain ISA1307, isolated from a sparkling wine plant
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Filipa Dias-Valada, Ulrich Güldener, Margarida Palma, Cecília Leão, Joana F. Guerreiro, Júlia Santos, Isabel Sá-Correia, Maria João Sousa, Fernando Rodrigues, Nuno P. Mira, Filipa de Canaveira Roque, Martin Münsterkötter, and Universidade do Minho
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Zygosaccharomyces bailii ,genome sequencing and annotation ,hybrid yeast strains ,weak acid food preservatives tolerance ,wine yeast strains ,Wine ,Zygosaccharomyces ,Genome ,Weak acid food preservatives tolerance ,Fungal Proteins ,Wine yeast strains ,Stress, Physiological ,Genetics ,Amino Acids ,DNA, Fungal ,Molecular Biology ,Genome size ,Gene ,Acetic Acid ,2. Zero hunger ,Whole genome sequencing ,Fungal protein ,Genome sequencing and annotation ,Science & Technology ,biology ,Base Sequence ,Chimera ,Chromosome Mapping ,Biological Transport ,Molecular Sequence Annotation ,General Medicine ,Full Papers ,biology.organism_classification ,Genes, Mating Type, Fungal ,Yeast ,Meiosis ,Hybrid yeast strains ,Karyotyping ,Carbohydrate Metabolism ,Genome, Fungal - Abstract
In this work, it is described the sequencing and annotation of the genome of the yeast strain ISA1307, isolated from a sparkling wine continuous production plant. This strain, formerly considered of the Zygosaccharomyces bailii species, has been used to study Z. bailii physiology, in particular, its extreme tolerance to acetic acid stress at low pH. The analysis of the genome sequence described in this work indicates that strain ISA1307 is an interspecies hybrid between Z. bailii and a closely related species. The genome sequence of ISA1307 is distributed through 154 scaffolds and has a size of around 21.2 Mb, corresponding to 96% of the genome size estimated by flow cytometry. Annotation of ISA1307 genome includes 4385 duplicated genes (~90% of the total number of predicted genes) and 1155 predicted single-copy genes. The functional categories including a higher number of genes are 'Metabolism and generation of energy', 'Protein folding, modification and targeting' and 'Biogenesis of cellular components'. The knowledge of the genome sequence of the ISA1307 strain is expected to contribute to accelerate systems-level understanding of stress resistance mechanisms in Z. bailii and to inspire and guide novel biotechnological applications of this yeast species/strain in fermentation processes, given its high resilience to acidic stress. The availability of the ISA1307 genome sequence also paves the way to a better understanding of the genetic mechanisms underlying the generation and selection of more robust hybrid yeast strains in the stressful environment of wine fermentations., This research was supported by FCT and FEDER through POFC-COMPETE [contracts PEst-OE/EQB/ LA0023/2011_ research line: Systems and Synthetic Biology PTDC/AGR-ALI/102608/2008, PEst-C/BIA/ UI4050/2011, and post-doctoral grant to M.P. (SFRH/BPD/73306/2010) and PhD grants to J.F.G. (SFRH/ BD/80065/2011) and F.C.R. (SFRH/BD/82226/2011)]. U.G. acknowledges the Austrian Science Fund (FWF, special research project F3705).
- Published
- 2014
14. Proteomic and phosphoproteomic analysis of polyethylene glycol-induced osmotic stress in root tips of common bean (Phaseolus vulgaris L.)
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Idupulapati M. Rao, Dejene Eticha, Walter J. Horst, Alain Van Dorsselaer, Barbara Schlingmann, Dimitri Heintz, Hendrik Führs, Zhong-Bao Yang, Daniel Ayoub, and Hans-Peter Braun
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root tips ,dehydrin ,Osmotic shock ,Physiology ,low water potentials ,ionically bound proteins ,Plant Science ,arabidopsis-thaliana ,Proteomics ,Plant Roots ,dehydrin-like proteins ,Polyethylene Glycols ,Cell wall ,Transcriptome ,proteomics ,salt-responsive proteins ,Osmotic Pressure ,s-adenosylmethionine synthetase ,Electrophoresis, Gel, Two-Dimensional ,Amino Acids ,Dewey Decimal Classification::500 | Naturwissenschaften ,cell-wall proteome ,nadp(+)-dependent isocitrate dehydrogenase ,elongation zone ,Plant Proteins ,Phaseolus ,common bean ,biology ,Phosphoproteomics ,phosphoproteomics ,biology.organism_classification ,Phosphoproteins ,apoplast ,maize primary root ,Metabolic pathway ,Biochemistry ,Proteome ,Carbohydrate Metabolism ,cell wall ,ddc:500 ,Research Paper - Abstract
Previous studies have shown that polyethylene glycol (PEG)-induced osmotic stress (OS) reduces cell-wall (CW) porosity and limits aluminium (Al) uptake by root tips of common bean (Phaseolus vulgaris L.). A subsequent transcriptomic study suggested that genes related to CW processes are involved in adjustment to OS. In this study, a proteomic and phosphoproteomic approach was applied to identify OS-induced protein regulation to further improve our understanding of how OS affects Al accumulation. Analysis of total soluble proteins in root tips indicated that, in total, 22 proteins were differentially regulated by OS; these proteins were functionally categorized. Seventy-seven per- cent of the total expressed proteins were involved in metabolic pathways, particularly of carbohydrate and amino acid metabolism. An analysis of the apoplastic proteome revealed that OS reduced the level of five proteins and increased that of seven proteins. Investigation of the total soluble phosphoproteome suggested that dehydrin responded to OS with an enhanced phosphorylation state without a change in abundance. A cellular immunolocalization analysis indicated that dehydrin was localized mainly in the CW. This suggests that dehydrin may play a major protective role in the OS-induced physical breakdown of the CW structure and thus maintenance of the reversibility of CW extensibility during recovery from OS. The proteomic and phosphoproteomic analyses provided novel insights into the complex mechanisms of OS-induced reduction of Al accumulation in the root tips of common bean and highlight a key role for modification of CW structure. BMZ/GTZ/05.7860.9-001.00 BMZ/GTZ/05.7860.9-001.00
- Published
- 2013
15. Atlas of Rice Grain Filling-Related Metabolism under High Temperature: Joint Analysis of Metabolome and Transcriptome Demonstrated Inhibition of Starch Accumulation and Induction of Amino Acid Accumulation
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Makoto Hakata and Hiromoto Yamakawa
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Hot Temperature ,Grain filling ,Starch ,Physiology ,Plant Science ,RNA, Transfer, Amino Acyl ,Biology ,Mass Spectrometry ,Caryopsis ,chemistry.chemical_compound ,Gene Expression Regulation, Plant ,Glycolysis ,Amino Acids ,Oligonucleotide Array Sequence Analysis ,chemistry.chemical_classification ,Gene Expression Profiling ,Regular Papers ,Electrophoresis, Capillary ,food and beverages ,Oryza ,Metabolism ,Cell Biology ,General Medicine ,High temperature ,Amino acid ,Metabolic pathway ,chemistry ,Gluconeogenesis ,Biochemistry ,RNA, Plant ,Seeds ,Metabolome ,Carbohydrate Metabolism ,Gene expression ,Rice ,Pyruvic acid ,Corrigendum - Abstract
High temperature impairs grain filling by inhibiting the deposition of storage materials such as starch and protein. To comprehend its impact on grain filling metabolism in rice (Oryza sativa), levels of metabolites and transcripts related to central pathways of metabolism were simultaneously determined in developing caryopses exposed to high temperature (33 degrees C/28 degrees C) and a control temperature (25 degrees C/20 degrees C) during the milky stage. A capillary electrophoresis-based metabolomic analysis revealed that high temperature increased the accumulation of sucrose and pyruvate/ oxaloacetate-derived amino acids and decreased levels of sugar phosphates and organic acids involved in glycolysis/gluconeogenesis and the tricarboxylic acid (TCA) cycle, respectively. A transcriptomic analysis using a whole genome-covering microarray unraveled the possible metabolic steps causing the shortage of storage materials under the elevated temperature. Starch deposition might be impaired by down-regulation of sucrose import/degradation and starch biosynthesis, and/or up-regulation of starch degradation as well as inefficient ATP production by an inhibited cytochrome respiration chain, as indicated by the response of gene expression to high temperature. Amino acid accumulation might be attributed to the heat-stable import of amino acids into the caryopsis and/or repression of protein synthesis especially the tRNA charging step under high temperature. An atlas showing the effect of high temperature on levels of metabolites and gene expression in the central metabolic pathways is presented.
- Published
- 2010
16. Production of Anticapsin by Streptomyces griseoplanus
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L. D. Boeck, K. L. Christy, and R. Shah
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Sucrose ,Hot Temperature ,Chemical Phenomena ,Chromatography, Paper ,Streptococcus pyogenes ,Metabolite ,Streptomyces griseoplanus ,Fructose ,Carbohydrate metabolism ,Streptomyces ,General Biochemistry, Genetics and Molecular Biology ,Phosphates ,chemistry.chemical_compound ,Cell Wall ,Ethers, Cyclic ,Polysaccharides ,Food science ,Amino Acids ,Hyaluronic Acid ,General Pharmacology, Toxicology and Pharmaceutics ,Metabolism and Products ,Minerals ,General Immunology and Microbiology ,biology ,General Medicine ,Hydrogen-Ion Concentration ,Ketones ,Carbohydrate ,biology.organism_classification ,Aerobiosis ,Anti-Bacterial Agents ,Culture Media ,Oxygen ,Chemistry ,Glucose ,chemistry ,Biochemistry ,Fermentation ,Carbohydrate Metabolism ,Tyrosine ,Biological Assay - Abstract
Anticapsin is a new fermentation product which inhibits formation of the hyaluronic acid capsule of Streptococcus pyogenes . Production of this metabolite in a complex medium by S. griseoplanus is enhanced by high levels of carbohydrate. A number of carbon sources support biosynthesis but sucrose is most effective, the optimum level being 150 g/liter. Neither glucose nor fructose, alone or in combination, serves as an equivalent substitute for sucrose. The addition of dibasic potassium phosphate to the medium further increases anticapsin production. Dissolved oxygen levels are important for synthesis and stability of the metabolite. Anticapsular activity diminishes rapidly in previously aerated broths which are held under static conditions. This decrease does not occur in pasteurized broths or unpasteurized filtrates.
