Key Metabolic Enzymes Underlying Astrocytic Upregulation of GABAergic Plasticity

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Przemysław T. Kaczor

2017-05-01

Full Text Available GABAergic plasticity is recognized as a key mechanism of shaping the activity of the neuronal networks. However, its description is challenging because of numerous neuron-specific mechanisms. In particular, while essential role of glial cells in the excitatory plasticity is well established, their involvement in GABAergic plasticity only starts to emerge. To address this problem, we used two models: neuronal cell culture (NC and astrocyte-neuronal co-culture (ANCC, where we chemically induced long-term potentiation at inhibitory synapses (iLTP. iLTP could be induced both in NC and ANCC but in ANCC its extent was larger. Importantly, this functional iLTP manifestation was accompanied by an increase in gephyrin puncta size. Furthermore, blocking astrocyte Krebs cycle with fluoroacetate (FA in ANCC prevented enhancement of both mIPSC amplitude and gephyrin puncta size but this effect was not observed in NC, indicating a key role in neuron-astrocyte cross-talk. Blockade of monocarboxylate transport with α-Cyano-4-hydroxycinnamic acid (4CIN abolished iLTP both in NC and ANCC and in the latter model prevented also enlargement of gephyrin puncta. Similarly, blockade of glycogen phosphorylase with BAYU6751 prevented enlargement of gephyrin puncta upon iLTP induction. Finally, block of glutamine synthetase with methionine sulfoxide (MSO nearly abolished mIPSC increase in both NMDA stimulated cell groups but did not prevent enlargement of gephyrin puncta. In conclusion, we provide further evidence that GABAergic plasticity is strongly regulated by astrocytes and the underlying mechanisms involve key metabolic enzymes. Considering the strategic role of GABAergic interneurons, the plasticity described here indicates possible mechanism whereby metabolism regulates the network activity.

Studies on the metabolism and possible mechanisms of atherogenesis of lipoprotein (a)

International Nuclear Information System (INIS)

Krempler, F.

1984-01-01

The mechanisms of atherogenesis are under intensive clinical and experimental investigation. It is commonly accepted that lipoproteins play a major role in atherogenesis. The results of several clinical studies suggest that lipoprotein(a) [Lp(a)] represents an independent risk factor for atherosclerosis. In order to obtain information on the physiological and pathological role of LP(a), studies were undertaken to investigate the metabolism, removal sites, and possible atherogenic mechanism of Lp(a). It was found that Lp(a) is not metabolic product of other apoprotein B containing lipoproteins, but appears to be synthesized as a separate lipoprotein. The turnover parameters of Lp(a) resemble those of LDL. Binding studies of Lp(a) with cultured human fibroblasts demonstrated that Lp(a) is bound by the B-E receptor. After binding, Lp(a) is internalized and inhibits cellular cholesterol synthesis. In the presence of dextran sulfate or antibodies to the specific Lp(a) apoprotein or apoprotein B, Lp(a) is avidly taken up by macrophages. A similar mechanism might be responsible for the atherogenic effect of Lp(a). (Author)

Metabolic self-destruction in critically ill patients: origins, mechanisms and therapeutic principles.

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Hartl, Wolfgang H; Jauch, Karl-Walter

2014-03-01

The aim of this study was to describe the evolution and nature of self-destructive metabolic responses observed in critically ill patients, and to analyze therapeutic principles on how best to avoid or diminish these responses. We electronically identified articles through a search of PubMed and Google Scholar. Metabolic reactions associated with surgical injury or infections comprise hyperglycemia, insulin resistance, increased hepatic glucose production, and muscle protein breakdown. From an evolutionary perspective, these responses have been necessary and successful to overcome spontaneously survivable insults (minor surgical trauma). If prolonged and exaggerated, however, these reactions may become self-destructive, causing secondary metabolic damage. There is overwhelming evidence that extreme metabolic responses have not been selected by evolution, but are brought about by modern medicine enabling survival of severe, otherwise lethal insults and giving patients the chance to develop such exaggerated self-destructive metabolic reactions. Poorly adapted metabolic responses to severe insults, however, may have persisted because of unavoidable evolutionary constraints. Self-destructive metabolic responses cannot be prevented by adjuvant therapies such as artificial nutrition, which may only help to ameliorate secondary metabolic damage. Minor surgical trauma is associated with a beneficial adaptive metabolic response. After a severe insult, however, emergence of self-destructive responses will be unavoidable if the patient survives the acute phase. Effective treatment is only possible by an aggressive therapy of underlying pathologies (such as shock, trauma or infection) thereby interrupting secondary metabolic trigger mechanisms at an early stage. Copyright © 2014 Elsevier Inc. All rights reserved.

Impeded Carbohydrate Metabolism in Rice Plants under Submergence Stress

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Malay Kumar ADAK

2011-06-01

Full Text Available The detrimental effects of submergence on physiological performances of some rice varieties with special references to carbohydrate metabolisms and their allied enzymes during post-flowering stages have been documented and clarified in the present investigation. It was found that photosynthetic rate and concomitant translocation of sugars into the panicles were both related to the yield. The detrimental effects of the complete submergence were recorded in generation of sucrose, starch, sucrose phosphate synthase and phosphorylase activity in the developing panicles of the plants as compared to those under normal or control (i.e. non-submerged condition. The accumulation of starch was significantly lower in plants under submergence and that was correlated with ADP-glucose pyrophosphorylase activity. Photosynthetic rate was most affected under submergence in varying days of post-flowering and was also related to the down regulation of Ribulose bisphosphate carboxylase activity. However, under normal or control condition, there recorded a steady maintenance of photosynthetic rate at the post-flowering stages and significantly higher values of Ribulose bisphosphate carboxylase activity. Still, photosynthetic rate of the plants under both control and submerged conditions had hardly any significant correlation with sugar accumulation and other enzymes of carbohydrate metabolism like invertase with grain yield. Finally, plants under submergence suffered significant loss of yield by poor grain filling which was related to impeded carbohydrate metabolism in the tissues. It is evident that loss of yield under submergence is attributed both by lower sink size or sink capacity (number of panicles, in this case as well as subdued carbohydrate metabolism in plants and its subsequent partitioning into the grains.

Biomechanical mechanisms underlying exosuit-induced improvements in walking economy after stroke.

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Bae, Jaehyun; Awad, Louis N; Long, Andrew; O'Donnell, Kathleen; Hendron, Katy; Holt, Kenneth G; Ellis, Terry D; Walsh, Conor J

2018-03-07

Stroke-induced hemiparetic gait is characteristically asymmetric and metabolically expensive. Weakness and impaired control of the paretic ankle contribute to reduced forward propulsion and ground clearance - walking subtasks critical for safe and efficient locomotion. Targeted gait interventions that improve paretic ankle function after stroke are therefore warranted. We have developed textile-based, soft wearable robots that transmit mechanical power generated by off-board or body-worn actuators to the paretic ankle using Bowden cables (soft exosuits) and have demonstrated the exosuits can overcome deficits in paretic limb forward propulsion and ground clearance, ultimately reducing the metabolic cost of hemiparetic walking. This study elucidates the biomechanical mechanisms underlying exosuit-induced reductions in metabolic power. We evaluated the relationships between exosuit-induced changes in the body center of mass (COM) power generated by each limb, individual joint power and metabolic power. Compared with walking with an exosuit unpowered, exosuit assistance produced more symmetrical COM power generation during the critical period of the step-to-step transition (22.4±6.4% more symmetric). Changes in individual limb COM power were related to changes in paretic ( R 2 =0.83, P= 0.004) and non-paretic ( R 2 = 0.73, P= 0.014) ankle power. Interestingly, despite the exosuit providing direct assistance to only the paretic limb, changes in metabolic power were related to changes in non-paretic limb COM power ( R 2 =0.80, P= 0.007), not paretic limb COM power ( P> 0.05). These findings contribute to a fundamental understanding of how individuals post-stroke interact with an exosuit to reduce the metabolic cost of hemiparetic walking. © 2018. Published by The Company of Biologists Ltd.

Biological mechanisms underlying the role of physical fitness in health and resilience

OpenAIRE

Silverman, Marni N.; Deuster, Patricia A.

2014-01-01

Physical fitness, achieved through regular exercise and/or spontaneous physical activity, confers resilience by inducing positive psychological and physiological benefits, blunting stress reactivity, protecting against potentially adverse behavioural and metabolic consequences of stressful events and preventing many chronic diseases. In this review, we discuss the biological mechanisms underlying the beneficial effects of physical fitness on mental and physical health. Physical fitness appear...

Proteins involved in flor yeast carbon metabolism under biofilm formation conditions.

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Moreno-García, Jaime; García-Martínez, Teresa; Moreno, Juan; Mauricio, Juan Carlos

2015-04-01

A lack of sugars during the production of biologically aged wines after fermentation of grape must causes flor yeasts to metabolize other carbon molecules formed during fermentation (ethanol and glycerol, mainly). In this work, a proteome analysis involving OFFGEL fractionation prior to LC/MS detection was used to elucidate the carbon metabolism of a flor yeast strain under biofilm formation conditions (BFC). The results were compared with those obtained under non-biofilm formation conditions (NBFC). Proteins associated to processes such as non-fermentable carbon uptake, the glyoxylate and TCA cycles, cellular respiration and inositol metabolism were detected at higher concentrations under BFC than under the reference conditions (NBFC). This study constitutes the first attempt at identifying the flor yeast proteins responsible for the peculiar sensory profile of biologically aged wines. A better metabolic knowledge of flor yeasts might facilitate the development of effective strategies for improved production of these special wines. Copyright © 2014 Elsevier Ltd. All rights reserved.

[Metabolic changes in cells under electromagnetic radiation of mobile communication systems].

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Iakimenko, I L; Sidorik, E P; Tsybulin, A S

2011-01-01

Review is devoted to the analysis of biological effects of microwaves. The results of last years' researches indicated the potential risks of long-term low-level microwaves exposure for human health. The analysis of metabolic changes in living cells under the exposure of microwaves from mobile communication systems indicates that this factor is stressful for cells. Among the reproducible effects of low-level microwave radiation are overexpression of heat shock proteins, an increase of reactive oxygen species level, an increase of intracellular Ca2+, damage of DNA, inhibition of DNA reparation, and induction of apoptosis. Extracellular-signal-regulated kinases ERK and stress-related kinases p38MAPK are involved in metabolic changes. Analysis of current data suggests that the concept of exceptionally thermal mechanism of biological effects of microwaves is not correct. In turn, this raises the question of the need to revaluation of modern electromagnetic standards based on thermal effects of non-ionizing radiation on biological systems.

Mechanisms underlying KCNQ1channel cell volume sensitivity

DEFF Research Database (Denmark)

Hammami, Sofia

Cells are constantly exposed to changes in cell volume during cell metabolism, nutrient uptake, cell proliferation, cell migration and salt and water transport. In order to cope with these perturbations, potassium channels in line with chloride channels have been shown to be likely contributors...... to the process of cell volume adjustments. A great diversity of potassium channels being members of either the 6TM, 4 TM or 2 TM K+ channel gene family have been shown to be strictly regulated by small, fast changes in cell volume. However, the precise mechanism underlying the K+ channel sensitivity to cell...... volume alterations is not yet fully understood. The KCNQ1 channel belonging to the voltage gated KCNQ family is considered a precise sensor of volume changes. The goal of this thesis was to elucidate the mechanism that induces cell volume sensitivity. Until now, a number of investigators have implicitly...

Diosgenin, 4-hydroxyisoleucine, and fiber from fenugreek: mechanisms of actions and potential effects on metabolic syndrome.

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Fuller, Scott; Stephens, Jacqueline M

2015-03-01

Metabolic syndrome and its complications continue to rise in prevalence and show no signs of abating in the immediate future. Therefore, the search for effective treatments is a high priority in biomedical research. Products derived from botanicals have a time-honored history of use in the treatment of metabolic diseases including type 2 diabetes. Trigonella foenum-graecum, commonly known as fenugreek, is an annual herbaceous plant that has been a staple of traditional herbal medicine in many cultures. Although fenugreek has been studied in both clinical and basic research settings, questions remain about its efficacy and biologic mechanisms of action. Diosgenin, 4-hydroxyisoleucine, and the fiber component of the plant are the most intensively studied bioactive constituents present in fenugreek. These compounds have been demonstrated to exert beneficial effects on several physiologic markers including glucose tolerance, inflammation, insulin action, liver function, blood lipids, and cardiovascular health. Although insights into the molecular mechanisms underlying the favorable effects of fenugreek have been gained, we still do not have definitive evidence establishing its role as a therapeutic agent in metabolic disease. This review aims to summarize the currently available evidence on the physiologic effects of the 3 best-characterized bioactive compounds of fenugreek, with particular emphasis on biologic mechanisms of action relevant in the context of metabolic syndrome. © 2015 American Society for Nutrition.

Systems biology analysis of drivers underlying hallmarks of cancer cell metabolism

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Zielinski, Daniel C.; Jamshidi, Neema; Corbett, Austin J.; Bordbar, Aarash; Thomas, Alex; Palsson, Bernhard O.

2017-01-01

Malignant transformation is often accompanied by significant metabolic changes. To identify drivers underlying these changes, we calculated metabolic flux states for the NCI60 cell line collection and correlated the variance between metabolic states of these lines with their other properties. The analysis revealed a remarkably consistent structure underlying high flux metabolism. The three primary uptake pathways, glucose, glutamine and serine, are each characterized by three features: (1) metabolite uptake sufficient for the stoichiometric requirement to sustain observed growth, (2) overflow metabolism, which scales with excess nutrient uptake over the basal growth requirement, and (3) redox production, which also scales with nutrient uptake but greatly exceeds the requirement for growth. We discovered that resistance to chemotherapeutic drugs in these lines broadly correlates with the amount of glucose uptake. These results support an interpretation of the Warburg effect and glutamine addiction as features of a growth state that provides resistance to metabolic stress through excess redox and energy production. Furthermore, overflow metabolism observed may indicate that mitochondrial catabolic capacity is a key constraint setting an upper limit on the rate of cofactor production possible. These results provide a greater context within which the metabolic alterations in cancer can be understood.