- Published
- 1971
17. Non-targeted GC–MS metabolomics-based differences in Indica rice seeds of different varieties.
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Zhou, Dahu, Jing, Hao, Yuan, Jun, Zhou, Mingming, Liu, Lin, Fu, Junru, Ouyang, Linjuan, Xu, Jie, Bian, Jianmin, Fu, Haihui, and He, Haohua
- Subjects
RICE seeds ,HUMAN growth ,CARBOHYDRATE metabolism ,GAS chromatography/Mass spectrometry (GC-MS) ,ORGANIC acids ,AMYLOSE - Abstract
Rice seeds of different varieties exhibited distinct metabolic profiles in our study. We analyzed the metabolites in seeds of six rice varieties (CH, HM, NX, YX, HY, and MX) using non-targeted GC–MS. Our findings revealed that amino acids, sugars, and organic acids were predominant in all varieties, with significant differences observed in CH compared to the others. Specifically phenylalanine and glycine content differed notably in NX and YX, respectively. Additionally, 1,5-anhydroglucitol content in NX, and glutamate, aspartate, and lactulose in NX, YX, HM, HY, and MX were up-regulated. Due to the biological functions of these amino acids and sugars, these indicated that compared to CH, rice of NX were more conducive to metabolism of carbohydrate and fat, and healthy growth maintenance in the human body, but mightThese variations suggest that NX rice may be more beneficial for carbohydrate and fat metabolism and overall health maintenance compared to CH. However, it may not be suitable for diabetic patients. YX rice may not be an ideal glycine supplement, rice ofwhile HM, HY, and MX rice could serve as potential lactulose sources. Furthermore, NX and YX rice exhibited higher levels of main storage proteins compared to CH. This study offers valuable insights into the metabolic differences among various rice varieties. [ABSTRACT FROM AUTHOR]
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- 2024
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18. [The influence of temperature on the content of some carbohydrates and amino acids in Spirogyra]
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U, Kull and G, Hentschel
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Aspartic Acid ,Alanine ,Chromatography, Paper ,Nitrogen ,Aminobutyrates ,Glutamine ,Temperature ,Eukaryota ,Starch ,Valine ,Fructose ,Glucose ,Glutamates ,Leucine ,Serine ,Carbohydrate Metabolism ,Amino Acids ,Asparagine - Published
- 1966
19. Inoculation with Lentilactobacillus buchneri alone or in combination with Lentilactobacillus hilgardii modifies gene expression, fermentation profile, and starch digestibility in high-moisture corn.
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Drouin, Pascal, da Silva, Érica Benjamim, Tremblay, Julien, Chevaux, Eric, Apper, Emmanuelle, and Castex, Mathieu
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GENE expression ,AMINO acid metabolism ,STARCH ,CARBOHYDRATE metabolism ,CORN as feed ,GENE expression profiling ,AMINO acids - Abstract
Inoculants combining Lentilactobacillus buchneri and Lentilactobacillus hilgardii have been shown to improve the aerobic stability of high-moisture corn (HMC) and whole-plant corn silage, but the mode of action of this co-inoculation remains to be elucidated. This study used metatranscriptomics to evaluate the effects of inoculation with L. buchneri alone or combined with L. hilgardii on the bacterial community, gene expression, fermentation profile, and starch digestibility in HMC. High-moisture corn not inoculated (Control) or inoculated with L. buchneri NCIMB 40788 (LB) or L. buchneri NCIMB 40788 combined with L. hilgardii CNCM-I-4785 (Combo) was ensiled in mini silo bags for 30, 60, 120, and 180 days. The fermentation profile was evaluated at all time points. Metatranscriptomics was performed on samples collected on day 120. Combo had a greater alpha diversity richness index of contigs than LB and Control, and inoculation with Combo and LB modified the beta-diversity of contigs compared to Control. Out of 69 genes of interest, 20 were differentially expressed in LB compared to Control and 25 in Combo compared to Control. Of those differently expressed genes, 16 (10 of which were associated with carbohydrate metabolism and six with amino acid metabolism) were differently expressed in both LB and Combo compared to Control, and all those genes were upregulated in the inoculated silages. When we compared Combo and LB, we found seven genes expressed differently, four associated with carbohydrate metabolism and downregulated in Combo, and three associated with amino acid metabolism and upregulated in Combo. At day 120, the inoculated silages had more culturable lactic acid bacteria, higher Lactobacillus relative abundance, and lower Leuconostoc relative abundance than Control. The concentration of acetic acid remained low throughout ensiling in Control, but in LB and Combo, it increased up to day 60 and remained stable from day 60 to 180. The 1,2-propanediol was only detected in LB and Combo. Inoculation did not affect the concentration of starch, but starch digestibility was greater in Combo than in Control. Inoculation of HMC with Combo modified the gene expression and fermentation profile compared to Control and LB, improving starch digestibility compared to uninoculated HMC. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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20. Metabolic Alterations in Canine Mammary Tumors.
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Tamarindo, Guilherme Henrique, Novais, Adriana Alonso, Chuffa, Luiz Gustavo Almeida, and Zuccari, Debora Aparecida Pires Campos
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GLUTAMINE ,GLUTAMINE synthetase ,FATTY acid oxidation ,CARBOHYDRATE metabolism ,FEMALE dogs ,MITOCHONDRIAL DNA ,TUMOR growth - Abstract
Simple Summary: Cancer cells usually have a short timeframe for proliferation, which favors tumor growth. Therefore, they require more energy and intermediates to sustain biosynthetic pathways that will supply all the requirements for cell division. This event is known as metabolic reprogramming and is described in all cancer types, it also being a vulnerability for therapy. However, metabolic alterations in canine mammary tumors are poorly explored. In this review, we compile the metabolic rewiring described in canine mammary tumors, which could be used as a therapeutic opportunity for treatment in veterinary oncology. Canine mammary tumors (CMTs) are among the most common diseases in female dogs and share similarities with human breast cancer, which makes these animals a model for comparative oncology studies. In these tumors, metabolic reprogramming is known as a hallmark of carcinogenesis whereby cells undergo adjustments to meet the high bioenergetic and biosynthetic demands of rapidly proliferating cells. However, such alterations are also vulnerabilities that may serve as a therapeutic strategy, which has mostly been tested in human clinical trials but is poorly explored in CMTs. In this dedicated review, we compiled the metabolic changes described for CMTs, emphasizing the metabolism of carbohydrates, amino acids, lipids, and mitochondrial functions. We observed key factors associated with the presence and aggressiveness of CMTs, such as an increase in glucose uptake followed by enhanced anaerobic glycolysis via the upregulation of glycolytic enzymes, changes in glutamine catabolism due to the overexpression of glutaminases, increased fatty acid oxidation, and distinct effects depending on lipid saturation, in addition to mitochondrial DNA, which is a hotspot for mutations. Therefore, more attention should be paid to this topic given that targeting metabolic fragilities could improve the outcome of CMTs. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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21. Transcriptomic profiling revealed important roles of amino acid metabolism in fruiting body formation at different ripening times in Hypsizygus marmoreus.
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Quanju Xiang, Muhammad Arshad, Yakun Li, Huijuan Zhang, Yunfu Gu, Xiumei Yu, Ke Zhao, Menggen Ma, Lingzi Zhang, Maolan He, and Qiang Chen
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FRUITING bodies (Fungi) ,AMINO acid metabolism ,CARBOHYDRATE metabolism ,TRANSCRIPTOMES ,LIPID metabolism ,AMINO acids ,HISTIDINE ,GENE ontology - Abstract
Introduction: Hypsizygus marmoreus is an industrial mushroom that is widely cultivated in East Asia. Its long postripening stage before fruiting severely limits its industrialized production. Methods: Five different mycelial ripening times (30, 50, 70, 90, and 100 d) were chosen and primordia (30P, 50P, 70P, 90P, and 110P) were collected for comparative transcriptomic analyses. The corresponding substrates (30F, 50F, 70F, 90F, and 110F) were used for nutrient content and enzyme activity determination. Results: In pairwise comparisons between 110P and other primordia, a total of 1,194, 977, 773, and 697 differentially expressed genes (DEGs) were identified in 30P_110P, 50P_110P, 70P_110P, and 90P_110P, respectively. Gene Ontology (GO) and Kyoto Encyclopedia of Genes Genomes (KEGG) functional enrichment analyses revealed that the DEGs were mainly associated with amino acid metabolism, and lipid and carbohydrate metabolism pathways. Tyrosine, tryptophan, phenylalanine and histidine metabolism were enriched in all groups. Among the main carbon nutrients, the contents of cellulose and hemicellulose were high, and the lignin content decreased with the extension of the ripening time. Laccase had the highest activity, and acid protease activity decreased with the extension of the ripening time. Discussion: The highly enrichment for amino acid metabolic pathways in primordia reveals that these pathways are essential for fruiting body formation in H. marmoreus, and these results will provide a basis for the optimization of its cultivation. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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22. Adaptation Strategies to High Hydrostatic Pressures in Pseudothermotoga species Revealed by Transcriptional Analyses.
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Fenouil, Romain, Pradel, Nathalie, Belahbib, Hassiba, Roumagnac, Marie, Bartoli, Manon, Ben Hania, Wajdi, Denis, Yann, Garel, Marc, Tamburini, Christian, Ollivier, Bernard, Summers, Zarath, Armougom, Fabrice, and Dolla, Alain
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HYDROSTATIC pressure ,AMINO acid transport ,AMINO acid metabolism ,PHYSIOLOGICAL adaptation ,CARBOHYDRATE metabolism ,AMINO acids ,GENOMICS - Abstract
Pseudothermotoga elfii strain DSM9442 and P. elfii subsp. lettingae strain DSM14385 are hyperthermophilic bacteria. P. elfii DSM9442 is a piezophile and was isolated from a depth of over 1600 m in an oil-producing well in Africa. P. elfii subsp. lettingae is piezotolerant and was isolated from a thermophilic bioreactor fed with methanol as the sole carbon and energy source. In this study, we analyzed both strains at the genomic and transcriptomic levels, paying particular attention to changes in response to pressure increases. Transcriptomic analyses revealed common traits of adaptation to increasing hydrostatic pressure in both strains, namely, variations in transport membrane or carbohydrate metabolism, as well as species-specific adaptations such as variations in amino acid metabolism and transport for the deep P. elfii DSM9442 strain. Notably, this work highlights the central role played by the amino acid aspartate as a key intermediate of the pressure adaptation mechanisms in the deep strain P. elfii DSM9442. Our comparative genomic and transcriptomic analysis revealed a gene cluster involved in lipid metabolism that is specific to the deep strain and that was differentially expressed at high hydrostatic pressures and might, thus, be a good candidate for a piezophilic gene marker in Pseudothermotogales. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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23. Knockout of Nur77 Leads to Amino Acid, Lipid, and Glucose Metabolism Disorders in Zebrafish.