Linking metabolomics data to underlying metabolic regulation

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Thomas eNägele

2014-11-01

Full Text Available The comprehensive experimental analysis of a metabolic constitution plays a central role in approaches of organismal systems biology.Quantifying the impact of a changing environment on the homeostasis of cellular metabolism has been the focus of numerous studies applying various metabolomics techniques. It has been proven that approaches which integrate different analytical techniques, e.g. LC-MS, GC-MS, CE-MS and H-NMR, can provide a comprehensive picture of a certain metabolic homeostasis. Identification of metabolic compounds and quantification of metabolite levels represent the groundwork for the analysis of regulatory strategies in cellular metabolism. This significantly promotes our current understanding of the molecular organization and regulation of cells, tissues and whole organisms.Nevertheless, it is demanding to elicit the pertinent information which is contained in metabolomics data sets.Based on the central dogma of molecular biology, metabolite levels and their fluctuations are the result of a directed flux of information from gene activation over transcription to translation and posttranslational modification.Hence, metabolomics data represent the summed output of a metabolic system comprising various levels of molecular organization.As a consequence, the inverse assignment of metabolomics data to underlying regulatory processes should yield information which-if deciphered correctly-provides comprehensive insight into a metabolic system.Yet, the deduction of regulatory principles is complex not only due to the high number of metabolic compounds, but also because of a high level of cellular compartmentalization and differentiation.Motivated by the question how metabolomics approaches can provide a representative view on regulatory biochemical processes, this article intends to present and discuss current metabolomics applications, strategies of data analysis and their limitations with respect to the interpretability in context of

Endophytic actinobacteria: Diversity, secondary metabolism and mechanisms to unsilence biosynthetic gene clusters.

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Dinesh, Raghavan; Srinivasan, Veeraraghavan; T E, Sheeja; Anandaraj, Muthuswamy; Srambikkal, Hamza

2017-09-01

Endophytic actinobacteria, which reside in the inner tissues of host plants, are gaining serious attention due to their capacity to produce a plethora of secondary metabolites (e.g. antibiotics) possessing a wide variety of biological activity with diverse functions. This review encompasses the recent reports on endophytic actinobacterial species diversity, in planta habitats and mechanisms underlying their mode of entry into plants. Besides, their metabolic potential, novel bioactive compounds they produce and mechanisms to unravel their hidden metabolic repertoire by activation of cryptic or silent biosynthetic gene clusters (BGCs) for eliciting novel secondary metabolite production are discussed. The study also reviews the classical conservative techniques (chemical/biological/physical elicitation, co-culturing) as well as modern microbiology tools (e.g. next generation sequencing) that are being gainfully employed to uncover the vast hidden scaffolds for novel secondary metabolites produced by these endophytes, which would subsequently herald a revolution in drug engineering. The potential role of these endophytes in the agro-environment as promising biological candidates for inhibition of phytopathogens and the way forward to thoroughly exploit this unique microbial community by inducing expression of cryptic BGCs for encoding unseen products with novel therapeutic properties are also discussed.

How does race get "under the skin"?: inflammation, weathering, and metabolic problems in late life.

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Das, Aniruddha

2013-01-01

Using nationally representative data from the 2005-2006 U.S. National Social Life, Health, and Aging Project, this study queries the mechanisms underlying worse metabolic outcomes--blood-sugar control and cardiovascular health--among black than white men ages 57-85. Results indicate that contrary to much of the academic literature as well as media accounts-implicitly rooted in a "culture of irresponsibility" model--older black men's social isolation, poor health behaviors, or obesity may not play a major role in their worse metabolic problems. Instead, these outcomes seem to derive more consistently from a factor almost unexamined in the literature--chronic inflammation, arguably a biological "weathering" mechanism induced by these men's cumulative and multi-dimensional stress. These findings highlight the necessity of focusing attention not simply on proximal behavioral interventions, but on broader stress-inducing social inequalities, to reduce men's race disparities in health. Copyright © 2012 Elsevier Ltd. All rights reserved.

Regulatory mechanisms of metabolic flexibility in the dark-eyed junco (Junco hyemalis).

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Stager, Maria; Swanson, David L; Cheviron, Zachary A

2015-03-01

Small temperate birds reversibly modify their aerobic performance to maintain thermoregulatory homeostasis under seasonally changing environmental conditions and these physiological adjustments may be attributable to changes in the expression of genes in the underlying regulatory networks. Here, we report the results of an experimental procedure designed to gain insight into the fundamental mechanisms of metabolic flexibility in the dark-eyed junco (Junco hyemalis). We combined genomic transcriptional profiles with measures of metabolic enzyme activities and whole-animal thermogenic performance from juncos exposed to four 6-week acclimation treatments that varied in temperature (cold, 3°C; warm, 24°C) and photoperiod (short day, 8 h light:16 h dark; long day, 16 h light:8 h dark). Cold-acclimated birds increased thermogenic capacity compared with warm-acclimated birds, and this enhanced performance was associated with upregulation of genes involved in muscle hypertrophy, angiogenesis, and lipid transport and oxidation, as well as with catabolic enzyme activities. These physiological changes occurred over ecologically relevant timescales, suggesting that birds make regulatory adjustments to interacting, hierarchical pathways in order to seasonally enhance thermogenic capacity. © 2015. Published by The Company of Biologists Ltd.

Fetal alcohol exposure disrupts metabolic signaling in hypothalamic proopiomelanocortin neurons via a circadian mechanism in male mice.

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Agapito, Maria A; Zhang, Changqing; Murugan, Sengottuvelan; Sarkar, Dipak K

2014-07-01

Early-life ethanol feeding (ELAF) alters the metabolic function of proopiomelanocortin (POMC)-producing neurons and the circadian expression of clock regulatory genes in the hypothalamus. We investigated whether the circadian mechanisms control the action of ELAF on metabolic signaling genes in POMC neurons. Gene expression measurements of Pomc and a selected group of metabolic signaling genes, Stat3, Sirt1, Pgc1-α, and Asb4 in laser-captured microdissected POMC neurons in the hypothalamus of POMC-enhanced green fluorescent protein mice showed circadian oscillations under light/dark and constant darkness conditions. Ethanol programmed these neurons such that the adult expression of Pomc, Stat3, Sirt, and Asb4 gene transcripts became arrhythmic. In addition, ELAF dampened the circadian peak of gene expression of Bmal1, Per1, and Per2 in POMC neurons. We crossed Per2 mutant mice with transgenic POMC-enhanced green fluorescent protein mice to determine the role of circadian mechanism in ELAF-altered metabolic signaling in POMC neurons. We found that ELAF failed to alter arrhythmic expression of most circadian genes, with the exception of the Bmal1 gene and metabolic signaling regulating genes in Per2 mutant mice. Comparison of the ELAF effects on the circadian blood glucose in wild-type and Per2 mutant mice revealed that ELAF dampened the circadian peak of glucose, whereas the Per2 mutation shifted the circadian cycle and prevented the ELAF dampening of the glucose peak. These data suggest the possibility that the Per2 gene mutation may regulate the ethanol actions on Pomc and the metabolic signaling genes in POMC neurons in the hypothalamus by blocking circadian mechanisms.

Metabolic Mechanism for l-Leucine-Induced Metabolome To Eliminate Streptococcus iniae.

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Du, Chao-Chao; Yang, Man-Jun; Li, Min-Yi; Yang, Jun; Peng, Bo; Li, Hui; Peng, Xuan-Xian

2017-05-05

Crucial metabolites that modulate hosts' metabolome to eliminate bacterial pathogens have been documented, but the metabolic mechanisms are largely unknown. The present study explores the metabolic mechanism for l-leucine-induced metabolome to eliminate Streptococcus iniae in tilapia. GC-MS-based metabolomics was used to investigate the tilapia liver metabolic profile in the presence of exogenous l-leucine. Thirty-seven metabolites of differential abundance were determined, and 11 metabolic pathways were enriched. Pattern recognition analysis identified serine and proline as crucial metabolites, which are the two metabolites identified in survived tilapias during S. iniae infection, suggesting that the two metabolites play crucial roles in l-leucine-induced elimination of the pathogen by the host. Exogenous l-serine reduces the mortality of tilapias infected by S. iniae, providing a robust proof supporting the conclusion. Furthermore, exogenous l-serine elevates expression of genes IL-1β and IL-8 in tilapia spleen, but not TNFα, CXCR4 and Mx, suggesting that the metabolite promotes a phagocytosis role of macrophages, which is consistent with the finding that l-leucine promotes macrophages to kill both Gram-positive and Gram-negative bacterial pathogens. Therefore, the ability of phagocytosis enhanced by exogenous l-leucine is partly attributed to elevation of l-serine. These results demonstrate a metabolic mechanism by which exogenous l-leucine modulates tilapias' metabolome to enhance innate immunity and eliminate pathogens.

Flower abscission in Vitis vinifera L. triggered by gibberellic acid and shade discloses differences in the underlying metabolic pathways

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Sara eDomingos

2015-06-01

Full Text Available Understanding abscission is both a biological and an agronomic challenge. Flower abscission induced independently by shade and gibberellic acid (GAc sprays was monitored in grapevine (Vitis vinifera L. growing under a soilless greenhouse system during two seasonal growing conditions, in an early and late production cycle. Physiological and metabolic changes triggered by each of the two distinct stimuli were determined. Environmental conditions exerted a significant effect on fruit set as showed by the higher natural drop rate recorded in the late production cycle with respect to the early cycle. Shade and GAc treatments increased the percentage of flower drop compared to the control, and at a similar degree, during the late production cycle. The reduction of leaf gas exchanges under shade conditions was not observed in GAc treated vines. The metabolic profile assessed in samples collected during the late cycle differently affected primary and secondary metabolisms and showed that most of the treatment-resulting variations occurred in opposite trends in inflorescences unbalanced in either hormonal or energy deficit abscission-inducing signals. Particularly concerning carbohydrates metabolism, sucrose, glucose, tricarboxylic acid (TCA metabolites and intermediates of the raffinose family oligosaccharides pathway were lower in shaded and higher in GAc samples. Altered oxidative stress remediation mechanisms and indolacetic acid (IAA concentration were identified as abscission signatures common to both stimuli. According to the global analysis performed, we report that grape flower abscission mechanisms triggered by GAc application and C-starvation are not based on the same metabolic pathways.

Survival under stress: molecular mechanisms of metabolic rate ...

African Journals Online (AJOL)

Studies in my laboratory are analysing the molecular mechanisms and regulatory events that underlie transitions to and from hypometabolic states In systems including anoxia-tolerant turtles and molluscs, estivating snails and toads, hibernating small mammals, and freeze tolerant frogs and insects. Our newest research ...

What fans the fire: insights into mechanisms of leptin in metabolic syndrome-associated heart diseases.

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Dong, Maolong; Ren, Jun

2014-01-01

Obesity and metabolic syndrome are one of the most devastating risk factors for cardiovascular diseases. The obesity gene product leptin plays a central role in the regulation of food intake and energy expenditure. The physiological and pathophysiological roles of leptin in cardiovascular system have been investigated extensively since its discovery in 1994. In addition to its well-established metabolic effects, more recent evidence have depicted a rather pivotal role of leptin in inflammation, oxidative stress, endoplasmic reticulum stress, apoptosis and tissue remodeling en route to the pathogenesis of type 2 diabetes mellitus, hypertension, atherosclerosis, and insulin resistance. Under physiological condition, leptin is known to reduce appetite, promote energy expenditure, increase sympathetic activity, facilitate glucose utilization and improve insulin sensitivity. In addition, leptin may regulate cardiac and vascular function through a nitric oxide-dependent mechanism. However, hyperleptinemia usually occurs with progressively increased body weight and metabolic syndrome development, leading to a state of global or selective leptin resistance. Both central and peripheral leptin resistance may be present under pathophysiological conditions such as inflammation, insulin resistance, hyperlipidemia and a cadre of other cardiovascular diseases including hypertension, atherosclerosis, obesity, ischemic heart disease and heart failure. In this review, we will discuss cardiovascular actions of leptin related to various components of metabolic syndrome. Particular emphasis will be given to insights derived from therapeutic interventions with lifestyle modification, cardiovascular drugs, anti-diabetic and anti-obesity drugs.

[Review: plant polyphenols modulate lipid metabolism and related molecular mechanism].

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Dai, Yan-li; Zou, Yu-xiao; Liu, Fan; Li, Hong-zhi

2015-11-01

Lipid metabolism disorder is an important risk factor to obesity, hyperlipidemia and type 2 diabetes as well as other chronic metabolic disease. It is also a key target in preventing metabolic syndrome, chronic disease prevention. Plant polyphenol plays an important role in maintaining or improving lipid profile in a variety of ways. including regulating cholesterol absorption, inhibiting synthesis and secretion of triglyceride, and lowering plasma low density lipoprotein oxidation, etc. The purpose of this article is to review the lipid regulation effects of plant polyphenols and its related mechanisms.

Metabolic flux analysis of Cyanothece sp. ATCC 51142 under mixotrophic conditions.

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Alagesan, Swathi; Gaudana, Sandeep B; Sinha, Avinash; Wangikar, Pramod P

2013-11-01

Cyanobacteria are a group of photosynthetic prokaryotes capable of utilizing solar energy to fix atmospheric carbon dioxide to biomass. Despite several "proof of principle" studies, low product yield is an impediment in commercialization of cyanobacteria-derived biofuels. Estimation of intracellular reaction rates by (13)C metabolic flux analysis ((13)C-MFA) would be a step toward enhancing biofuel yield via metabolic engineering. We report (13)C-MFA for Cyanothece sp. ATCC 51142, a unicellular nitrogen-fixing cyanobacterium, known for enhanced hydrogen yield under mixotrophic conditions. Rates of reactions in the central carbon metabolism under nitrogen-fixing and -non-fixing conditions were estimated by monitoring the competitive incorporation of (12)C and (13)C from unlabeled CO2 and uniformly labeled glycerol, respectively, into terminal metabolites such as amino acids. The observed labeling patterns suggest mixotrophic growth under both the conditions, with a larger fraction of unlabeled carbon in nitrate-sufficient cultures asserting a greater contribution of carbon fixation by photosynthesis and an anaplerotic pathway. Indeed, flux analysis complements the higher growth observed under nitrate-sufficient conditions. On the other hand, the flux through the oxidative pentose phosphate pathway and tricarboxylic acid cycle was greater in nitrate-deficient conditions, possibly to supply the precursors and reducing equivalents needed for nitrogen fixation. In addition, an enhanced flux through fructose-6-phosphate phosphoketolase possibly suggests the organism's preferred mode under nitrogen-fixing conditions. The (13)C-MFA results complement the reported predictions by flux balance analysis and provide quantitative insight into the organism's distinct metabolic features under nitrogen-fixing and -non-fixing conditions.

Deciphering the mechanisms involved in Portulaca oleracea (C4) response to drought: metabolic changes including crassulacean acid-like metabolism induction and reversal upon re-watering.