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Xu, Yang, Tian, Juanjuan, Kang, Qi, Yuan, Hang, Liu, Chengdong, Li, Zhehui, Liu, Jie, and Li, Mingyu
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GLUCOSE metabolism disorders ,WARBURG Effect (Oncology) ,AMINO acids ,CARBOHYDRATE metabolism ,BRACHYDANIO ,LIPID metabolism - Abstract
Orphan nuclear receptor Nur77 has been reported to be implicated in a diverse range of metabolic processes, including carbohydrate metabolism and lipid metabolism. However, the detailed mechanism of Nur77 in the regulation of metabolic pathway still needs to be further investigated. In this study, we created a global nur77 knockout zebrafish model by CRISPR/Cas9 technique, and then performed whole-organism RNA sequencing analysis in wildtype and nur77 -deficient zebrafish to dissect the genetic changes in metabolic-related pathways. We found that many genes involved in amino acid, lipid, and carbohydrate metabolism changed by more than twofold. Furthermore, we revealed that nur77
−/− mutant displayed increased total cholesterol (TC) and triglyceride (TG), alteration in total amino acids, as well as elevated glucose. We also demonstrated that the elevated glucose was not due to the change of glucose uptake but was likely caused by the disorder of glycolysis/gluconeogenesis and the impaired β-cell function, including downregulated insb expression, reduced β-cell mass, and suppressed insulin secretion. Importantly, we also verified that targeted expression of Nur77 in the β cells is sufficient to rescue the β-cell defects in global nur77−/− larvae zebrafish. These results provide new information about the global metabolic network that Nur77 signaling regulates, as well as the role of Nur77 in β-cell function. [ABSTRACT FROM AUTHOR]- Published
- 2022
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24. Fullerenol changes metabolite responses differently depending on the iron status of cucumber plants.
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Bityutskii, Nikolai P., Yakkonen, Kirill L., Puzanskiy, Roman, Lukina, Kseniia A., Shavarda, Alexey L., and Semenov, Konstantin N.
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CUCUMBERS ,AMINO acid metabolism ,CARBOHYDRATE metabolism ,ORGANIC acids ,IRON ions ,IRON ,AMINO acids ,CROP yields - Abstract
The unique properties of carbon-based nanomaterials, including fullerenol, have attracted great interest in agricultural and environmental applications. Iron (Fe) is an essential micronutrient for major metabolic processes, for which a shortage causes chlorosis and reduces the yield of many crops cultivated worldwide. In the current study, the metabolic responses of Cucumis sativus (a Strategy I plant) to fullerenol treatments were investigated depending on the Fe status of plants. Cucumber plants were grown hydroponically, either with [+Fe
II (ferrous) and +FeIII (ferric)] or in Fe-free (−FeII and −FeIII ) nutrient solution, with (+F) or without (−F) a fullerenol supply. Iron species-dependent effects were observed in either Fe-fed or Fe-starved plants, with alteration of metabolites involved in the metabolism of carbohydrates, amino acids, organic acids, lipophilic compounds. Metabolic perturbations triggered by fullerenol in the FeIII -treated plants were in the opposite kind from those in the FeII -treated plants. Whereas in the FeIII -fed plants, fullerenol activated the metabolisation of carbohydrates and amino acids, in the FeII -fed plants, fullerenol activated the metabolisation of lipophilic compounds and repressed the metabolisation of carbohydrates and amino acids. In FeIII -deficient plants, fullerenol stimulated the metabolism of C3 carboxylates and lipophilic compounds while repressing the metabolism of amino acids, hexoses and dicarboxylates, while in FeII -deficient plants, activations of the metabolism of amino acids and dicarboxylates and repression of sterol metabolism by fullerenol were observed. The results indicated that the valence state of Fe sources is of importance for re-programming metabolome responses in cucumber to fullerenol either in Fe-sufficient or Fe-deficient conditions. These investigations are significant for understanding fullerenol interactions and risk assessment in plants with different Fe statuses. [ABSTRACT FROM AUTHOR]- Published
- 2021
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25. Blood microbiota and metabolomic signature of major depression before and after antidepressant treatment: a prospective case--control study.
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Ciocan, Dragos, Cassard, Anne-Marie, Becquemont, Laurent, Verstuyft, Céline, Sebastian Voican, Cosmin, Asmar, Khalil El, Colle, Romain, David, Denis, Trabado, Séverine, Feve, Bruno, Chanson, Philippe, Perlemuter, Gabriel, and Corruble, Emmanuelle
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LIPID metabolism ,TRYPTOPHAN metabolism ,BLOOD microbiology ,MENTAL depression risk factors ,BIOMARKERS ,ANTIDEPRESSANTS ,SEQUENCE analysis ,CARBOHYDRATE metabolism ,METABOLOMICS ,LIQUID chromatography ,GRAM-negative bacteria ,CASE-control method ,METABOLISM ,RISK assessment ,TREATMENT effectiveness ,TRYPTOPHAN ,HUMAN microbiota ,MENTAL depression ,MASS spectrometry ,GRAM-negative aerobic bacteria ,NEISSERIA ,GENOMICS ,AMINO acids ,XENOBIOTICS ,METABOLITES ,BACTERIA ,PHARMACODYNAMICS - Abstract
Background: The microbiota interacts with the brain through the gut--brain axis, and a distinct dysbiosis may lead to major depressive episodes. Bacteria can pass through the gut barrier and be found in the blood. Using a multiomic approach, we investigated whether a distinct blood microbiome and metabolome was associated with major depressive episodes, and how it was modulated by treatment. Methods: In this case--control multiomic study, we analyzed the blood microbiome composition, inferred bacterial functions and metabolomic profile of 56 patients experiencing a current major depressive episode and 56 matched healthy controls, before and after treatment, using 16S rDNA sequencing and liquid chromatography coupled to tandem mass spectrometry. Results: The baseline blood microbiome in patients with a major depressive episode was distinct from that of healthy controls (patients with a major depressive episode had a higher proportion of Janthinobacterium and lower levels of Neisseria) and changed after antidepressant treatment. Predicted microbiome functions confirmed by metabolomic profiling showed that patients who were experiencing a major depressive episode had alterations in the cyanoamino acid pathway at baseline. High baseline levels of Firmicutes and low proportions of Bosea and Tetrasphaera were associated with response to antidepressant treatment. Based on inferred baseline metagenomic profiles, bacterial pathways that were significantly associated with treatment response were related to xenobiotics, amino acids, and lipid and carbohydrate metabolism, including tryptophan and drug metabolism. Metabolomic analyses showed that plasma tryptophan levels are independently associated with response to antidepressant treatment. Limitations: Our study has some limitations, including a lack of information on blood microbiome origin and the lack of a validation cohort to confirm our results. Conclusion: Patients with depression have a distinct blood microbiome and metabolomic signature that changes after treatment. Dysbiosis could be a new therapeutic target and prognostic tool for the treatment of patients who are experiencing a major depressive episode. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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26. A metabolic core model elucidates how enhanced utilization of glucose and glutamine, with enhanced glutamine-dependent lactate production, promotes cancer cell growth
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Damiani, Chiara, Colombo, Riccardo, Gaglio, Daniela, Mastroianni, Fabrizia, Pescini, Dario, Westerhoff, Hans Victor, Mauri, Giancarlo, Vanoni, Marco, Alberghina, Lilia, Damiani, C, Colombo, R, Gaglio, D, Mastroianni, F, Pescini, D, Westerhoff, H, Mauri, G, Vanoni, M, Alberghina, L, Synthetic Systems Biology (SILS, FNWI), Molecular Cell Physiology, and AIMMS
- Subjects
Metabolic Processes ,0301 basic medicine ,Glucose uptake ,Glutamine ,Biochemistry ,7. Clean energy ,Glucose Metabolism ,Drug Metabolism ,Metabolic Flux Analysi ,Neoplasms ,Metabolic flux analysis ,Medicine and Health Sciences ,Amino Acids ,lcsh:QH301-705.5 ,Ecology ,Organic Compounds ,Acidic Amino Acids ,Monosaccharides ,Ketones ,Enzymes ,Flux balance analysis ,Chemistry ,Computational Theory and Mathematics ,Modeling and Simulation ,Physical Sciences ,Carbohydrate Metabolism ,Oxidoreductases ,Metabolic Networks and Pathways ,Research Article ,Chemical Elements ,Human ,Pyruvate ,Citric Acid Cycle ,Carbohydrates ,Biology ,Models, Biological ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Genetic ,Manchester Institute of Biotechnology ,Genetics ,Animals ,Humans ,Pharmacokinetics ,Computer Simulation ,Lactic Acid ,Molecular Biology ,Dehydrogenases ,Ecology, Evolution, Behavior and Systematics ,Cell Proliferation ,Pharmacology ,Organic Chemistry ,Chemical Compounds ,Biology and Life Sciences ,Proteins ,Metabolic Networks and Pathway ,Metabolism ,ResearchInstitutes_Networks_Beacons/manchester_institute_of_biotechnology ,Metabolic Flux Analysis ,Oxygen ,Citric acid cycle ,Metabolic pathway ,030104 developmental biology ,Glucose ,lcsh:Biology (General) ,Enzymology ,Acids ,Flux (metabolism) - Abstract
Cancer cells share several metabolic traits, including aerobic production of lactate from glucose (Warburg effect), extensive glutamine utilization and impaired mitochondrial electron flow. It is still unclear how these metabolic rearrangements, which may involve different molecular events in different cells, contribute to a selective advantage for cancer cell proliferation. To ascertain which metabolic pathways are used to convert glucose and glutamine to balanced energy and biomass production, we performed systematic constraint-based simulations of a model of human central metabolism. Sampling of the feasible flux space allowed us to obtain a large number of randomly mutated cells simulated at different glutamine and glucose uptake rates. We observed that, in the limited subset of proliferating cells, most displayed fermentation of glucose to lactate in the presence of oxygen. At high utilization rates of glutamine, oxidative utilization of glucose was decreased, while the production of lactate from glutamine was enhanced. This emergent phenotype was observed only when the available carbon exceeded the amount that could be fully oxidized by the available oxygen. Under the latter conditions, standard Flux Balance Analysis indicated that: this metabolic pattern is optimal to maximize biomass and ATP production; it requires the activity of a branched TCA cycle, in which glutamine-dependent reductive carboxylation cooperates to the production of lipids and proteins; it is sustained by a variety of redox-controlled metabolic reactions. In a K-ras transformed cell line we experimentally assessed glutamine-induced metabolic changes. We validated computational results through an extension of Flux Balance Analysis that allows prediction of metabolite variations. Taken together these findings offer new understanding of the logic of the metabolic reprogramming that underlies cancer cell growth., Author summary Hallmarks describing common key events in initiation, maintenance and progression of cancer have been identified. One hallmark deals with rewiring of metabolic reactions required to sustain enhanced cell proliferation. The availability of molecular, mechanistic models of cancer hallmarks will mightily improve optimized personal treatment and new drug discovery. Metabolism is the only hallmark for which it is currently possible to derive large scale mathematical models, which have predictive ability. In this paper, we exploit a constraint-based model of the core metabolism required for biomass conversion of the most relevant nutrients—glucose and glutamine—to clarify the logic of control of cancer metabolism. We newly report that, when available oxygen is not sufficient to fully oxidize available glucose and glutamine carbons–a situation compatible with that observed under normal oxygen conditions in human and in cancer cells growing in vitro—utilization of glutamine by reductive carboxylation and conversion of glucose and glutamine to lactate confer advantage for biomass production. Redox homeostasis can be maintained through the use of different alternative pathways. In conclusion, this paper offers a logic interpretation to the link between metabolic rewiring and enhanced proliferation, which may offer new approaches to targeted drug discovery and utilization.