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D'Andrea, Rodrigo Matías; Andreo, Carlos Santiago; Lara, María Valeria

2014-11-01

Portulaca oleracea is a C(4) plant; however, under drought it can change its carbon fixation metabolism into a crassulacean acid metabolism (CAM)-like one. While the C(3) -CAM shift is well known, the C(4) -CAM transition has only been described in Portulaca. Here, a CAM-like metabolism was induced in P. oleracea by drought and then reversed by re-watering. Physiological and biochemical approaches were undertaken to evaluate the drought and recovery responses. In CAM-like plants, chlorophyll fluorescence parameters were transitory affected and non-radiative energy dissipation mechanisms were induced. Induction of flavonoids, betalains and antioxidant machinery may be involved in photosynthetic machinery protection. Metabolic analysis highlights a clear metabolic shift, when a CAM-like metabolism is induced and then reversed. Increases in nitrogenous compounds like free amino acids and urea, and of pinitol could contribute to withstand drought. Reciprocal variations in arginase and urease in drought-stressed and in re-watered plants suggest urea synthesis is strictly regulated. Recovery of C(4) metabolism was accounted by CO(2) assimilation pattern and malate levels. Increases in glycerol and in polyamines would be of importance of re-watered plants. Collectively, in P. oleracea multiple strategies, from induction of several metabolites to the transitory development of a CAM-like metabolism, participate to enhance its adaptation to drought. © 2014 Scandinavian Plant Physiology Society.

Dissecting the genetic and metabolic mechanisms of adaptation to the knockout of a major metabolic enzyme in Escherichia coli

DEFF Research Database (Denmark)

Long, Christopher P.; Gonzalez, Jacqueline E.; Feist, Adam M.

2018-01-01

Unraveling the mechanisms of microbial adaptive evolution following genetic or environmental challenges is of fundamental interest in biological science and engineering. When the challenge is the loss of a metabolic enzyme, adaptive responses can also shed significant insight into metabolic...

Concerted changes in N and C primary metabolism in alfalfa (Medicago sativa) under water restriction.

Science.gov (United States)

Aranjuelo, Iker; Tcherkez, Guillaume; Molero, Gemma; Gilard, Françoise; Avice, Jean-Christophe; Nogués, Salvador

2013-02-01

Although the mechanisms of nodule N(2) fixation in legumes are now well documented, some uncertainty remains on the metabolic consequences of water deficit. In most cases, little consideration is given to other organs and, therefore, the coordinated changes in metabolism in leaves, roots, and nodules are not well known. Here, the effect of water restriction on exclusively N(2)-fixing alfalfa (Medicago sativa L.) plants was investigated, and proteomic, metabolomic, and physiological analyses were carried out. It is shown that the inhibition of nitrogenase activity caused by water restriction was accompanied by concerted alterations in metabolic pathways in nodules, leaves, and roots. The data suggest that nodule metabolism and metabolic exchange between plant organs nearly reached homeostasis in asparagine synthesis and partitioning, as well as the N demand from leaves. Typically, there was (i) a stimulation of the anaplerotic pathway to sustain the provision of C skeletons for amino acid (e.g. glutamate and proline) synthesis; (ii) re-allocation of glycolytic products to alanine and serine/glycine; and (iii) subtle changes in redox metabolites suggesting the implication of a slight oxidative stress. Furthermore, water restriction caused little change in both photosynthetic efficiency and respiratory cost of N(2) fixation by nodules. In other words, the results suggest that under water stress, nodule metabolism follows a compromise between physiological imperatives (N demand, oxidative stress) and the lower input to sustain catabolism.

Flexibility in metabolic rate confers a growth advantage under changing food availability.

Science.gov (United States)

Auer, Sonya K; Salin, Karine; Rudolf, Agata M; Anderson, Graeme J; Metcalfe, Neil B

2015-09-01

1. Phenotypic flexibility in physiological, morphological and behavioural traits can allow organisms to cope with environmental challenges. Given recent climate change and the degree of habitat modification currently experienced by many organisms, it is therefore critical to quantify the degree of phenotypic variation present within populations, individual capacities to change and what their consequences are for fitness. 2. Flexibility in standard metabolic rate (SMR) may be particularly important since SMR reflects the minimal energetic cost of living and is one of the primary traits underlying organismal performance. SMR can increase or decrease in response to food availability, but the consequences of these changes for growth rates and other fitness components are not well known. 3. We examined individual variation in metabolic flexibility in response to changing food levels and its consequences for somatic growth in juvenile brown trout (Salmo trutta). 4. SMR increased when individuals were switched to a high food ration and decreased when they were switched to a low food regime. These shifts in SMR, in turn, were linked with individual differences in somatic growth; those individuals that increased their SMR more in response to elevated food levels grew fastest, while growth at the low food level was fastest in those individuals that depressed their SMR most. 5. Flexibility in energy metabolism is therefore a key mechanism to maximize growth rates under the challenges imposed by variability in food availability and is likely to be an important determinant of species' resilience in the face of global change. © 2015 The Authors. Journal of Animal Ecology published by John Wiley & Sons Ltd on behalf of British Ecological Society.

Various Wolbachia genotypes differently influence host Drosophila dopamine metabolism and survival under heat stress conditions.

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Gruntenko, Nataly Е; Ilinsky, Yury Yu; Adonyeva, Natalya V; Burdina, Elena V; Bykov, Roman A; Menshanov, Petr N; Rauschenbach, Inga Yu

2017-12-28

One of the most widespread prokaryotic symbionts of invertebrates is the intracellular bacteria of Wolbachia genus which can be found in about 50% of insect species. Wolbachia causes both parasitic and mutualistic effects on its host that include manipulating the host reproductive systems in order to increase their transmission through the female germline, and increasing the host fitness. One of the mechanisms, promoting adaptation in biological organisms, is a non-specific neuroendocrine stress reaction. In insects, this reaction includes catecholamines, dopamine, serotonin and octopamine, which act as neurotransmitters, neuromodulators and neurohormones. The level of dopamine metabolism correlates with heat stress resistance in Drosophila adults. To examine Wolbachia effect on Drosophila survival under heat stress and dopamine metabolism we used five strains carrying the nuclear background of interbred Bi90 strain and cytoplasmic backgrounds with different genotype variants of Wolbachia (produced by 20 backcrosses of Bi90 males with appropriate source of Wolbachia). Non-infected Bi90 strain (treated with tetracycline for 3 generations) was used as a control group. We demonstrated that two of five investigated Wolbachia variants promote changes in Drosophila heat stress resistance and activity of enzymes that produce and degrade dopamine, alkaline phosphatase and dopamine-dependent arylalkylamine N-acetyltransferase. What is especially interesting, wMelCS genotype of Wolbachia increases stress resistance and the intensity of dopamine metabolism, whereas wMelPop strain decreases them. wMel, wMel2 and wMel4 genotypes of Wolbachia do not show any effect on the survival under heat stress or dopamine metabolism. L-DOPA treatment, known to increase the dopamine content in Drosophila, levels the difference in survival under heat stress between all studied groups. The genotype of symbiont determines the effect that the symbiont has on the stress resistance of the host

In vivo analysis of NH4+ transport and central N-metabolism of Saccharomyces cerevisiae under aerobic N-limited conditions.

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Cueto-Rojas, H F; Maleki Seifar, R; Ten Pierick, A; van Helmond, W; Pieterse M, M; Heijnen, J J; Wahl, S A

2016-09-16

Ammonium is the most common N-source for yeast fermentations. Although, its transport and assimilation mechanisms are well documented, there have been only few attempts to measure the in vivo intracellular concentration of ammonium and assess its impact on gene expression. Using an isotope dilution mass spectrometry (IDMS)-based method we were able to measure the intracellular ammonium concentration in N-limited aerobic chemostat cultivations using three different N-sources (ammonium, urea and glutamate) at the same growth rate (0.05 h -1 ). The experimental results suggest that, at this growth rate, a similar concentration of intracellular ammonium, about 3.6 mmol NH 4 + /L IC , is required to supply the reactions in the central N-metabolism independent of the N-source. Based on the experimental results and different assumptions, the vacuolar and cytosolic ammonium concentrations were estimated. Furthermore, we identified a futile cycle caused by NH 3 leakage to the extracellular space, which can cost up to 30% of the ATP production of the cell under N-limited conditions, and a futile redox cycle between reactions Gdh1 and Gdh2. Finally, using shotgun proteomics with labeled reference-relative protein expression, differences between the various environmental conditions were identified and correlated with previously identified N-compound sensing mechanisms. In our work, we study central N-metabolism using quantitative approaches. First, intracellular ammonium was measured under different N-sources. The results suggest that Saccharomyces cerevisiae cells keep a constant NH 4 + concentration (around 3 mmol NH 4 + /L IC ), independent of the applied nitrogen source. We hypothesize that this amount of intracellular ammonium is required to obtain sufficient thermodynamic driving force.Furthermore, our calculations based on thermodynamic analysis of the transport mechanisms of ammonium suggest that ammonium is not equally distributed, indicating a high degree of

Ketone-Based Metabolic Therapy: Is Increased NAD+ a Primary Mechanism?

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Marwa Elamin

2017-11-01

Full Text Available The ketogenic diet’s (KD anticonvulsant effects have been well-documented for nearly a century, including in randomized controlled trials. Some patients become seizure-free and some remain so after diet cessation. Many recent studies have explored its expanded therapeutic potential in diverse neurological disorders, yet no mechanism(s of action have been established. The diet’s high fat, low carbohydrate composition reduces glucose utilization and promotes the production of ketone bodies. Ketone bodies are a more efficient energy source than glucose and improve mitochondrial function and biogenesis. Cellular energy production depends on the metabolic coenzyme nicotinamide adenine dinucleotide (NAD, a marker for mitochondrial and cellular health. Furthermore, NAD activates downstream signaling pathways (such as the sirtuin enzymes associated with major benefits such as longevity and reduced inflammation; thus, increasing NAD is a coveted therapeutic endpoint. Based on differential NAD+ utilization during glucose- vs. ketone body-based acetyl-CoA generation for entry into the tricarboxylic cycle, we propose that a KD will increase the NAD+/NADH ratio. When rats were fed ad libitum KD, significant increases in hippocampal NAD+/NADH ratio and blood ketone bodies were detected already at 2 days and remained elevated at 3 weeks, indicating an early and persistent metabolic shift. Based on diverse published literature and these initial data we suggest that increased NAD during ketolytic metabolism may be a primary mechanism behind the beneficial effects of this metabolic therapy in a variety of brain disorders and in promoting health and longevity.

Effects of epigallocatechin gallate on lipid metabolism and its underlying molecular mechanism in broiler chickens.

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Huang, J B; Zhang, Y; Zhou, Y B; Wan, X C; Zhang, J S

2015-08-01

The objective of this study was to investigate the effects of epigallocatechin gallate (EGCG) on fat metabolism and to establish the molecular mechanism of these effects in broilers. Seventy-two 28-day-old male Ross 308 broiler chickens were divided into three groups with different levels of EGCG supplementation for 4 weeks: normal control (NC) group, L-EGCG (a low-level supplement of EGCG, 40 mg/kg body weight daily) and H-EGCG (a high-level supplement of EGCG, 80 mg/kg body weight daily). After 4 weeks of oral administration, EGCG significantly reduced the level of abdominal fat deposition in broilers. The serum triglycerides and low-density lipoprotein cholesterol of chickens in H-EGCG group were also significantly decreased compared with the NC group, and the high-density lipoprotein cholesterol was notably increased at the same time. Moreover, the vital role of the liver and abdominal adipose tissue in lipid metabolism of poultry animals was examined through gene expression and enzyme activities related to fat anabolism and catabolism in these organs. Our data show that EGCG supplementation for 2 weeks significantly downregulated the expression of fatty acid synthesis and fat deposition-related genes, and upregulated the expression of genes involved in fatty acid β-oxidation and lipolysis genes. Simultaneously, the activities of hepatic fatty acid synthesis enzymes (fatty acid synthase and acetyl CoA carboxylase) were significantly decreased, and the activity of carnitine palmitoyl transferase-1 was notably elevated. The results suggest that EGCG could alleviate fat deposition in broilers through inhibiting fat anabolism and stimulating lipid catabolism in broilers. Journal of Animal Physiology and Animal Nutrition © 2014 Blackwell Verlag GmbH.

Commentary: Potential Neurobiologic Mechanisms through Which Metabolic Disorders Could Relate to Autism.

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Johnston, Michael V.

2000-01-01

To illustrate the possible relationships between metabolic disorders and autism, this commentary reviews findings from studies on the characteristics of individuals with Rett syndrome that indicate the genetic mechanism of transcriptional dysregulation can produce pathologic phenotypes which resemble metabolic disorders that stunt axonodendritic…

Mechanism of microsomal metabolism of benzene to phenol

Energy Technology Data Exchange (ETDEWEB)

Hinson, J.A.; Freeman, J.P.; Potter, D.W.; Mitchum, R.K.; Evans, F.E.

1985-05-01

The mechanism of microsomal hydroxylation of benzene to phenol has been studied by examining the microsomal metabolism of the specifically deuterated derivative 1,3,5-(/sub 2/H/sup 3/)benzene. Evidence for the formation of the following four products was obtained: 2,3,5-(/sub 2/H/sup 3/)phenol, 3,5-(/sub 2/H/sup 2/)phenol, 2,4,6-(/sub 2/H/sup 3/)phenol, and 2,4-(/sub 2/H/sup 2/)phenol. The presence of 2,3,5-(2H3)phenol and 2,4-(/sub 2/H/sup 2/)phenol shows that, in the microsomal metabolism of benzene to phenol, a NIH shift had occurred. A deuterium isotope effect (kH/kD) of approximately 4 was detected in both the meta- and para-deuterated phenols. This finding indicates that cyclohexadienone, formed either by isomerization of the epoxide or directly from the enzyme-substrate complex, is a major intermediate in the metabolism of benzene to phenol.

DRUM: a new framework for metabolic modeling under non-balanced growth. Application to the carbon metabolism of unicellular microalgae.

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Baroukh, Caroline; Muñoz-Tamayo, Rafael; Steyer, Jean-Philippe; Bernard, Olivier

2014-01-01

Metabolic modeling is a powerful tool to understand, predict and optimize bioprocesses, particularly when they imply intracellular molecules of interest. Unfortunately, the use of metabolic models for time varying metabolic fluxes is hampered by the lack of experimental data required to define and calibrate the kinetic reaction rates of the metabolic pathways. For this reason, metabolic models are often used under the balanced growth hypothesis. However, for some processes such as the photoautotrophic metabolism of microalgae, the balanced-growth assumption appears to be unreasonable because of the synchronization of their circadian cycle on the daily light. Yet, understanding microalgae metabolism is necessary to optimize the production yield of bioprocesses based on this microorganism, as for example production of third-generation biofuels. In this paper, we propose DRUM, a new dynamic metabolic modeling framework that handles the non-balanced growth condition and hence accumulation of intracellular metabolites. The first stage of the approach consists in splitting the metabolic network into sub-networks describing reactions which are spatially close, and which are assumed to satisfy balanced growth condition. The left metabolites interconnecting the sub-networks behave dynamically. Then, thanks to Elementary Flux Mode analysis, each sub-network is reduced to macroscopic reactions, for which simple kinetics are assumed. Finally, an Ordinary Differential Equation system is obtained to describe substrate consumption, biomass production, products excretion and accumulation of some internal metabolites. DRUM was applied to the accumulation of lipids and carbohydrates of the microalgae Tisochrysis lutea under day/night cycles. The resulting model describes accurately experimental data obtained in day/night conditions. It efficiently predicts the accumulation and consumption of lipids and carbohydrates.

DRUM: a new framework for metabolic modeling under non-balanced growth. Application to the carbon metabolism of unicellular microalgae.

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Caroline Baroukh

Full Text Available Metabolic modeling is a powerful tool to understand, predict and optimize bioprocesses, particularly when they imply intracellular molecules of interest. Unfortunately, the use of metabolic models for time varying metabolic fluxes is hampered by the lack of experimental data required to define and calibrate the kinetic reaction rates of the metabolic pathways. For this reason, metabolic models are often used under the balanced growth hypothesis. However, for some processes such as the photoautotrophic metabolism of microalgae, the balanced-growth assumption appears to be unreasonable because of the synchronization of their circadian cycle on the daily light. Yet, understanding microalgae metabolism is necessary to optimize the production yield of bioprocesses based on this microorganism, as for example production of third-generation biofuels. In this paper, we propose DRUM, a new dynamic metabolic modeling framework that handles the non-balanced growth condition and hence accumulation of intracellular metabolites. The first stage of the approach consists in splitting the metabolic network into sub-networks describing reactions which are spatially close, and which are assumed to satisfy balanced growth condition. The left metabolites interconnecting the sub-networks behave dynamically. Then, thanks to Elementary Flux Mode analysis, each sub-network is reduced to macroscopic reactions, for which simple kinetics are assumed. Finally, an Ordinary Differential Equation system is obtained to describe substrate consumption, biomass production, products excretion and accumulation of some internal metabolites. DRUM was applied to the accumulation of lipids and carbohydrates of the microalgae Tisochrysis lutea under day/night cycles. The resulting model describes accurately experimental data obtained in day/night conditions. It efficiently predicts the accumulation and consumption of lipids and carbohydrates.

Damage mechanisms in PBT-GF30 under thermo-mechanical cyclic loading

International Nuclear Information System (INIS)

Schaaf, A.; De Monte, M.; Hoffmann, C.; Vormwald, M.; Quaresimin, M.

2014-01-01

The scope of this paper is the investigation of damage mechanisms at microscopic scale on a short glass fiber reinforced polybutylene terephthalate (PBT-GF30) under thermo-mechanical cyclic loading. In addition the principal mechanisms are verified through micro mechanical FE models. In order to investigate the fatigue behavior of the material both isothermal strain controlled fatigue (ISCF) tests at three different temperatures and thermo-mechanical fatigue (TMF) tests were conducted on plain and notched specimens, manufactured by injection molding. The goal of the work is to determine the damage mechanisms occurring under TMF conditions and to compare them with the mechanisms occurring under ISCF. For this reason fracture surfaces of TMF and ISCF samples loaded at different temperature levels were analyzed using scanning electron microscopy. Furthermore, specimens that failed under TMF were examined on microsections revealing insight into both crack initiation and crack propagation. The findings of this investigation give valuable information about the main damage mechanisms of PBT-GF30 under TMF loading and serve as basis for the development of a TMF life estimation methodology

The neuropeptide allatostatin A regulates metabolism and feeding decisions in Drosophila

DEFF Research Database (Denmark)

Hentze, Julie Lilith; Carlsson, Mikael A.; Kondo, Shu

2015-01-01

Coordinating metabolism and feeding is important to avoid obesity and metabolic diseases, yet the underlying mechanisms, balancing nutrient intake and metabolic expenditure, are poorly understood. Several mechanisms controlling these processes are conserved in Drosophila, where homeostasis and en...

Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia

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Metallo, Christian M.; Gameiro, Paulo A.; Bell, Eric L.; Mattaini, Katherine R.; Yang, Juanjuan; Hiller, Karsten; Jewell, Christopher M.; Johnson, Zachary R.; Irvine, Darrell J.; Guarente, Leonard; Kelleher, Joanne K.; Vander Heiden, Matthew G.; Iliopoulos, Othon; Stephanopoulos, Gregory

2013-01-01

Acetyl coenzyme A (AcCoA) is the central biosynthetic precursor for fatty acid synthesis and protein acetylation. In the conventional view of mammalian cell metabolism, AcCoA is primarily generated from glucose-derived pyruvate through the citrate shuttle and adenosine triphosphate citrate lyase (ACL) in the cytosol1-3. However, proliferating cells that exhibit aerobic glycolysis and those exposed to hypoxia convert glucose to lactate at near stoichiometric levels, directing glucose carbon away from the tricarboxylic acid cycle (TCA) and fatty acid synthesis4. Although glutamine is consumed at levels exceeding that required for nitrogen biosynthesis5, the regulation and utilization of glutamine metabolism in hypoxic cells is not well understood. Here we show that human cells employ reductive metabolism of alpha-ketoglutarate (αKG) to synthesize AcCoA for lipid synthesis. This isocitrate dehydrogenase 1 (IDH1) dependent pathway is active in most cell lines under normal culture conditions, but cells grown under hypoxia rely almost exclusively on the reductive carboxylation of glutamine-derived αKG for de novo lipogenesis. Furthermore, renal cell lines deficient in the von Hippel-Lindau (VHL) tumor suppressor protein preferentially utilize reductive glutamine metabolism for lipid biosynthesis even at normal oxygen levels. These results identify a critical role for oxygen in regulating carbon utilization in order to produce AcCoA and support lipid synthesis in mammalian cells. PMID:22101433

Metabolism of vertebrate amino sugars with N-glycolyl groups: mechanisms underlying gastrointestinal incorporation of the non-human sialic acid xeno-autoantigen N-glycolylneuraminic acid.

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Banda, Kalyan; Gregg, Christopher J; Chow, Renee; Varki, Nissi M; Varki, Ajit

2012-08-17

Although N-acetyl groups are common in nature, N-glycolyl groups are rare. Mammals express two major sialic acids, N-acetylneuraminic acid and N-glycolylneuraminic acid (Neu5Gc). Although humans cannot produce Neu5Gc, it is detected in the epithelial lining of hollow organs, endothelial lining of the vasculature, fetal tissues, and carcinomas. This unexpected expression is hypothesized to result via metabolic incorporation of Neu5Gc from mammalian foods. This accumulation has relevance for diseases associated with such nutrients, via interaction with Neu5Gc-specific antibodies. Little is known about how ingested sialic acids in general and Neu5Gc in particular are metabolized in the gastrointestinal tract. We studied the gastrointestinal and systemic fate of Neu5Gc-containing glycoproteins (Neu5Gc-glycoproteins) or free Neu5Gc in the Neu5Gc-free Cmah(-/-) mouse model. Ingested free Neu5Gc showed rapid absorption into the circulation and urinary excretion. In contrast, ingestion of Neu5Gc-glycoproteins led to Neu5Gc incorporation into the small intestinal wall, appearance in circulation at a steady-state level for several hours, and metabolic incorporation into multiple peripheral tissue glycoproteins and glycolipids, thus conclusively proving that Neu5Gc can be metabolically incorporated from food. Feeding Neu5Gc-glycoproteins but not free Neu5Gc mimics the human condition, causing tissue incorporation into human-like sites in Cmah(-/-) fetal and adult tissues, as well as developing tumors. Thus, glycoproteins containing glycosidically linked Neu5Gc are the likely dietary source for human tissue accumulation, and not the free monosaccharide. This human-like model can be used to elucidate specific mechanisms of Neu5Gc delivery from the gut to tissues, as well as general mechanisms of metabolism of ingested sialic acids.

Altered drug metabolism during pregnancy: hormonal regulation of drug-metabolizing enzymes.

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Jeong, Hyunyoung

2010-06-01

Medication use during pregnancy is prevalent, but pharmacokinetic information of most drugs used during pregnancy is lacking in spite of known effects of pregnancy on drug disposition. Accurate pharmacokinetic information is essential for optimal drug therapy in mother and fetus. Thus, understanding how pregnancy influences drug disposition is important for better prediction of pharmacokinetic changes of drugs in pregnant women. Pregnancy is known to affect hepatic drug metabolism, but the underlying mechanisms remain unknown. Physiological changes accompanying pregnancy are probably responsible for the reported alteration in drug metabolism during pregnancy. These include elevated concentrations of various hormones such as estrogen, progesterone, placental growth hormones and prolactin. This review covers how these hormones influence expression of drug-metabolizing enzymes (DMEs), thus potentially responsible for altered drug metabolism during pregnancy. The reader will gain a greater understanding of the altered drug metabolism in pregnant women and the regulatory effects of pregnancy hormones on expression of DMEs. In-depth studies in hormonal regulatory mechanisms as well as confirmatory studies in pregnant women are warranted for systematic understanding and prediction of the changes in hepatic drug metabolism during pregnancy.

The redox mechanism for vascular barrier dysfunction associated with metabolic disorders: Glutathionylation of Rac1 in endothelial cells.

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Han, Jingyan; Weisbrod, Robert M; Shao, Di; Watanabe, Yosuke; Yin, Xiaoyan; Bachschmid, Markus M; Seta, Francesca; Janssen-Heininger, Yvonne M W; Matsui, Reiko; Zang, Mengwei; Hamburg, Naomi M; Cohen, Richard A

2016-10-01

Oxidative stress is implicated in increased vascular permeability associated with metabolic disorders, but the underlying redox mechanism is poorly defined. S-glutathionylation, a stable adduct of glutathione with protein sulfhydryl, is a reversible oxidative modification of protein and is emerging as an important redox signaling paradigm in cardiovascular physiopathology. The present study determines the role of protein S-glutathionylation in metabolic stress-induced endothelial cell permeability. In endothelial cells isolated from patients with type-2 diabetes mellitus, protein S-glutathionylation level was increased. This change was also observed in aortic endothelium in ApoE deficient (ApoE -/- ) mice fed on Western diet. Metabolic stress-induced protein S-glutathionylation in human aortic endothelial cells (HAEC) was positively correlated with elevated endothelial cell permeability, as reflected by disassembly of cell-cell adherens junctions and cortical actin structures. These impairments were reversed by adenoviral overexpression of a specific de-glutathionylation enzyme, glutaredoxin-1 in cultured HAECs. Consistently, transgenic overexpression of human Glrx-1 in ApoE -/- mice fed the Western diet attenuated endothelial protein S-glutathionylation, actin cytoskeletal disorganization, and vascular permeability in the aorta. Mechanistically, glutathionylation and inactivation of Rac1, a small RhoGPase, were associated with endothelial hyperpermeability caused by metabolic stress. Glutathionylation of Rac1 on cysteine 81 and 157 located adjacent to guanine nucleotide binding site was required for the metabolic stress to inhibit Rac1 activity and promote endothelial hyperpermeability. Glutathionylation and inactivation of Rac1 in endothelial cells represent a novel redox mechanism of vascular barrier dysfunction associated with metabolic disorders. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Evidence for transgenerational metabolic programming in Drosophila

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Jessica L. Buescher

2013-09-01

Worldwide epidemiologic studies have repeatedly demonstrated an association between prenatal nutritional environment, birth weight and susceptibility to adult diseases including obesity, cardiovascular disease and type 2 diabetes. Despite advances in mammalian model systems, the molecular mechanisms underlying this phenomenon are unclear, but might involve programming mechanisms such as epigenetics. Here we describe a new system for evaluating metabolic programming mechanisms using a simple, genetically tractable Drosophila model. We examined the effect of maternal caloric excess on offspring and found that a high-sugar maternal diet alters body composition of larval offspring for at least two generations, augments an obese-like phenotype under suboptimal (high-calorie feeding conditions in adult offspring, and modifies expression of metabolic genes. Our data indicate that nutritional programming mechanisms could be highly conserved and support the use of Drosophila as a model for evaluating the underlying genetic and epigenetic contributions to this phenomenon.

Invariability of Central Metabolic Flux Distribution in Shewanella oneidensis MR-1 Under Environmental or Genetic Perturbations

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Tang, Yinjie; Martin, Hector Garcia; Deutschbauer, Adam; Feng, Xueyang; Huang, Rick; Llora, Xavier; Arkin, Adam; Keasling, Jay D.

2009-04-21

An environmentally important bacterium with versatile respiration, Shewanella oneidensis MR-1, displayed significantly different growth rates under three culture conditions: minimal medium (doubling time {approx} 3 hrs), salt stressed minimal medium (doubling time {approx} 6 hrs), and minimal medium with amino acid supplementation (doubling time {approx}1.5 hrs). {sup 13}C-based metabolic flux analysis indicated that fluxes of central metabolic reactions remained relatively constant under the three growth conditions, which is in stark contrast to the reported significant changes in the transcript and metabolite profiles under various growth conditions. Furthermore, ten transposon mutants of S. oneidensis MR-1 were randomly chosen from a transposon library and their flux distributions through central metabolic pathways were revealed to be identical, even though such mutational processes altered the secondary metabolism, for example, glycine and C1 (5,10-Me-THF) metabolism.

Distinct age and differentiation-state dependent metabolic profiles of oligodendrocytes under optimal and stress conditions.