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- 2017
27. Metabolite Concentration Changes in Humans After a Bout of Exercise: a Systematic Review of Exercise Metabolomics Studies.
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Schranner, Daniela, Kastenmüller, Gabi, Schönfelder, Martin, Römisch-Margl, Werner, and Wackerhage, Henning
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META-analysis ,METABOLOMICS ,EXERCISE ,ISOMETRIC exercise ,SMALL molecules ,RESISTANCE training ,ONLINE information services ,ENERGY metabolism ,TRICARBOXYLIC acids ,ENDURANCE sports training ,CARBOHYDRATE metabolism ,SYSTEMATIC reviews ,EXERCISE physiology ,NUCLEAR magnetic resonance spectroscopy ,NUCLEOTIDES ,RESEARCH funding ,MASS spectrometry ,MEDLINE ,AMINO acids ,METABOLITES ,PEPTIDES ,LIPIDS - Abstract
Background: Exercise changes the concentrations of many metabolites, which are small molecules (< 1.5 kDa) metabolized by the reactions of human metabolism. In recent years, especially mass spectrometry-based metabolomics methods have allowed researchers to measure up to hundreds of metabolites in a single sample in a non-biased fashion. To summarize human exercise metabolomics studies to date, we conducted a systematic review that reports the results of experiments that found metabolite concentrations changes after a bout of human endurance or resistance exercise. Methods: We carried out a systematic review following PRISMA guidelines and searched for human metabolomics studies that report metabolite concentrations before and within 24 h after endurance or resistance exercise in blood, urine, or sweat. We then displayed metabolites that significantly changed their concentration in at least two experiments. Results: Twenty-seven studies and 57 experiments matched our search criteria and were analyzed. Within these studies, 196 metabolites changed their concentration significantly within 24 h after exercise in at least two experiments. Human biofluids contain mainly unphosphorylated metabolites as the phosphorylation of metabolites such as ATP, glycolytic intermediates, or nucleotides traps these metabolites within cells. Lactate, pyruvate, TCA cycle intermediates, fatty acids, acylcarnitines, and ketone bodies all typically increase after exercise, whereas bile acids decrease. In contrast, the concentrations of proteinogenic and non-proteinogenic amino acids change in different directions. Conclusion: Across different exercise modes and in different subjects, exercise often consistently changes the average concentrations of metabolites that belong to energy metabolism and other branches of metabolism. This dataset is a useful resource for those that wish to study human exercise metabolism. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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28. Metabolomic analyses reveal substances that contribute to the increased freezing tolerance of alfalfa (Medicago sativa L.) after continuous water deficit.
- Author
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Xu, Hongyu, Li, Zhenyi, Tong, Zongyong, He, Feng, and Li, Xianglin
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ALFALFA ,BETAINE ,UNSATURATED fatty acids ,CARBOHYDRATE metabolism ,OSMOREGULATION ,AMINO acids - Abstract
Background: Alfalfa is a high-quality forage cultivated widely in northern China. Recently, the failure of alfalfa plants to survive the winter has caused substantial economic losses. Water management has attracted considerable attention as a method for the potential improvement of winter survival. The aim of this study was to determine whether and how changes in the water regime affect the freezing tolerance of alfalfa. Results: The alfalfa variety WL353LH was cultivated under water regimes of 80 and 25% of water-holding capacity, and all the plants were subjected to low temperatures at 4/0 °C (light/dark) and then − 2/− 6 °C (light/dark). The semi-lethal temperatures were lower for water-stressed than well-watered alfalfa. The pool sizes of total soluble sugars, total amino acids, and proline changed substantially under water-deficit and low-temperature conditions. Metabolomics analyses revealed 72 subclasses of differential metabolites, among which lipid and lipid-like molecules (e.g., fatty acids, unsaturated fatty acids, and glycerophospholipids) and amino acids, peptides, and analogues (e.g., proline betaine) were upregulated under water-deficit conditions. Some carbohydrates (e.g., D-maltose and raffinose) and flavonoids were also upregulated at low temperatures. Finally, Kyoto Encyclopedia of Genes and Genomes analyses revealed 18 significantly enriched pathways involved in the biosynthesis and metabolism of carbohydrates, unsaturated fatty acids, amino acids, and glycerophospholipids. Conclusions: Water deficit significantly enhanced the alfalfa' freezing tolerance, and this was correlated with increased soluble sugar, amino acid, and lipid and lipid-like molecule contents. These substances are involved in osmotic regulation, cryoprotection, and the synthesis, fluidity, and stability of the cellular membrane. Our study provides a reference for improving alfalfa' winter survival through water management. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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29. Metabolomic profiles in yak mammary gland tissue during the lactation cycle.
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Li, Zhixiong and Jiang, Mingfeng
- Subjects
MAMMARY glands ,YAK ,LACTATION ,OXALIC acid ,MILKING ,MILK yield - Abstract
The yak is one of the most important domestic animals in Tibetan life for providing basic resources such as milk, meat and transportation. Although yak milk production is not elevated, yak milk is superior to dairy cow milk in nutrient composition (protein and fat). However, the understanding of the metabolic mechanisms of yak mammary gland tissue during the lactation cycle remains elusive. In this study, GC-MS-based metabolomics was employed to study the metabolic variations in the yak mammary gland during the lactation cycle (pregnancy, lactation and dry period). Twenty-nine metabolites were up or downregulated during the lactation period. Compared to the dry period, during the lactation period the levels of oxalic acid were upregulated, while glycine and uridine were downregulated. Thirty-seven pathways were obtained when the 29 differential metabolites were imported into the KEGG pathway analysis. The most impacted pathways during the lactation cycle were glycine, serine and threonine metabolism; alanine, aspartate and glutamate metabolism; TCA cycle; glyoxylate and dicarboxylate metabolism; and pyrimidine metabolism. Our results provide important insights into the metabolic events involved in yak mammary gland development, lactogenesis and lactation, which can guide further research to improve milk yield and enhance the constituents of yak milk. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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30. Metabolic reprogramming dynamics in tumor spheroids: Insights from a multicellular, multiscale model.
- Author
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Roy, Mahua and Finley, Stacey D.
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BIOLOGICAL mathematical modeling ,TUMOR growth ,CANCER cell growth ,CANCER cell proliferation ,CANCER prevention - Abstract
Mathematical modeling provides the predictive ability to understand the metabolic reprogramming and complex pathways that mediate cancer cells’ proliferation. We present a mathematical model using a multiscale, multicellular approach to simulate avascular tumor growth, applied to pancreatic cancer. The model spans three distinct spatial and temporal scales. At the extracellular level, reaction diffusion equations describe nutrient concentrations over a span of seconds. At the cellular level, a lattice-based energy driven stochastic approach describes cellular phenomena including adhesion, proliferation, viability and cell state transitions, occurring on the timescale of hours. At the sub-cellular level, we incorporate a detailed kinetic model of intracellular metabolite dynamics on the timescale of minutes, which enables the cells to uptake and excrete metabolites and use the metabolites to generate energy and building blocks for cell growth. This is a particularly novel aspect of the model. Certain defined criteria for the concentrations of intracellular metabolites lead to cancer cell growth, proliferation or death. Overall, we model the evolution of the tumor in both time and space. Starting with a cluster of tumor cells, the model produces an avascular tumor that quantitatively and qualitatively mimics experimental measurements of multicellular tumor spheroids. Through our model simulations, we can investigate the response of individual intracellular species under a metabolic perturbation and investigate how that response contributes to the response of the tumor as a whole. The predicted response of intracellular metabolites under various targeted strategies are difficult to resolve with experimental techniques. Thus, the model can give novel predictions as to the response of the tumor as a whole, identifies potential therapies to impede tumor growth, and predicts the effects of those therapeutic strategies. In particular, the model provides quantitative insight into the dynamic reprogramming of tumor cells at the intracellular level in response to specific metabolic perturbations. Overall, the model is a useful framework to study targeted metabolic strategies for inhibiting tumor growth. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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31. Obesity-associated, but not obesity-independent, tumors respond to insulin by increasing mitochondrial glucose oxidation.