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Vijayaraghava T S Rao

Full Text Available Within the microenvironment of multiple sclerosis lesions, oligodendrocytes are subject to metabolic stress reflecting effects of focal ischemia and inflammation. Previous studies have shown that under optimal conditions in vitro, the respiratory activity of human adult brain-derived oligodendrocytes is lower and more predominantly glycolytic compared to oligodendrocytes differentiated in vitro from post natal rat brain oligodendrocyte progenitor cells. In response to sub-lethal metabolic stress, adult human oligodendrocytes reduce overall energy production rate impacting the capacity to maintain myelination. Here, we directly compare the metabolic profiles of oligodendrocytes derived from adult rat brain with oligodendrocytes newly differentiated in vitro from oligodendrocyte progenitor cells obtained from the post natal rat brain, under both optimal culture and metabolic stress (low/no glucose conditions. Oxygen consumption and extracellular acidification rates were measured using a Seahorse extracellular flux analyzer. Our findings indicate that under optimal conditions, adult rat oligodendrocytes preferentially use glycolysis whereas newly differentiated post natal rat oligodendrocytes, and the oligodendrocyte progenitor cells from which they are derived, mainly utilize oxidative phosphorylation to produce ATP. Metabolic stress increases the rate of ATP production via oxidative phosphorylation and significantly reduces glycolysis in adult oligodendrocytes. The rate of ATP production was relatively unchanged in newly differentiated post natal oligodendrocytes under these stress conditions, while it was significantly reduced in oligodendrocyte progenitor cells. Our study indicates that both age and maturation influence the metabolic profile under optimal and stressed conditions, emphasizing the need to consider these variables for in vitro studies that aim to model adult human disease.

Exogenous trehalose improves growth under limiting nitrogen through upregulation of nitrogen metabolism.

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Lin, Yingchao; Zhang, Jie; Gao, Weichang; Chen, Yi; Li, Hongxun; Lawlor, David W; Paul, Matthew J; Pan, Wenjie

2017-12-19

The trehalose (Tre) pathway has strong effects on growth and development in plants through regulation of carbon metabolism. Altering either Tre or trehalose 6-phosphate (T6P) can improve growth and productivity of plants as observed under different water availability. As yet, there are no reports of the effects of modification of Tre orT6P on plant performance under limiting nutrition. Here we report that nitrogen (N) metabolism is positively affected by exogenous application of Tre in nitrogen-deficient growing conditions. Spraying foliage of tobacco (Nicotiana tabacum) with trehalose partially alleviated symptoms of nitrogen deficiency through upregulation of nitrate and ammonia assimilation and increasing activities of nitrate reductase (NR), glycolate oxidase (GO), glutamine synthetase (GS) and glutamine oxoglutarate aminotransferase (GOGAT) with concomitant changes in ammonium (NH 4 + ) and nitrate (NO 3 - ) concentrations, glutamine and amino acids. Chlorophyll and total nitrogen content of leaves and rates of photosynthesis were increased compared to nitrogen-deficient plants without applied Tre. Total plant biomass accumulation was also higher in Tre -fed nitrogen-deficient plants, with a smaller proportion of dry weight partitioned to roots, compared to nitrogen-deficient plants without applied Tre. Consistent with higher nitrogen assimilation and growth, Tre application reduced foliar starch. Minimal effects of Tre feeding were observed on nitrogen-sufficient plants. The data show, for the first time, significant stimulatory effects of exogenous Tre on nitrogen metabolism and growth in plants growing under deficient nitrogen. Under such adverse conditions metabolism is regulated for survival rather than productivity. Application of Tre can alter this regulation towards maintenance of productive functions under low nitrogen. This has implications for considering approaches to modifying the Tre pathway for to improve crop nitrogen-use efficiency and

Quantum Mechanics/Molecular Mechanics Modeling of Drug Metabolism: Mexiletine N-Hydroxylation by Cytochrome P450 1A2.

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Lonsdale, Richard; Fort, Rachel M; Rydberg, Patrik; Harvey, Jeremy N; Mulholland, Adrian J

2016-06-20

The mechanism of cytochrome P450(CYP)-catalyzed hydroxylation of primary amines is currently unclear and is relevant to drug metabolism; previous small model calculations have suggested two possible mechanisms: direct N-oxidation and H-abstraction/rebound. We have modeled the N-hydroxylation of (R)-mexiletine in CYP1A2 with hybrid quantum mechanics/molecular mechanics (QM/MM) methods, providing a more detailed and realistic model. Multiple reaction barriers have been calculated at the QM(B3LYP-D)/MM(CHARMM27) level for the direct N-oxidation and H-abstraction/rebound mechanisms. Our calculated barriers indicate that the direct N-oxidation mechanism is preferred and proceeds via the doublet spin state of Compound I. Molecular dynamics simulations indicate that the presence of an ordered water molecule in the active site assists in the binding of mexiletine in the active site, but this is not a prerequisite for reaction via either mechanism. Several active site residues play a role in the binding of mexiletine in the active site, including Thr124 and Phe226. This work reveals key details of the N-hydroxylation of mexiletine and further demonstrates that mechanistic studies using QM/MM methods are useful for understanding drug metabolism.

Training-induced acceleration of oxygen uptake kinetics in skeletal muscle: the underlying mechanisms.

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Zoladz, J A; Korzeniewski, B; Grassi, B

2006-11-01

It is well known that the oxygen uptake kinetics during rest-to-work transition (V(O2) on-kinetics) in trained subjects is significantly faster than in untrained individuals. It was recently postulated that the main system variable that determines the transition time (t(1/2)) of the V(O2) on-kinetics in skeletal muscle, at a given moderate ATP usage/work intensity, and under the assumption that creatine kinase reaction works near thermodynamic equilibrium, is the absolute (in mM) decrease in [PCr] during rest-to-work transition. Therefore we postulate that the training-induced acceleration of the V(O2) on-kinetics is a marker of an improvement of absolute metabolic stability in skeletal muscles. The most frequently postulated factor responsible for enhancement of muscle metabolic stability is the training-induced increase in mitochondrial proteins. However, the mechanism proposed by Gollnick and Saltin (1982) can improve absolute metabolic stability only if training leads to a decrease in resting [ADP(free)]. This effect is not observed in many examples of training causing an acceleration of the V(O2) on-kinetics, especially in early stages of training. Additionally, this mechanism cannot account for the significant training-induced increase in the relative (expressed in % or as multiples of the resting values) metabolic stability at low work intensities, condition in which oxidative phosphorylation is not saturated with [ADP(free)]. Finally, it was reported that in the early stage of training, acceleration in the V(O2) on-kinetics and enhancement of muscle metabolic stability may precede adaptive responses in mitochondrial enzymes activities or mitochondria content. We postulate that the training-induced acceleration in the V(O2) on-kinetics and the improvement of the metabolite stability during moderate intensity exercise in the early stage of training is mostly caused by an intensification of the "parallel activation" of ATP consumption and ATP supply pathways

Myocardial Oxidative Metabolism and Protein Synthesis during Mechanical Circulatory Support by Extracorporeal Membrane Oxygenation

Energy Technology Data Exchange (ETDEWEB)

Priddy, MD, Colleen M.; Kajimoto, Masaki; Ledee, Dolena; Bouchard, Bertrand; Isern, Nancy G.; Olson, Aaron; Des Rosiers, Christine; Portman, Michael A.

2013-02-01

Extracorporeal membrane oxygenation (ECMO) provides mechanical circulatory support essential for survival in infants and children with acute cardiac decompensation. However, ECMO also causes metabolic disturbances, which contribute to total body wasting and protein loss. Cardiac stunning can also occur which prevents ECMO weaning, and contributes to high mortality. The heart may specifically undergo metabolic impairments, which influence functional recovery. We tested the hypothesis that ECMO alters oxidative. We focused on the amino acid leucine, and integration with myocardial protein synthesis. We used a translational immature swine model in which we assessed in heart (i) the fractional contribution of leucine (FcLeucine) and pyruvate (FCpyruvate) to mitochondrial acetyl-CoA formation by nuclear magnetic resonance and (ii) global protein fractional synthesis (FSR) by gas chromatography-mass spectrometry. Immature mixed breed Yorkshire male piglets (n = 22) were divided into four groups based on loading status (8 hours of normal circulation or ECMO) and intracoronary infusion [13C6,15N]-L-leucine (3.7 mM) alone or with [2-13C]-pyruvate (7.4 mM). ECMO decreased pulse pressure and correspondingly lowered myocardial oxygen consumption (~ 40%, n = 5), indicating decreased overall mitochondrial oxidative metabolism. However, FcLeucine was maintained and myocardial protein FSR was marginally increased. Pyruvate addition decreased tissue leucine enrichment, FcLeucine, and Fc for endogenous substrates as well as protein FSR. Conclusion: The heart under ECMO shows reduced oxidative metabolism of substrates, including amino acids, while maintaining (i) metabolic flexibility indicated by ability to respond to pyruvate, and (ii) a normal or increased capacity for global protein synthesis, suggesting an improved protein balance.

Metabolic state alters economic decision making under risk in humans.

Directory of Open Access Journals (Sweden)

Mkael Symmonds

2010-06-01

Full Text Available Animals' attitudes to risk are profoundly influenced by metabolic state (hunger and baseline energy stores. Specifically, animals often express a preference for risky (more variable food sources when below a metabolic reference point (hungry, and safe (less variable food sources when sated. Circulating hormones report the status of energy reserves and acute nutrient intake to widespread targets in the central nervous system that regulate feeding behaviour, including brain regions strongly implicated in risk and reward based decision-making in humans. Despite this, physiological influences per se have not been considered previously to influence economic decisions in humans. We hypothesised that baseline metabolic reserves and alterations in metabolic state would systematically modulate decision-making and financial risk-taking in humans.We used a controlled feeding manipulation and assayed decision-making preferences across different metabolic states following a meal. To elicit risk-preference, we presented a sequence of 200 paired lotteries, subjects' task being to select their preferred option from each pair. We also measured prandial suppression of circulating acyl-ghrelin (a centrally-acting orexigenic hormone signalling acute nutrient intake, and circulating leptin levels (providing an assay of energy reserves. We show both immediate and delayed effects on risky decision-making following a meal, and that these changes correlate with an individual's baseline leptin and changes in acyl-ghrelin levels respectively.We show that human risk preferences are exquisitely sensitive to current metabolic state, in a direction consistent with ecological models of feeding behaviour but not predicted by normative economic theory. These substantive effects of state changes on economic decisions perhaps reflect shared evolutionarily conserved neurobiological mechanisms. We suggest that this sensitivity in human risk-preference to current metabolic state has

Transcriptome-based analysis on carbon metabolism of Haematococcus pluvialis mutant under 15% CO2.

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Li, Ke; Cheng, Jun; Lu, Hongxiang; Yang, Weijuan; Zhou, Junhu; Cen, Kefa

2017-06-01

To elucidate the mechanism underlying the enhanced growth rate in the Haematococcus pluvialis mutated with 60 Co-γ rays and domesticated with 15% CO 2 , transcriptome sequencing was conducted to clarify the carbon metabolic pathways of mutant cells. The CO 2 fixation rate of mutant cells increased to 2.57gL -1 d -1 under 15% CO 2 due to the enhanced photosynthesis, carbon fixation, glycolysis pathways. The upregulation of PetH, ATPF0A and PetJ related to photosynthetic electron transport, ATP synthase and NADPH generation promoted the photosynthesis. The upregulation of genes related to Calvin cycle and ppdK promoted carbon fixation in both C3 and C4 photosynthetic pathways. The reallocation of carbon was also enhanced under 15% CO 2 . The 19-, 14- and 3.5-fold upregulation of FBA, TPI and PK genes, respectively, remarkably promoted the glycolysis pathways. This accelerated the conversion of photosynthetic carbon to pyruvate, which was an essential precursor for astaxanthin and lipids biosynthesis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Molecular Mechanisms Underlying γ-Aminobutyric Acid (GABA) Accumulation in Giant Embryo Rice Seeds.

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Zhao, Guo-Chao; Xie, Mi-Xue; Wang, Ying-Cun; Li, Jian-Yue

2017-06-21

To uncover the molecular mechanisms underlying GABA accumulation in giant embryo rice seeds, we analyzed the expression levels of GABA metabolism genes and contents of GABA and GABA metabolic intermediates in developing grains and germinated brown rice of giant embryo rice 'Shangshida No. 5' and normal embryo rice 'Chao2-10' respectively. In developing grains, the higher GABA contents in 'Shangshida No. 5' were accompanied with upregulation of gene transcripts and intermediate contents in the polyamine pathway and downregulation of GABA catabolic gene transcripts, as compared with those in 'Chao2-10'. In germinated brown rice, the higher GABA contents in 'Shangshida No. 5' were parallel with upregulation of OsGAD and polyamine pathway gene transcripts and Glu and polyamine pathway intermediate contents and downregulation of GABA catabolic gene transcripts. These results are the first to indicate that polyamine pathway and GABA catabolic genes play a crucial role in GABA accumulation in giant embryo rice seeds.

Metabolic Syndrome and Cardio-Cerebrovascular Risk Disparities Between Pilots and Aircraft Mechanics.

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Kim, Myeong-Bo; Kim, Hyun-Jin; Kim, Soo-Hyeon; Lee, Suk-Ho; Lee, Se-Ho; Park, Won-Ju

2017-09-01

In the Republic of Korea Air Force, the health of pilots is strictly supervised, but there is comparatively not enough interest in aircraft mechanics' health. Among mechanics, who are heavily involved in military aircraft maintenance, the occurrence of sudden cardio-cerebrovascular diseases (CCVDs) is a possible risk factor during the maintenance process, which should be performed perfectly. We performed health examinations on 2123 male aircraft pilots and 1271 aircraft mechanics over 30 yr of age and determined the prevalence of metabolic syndrome (MetS), an important risk factor for CCVDs. The prevalence of MetS in the aircraft mechanics (21.3%) was significantly higher than in the pilots (12.6%), and the gap in prevalence tended to grow as age increased. Among aircraft mechanics in their 30s and 40s, the prevalence of MetS was lower than in the general population. However, the prevalence of MetS among aircraft mechanics in their 50s (36.0%) was similar to that in the general population (35.7%). Systematic health management is needed for aircraft mechanics for aviation safety and for the maintenance of military strength via the prevention of CCVDs.Kim M-B, Kim H-J, Kim S-H, Lee S-H, Lee S-H, Park W-J. Metabolic syndrome and cardio-cerebrovascular risk disparities between pilots and aircraft mechanics. Aerosp Med Hum Perform. 2017; 88(9):866-870.

Increased heme synthesis in yeast induces a metabolic switch from fermentation to respiration even under conditions of glucose repression.