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Rabin-Court, Aviva, Rodrigues, Marcos R., Zhang, Xian-Man, and Perry, Rachel J.
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OXIDATION of glucose ,SMALL cell lung cancer ,INSULIN ,CITRATE synthase ,ANAPLASTIC lymphoma kinase ,CELL division - Abstract
Obesity is associated with increased incidence and worse prognosis of more than one dozen tumor types; however, the molecular mechanisms for this association remain under debate. We hypothesized that insulin, which is elevated in obesity-driven insulin resistance, would increase tumor glucose oxidation in obesity-associated tumors. To test this hypothesis, we applied and validated a stable isotope method to measure the ratio of pyruvate dehydrogenase flux to citrate synthase flux (V
PDH /VCS , i.e. the percent of total mitochondrial oxidation fueled by glucose) in tumor cells. Using this method, we found that three tumor cell lines associated with obesity (colon cancer [MC38], breast cancer [4T1], and prostate cancer [TRAMP-C3] cells) increase VPDH /VCS in response to physiologic concentrations of insulin. In contrast, three tumor cell lines that are not associated with obesity (melanoma [YUMM1.7], B cell lymphoma [BCL1 clone 5B1b], and small cell lung cancer [NCI-H69] cells) exhibited no oxidative response to insulin. The observed increase in glucose oxidation in response to insulin correlated with a dose-dependent increase in cell division in obesity-associated tumor cell lines when grown in insulin, whereas no alteration in cell division was seen in tumor types not associated with obesity. These data reveal that a shift in substrate preference in the setting of physiologic insulin may comprise a metabolic signature of obesity-associated tumors that differs from that of those not associated with obesity. [ABSTRACT FROM AUTHOR]- Published
- 2019
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32. NMR-based metabolic profiling of urine, serum, fecal, and pancreatic tissue samples from the Ptf1a-Cre; LSL-KrasG12D transgenic mouse model of pancreatic cancer.
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Schmahl, Michelle J., Regan, Daniel P., Rivers, Adam C., Joesten, William C., and Kennedy, Michael A.
- Subjects
PANCREATIC cancer ,NUCLEAR magnetic resonance spectroscopy ,LABORATORY mice ,CANCER-related mortality ,TUMOR markers - Abstract
Pancreatic cancer is the third leading cause of cancer deaths in the United States with more than 53,000 expected to be diagnosed with the disease in 2018. The median survival time after diagnosis is four to six months. The poor survival statistics are due in part to the fact that pancreatic cancer is typically asymptomatic until it reaches advanced stages of the disease. Although surgical resection provides the best chance of survival, pancreatic cancer is rarely detected when surgery is still possible due, in part, to lack of effective biomarkers for early detection. The goal of the research reported here was to determine if it was possible to identify metabolic biomarkers for detection of pre-cancerous pancreatic intraepithelial neoplasia (PanIN) that precede pancreatic adenocarcinoma. The transgenic Ptf1a-Cre; LSL-KrasG12D mouse strain was used as a model of pancreatic cancer progression. Nuclear magnetic resonance (NMR) spectroscopy was employed to compare metabolic profiles of urine, sera, fecal extracts, and pancreatic tissue extracts collected from control and study mice aged 5, 11, and 15 months, including 47 mice with tumors. We were able to identify the following potential biomarkers: decreased 3-indoxylsulfate, benzoate and citrate in urine, decreased glucose, choline, and lactate in blood, and decreased phenylalanine and benzoate and increased acetoin in fecal extracts. Potential biomarkers were validated by p-values, PLS-DA VIP scores, and accuracies based on area under ROC curve analyses. Essentially, all of the metabolic profiling changes could be explained as being associated with the consequences of bicarbonate wasting caused by a complete substitution of the normal pancreatic acinar tissue by tissue entirely composed of PanIN. Given the nature of the mouse model used here, our results indicate that it may be possible to use NMR-based metabolic profiling to identify biomarkers for detection of precancerous PanIN that immediately precede pancreatic cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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33. Lens metabolomic profiling as a tool to understand cataractogenesis in Atlantic salmon and rainbow trout reared at optimum and high temperature.
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Remø, Sofie Charlotte, Hevrøy, Ernst Morten, Breck, Olav, Olsvik, Pål Asgeir, and Waagbø, Rune
- Subjects
METABOLOMICS ,SYSTEMS biology ,RAINBOW trout ,ONCORHYNCHUS ,ATLANTIC salmon - Abstract
Periods of high or fluctuating seawater temperatures result in several physiological challenges for farmed salmonids, including an increased prevalence and severity of cataracts. The aim of the present study was to compare cataractogenesis in Atlantic salmon (Salmo salar L.) and rainbow trout (Oncorhynchus mykiss) reared at two temperatures, and investigate whether temperature influences lens metabolism and cataract development. Atlantic salmon (101±2 g) and rainbow trout (125±3 g) were reared in seawater at either 13°C (optimum for growth) or 19°C during the 35 days experiment (n = 4 tanks for each treatment). At the end of the experiment, the prevalence of cataracts was nearly 100% for Atlantic salmon compared to ~50% for rainbow trout, irrespective of temperature. The severity of the cataracts, as evaluated by slit-lamp inspection of the lens, was almost three fold higher in Atlantic salmon compared to rainbow trout. The global metabolic profile revealed differences in lens composition and metabolism between the two species, which may explain the observed differences in cataract susceptibility between the species. The largest differences were seen in the metabolism of amino acids, especially the histidine metabolism, and this was confirmed by a separate quantitative analysis. The global metabolic profile showed temperature dependent differences in the lens carbohydrate metabolism, osmoregulation and redox homeostasis. The results from the present study give new insight in cataractogenesis in Atlantic salmon and rainbow trout reared at high temperature, in addition to identifying metabolic markers for cataract development. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
34. Mated Drosophila melanogaster females consume more amino acids during the dark phase.
- Author
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Uchizono, Shun, Tabuki, Yumi, Kawaguchi, Natsumi, Tanimura, Teiichi, and Itoh, Taichi Q.
- Subjects
HOMEOSTASIS ,DROSOPHILA melanogaster ,AMINO acid deficiency ,AMINO acids ,CIRCADIAN rhythms - Abstract
To maintain homeostasis, animals must ingest appropriate quantities, determined by their internal nutritional state, of suitable nutrients. In the fruit fly Drosophila melanogaster, an amino acid deficit induces a specific appetite for amino acids and thus results in their increased consumption. Although multiple processes of physiology, metabolism, and behavior are under circadian control in many organisms, it is unclear whether the circadian clock also modulates such motivated behavior driven by an internal need. Differences in levels of amino acid consumption by flies between the light and dark phases of the day:night cycle were examined using a capillary feeder assay following amino acid deprivation. Female flies exhibited increased consumption of amino acids during the dark phase compared with the light phase. Investigation of mutants lacking a functional period gene (per
0 ), a well-characterized clock gene in Drosophila, found no difference between the light and dark phases in amino acid consumption by per0 flies. Furthermore, increased consumption of amino acids during the dark phase was observed in mated but not in virgin females, which strongly suggested that mating is involved in the rhythmic modulation of amino acid intake. Egg production, which is induced by mating, did not affect the rhythmic change in amino acid consumption, although egg-laying behavior showed a per0 -dependent change in rhythm. Elevated consumption of amino acids during the dark phase was partly induced by the action of a seminal protein, sex peptide (SP), on the sex peptide receptor (SPR) in females. Moreover, we showed that the increased consumption of amino acids during the dark phase is induced in mated females independently of their internal level of amino acids. These results suggest that a post-mating SP/SPR signal elevates amino acid consumption during the dark phase via the circadian clock. [ABSTRACT FROM AUTHOR]- Published
- 2017
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35. Aligning Metabolic Pathways Exploiting Binary Relation of Reactions.
- Author
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Huang, Yiran, Zhong, Cheng, Lin, Hai Xiang, and Huang, Jing
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AMINO acid metabolism ,SUBGRAPHS ,MULTIPLICATION ,SEQUENCE alignment ,MATHEMATICAL mappings ,BIOCHEMICAL research - Abstract
Metabolic pathway alignment has been widely used to find one-to-one and/or one-to-many reaction mappings to identify the alternative pathways that have similar functions through different sets of reactions, which has important applications in reconstructing phylogeny and understanding metabolic functions. The existing alignment methods exhaustively search reaction sets, which may become infeasible for large pathways. To address this problem, we present an effective alignment method for accurately extracting reaction mappings between two metabolic pathways. We show that connected relation between reactions can be formalized as binary relation of reactions in metabolic pathways, and the multiplications of zero-one matrices for binary relations of reactions can be accomplished in finite steps. By utilizing the multiplications of zero-one matrices for binary relation of reactions, we efficiently obtain reaction sets in a small number of steps without exhaustive search, and accurately uncover biologically relevant reaction mappings. Furthermore, we introduce a measure of topological similarity of nodes (reactions) by comparing the structural similarity of the k-neighborhood subgraphs of the nodes in aligning metabolic pathways. We employ this similarity metric to improve the accuracy of the alignments. The experimental results on the KEGG database show that when compared with other state-of-the-art methods, in most cases, our method obtains better performance in the node correctness and edge correctness, and the number of the edges of the largest common connected subgraph for one-to-one reaction mappings, and the number of correct one-to-many reaction mappings. Our method is scalable in finding more reaction mappings with better biological relevance in large metabolic pathways. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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- View/download PDF
36. Molecular Responses to Small Regulating Molecules against Huanglongbing Disease.
- Author
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Martinelli, Federico, Dolan, David, Fileccia, Veronica, Reagan, Russell L., Phu, My, Spann, Timothy M., McCollum, Thomas G., and Dandekar, Abhaya M.
- Subjects
CITRUS greening disease ,EARLY diagnosis ,PLANT molecular biology ,ADENINE ,INSECTS as carriers of disease - Abstract
Huanglongbing (HLB; citrus greening) is the most devastating disease of citrus worldwide. No cure is yet available for this disease and infected trees generally decline after several months. Disease management depends on early detection of symptoms and chemical control of insect vectors. In this work, different combinations of organic compounds were tested for the ability to modulate citrus molecular responses to HLB disease beneficially. Three small-molecule regulating compounds were tested: 1) L-arginine, 2) 6-benzyl-adenine combined with gibberellins, and 3) sucrose combined with atrazine. Each treatment contained K-phite mineral solution and was tested at two different concentrations. Two trials were conducted: one in the greenhouse and the other in the orchard. In the greenhouse study, responses of 42 key genes involved in sugar and starch metabolism, hormone-related pathways, biotic stress responses, and secondary metabolism in treated and untreated mature leaves were analyzed. TGA5 was significantly induced by arginine. Benzyladenine and gibberellins enhanced two important genes involved in biotic stress responses: WRKY54 and WRKY59. Sucrose combined with atrazine mainly upregulated key genes involved in carbohydrate metabolism such as sucrose-phosphate synthase, sucrose synthase, starch synthase, and α-amylase. Atrazine also affected expression of some key genes involved in systemic acquired resistance such as EDS1, TGA6, WRKY33, and MYC2. Several treatments upregulated HSP82, which might help protect protein folding and integrity. A subset of key genes was chosen as biomarkers for molecular responses to treatments under field conditions. GPT2 was downregulated by all small-molecule treatments. Arginine-induced genes involved in systemic acquired resistance included PR1, WRKY70, and EDS1. These molecular data encourage long-term application of treatments that combine these regulating molecules in field trials. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
37. Extracellular pH Modulates Neuroendocrine Prostate Cancer Cell Metabolism and Susceptibility to the Mitochondrial Inhibitor Niclosamide.
- Author
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Ippolito, Joseph E., Brandenburg, Matthew W., Ge, Xia, Crowley, Jan R., Kirmess, Kristopher M., Som, Avik, D’Avignon, D. Andre, Arbeit, Jeffrey M., Achilefu, Samuel, Yarasheski, Kevin E., and Milbrandt, Jeffrey
- Subjects
NEUROENDOCRINOLOGY ,PROSTATE cancer ,CANCER cells ,METABOLISM ,HYPOXEMIA ,DRUG efficacy - Abstract
Neuroendocrine prostate cancer is a lethal variant of prostate cancer that is associated with castrate-resistant growth, metastasis, and mortality. The tumor environment of neuroendocrine prostate cancer is heterogeneous and characterized by hypoxia, necrosis, and numerous mitoses. Although acidic extracellular pH has been implicated in aggressive cancer features including metastasis and therapeutic resistance, its role in neuroendocrine prostate cancer physiology and metabolism has not yet been explored. We used the well-characterized PNEC cell line as a model to establish the effects of extracellular pH (pH 6.5, 7.4, and 8.5) on neuroendocrine prostate cancer cell metabolism. We discovered that alkalinization of extracellular pH converted cellular metabolism to a nutrient consumption-dependent state that was susceptible to glucose deprivation, glutamine deprivation, and 2-deoxyglucose (2-DG) mediated inhibition of glycolysis. Conversely, acidic pH shifted cellular metabolism toward an oxidative phosphorylation (OXPHOS)-dependent state that was susceptible to OXPHOS inhibition. Based upon this mechanistic knowledge of pH-dependent metabolism, we identified that the FDA-approved anti-helminthic niclosamide depolarized mitochondrial potential and depleted ATP levels in PNEC cells whose effects were enhanced in acidic pH. To further establish relevance of these findings, we tested the effects of extracellular pH on susceptibility to nutrient deprivation and OXPHOS inhibition in a cohort of castrate-resistant prostate cancer cell lines C4-2B, PC-3, and PC-3M. We discovered similar pH-dependent toxicity profiles among all cell lines with these treatments. These findings underscore a potential importance to acidic extracellular pH in the modulation of cell metabolism in tumors and development of an emerging paradigm that exploits the synergy of environment and therapeutic efficacy in cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
38. Sexual Preferences in Nutrient Utilization Regulate Oxygen Consumption and Reactive Oxygen Species Generation in Schistosoma mansoni: Potential Implications for Parasite Redox Biology.
- Author
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Oliveira, Matheus P., Correa Soares, Juliana B. R., and Oliveira, Marcus F.
- Subjects
SCHISTOSOMA mansoni ,SCHISTOSOMIASIS ,OXYGEN consumption ,REACTIVE oxygen species ,CANCER chemotherapy - Abstract
Schistosoma mansoni, one of the causative agents of human schistosomiasis, has a unique antioxidant network that is key to parasite survival and a valuable chemotherapeutic target. The ability to detoxify and tolerate reactive oxygen species increases along S. mansoni development in the vertebrate host, suggesting that adult parasites are more exposed to redox challenges than young stages. Indeed, adult parasites are exposed to multiple redox insults generated from blood digestion, activated immune cells, and, potentially, from their own parasitic aerobic metabolism. However, it remains unknown how reactive oxygen species are produced by S. mansoni metabolism, as well as their biological effects on adult worms. Here, we assessed the contribution of nutrients and parasite gender to oxygen utilization pathways, and reactive oxygen species generation in whole unpaired adult S. mansoni worms. We also determined the susceptibilities of both parasite sexes to a pro-oxidant challenge. We observed that glutamine and serum importantly contribute to both respiratory and non-respiratory oxygen utilization in adult worms, but with different proportions among parasite sexes. Analyses of oxygen utilization pathways revealed that respiratory rates were high in male worms, which contrast with high non-respiratory rates in females, regardless nutritional sources. Interestingly, mitochondrial complex I-III activity was higher than complex IV specifically in females. We also observed sexual preferences in substrate utilization to sustain hydrogen peroxide production towards glucose in females, and glutamine in male worms. Despite strikingly high oxidant levels and hydrogen peroxide production rates, female worms were more resistant to a pro-oxidant challenge than male parasites. The data presented here indicate that sexual preferences in nutrient metabolism in adult S. mansoni worms regulate oxygen utilization and reactive oxygen species production, which may differently contribute to redox biology among parasite sexes. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
39. Post-Bariatric Surgery Changes in Quinolinic and Xanthurenic Acid Concentrations Are Associated with Glucose Homeostasis.
- Author
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Favennec, Marie, Hennart, Benjamin, Verbanck, Marie, Pigeyre, Marie, Caiazzo, Robert, Raverdy, Violeta, Verkindt, Hélène, Leloire, Audrey, Guillemin, Gilles J., Yengo, Loïc, Allorge, Delphine, Froguel, Philippe, Pattou, François, and Poulain-Godefroy, Odile
- Subjects
BARIATRIC surgery ,QUINOLINE ,PHYSIOLOGICAL effects of glucose ,BIOACTIVE compounds ,TRYPTOPHAN ,HOMEOSTASIS - Abstract
Background: An increase of plasma kynurenine concentrations, potentially bioactive metabolites of tryptophan, was found in subjects with obesity, resulting from low-grade inflammation of the white adipose tissue. Bariatric surgery decreases low-grade inflammation associated with obesity and improves glucose control. Objective: Our goal was to determine the concentrations of all kynurenine metabolites after bariatric surgery and whether they were correlated with glucose control improvement. Design: Kynurenine metabolite concentrations, analysed by liquid or gas chromatography coupled with tandem mass spectrometry, circulating inflammatory markers, metabolic traits, and BMI were measured before and one year after bariatric surgery in 44 normoglycemic and 47 diabetic women with obesity. Associations between changes in kynurenine metabolites concentrations and in glucose control and metabolic traits were analysed between baseline and twelve months after surgery. Results: Tryptophan and kynurenine metabolite concentrations were significantly decreased one year after bariatric surgery and were correlated with the decrease of the usCRP in both groups. Among all the kynurenine metabolites evaluated, only quinolinic acid and xanthurenic acid were significantly associated with glucose control improvement. The one year delta of quinolinic acid concentrations was negatively associated with the delta of fasting glucose (p = 0.019) and HbA1c (p = 0.014), whereas the delta of xanthurenic acid was positively associated with the delta of insulin sensitivity index (p = 0.0018). Conclusion: Bariatric surgery has induced a global down-regulation of kynurenine metabolites, associated with weight loss. Our results suggest that, since kynurenine monoxygenase diverts the kynurenine pathway toward the synthesis of xanthurenic acid, its inhibition may also contribute to glucose homeostasis. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
40. Overexpression of L-Type Amino Acid Transporter 1 (LAT1) and 2 (LAT2): Novel Markers of Neuroendocrine Tumors.
- Author
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Barollo, Susi, Bertazza, Loris, Watutantrige-Fernando, Sara, Censi, Simona, Cavedon, Elisabetta, Galuppini, Francesca, Pennelli, Gianmaria, Fassina, Ambrogio, Citton, Marilisa, Rubin, Beatrice, Pezzani, Raffaele, Benna, Clara, Opocher, Giuseppe, Iacobone, Maurizio, and Mian, Caterina
- Subjects
PHEOCHROMOCYTOMA ,AMINO acids ,NEUROENDOCRINE tumors ,GENETIC overexpression ,POLYMERASE chain reaction ,GENETICS ,DIAGNOSIS ,THERAPEUTICS - Abstract
Background: 6-18F-fluoro-L-3,4-dihydroxyphenylalanine (
18 F-FDOPA) PET is a useful tool in the clinical management of pheochromocytoma (PHEO) and medullary thyroid carcinoma (MTC).18 F-FDOPA is a large neutral amino acid biochemically resembling endogenous L-DOPA and taken up by the L-type amino acid transporters (LAT1 and LAT2). This study was conducted to examine the expression of the LAT system in PHEO and MTC. Methods: Real-time PCR and Western blot analyses were used to assess LAT1 and LAT2 gene and protein expression in 32 PHEO, 38 MTC, 16 normal adrenal medulla and 15 normal thyroid tissue samples. Immunohistochemistry method was applied to identify the proteins’ subcellular localization. Results: LAT1 and LAT2 were overexpressed in both PHEO and MTC by comparison with normal tissues. LAT1 presented a stronger induction than LAT2, and their greater expression was more evident in PHEO (15.1- and 4.1-fold increases, respectively) than in MTC (9.9- and 4.1-fold increases, respectively). Furthermore we found a good correlation between LAT1/2 and GLUT1 expression levels. A positive correlation was also found between urinary noradrenaline and adrenaline levels and LAT1 gene expression in PHEO. The increased expression of LAT1 is also confirmed at the protein level, in both PHEO and MTC, with a strong cytoplasmic localization. Conclusions: The present study is the first to provide experimental evidence of the overexpression in some NET cancers (such as PHEO or MTC) of L-type amino acid transporters, and the LAT1 isoform in particular, giving the molecular basis to explain the increase of the DOPA uptake seen in such tumor cells. [ABSTRACT FROM AUTHOR]- Published