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Zhang, Tiantian; Bu, Pengli; Zeng, Joey; Vancura, Ales

2017-10-13

Regulation of mitochondrial biogenesis and respiration is a complex process that involves several signaling pathways and transcription factors as well as communication between the nuclear and mitochondrial genomes. Under aerobic conditions, the budding yeast Saccharomyces cerevisiae metabolizes glucose predominantly by glycolysis and fermentation. We have recently shown that altered chromatin structure in yeast induces respiration by a mechanism that requires transport and metabolism of pyruvate in mitochondria. However, how pyruvate controls the transcriptional responses underlying the metabolic switch from fermentation to respiration is unknown. Here, we report that this pyruvate effect involves heme. We found that heme induces transcription of HAP4 , the transcriptional activation subunit of the Hap2/3/4/5p complex, required for growth on nonfermentable carbon sources, in a Hap1p- and Hap2/3/4/5p-dependent manner. Increasing cellular heme levels by inactivating ROX1 , which encodes a repressor of many hypoxic genes, or by overexpressing HEM3 or HEM12 induced respiration and elevated ATP levels. Increased heme synthesis, even under conditions of glucose repression, activated Hap1p and the Hap2/3/4/5p complex and induced transcription of HAP4 and genes required for the tricarboxylic acid (TCA) cycle, electron transport chain, and oxidative phosphorylation, leading to a switch from fermentation to respiration. Conversely, inhibiting metabolic flux into the TCA cycle reduced cellular heme levels and HAP4 transcription. Together, our results indicate that the glucose-mediated repression of respiration in budding yeast is at least partly due to the low cellular heme level. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Metabolic epidermal necrosis in two dogs with different underlying diseases.

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Bond, R; McNeil, P E; Evans, H; Srebernik, N

1995-05-06

Two dogs with metabolic epidermal necrosis had hyperkeratosis of the footpads accompanied by erythematous, erosive and crusting lesions affecting the muzzle, external genitalia, perineum and periocular regions. Histopathological examination of skin biopsies revealed a superficial hydropic dermatitis with marked parakeratosis. Both dogs had high plasma activities of alkaline phosphatase and alanine aminotransferase and high concentrations of glucose, and also a marked hypoaminoacidaemia. Despite these similarities, the cutaneous eruptions were associated with different underlying diseases. One dog had a pancreatic carcinoma which had metastasised widely; the primary tumour and the metastases showed glucagon immunoreactivity on immunocytochemical staining, and the dog's plasma glucagon concentration was markedly greater than that of control dogs. The other dog had diffuse hepatic disease; its plasma glucagon concentration was similar to that of control samples and cirrhosis was identified post mortem. Metabolic epidermal necrosis in dogs is a distinct cutaneous reaction pattern which may be associated with different underlying systemic diseases; however, the pathogenesis of the skin lesions remains unclear.

Metabolic profiling reveals ethylene mediated metabolic changes and a coordinated adaptive mechanism of 'Jonagold' apple to low oxygen stress.

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Bekele, Elias A; Beshir, Wasiye F; Hertog, Maarten L A T M; Nicolai, Bart M; Geeraerd, Annemie H

2015-11-01

Apples are predominantly stored in controlled atmosphere (CA) storage to delay ripening and prolong their storage life. Profiling the dynamics of metabolic changes during ripening and CA storage is vital for understanding the governing molecular mechanism. In this study, the dynamics of the primary metabolism of 'Jonagold' apples during ripening in regular air (RA) storage and initiation of CA storage was profiled. 1-Methylcyclopropene (1-MCP) was exploited to block ethylene receptors and to get insight into ethylene mediated metabolic changes during ripening of the fruit and in response to hypoxic stress. Metabolic changes were quantified in glycolysis, the tricarboxylic acid (TCA) cycle, the Yang cycle and synthesis of the main amino acids branching from these metabolic pathways. Partial least square discriminant analysis of the metabolic profiles of 1-MCP treated and control apples revealed a metabolic divergence in ethylene, organic acid, sugar and amino acid metabolism. During RA storage at 18°C, most amino acids were higher in 1-MCP treated apples, whereas 1-aminocyclopropane-1-carboxylic acid (ACC) was higher in the control apples. The initial response of the fruit to CA initiation was accompanied by an increase of alanine, succinate and glutamate, but a decline in aspartate. Furthermore, alanine and succinate accumulated to higher levels in control apples than 1-MCP treated apples. The observed metabolic changes in these interlinked metabolites may indicate a coordinated adaptive strategy to maximize energy production. © 2015 Scandinavian Plant Physiology Society.

The molecular mechanism underlying anthocyanin metabolism in apple using the MdMYB16 and MdbHLH33 genes.

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Xu, Haifeng; Wang, Nan; Liu, Jingxuan; Qu, Changzhi; Wang, Yicheng; Jiang, Shenghui; Lu, Ninglin; Wang, Deyun; Zhang, Zongying; Chen, Xuesen

2017-05-01

MdMYB16 forms homodimers and directly inhibits anthocyanin synthesis via its C-terminal EAR repressor. It weakened the inhibitory effect of MdMYB16 on anthocyanin synthesis when overexpressing MdbHLH33 in callus overexpressing MdMYB16. MdMYB16 could interact with MdbHLH33. Anthocyanins are strong antioxidants that play a key role in the prevention of cardiovascular disease, cancer, and diabetes. The germplasm of Malus sieversii f. neidzwetzkyana is important for the study of anthocyanin metabolism. To date, only limited studies have examined the negative regulatory mechanisms underlying anthocyanin synthesis in apple. Here, we analyzed the relationship between anthocyanin levels and MdMYB16 expression in mature Red Crisp 1-5 apple (M. domestica) fruit, generated an evolutionary tree, and identified an EAR suppression sequence and a bHLH binding motif of the MdMYB16 protein using protein sequence analyses. Overexpression of MdMYB16 or MdMYB16 without bHLH binding sequence (LBSMdMYB16) in red-fleshed callus inhibited MdUFGT and MdANS expression and anthocyanin synthesis. However, overexpression of MdMYB16 without the EAR sequence (LESMdMYB16) in red-fleshed callus had no inhibitory effect on anthocyanin. The yeast one-hybrid assay showed that MdMYB16 and LESMdMYB16 interacted the promoters of MdANS and MdUFGT, respectively. Yeast two-hybrid, pull-down, and bimolecular fluorescence complementation assays showed that MdMYB16 formed homodimers and interacted with MdbHLH33, however, the LBSMdMYB16 could not interact with MdbHLH33. We overexpressed MdbHLH33 in callus overexpressing MdMYB16 and found that it weakened the inhibitory effect of MdMYB16 on anthocyanin synthesis. Together, these results suggested that MdMYB16 and MdbHLH33 may be important part of the regulatory network controlling the anthocyanin biosynthetic pathway.

Organ-specific proteomics analysis for identification of response mechanism in soybean seedlings under flooding stress.

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Khatoon, Amana; Rehman, Shafiq; Hiraga, Susumu; Makino, Takahiro; Komatsu, Setsuko

2012-10-22

Flooding is one of the severe environmental factors which impair growth and yield in soybean plant. To investigate the organ specific response mechanism of soybean under flooding stress, changes in protein species were analyzed using a proteomics approach. Two-day-old soybeans were subjected to flooding for 5 days. Proteins were extracted from root, hypocotyl and leaf, and separated by two-dimensional polyacrylamide gel electrophoresis. In root, hypocotyl and leaf, 51, 66 and 51 protein species were significantly changed, respectively, under flooding stress. In root, metabolism related proteins were increased; however these proteins were decreased in hypocotyl and leaf. In all 3 organs, cytoplasm localized proteins were decreased, and leaf chloroplastic proteins were also decreased. Isoflavone reductase was commonly decreased at protein level in all 3 organs; however, mRNA of isoflavone reductase gene was up-regulated in leaf under flooding stress. Biophoton emission was increased in all 3 organs under flooding stress. The up-regulation of isoflavone reductase gene at transcript level; while decreased abundance at protein level indicated that flooding stress affected the mRNA translation to proteins. These results suggest that concurrence in expression of isoflavone reductase gene at mRNA and protein level along with imbalance in other disease/defense and metabolism related proteins might lead to impaired growth of root, hypocotyl and leaf of soybean seedlings under flooding stress. Copyright © 2012 Elsevier B.V. All rights reserved.

Hungry Neurons: Metabolic Insights on Seizure Dynamics

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Paolo Bazzigaluppi

2017-10-01

Full Text Available Epilepsy afflicts up to 1.6% of the population and the mechanisms underlying the appearance of seizures are still not understood. In past years, many efforts have been spent trying to understand the mechanisms underlying the excessive and synchronous firing of neurons. Traditionally, attention was pointed towards synaptic (dysfunction and extracellular ionic species (dysregulation. Recently, novel clinical and preclinical studies explored the role of brain metabolism (i.e., glucose utilization of seizures pathophysiology revealing (in most cases reduced metabolism in the inter-ictal period and increased metabolism in the seconds preceding and during the appearance of seizures. In the present review, we summarize the clinical and preclinical observations showing metabolic dysregulation during epileptogenesis, seizure initiation, and termination, and in the inter-ictal period. Recent preclinical studies have shown that 2-Deoxyglucose (2-DG, a glycolysis blocker is a novel therapeutic approach to reduce seizures. Furthermore, we present initial evidence for the effectiveness of 2-DG in arresting 4-Aminopyridine induced neocortical seizures in vivo in the mouse.

Evaluation of hepatic metabolism and pharmacokinetics of ibuprofen in rats under chronic hypobaric hypoxia for targeted therapy at high altitude.

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Gola, Shefali; Gupta, Asheesh; Keshri, Gaurav K; Nath, Madhu; Velpandian, Thirumurthy

2016-03-20

With studies indicative of altered drug metabolism and pharmacokinetics (DMPK) under high altitude (HA)-induced hypobaric hypoxia, consideration of better therapeutic approaches has continuously been aimed in research for HA related illness management. DMPK of drugs like ibuprofen may get affected under hypoxia which establishes the requirement of different therapeutic dose regimen to ensure safe and effective therapy at HA. This study examined the effects of the chronic hypobaric hypoxia (CHH) on hepatic DMPK of ibuprofen in rats. Experimental animals were exposed to simulated altitude of 7620 m (∼25,000 ft) for CHH exposure (7 or 14 days) in decompression chamber and administered with ibuprofen (80 mg/kg, body weight, p.o.). Results demonstrated that CHH significantly altered PK variables of ibuprofen and activities of both phase-I and II hepatic metabolic enzymes as compared to the animals under normoxic conditions. Hepatic histopathological observations also revealed marked alterations. Increase in pro-inflammatory cytokines/chemokines viz. IL-1β, IL-2, IFN-γ, TNF-α exhibited close relevance with diminished CYP2C9 expression under CHH. Moreover, the down-regulated CYP2C9 level further supported the underlying mechanism for reduced metabolism of ibuprofen and as a result, increased retention of parent drug in the system. Increased mean retention time, Vd, T½ of ibuprofen, and decreased AUC, Cmax and clearance during CHH further strengthened the present findings. In conclusion, CHH exposure significantly affects hepatic DMPK of ibuprofen, which may further influence the usual therapeutic dose-regimen. Further, there is requirement of human studies to evaluate their susceptibility toward hypobaric hypoxia. Copyright © 2016 Elsevier B.V. All rights reserved.

Effects of lanthanum(III) on nitrogen metabolism of soybean seedlings under elevated UV-B radiation.

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Cao, Rui; Huang, Xiao-hua; Zhou, Qing; Cheng, Xiao-ying

2007-01-01

The hydroponic culture experiments of soybean bean seedlings were conducted to investigate the effect of lanthanum (La) on nitrogen metabolism under two different levels of elevated UV-B radiation (UV-B, 280-320 nm). The whole process of nitrogen metabolism involves uptake and transport of nitrate, nitrate assimilation, ammonium assimilation, amino acid biosynthesis, and protein synthesis. Compared with the control, UV-B radiation with the intensity of low level 0.15 W/m2 and high level 0.45 W/m2 significantly affected the whole nitrogen metabolism in soybean seedlings (p nitrogen-metabolism-related enzymes, such as: nitrate reductase (NR) to the nitrate reduction, glutamine systhetase (GS) and glutamine synthase (GOGAT) to the ammonia assimilation, while it increased the content of free amino acids and decreased that of soluble protein as well. The damage effect of high level of UV-B radiation on nitrogen metabolism was greater than that of low level. And UV-B radiation promoted the activity of the anti-adversity enzyme glutamate dehydrogenase (GDH), which reduced the toxicity of excess ammonia in plant. After pretreatment with the optimum concentration of La (20 mg/L), La could increase the activity of NR, GS, GOGAT, and GDH, and ammonia assimilation, but decrease nitrate and ammonia accumulation. In conclusion, La could relieve the damage effect of UV-B radiation on plant by regulating nitrogen metabolism process, and its alleviating effect under low level was better than that under the high one.

Glucose metabolism in different regions of the rat brain under hypokinetic stress influence

Science.gov (United States)

Konitzer, K.; Voigt, S.

1980-01-01

Glucose metabolism in rats kept under long term hypokinetic stress was studied in 7 brain regions. Determination was made of the regional levels of glucose, lactate, glutamate, glutamine, aspartate, gamma-aminobutyrate and the incorporation of C-14 from plasma glucose into these metabolites, in glycogen and protein. From the content and activity data the regional glucose flux was approximated quantitatively. Under normal conditions the activity gradient cortex and frontal pole cerebellum, thalamus and mesencephalon, hypothalamus and pons and medulla is identical with that of the regional blood supply (measured with I131 serum albumin as the blood marker). Within the first days of immobilization a functional hypoxia occurred in all brain regions and the utilization of cycle amino acids for protein synthesis was strongly diminished. After the first week of stress the capillary volumes of all regions increased, aerobic glucose metabolism was enhanced (factors 1.3 - 2.0) and the incorporation of glucose C-14 via cycle amino acids into protein was considerably potentiated. The metabolic parameters normalized between the 7th and 11th week of stress. Blood supply and metabolic rate increased most in the hypothalamus.

Metabolic therapy for temporal lobe epilepsy in a dish: investigating mechanisms of ketogenic diet using electrophysiological recordings in hippocampal slices

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Masahito Kawamura

2016-11-01

Full Text Available The hippocampus is prone to epileptic seizures and is a key brain region and experimental platform for investigating mechanisms associated with the abnormal neuronal excitability that characterizes a seizure. Accordingly, the hippocampal slice is a common in vitro model to study treatments that may prevent or reduce seizure activity. The ketogenic diet is a metabolic therapy used to treat epilepsy in adults and children for nearly 100 years; it can reduce or eliminate even severe or refractory seizures. New insights into its underlying mechanisms have been revealed by diverse types of electrophysiological recordings in hippocampal slices. Here we review these reports and their relevant mechanistic findings. We acknowledge that a major difficulty in using hippocampal slices is the inability to reproduce precisely the in vivo condition of ketogenic diet feeding in any in vitro preparation, and progress has been made in this in vivo/in vitro transition. Thus far at least three different approaches are reported to reproduce relevant diet effects in the hippocampal slices: (1 direct application of ketone bodies, (2 mimicking the ketogenic diet condition during a whole-cell patch-clamp technique, and (3 reduced glucose incubation of hippocampal slices from ketogenic diet–fed animals. Significant results have been found with each of these methods and provide options for further study into short- and long-term mechanisms including ATP-sensitive potassium channels, vesicular glutamate transporter, pannexin channels and adenosine receptors underlying ketogenic diet and other forms of metabolic therapy.