- 2016
- Full Text
- View/download PDF
41. Contribution of Drosophila TRPA1 to Metabolism.
- Author
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Lee, Jung-Eun, Kim, Yunjung, Kim, Kyoung Heon, Lee, Do Yup, and Lee, Youngseok
- Subjects
TRP channels ,DROSOPHILA ,INSECT metabolism ,PROTEIN expression ,SOMATOMEDIN - Abstract
Transient receptor potential (TRP) cation channels are highly conserved in humans and insects. Some of these channels are expressed in internal organs and their functions remain incompletely understood. By direct knock-in of the GAL4 gene into the trpA1 locus in Drosophila, we identified the expression of this gene in the subesophageal ganglion (SOGs) region. In addition, the neurites present in the dorsal posterior region as well as the drosophila insulin-like peptide 2 (dILP2)-positive neurons send signals to the SOGs. The signal is sent to the crop, which is an enlarged organ of the esophagus and functions as a storage place for food in the digestive system. To systematically investigate the role of TRPA1 in metabolism, we applied non-targeted metabolite profiling analysis together with gas-chromatography/time-of-flight mass spectrometry, with an aim to identify a wide range of primary metabolites. We effectively captured distinctive metabolomic phenotypes and identified specific metabolic dysregulation triggered by TRPA1 mutation based on reconstructed metabolic network analysis. Primarily, the network analysis pinpointed the simultaneous down-regulation of intermediates in the methionine salvation pathway, in contrast to the synchronized up-regulation of a range of free fatty acids. The gene dosage-dependent dynamics of metabolite levels among wild-type, hetero- and homozygous mutants, and their coordinated metabolic modulation under multiple gene settings across five different genotypes confirmed the direct linkages of TRPA1 to metabolism. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
42. Protein Kinase A Activation Promotes Cancer Cell Resistance to Glucose Starvation and Anoikis.
- Author
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Palorini, Roberta, Votta, Giuseppina, Pirola, Yuri, De Vitto, Humberto, De Palma, Sara, Airoldi, Cristina, Vasso, Michele, Ricciardiello, Francesca, Lombardi, Pietro Paolo, Cirulli, Claudia, Rizzi, Raffaella, Nicotra, Francesco, Hiller, Karsten, Gelfi, Cecilia, Alberghina, Lilia, and Chiaradonna, Ferdinando
- Subjects
CYCLIC-AMP-dependent protein kinase genetics ,CANCER cells ,CELLULAR immunity ,CELL metabolism ,GLYCOLYSIS ,ANOIKIS - Abstract
Cancer cells often rely on glycolysis to obtain energy and support anabolic growth. Several studies showed that glycolytic cells are susceptible to cell death when subjected to low glucose availability or to lack of glucose. However, some cancer cells, including glycolytic ones, can efficiently acquire higher tolerance to glucose depletion, leading to their survival and aggressiveness. Although increased resistance to glucose starvation has been shown to be a consequence of signaling pathways and compensatory metabolic routes activation, the full repertoire of the underlying molecular alterations remain elusive. Using omics and computational analyses, we found that cyclic adenosine monophosphate-Protein Kinase A (cAMP-PKA) axis activation is fundamental for cancer cell resistance to glucose starvation and anoikis. Notably, here we show that such a PKA-dependent survival is mediated by parallel activation of autophagy and glutamine utilization that in concert concur to attenuate the endoplasmic reticulum (ER) stress and to sustain cell anabolism. Indeed, the inhibition of PKA-mediated autophagy or glutamine metabolism increased the level of cell death, suggesting that the induction of autophagy and metabolic rewiring by PKA is important for cancer cellular survival under glucose starvation. Importantly, both processes actively participate to cancer cell survival mediated by suspension-activated PKA as well. In addition we identify also a PKA/Src mechanism capable to protect cancer cells from anoikis. Our results reveal for the first time the role of the versatile PKA in cancer cells survival under chronic glucose starvation and anoikis and may be a novel potential target for cancer treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
43. Burkholderia pseudomallei Colony Morphotypes Show a Synchronized Metabolic Pattern after Acute Infection.
- Author
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Gierok, Philipp, Kohler, Christian, Steinmetz, Ivo, and Lalk, Michael
- Subjects
BURKHOLDERIA pseudomallei ,SOIL microbiology ,OXIDATIVE stress ,AMINO acids ,METABOLITES ,DNA replication - Abstract
Background: Burkholderia pseudomallei is a water and soil bacterium and the causative agent of melioidosis. A characteristic feature of this bacterium is the formation of different colony morphologies which can be isolated from environmental samples as well as from clinical samples, but can also be induced in vitro. Previous studies indicate that morphotypes can differ in a number of characteristics such as resistance to oxidative stress, cellular adhesion and intracellular replication. Yet the metabolic features of B. pseudomallei and its different morphotypes have not been examined in detail so far. Therefore, this study aimed to characterize the exometabolome of B. pseudomallei morphotypes and the impact of acute infection on their metabolic characteristics. Methods and Principal Findings: We applied nuclear magnetic resonance spectroscopy (
1 H-NMR) in a metabolic footprint approach to compare nutrition uptake and metabolite secretion of starvation induced morphotypes of the B. pseudomallei strains K96243 and E8. We observed gluconate production and uptake in all morphotype cultures. Our study also revealed that among all morphotypes amino acids could be classified with regard to their fast and slow consumption. In addition to these shared metabolic features, the morphotypes varied highly in amino acid uptake profiles, secretion of branched chain amino acid metabolites and carbon utilization. After intracellular passage in vitro or murine acute infection in vivo, we observed a switch of the various morphotypes towards a single morphotype and a synchronization of nutrient uptake and metabolite secretion. Conclusion: To our knowledge, this study provides first insights into the basic metabolism of B. pseudomallei and its colony morphotypes. Furthermore, our data suggest, that acute infection leads to the synchronization of B. pseudomallei colony morphology and metabolism through yet unknown host signals and bacterial mechanisms. [ABSTRACT FROM AUTHOR]- Published
- 2016
- Full Text
- View/download PDF
44. Metabolic Changes Precede the Development of Pulmonary Hypertension in the Monocrotaline Exposed Rat Lung.
- Author
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Rafikova, Olga, Meadows, Mary L., Kinchen, Jason M., Mohney, Robert P., Maltepe, Emin, Desai, Ankit A., Yuan, Jason X.-J., Garcia, Joe G. N., Fineman, Jeffrey R., Rafikov, Ruslan, and Black, Stephen M.
- Subjects
PULMONARY hypertension diagnosis ,METABOLIC profile tests ,MONOCROTALINE ,LABORATORY rats ,DISEASE progression - Abstract
There is increasing interest in the potential for metabolic profiling to evaluate the progression of pulmonary hypertension (PH). However, a detailed analysis of the metabolic changes in lungs at the early stage of PH, characterized by increased pulmonary artery pressure but prior to the development of right ventricle hypertrophy and failure, is lacking in a preclinical animal model of PH. Thus, we undertook a study using rats 14 days after exposure to monocrotaline (MCT), to determine whether we could identify early stage metabolic changes prior to the manifestation of developed PH. We observed changes in multiple pathways associated with the development of PH, including activated glycolysis, increased markers of proliferation, disruptions in carnitine homeostasis, increased inflammatory and fibrosis biomarkers, and a reduction in glutathione biosynthesis. Further, our global metabolic profile data compare favorably with prior work carried out in humans with PH. We conclude that despite the MCT-model not recapitulating all the structural changes associated with humans with advanced PH, including endothelial cell proliferation and the formation of plexiform lesions, it is very similar at a metabolic level. Thus, we suggest that despite its limitations it can still serve as a useful preclinical model for the study of PH. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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- View/download PDF
45. The Role of the Carbohydrate Recognition Domain of Placental Protein 13 (PP13) in Pregnancy Evaluated with Recombinant PP13 and the DelT221 PP13 Variant.