Metabolic Therapy for Temporal Lobe Epilepsy in a Dish: Investigating Mechanisms of Ketogenic Diet using Electrophysiological Recordings in Hippocampal Slices

Science.gov (United States)

Kawamura, Masahito Jr.; Ruskin, David N.; Masino, Susan A.

2016-01-01

The hippocampus is prone to epileptic seizures and is a key brain region and experimental platform for investigating mechanisms associated with the abnormal neuronal excitability that characterizes a seizure. Accordingly, the hippocampal slice is a common in vitro model to study treatments that may prevent or reduce seizure activity. The ketogenic diet is a metabolic therapy used to treat epilepsy in adults and children for nearly 100 years; it can reduce or eliminate even severe or refractory seizures. New insights into its underlying mechanisms have been revealed by diverse types of electrophysiological recordings in hippocampal slices. Here we review these reports and their relevant mechanistic findings. We acknowledge that a major difficulty in using hippocampal slices is the inability to reproduce precisely the in vivo condition of ketogenic diet feeding in any in vitro preparation, and progress has been made in this in vivo/in vitro transition. Thus far at least three different approaches are reported to reproduce relevant diet effects in the hippocampal slices: (1) direct application of ketone bodies; (2) mimicking the ketogenic diet condition during a whole-cell patch-clamp technique; and (3) reduced glucose incubation of hippocampal slices from ketogenic diet–fed animals. Significant results have been found with each of these methods and provide options for further study into short- and long-term mechanisms including Adenosine triphosphate (ATP)-sensitive potassium (KATP) channels, vesicular glutamate transporter (VGLUT), pannexin channels and adenosine receptors underlying ketogenic diet and other forms of metabolic therapy. PMID:27847463

The Role of Androgen Excess in Metabolic Dysfunction in Women : Androgen Excess and Female Metabolic Dysfunction.

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Escobar-Morreale, Héctor F

2017-01-01

Polycystic ovary syndrome (PCOS) is characterized by the association of androgen excess with chronic oligoovulation and/or polycystic ovarian morphology, yet metabolic disorders and classic and nonclassic cardiovascular risk factors cluster in these women from very early in life. This chapter focuses on the mechanisms underlying the association of PCOS with metabolic dysfunction, focusing on the role of androgen excess on the development of visceral adiposity and adipose tissue dysfunction.

Investigation of the role of the calvin cycle and C1 metabolism during HCHO metabolism in gaseous HCHO-treated petunia under light and dark conditions using 13C-NMR.

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Sun, Huiqun; Zhang, Wei; Tang, Lijuan; Han, Shuang; Wang, Xinjia; Zhou, Shengen; Li, Kunzhi; Chen, Limei

2015-01-01

It has been shown that formaldehyde (HCHO) absorbed by plants can be assimilated through the Calvin cycle or C1 metabolism. Our previous study indicated that Petunia hybrida could effectively eliminate HCHO from HCHO-polluted air. To understand the roles of C1 metabolism and the Calvin cycle during HCHO metabolism and detoxification in petunia plants treated with gaseous H(13)CHO under light and dark conditions. Aseptically grown petunia plants were treated with gaseous H(13)CHO under dark and light conditions. The metabolites generated from HCHO detoxification in petunia were investigated using (13)C-NMR. [2-(13)C]glycine (Gly) was generated via C1 metabolism and [U-(13)C]glucose (Gluc) was produced through the Calvin cycle simultaneously in petunia treated with low-level gaseous H(13)CHO under light conditions. Generation of [2-(13)C]Gly decreased whereas [U-(13) C]Gluc and [U-(13)C]fructose (Fruc) production increased greatly under high-level gaseous H(13)CHO stress in the light. In contrast, [U-(13)C]Gluc and [U-(13)C] Fruc production decreased greatly and [2-(13)C]Gly generation increased significantly under low-level and high-level gaseous H(13)CHO stress in the dark. C1 metabolism and the Calvin cycle contributed differently to HCHO metabolism and detoxification in gaseous H(13CHO-treated petunia plants. As the level of gaseous HCHO increased, the role of C1 metabolism decreased and the role of the Calvin cycle increased under light conditions. However, opposite changes were observed in petunia plants under dark conditions. Copyright © 2015 John Wiley & Sons, Ltd.

Expression of muscle anabolic and metabolic factors in mechanically loaded MLO-Y4 osteocytes

NARCIS (Netherlands)

Juffer, P.; Jaspers, R.T.; Lips, P.; Bakker, A.D.; Klein-Nulend, J.

2012-01-01

Lack of physical activity results in muscle atrophy and bone loss, which can be counteracted by mechanical loading. Similar molecular signaling pathways are involved in the adaptation of muscle and bone mass to mechanical loading. Whether anabolic and metabolic factors regulating muscle mass, i.e.,

Regulation of Metabolic Activity by p53

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Jessica Flöter

2017-05-01

Full Text Available Metabolic reprogramming in cancer cells is controlled by the activation of multiple oncogenic signalling pathways in order to promote macromolecule biosynthesis during rapid proliferation. Cancer cells also need to adapt their metabolism to survive and multiply under the metabolically compromised conditions provided by the tumour microenvironment. The tumour suppressor p53 interacts with the metabolic network at multiple nodes, mostly to reduce anabolic metabolism and promote preservation of cellular energy under conditions of nutrient restriction. Inactivation of this tumour suppressor by deletion or mutation is a frequent event in human cancer. While loss of p53 function lifts an important barrier to cancer development by deleting cell cycle and apoptosis checkpoints, it also removes a crucial regulatory mechanism and can render cancer cells highly sensitive to metabolic perturbation. In this review, we will summarise the major concepts of metabolic regulation by p53 and explore how this knowledge can be used to selectively target p53 deficient cancer cells in the context of the tumour microenvironment.

Mechanisms underlying the neurotoxicity induced by glyphosate-based herbicide in immature rat hippocampus: Involvement of glutamate excitotoxicity

International Nuclear Information System (INIS)

Cattani, Daiane; Oliveira Cavalli, Liz Vera Lúcia de; Heinz Rieg, Carla Elise; Domingues, Juliana Tonietto; Dal-Cim, Tharine; Tasca, Carla Inês; Mena Barreto Silva, Fátima Regina; Zamoner, Ariane

2014-01-01

Graphical abstract: - Highlights: • Roundup ® induces Ca 2+ influx through L-VDCC and NMDA receptor activation. • The mechanisms underlying Roundup ® neurotoxicity involve glutamatergic excitotoxicity. • Kinase pathways participate in Roundup ® -induced neural toxicity. • Roundup ® alters glutamate uptake, release and metabolism in hippocampal cells. - Abstract: Previous studies demonstrate that glyphosate exposure is associated with oxidative damage and neurotoxicity. Therefore, the mechanism of glyphosate-induced neurotoxic effects needs to be determined. The aim of this study was to investigate whether Roundup ® (a glyphosate-based herbicide) leads to neurotoxicity in hippocampus of immature rats following acute (30 min) and chronic (pregnancy and lactation) pesticide exposure. Maternal exposure to pesticide was undertaken by treating dams orally with 1% Roundup ® (0.38% glyphosate) during pregnancy and lactation (till 15-day-old). Hippocampal slices from 15 day old rats were acutely exposed to Roundup ® (0.00005–0.1%) during 30 min and experiments were carried out to determine whether glyphosate affects 45 Ca 2+ influx and cell viability. Moreover, we investigated the pesticide effects on oxidative stress parameters, 14 C-α-methyl-amino-isobutyric acid ( 14 C-MeAIB) accumulation, as well as glutamate uptake, release and metabolism. Results showed that acute exposure to Roundup ® (30 min) increases 45 Ca 2+ influx by activating NMDA receptors and voltage-dependent Ca 2+ channels, leading to oxidative stress and neural cell death. The mechanisms underlying Roundup ® -induced neurotoxicity also involve the activation of CaMKII and ERK. Moreover, acute exposure to Roundup ® increased 3 H-glutamate released into the synaptic cleft, decreased GSH content and increased the lipoperoxidation, characterizing excitotoxicity and oxidative damage. We also observed that both acute and chronic exposure to Roundup ® decreased 3 H-glutamate uptake and

Hungry Neurons: Metabolic Insights on Seizure Dynamics

OpenAIRE

Paolo Bazzigaluppi; Azin Ebrahim Amini; Iliya Weisspapir; Bojana Stefanovic; Peter L. Carlen

2017-01-01

Epilepsy afflicts up to 1.6% of the population and the mechanisms underlying the appearance of seizures are still not understood. In past years, many efforts have been spent trying to understand the mechanisms underlying the excessive and synchronous firing of neurons. Traditionally, attention was pointed towards synaptic (dys)function and extracellular ionic species (dys)regulation. Recently, novel clinical and preclinical studies explored the role of brain metabolism (i.e., glucose utilizat...

The impact of music on metabolism.

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Yamasaki, Alisa; Booker, Abigail; Kapur, Varun; Tilt, Alexandra; Niess, Hanno; Lillemoe, Keith D; Warshaw, Andrew L; Conrad, Claudius

2012-01-01

The study of music and medicine is a rapidly growing field that in the past, has been largely focused on the use of music as a complementary therapy. Increasing interest has been centered on understanding the physiologic mechanisms underlying the effects of music and, more recently, the suggested role of music in modulating metabolic responses. Research has established a role for music in the regulation of the hypothalamic-pituitary axis, the sympathetic nervous system, and the immune system, which have key functions in the regulation of metabolism and energy balance. More recent findings have shown a role for music in the metabolic recovery from stress, the regulation of gastric and intestinal motility, the moderation of cancer-related gastrointestinal symptoms, and the increase of lipid metabolism and lactic acid clearance during exercise and postexercise recovery. The purpose of this article is to summarize the most current understanding of the mechanisms by which music affects the metabolic responses in the context of potential applications. Copyright © 2012 Elsevier Inc. All rights reserved.

Creatine Supplementation and Skeletal Muscle Metabolism for Building Muscle Mass- Review of the Potential Mechanisms of Action.

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Farshidfar, Farnaz; Pinder, Mark A; Myrie, Semone B

2017-01-01

Creatine, a very popular supplement among athletic populations, is of growing interest for clinical applications. Since over 90% of creatine is stored in skeletal muscle, the effect of creatine supplementation on muscle metabolism is a widely studied area. While numerous studies over the past few decades have shown that creatine supplementation has many favorable effects on skeletal muscle physiology and metabolism, including enhancing muscle mass (growth/hypertrophy); the underlying mechanisms are poorly understood. This report reviews studies addressing the mechanisms of action of creatine supplementation on skeletal muscle growth/hypertrophy. Early research proposed that the osmotic effect of creatine supplementation serves as a cellular stressor (osmosensing) that acts as an anabolic stimulus for protein synthesis signal pathways. Other reports indicated that creatine directly affects muscle protein synthesis via modulations of components in the mammalian target of rapamycin (mTOR) pathway. Creatine may also directly affect the myogenic process (formation of muscle tissue), by altering secretions of myokines, such as myostatin and insulin-like growth factor-1, and expressions of myogenic regulatory factors, resulting in enhanced satellite cells mitotic activities and differentiation into myofiber. Overall, there is still no clear understanding of the mechanisms of action regarding how creatine affects muscle mass/growth, but current evidence suggests it may exert its effects through multiple approaches, with converging impacts on protein synthesis and myogenesis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Extracellular matrix metabolism disorder induced by mechanical strain on human parametrial ligament fibroblasts.

Science.gov (United States)

Min, Jie; Li, Bingshu; Liu, Cheng; Guo, Wenjun; Hong, Shasha; Tang, Jianming; Hong, Li

2017-05-01

Pelvic organ prolapse (POP) is a global health problem that may seriously impact the quality of life of the sufferer. The present study aimed to investigate the potential mechanisms underlying alterations in extracellular matrix (ECM) metabolism in the pathogenesis of POP, by investigating the expression of ECM components in human parametrial ligament fibroblasts (hPLFs) subject to various mechanical strain loads. Fibroblasts derived from parametrial ligaments were cultured from patients with POP and without malignant tumors, who underwent vaginal hysterectomy surgery. Fibroblasts at generations 3‑6 of exponential phase cells were selected, and a four‑point bending device was used for 0, 1,333 or 5,333 µ mechanical loading of cells at 0.5 Hz for 4 h. mRNA and protein expression levels of collagen type I α 1 chain (COL1A1), collagen type III α 1 chain (COL3A1), elastin, matrix metalloproteinase (MMP) ‑2 and ‑9, and transforming growth factor (TGF)‑β1 were detected by reverse transcription‑quantitative polymerase chain reaction and western blotting, respectively. Under increased mechanical strain (5,333 µ), mRNA and protein expression levels of COL1A1, COL3A1 elastin and TGF‑β1 decreased, particularly COL1A1; however, mRNA and protein expression levels of MMP‑2 and ‑9 were significantly increased, compared with the control group (0 µ strain). Following 1,333 µ mechanical strain, mRNA and protein expression levels of COL1A1, COL3A1 elastin and MMP‑2 increased, and MMP‑9 decreased, whereas no significant differences were observed in TGF‑β1 mRNA and protein expression levels. In conclusion, ECM alterations may be involved in pathogenesis of POP, with decreased synthesis and increased degradation of collagen and elastin. Furthermore, the TGF‑β1 signaling pathway may serve an important role in this process and thus may supply a new target and strategy for understanding the etiology and therapy of POP.

Mechanisms underlying metabolic and neural defects in zebrafish and human multiple acyl-CoA dehydrogenase deficiency (MADD.