- Author
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Sammar, Marei, Nisamblatt, Shahar, Gonen, Ron, Huppertz, Berthold, Gizurarson, Sveinbjorn, Osol, George, and Meiri, Hamutal
- Subjects
PREGNANCY proteins ,PREGNANCY complications ,RECOMBINANT proteins ,CARBOHYDRATE metabolism ,PREECLAMPSIA ,AMINO acids - Abstract
Introduction: Placental protein 13 (PP13), a placenta specific protein, is reduced in the first trimester of pregnancy in women who subsequently develop preeclampsia. A naturally occurring PP13 deletion of thymidine at position 221 (DelT
221 or truncated variant) is associated with increased frequency of severe preeclampsia. In this study we compared the full length (wildtype) PP13 and the truncated variant. Methods: Full length PP13 or its DelT221 variant were cloned, expressed and purified from E-Coli. Both variants were administrated into pregnant rats at day 8 of pregnancy for slow release (>5 days) through osmotic pumps and rat blood pressure was measured. Animals were sacrificed at day 15 or day 21 and their utero-placental vasculature was examined. Results: The DelT221 variant (11 kDA) lacked exon 4 and a part of exon 3, and is short of 2 amino acids involved in the carbohydrate (CRD) binding of the wildtype (18 kDA). Unlike the wildtype PP13, purification of DelT221 variant required special refolding. PP13 specific poly- clonal antibodies recognized both PP13 and DelT221 but PP13 specific monoclonal antibodies recognized only the wildtype, indicating the loss of major epitopes. Wildtype PP13 mRNA and its respective proteins were both lower in PE patients compared to normal pregnancies. The DelT221 mutant was not found in a large Caucasian cohort. Pregnant rats exposed to wildtype or DelT221 PP13 variants had significantly lower blood pressure compared to control. The wildtype but not the DelT221 mutant caused extensive vein expansion. Conclusion: This study revealed the importance of PP13 in regulating blood pressure and expanding the utero-placental vasculature in pregnant rats. PP13 mutant lacking amino acids of the PP13 CRD domain fails to cause vein expansion but did reduce blood pressure. The study provides a basis for replenishing patients at risk for preeclampsia by the full length but not the truncated PP13. [ABSTRACT FROM AUTHOR]- Published
- 2014
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- View/download PDF
46. HIF1α and HIF2α Exert Distinct Nutrient Preferences in Renal Cells.
- Author
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Arreola, Alexandra, Cowey, C. Lance, Coloff, Jonathan L., Rathmell, Jeffrey C., and Rathmell, W. Kimryn
- Subjects
HYPOXIA-inducible factors ,RENAL cell carcinoma ,CANCER cell growth ,CELL metabolism ,TRANSCRIPTION factors ,GENE expression ,GLYCOLYSIS - Abstract
Background: Hypoxia Inducible Factors (HIF1α and HIF2α) are commonly stabilized and play key roles related to cell growth and metabolic programming in clear cell renal cell carcinoma. The relationship of these factors to discretely alter cell metabolic activities has largely been described in cancer cells, or in hypoxic conditions, where other confounding factors undoubtedly compete. These transcription factors and their specific roles in promoting cancer metabolic phenotypes from the earliest stages are poorly understood in pre-malignant cells. Methods: We undertook an analysis of SV40-transformed primary kidney epithelial cells derived from newborn mice genetically engineered to express a stabilized HIF1α or HIF2α transgene. We examined the metabolic profile in relation to each gene. Results: Although the cells proliferated similarly, the metabolic profile of each genotype of cell was markedly different and correlated with altered gene expression of factors influencing components of metabolic signaling. HIF1α promoted high levels of glycolysis as well as increased oxidative phosphorylation in complete media, but oxidative phosphorylation was suppressed when supplied with single carbon source media. HIF2α, in contrast, supported oxidative phosphorylation in complete media or single glucose carbon source, but these cells were not responsive to glutamine nutrient sources. This finding correlates to HIF2α-specific induction of Glul, effectively reducing glutamine utilization by limiting the glutamate pool, and knockdown of Glul allows these cells to perform oxidative phosphorylation in glutamine media. Conclusion: HIF1α and HIF2α support highly divergent patterns of kidney epithelial cell metabolic phenotype. Expression of these factors ultimately alters the nutrient resource utilization and energy generation strategy in the setting of complete or limiting nutrients. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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- View/download PDF
47. A Simple Approach for COnsumption and RElease (CORE) Analysis of Metabolic Activity in Single Mammalian Embryos.
- Author
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Guerif, Fabrice, McKeegan, Paul, Leese, Henry J., and Sturmey, Roger G.
- Subjects
BIOTRANSFORMATION (Metabolism) ,MAMMAL embryology ,BIOLOGICAL assay ,FERTILIZATION in vitro ,LACTATES ,PYRUVATES ,HIGH performance liquid chromatography - Abstract
Non-invasive assay of the consumption and release of metabolites by individual human embryos could allow selection at the cleavage stage of development and facilitate Single Embryo Transfer in clinical IVF but will require simple, high throughput, sensitive methods applicable to small volume samples. A rapid, simple, non-invasive method has therefore been devised using a standard fluorescence plate reader, and used to measure the consumption of pyruvate and glucose, and release of lactate by single bovine embryos at all stages of preimplantation development in culture; amino acid profiles have been determined using HPLC. Early embryos with an ‘intermediate’ level (6.14±0.27 pmol/embryo/h) of pyruvate uptake were associated with the highest rate (68.3%) of blastocyst development indicating that a mid “optimum” range of pyruvate consumption correlates with high viability in this bovine model. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
48. High Environmental Temperature Increases Glucose Requirement in the Developing Chicken Embryo.
- Author
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Molenaar, Roos, van den Borne, Joost J. G. C., Hazejager, Ewoud, Kristensen, Niels B., Heetkamp, Marcel J. W., Meijerhof, Ron, Kemp, Bas, and van den Brand, Henry
- Subjects
CHICKEN embryos ,DEVELOPMENTAL biology ,HIGH temperatures ,GLUCOSE metabolism ,URIC acid ,GLUCONEOGENESIS ,AMINO acids - Abstract
Environmental conditions during the perinatal period influence metabolic and developmental processes in mammals and avian species, which could impact pre- and postnatal survival and development. The current study investigated the effect of eggshell temperature (EST) on glucose metabolism in broiler chicken embryos. Broiler eggs were incubated at a high (38.9°C) or normal (37.8°C) EST from day 10.5 of incubation onward and were injected with a bolus of [U-
13 C]glucose in the chorio-allantoic fluid at day 17.5 of incubation. After [U-13 C]glucose administration,13 C enrichment was determined in intermediate pools and end-products of glucose metabolism. Oxidation of labeled glucose occurred for approximately 3 days after injection. Glucose oxidation was higher in the high than in the normal EST treatment from day 17.6 until 17.8 of incubation. The overall recovery of13 CO2 tended to be 4.7% higher in the high than in the normal EST treatment. An increase in EST (38.9°C vs 37.8°C) increased13 C enrichment in plasma lactate at day 17.8 of incubation and13 C in hepatic glycogen at day 18.8 of incubation. Furthermore, high compared to normal EST resulted in a lower yolk-free body mass at day 20.9 (−2.74 g) and 21.7 (−3.81 g) of incubation, a lower hepatic glycogen concentration at day 18.2 (−4.37 mg/g) and 18.8 (−4.59 mg/g) of incubation, and a higher plasma uric acid concentration (+2.8 mg/mL/+43%) at day 21.6 of incubation. These results indicate that the glucose oxidation pattern is relatively slow, but the intensity increased consistently with an increase in developmental stage of the embryo. High environmental temperatures in the perinatal period of chicken embryos increased glucose oxidation and decreased hepatic glycogen prior to the hatching process. This may limit glucose availability for successful hatching and could impact body development, probably by increased gluconeogenesis from glucogenic amino acids to allow anaerobic glycolysis. [ABSTRACT FROM AUTHOR]- Published
- 2013
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49. Mathematical Model of Metabolism and Electrophysiology of Amino Acid and Glucose Stimulated Insulin Secretion: In Vitro Validation Using a β-Cell Line.
- Author
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Salvucci, Manuela, Neufeld, Zoltan, and Newsholme, Philip
- Subjects
ELECTROPHYSIOLOGY ,AMINO acids ,INSULIN resistance ,METABOLISM ,MATHEMATICAL models ,ORDINARY differential equations ,DATA analysis - Abstract
We integrated biological experimental data with mathematical modelling to gain insights into the role played by L-alanine in amino acid-stimulated insulin secretion (AASIS) and in D-glucose-stimulated insulin secretion (GSIS), details important to the understanding of complex β-cell metabolic coupling relationships. We present an ordinary differential equations (ODEs) based simplified kinetic model of core metabolic processes leading to ATP production (glycolysis, TCA cycle, L-alanine-specific reactions, respiratory chain, ATPase and proton leak) and Ca
2+ handling (essential channels and pumps in the plasma membrane) in pancreatic β-cells and relate these to insulin secretion. Experimental work was performed using a clonal rat insulin-secreting cell line (BRIN-BD11) to measure the consumption or production of a range of important biochemical parameters (D-glucose, L-alanine, ATP, insulin secretion) and Ca2+ levels. These measurements were then used to validate the theoretical model and fine-tune the parameters. Mathematical modelling was used to predict L-lactate and L-glutamate concentrations following D-glucose and/or L-alanine challenge and Ca2+ levels upon stimulation with a non metabolizable L-alanine analogue. Experimental data and mathematical model simulations combined suggest that L-alanine produces a potent insulinotropic effect via both a stimulatory impact on β-cell metabolism and as a direct result of the membrane depolarization due to Ca2+ influx triggered by L-alanine/Na+ co-transport. Our simulations indicate that both high intracellular ATP and Ca2+ concentrations are required in order to develop full insulin secretory responses. The model confirmed that K+ ATP channel independent mechanisms of stimulation of intracellular Ca2+ levels, via generation of mitochondrial coupling messengers, are essential for promotion of the full and sustained insulin secretion response in β-cells. [ABSTRACT FROM AUTHOR]- Published
- 2013
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50. Expression of an Escherichia coli phosphoglucomutase in potato ( Solanum tuberosum L.) results in minor changes in tuber metabolism and a considerable delay in tuber sprouting.
- Author
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Lytovchenko, Anna, Hajirezaei, Mohammad, Eickmeier, Ira, Mittendorf, Volker, Sonnewald, Uwe, Willmitzer, Lothar, and Fernie, Alisdair
- Subjects
ESCHERICHIA coli ,PLANT genetic engineering ,TRANSGENIC organisms ,PLANT stems ,PHOTOSYNTHESIS ,AMINO acids - Abstract
The aim of this work was to evaluate the influence of elevating the cytosolic activity of phosphoglucomutase (PGM; EC 5.4.2.2) on photosynthesis, growth and heterotrophic metabolism. Here we describe the generation of novel transgenic plants expressing an Escherichia coli phosphoglucomutase ( EcPGM) under the control of the 35S promoter. These lines were characterised by an accumulation of leaf sucrose, despite displaying no alterations in photosynthetic carbon partitioning, and a reduced tuber starch content. Determinations of the levels of a wide range of other metabolites revealed dramatic reductions in maltose and other sugars in leaves of the transformants, as well as a modification of the pattern of organic and amino acid content in tubers of these lines. Intriguingly, the transgenics also displayed a dramatically delayed rate of sprouting and significantly enhanced rate of respiration, however, it is important to note that the severity of these traits did not always correlate with the level of transgene expression. These results are discussed in the context of current understanding of the control of respiration and the breaking of tuber dormancy. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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