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Yuanquan Song

2009-12-01

Full Text Available In humans, mutations in electron transfer flavoprotein (ETF or electron transfer flavoprotein dehydrogenase (ETFDH lead to MADD/glutaric aciduria type II, an autosomal recessively inherited disorder characterized by a broad spectrum of devastating neurological, systemic and metabolic symptoms. We show that a zebrafish mutant in ETFDH, xavier, and fibroblast cells from MADD patients demonstrate similar mitochondrial and metabolic abnormalities, including reduced oxidative phosphorylation, increased aerobic glycolysis, and upregulation of the PPARG-ERK pathway. This metabolic dysfunction is associated with aberrant neural proliferation in xav, in addition to other neural phenotypes and paralysis. Strikingly, a PPARG antagonist attenuates aberrant neural proliferation and alleviates paralysis in xav, while PPARG agonists increase neural proliferation in wild type embryos. These results show that mitochondrial dysfunction, leading to an increase in aerobic glycolysis, affects neurogenesis through the PPARG-ERK pathway, a potential target for therapeutic intervention.

Cytochrome P450s: mechanisms and biological implications in drug metabolism and its interaction with oxidative stress.

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Bhattacharyya, Sudip; Sinha, Krishnendu; Sil, Parames C

2014-01-01

Cytochrome monooxygenases P450 enzymes (CYPs) are terminal oxidases, belonging to the multi-gene family of heme-thiolate enzymes and located in multiple sites of ER, cytosol and mitochondria. CYPs act as catalysts in drugs metabolism. This review highlights the mitochondrial and microsomal CYPs metabolic functions, CYPs mediated ROS generation and its feedback, bioactivation of drugs and related hypersensitivity, metabolic disposition as well as the therapeutic approaches. CYPs mediated drugs bioactivation may trigger oxidative stress and cause pathophysiology. Almost all drugs show some adverse reactions at high doses or accidental overdoses. Drugs lead to hypersensitivity reactions while metabolic predisposition to drug hypersensitivity exaggerates it. Mostly different intermediate bioactive products of CYPs mediated drug metabolism is the principal issue in this respect. On the other hand, CYPs are the main source of ROS. Their generation and feedback are of major concern of this review. Besides drug metabolism, CYPs also contribute significantly to carcinogen metabolism. Ultimately other enzymes in drug metabolism and antioxidant therapy are indispensible. Importance of this field: In a global sense, understanding of exact mechanism can facilitate pharmaceutical industries' challenge of developing drugs without toxicity. Ultimate message: This review would accentuate the recent advances in molecular mechanism of CYPs mediated drug metabolism and complex cross-talks between various restorative novel strategies evolved by CYPs to sustain the redox balance and limit the source of oxidative stress.

Curcumin-mediated regulation of intestinal barrier function: The mechanism underlying its beneficial effects.

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Ghosh, Siddhartha S; He, Hongliang; Wang, Jing; Gehr, Todd W; Ghosh, Shobha

2018-01-02

Curcumin has anti-inflammatory, anti-oxidant and anti-proliferative properties established largely by in vitro studies. Accordingly, oral administration of curcumin beneficially modulates many diseases including diabetes, fatty-liver disease, atherosclerosis, arthritis, cancer and neurological disorders such as depression, Alzheimer's or Parkinson's disease. However, limited bioavailability and inability to detect curcumin in circulation or target tissues has hindered the validation of a causal role. We established curcumin-mediated decrease in the release of gut bacteria-derived lipopolysaccharide (LPS) into circulation by maintaining the integrity of the intestinal barrier function as the mechanism underlying the attenuation of metabolic diseases (diabetes, atherosclerosis, kidney disease) by curcumin supplementation precluding the need for curcumin absorption. In view of the causative role of circulating LPS and resulting chronic inflammation in the development of diseases listed above, this review summarizes the mechanism by which curcumin affects the several layers of the intestinal barrier and, despite negligible absorption, can beneficially modulate these diseases.

Surface Damage Mechanism of Monocrystalline Si Under Mechanical Loading

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Zhao, Qingliang; Zhang, Quanli; To, Suet; Guo, Bing

2017-03-01

Single-point diamond scratching and nanoindentation on monocrystalline silicon wafer were performed to investigate the surface damage mechanism of Si under the contact loading. The results showed that three typical stages of material removal appeared during dynamic scratching, and a chemical reaction of Si with the diamond indenter and oxygen occurred under the high temperature. In addition, the Raman spectra of the various points in the scratching groove indicated that the Si-I to β-Sn structure (Si-II) and the following β-Sn structure (Si-II) to amorphous Si transformation appeared under the rapid loading/unloading condition of the diamond grit, and the volume change induced by the phase transformation resulted in a critical depth (ductile-brittle transition) of cut (˜60 nm ± 15 nm) much lower than the theoretical calculated results (˜387 nm). Moreover, it also led to abnormal load-displacement curves in the nanoindentation tests, resulting in the appearance of elbow and pop-out effects (˜270 nm at 20 s, 50 mN), which were highly dependent on the loading/unloading conditions. In summary, phase transformation of Si promoted surface deformation and fracture under both static and dynamic mechanical loading.

Underlying mechanism of drug-drug interaction between pioglitazone and gemfibrozil: Gemfibrozil acyl-glucuronide is a mechanism-based inhibitor of CYP2C8.

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Takagi, Motoi; Sakamoto, Masaya; Itoh, Tomoo; Fujiwara, Ryoichi

2015-08-01

While co-administered gemfibrozil can increase the area under the concentration/time curve (AUC) of pioglitazone more than 3-fold, the underlying mechanism of the drug-drug interaction between gemfibrozil and pioglitazone has not been fully understood. In the present study, gemfibrozil preincubation time-dependently inhibited the metabolism of pioglitazone in the cytochrome P450 (CYP)- and UDP-glucuronosyltransferase (UGT)-activated human liver microsomes. We estimated the kinact and K'app values, which are the maximum inactivation rate constant and the apparent dissociation constant, of gemfibrozil to be 0.071 min(-1) and 57.3 μM, respectively. In this study, the kobs, in vivo value was defined as a parameter that indicates the potency of the mechanism-based inhibitory effect at the blood drug concentration in vivo. The kobs, in vivo values of potent mechanism-based inhibitors, clarithromycin and erythromycin, were estimated to be 0.0096 min(-1) and 0.0051 min(-1), respectively. The kobs, in vivo value of gemfibrozil was 0.0060 min(-1), which was comparable to those of clarithromycin and erythromycin, suggesting that gemfibrozil could be a mechanism-based inhibitor as potent as clarithromycin and erythromycin in vivo. Copyright © 2015 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Cellular energy metabolism in T-lymphocytes.

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Gaber, Timo; Strehl, Cindy; Sawitzki, Birgit; Hoff, Paula; Buttgereit, Frank

2015-01-01

Energy homeostasis is a hallmark of cell survival and maintenance of cell function. Here we focus on the impact of cellular energy metabolism on T-lymphocyte differentiation, activation, and function in health and disease. We describe the role of transcriptional and posttranscriptional regulation of lymphocyte metabolism on immune functions of T cells. We also summarize the current knowledge about T-lymphocyte adaptations to inflammation and hypoxia, and the impact on T-cell behavior of pathophysiological hypoxia (as found in tumor tissue, chronically inflamed joints in rheumatoid arthritis and during bone regeneration). A better understanding of the underlying mechanisms that control immune cell metabolism and immune response may provide therapeutic opportunities to alter the immune response under conditions of either immunosuppression or inflammation, potentially targeting infections, vaccine response, tumor surveillance, autoimmunity, and inflammatory disorders.

Mechanical properties of cork under contact stresses

International Nuclear Information System (INIS)

Parralejo, A. D.; Guiberteau, F.; Fortes, M. A.; Rosa, M. E.

2001-01-01

In this work our interest is focussed on the mechanical behaviour of natural cork under contact stresses. Many of the applications of this curious material are related with its mechanical response under such a stress field, however this topic has not been still sufficiently considered in the scientific literature. For this purpose, we proposed the use of Hertzian indentation tests. By using this mythology we have investigated the cork structure influence on the corresponding mechanical properties. Our results reveal a clear mechanical anisotropy effect. Moreover, the elastic modulus corresponding to specific directions have been estimated. Several are the main advantages of this specific test mythology versus traditional uniaxial compression tests, specially simplicity and local character. (Author) 9 refs

Mechanisms of triglyceride metabolism in patients with bile acid diarrhea.

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Sagar, Nidhi Midhu; McFarlane, Michael; Nwokolo, Chuka; Bardhan, Karna Dev; Arasaradnam, Ramesh Pulendran

2016-08-14

Bile acids (BAs) are essential for the absorption of lipids. BA synthesis is inhibited through intestinal farnesoid X receptor (FXR) activity. BA sequestration is known to influence BA metabolism and control serum lipid concentrations. Animal data has demonstrated a regulatory role for the FXR in triglyceride metabolism. FXR inhibits hepatic lipogenesis by inhibiting the expression of sterol regulatory element binding protein 1c via small heterodimer primer activity. Conversely, FXR promotes free fatty acids oxidation by inducing the expression of peroxisome proliferator-activated receptor α. FXR can reduce the expression of microsomal triglyceride transfer protein, which regulates the assembly of very low-density lipoproteins (VLDL). FXR activation in turn promotes the clearance of circulating triglycerides by inducing apolipoprotein C-II, very low-density lipoproteins receptor (VLDL-R) and the expression of Syndecan-1 together with the repression of apolipoprotein C-III, which increases lipoprotein lipase activity. There is currently minimal clinical data on triglyceride metabolism in patients with bile acid diarrhoea (BAD). Emerging data suggests that a third of patients with BAD have hypertriglyceridemia. Further research is required to establish the risk of hypertriglyceridaemia in patients with BAD and elicit the mechanisms behind this, allowing for targeted treatment.

Human Cytomegalovirus: Coordinating Cellular Stress, Signaling, and Metabolic Pathways.

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Shenk, Thomas; Alwine, James C

2014-11-01

Viruses face a multitude of challenges when they infect a host cell. Cells have evolved innate defenses to protect against pathogens, and an infecting virus may induce a stress response that antagonizes viral replication. Further, the metabolic, oxidative, and cell cycle state may not be conducive to the viral infection. But viruses are fabulous manipulators, inducing host cells to use their own characteristic mechanisms and pathways to provide what the virus needs. This article centers on the manipulation of host cell metabolism by human cytomegalovirus (HCMV). We review the features of the metabolic program instituted by the virus, discuss the mechanisms underlying these dramatic metabolic changes, and consider how the altered program creates a synthetic milieu that favors efficient HCMV replication and spread.

Unraveling the Root Proteome Changes and Its Relationship to Molecular Mechanism Underlying Salt Stress Response in Radish (Raphanus sativus L.

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Xiaochuan Sun

2017-07-01

Full Text Available To understand the molecular mechanism underlying salt stress response in radish, iTRAQ-based proteomic analysis was conducted to investigate the differences in protein species abundance under different salt treatments. In total, 851, 706, and 685 differential abundance protein species (DAPS were identified between CK vs. Na100, CK vs. Na200, and Na100 vs. Na200, respectively. Functional annotation analysis revealed that salt stress elicited complex proteomic alterations in radish roots involved in carbohydrate and energy metabolism, protein metabolism, signal transduction, transcription regulation, stress and defense and transport. Additionally, the expression levels of nine genes encoding DAPS were further verified using RT-qPCR. The integrative analysis of transcriptomic and proteomic data in conjunction with miRNAs was further performed to strengthen the understanding of radish response to salinity. The genes responsible for signal transduction, ROS scavenging and transport activities as well as several key miRNAs including miR171, miR395, and miR398 played crucial roles in salt stress response in radish. Based on these findings, a schematic genetic regulatory network of salt stress response was proposed. This study provided valuable insights into the molecular mechanism underlying salt stress response in radish roots and would facilitate developing effective strategies toward genetically engineered salt-tolerant radish and other root vegetable crops.

Mechanisms underlying reduced fertility in anovular dairy cows.

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Santos, J E P; Bisinotto, R S; Ribeiro, E S

2016-07-01

Resumption of ovulation after parturition is a coordinated process that involves recoupling of the GH/insulin-like growth factor 1 axis in the liver, increase in follicular development and steroidogenesis, and removal of negative feedback from estradiol in the hypothalamus. Infectious diseases and metabolic disorders associated with extensive negative energy balance during early lactation disrupt this pathway and delay first ovulation postpartum. Extended periods of anovulation postpartum exert long-lasting effects on fertility in dairy cows including the lack of spontaneous estrus, reduced pregnancy per artificial insemination (P/AI), and increased risk of pregnancy loss. Concentrations of progesterone in anovular cows subjected to synchronized programs for AI are insufficient to optimize follicular maturation, oocyte competence, and subsequent fertility to AI. Ovulation of first wave follicles, which develop under low concentrations of progesterone, reduces embryo quality in the first week after fertilization and P/AI in dairy cows. Although the specific mechanisms by which anovulation and low concentrations of progesterone impair oocyte quality have not been defined, studies with persistent follicles support the involvement of premature resumption of meiosis and degradation of maternal RNA. Suboptimal concentrations of progesterone before ovulation also increase the synthesis of PGF2α in response to oxytocin during the subsequent estrous cycle, which explains the greater incidence of short luteal phases after the first AI postpartum in anovular cows compared with estrous cyclic herd mates. It is suggested that increased spontaneous luteolysis early in the estrous cycle is one of the mechanisms that contributes to early embryonic losses in anovular cows. Anovulation also leads to major shifts in gene expression in elongated conceptuses during preimplantation stages of pregnancy. Transcripts involved with control of energy metabolism and DNA repair were

Foliar urea application affects nitric oxide burst and glycine betaine metabolism in two maize cultivars under drought

International Nuclear Information System (INIS)

Zhang, L.; Zhang, X.; Wang, K.; Zhao, Y.; Zhai, Y.; Gao, M.

2011-01-01

Foliar urea has been proved to act a better role in alleviation of the negative effects of drought stress (DS). However, the modulation mechanism of foliar urea are not conclusive in view of nitric oxide (NO) burst and glycine betaine metabolism and their relationship. Two maize ( Zea mays L.) cultivars (Zhengdan 958, JD958, Jundan 20, ZD20) were grown in hydroponic medium, which were treated with spraying of urea concentration of 15 g L/sup -1/ and two water regimes (non-stress and DS simulated by the addition of polyethylene glycol (PEG, 15% w/v, MW 6000). The ten-day DS treatment increased betaine aldehyde dehydrogenase (BADH) activity, choline content and nitric oxide (NO) content acted as the key enzyme, initial substrate and a nitrogenous signal substance respectively in GB synthesis metabolism, thus, induced to great GB accumulation. The accumulation of NO reached the summit earlier than that of GB. The more positive/less negative responses were recorded in JD958 as compared with ZD20 to DS. Addition of foliar ur ea could increase accumulation of choline and BADH activity as well as NO content, thereby, increase GB accumulation under DS. These positive effects of urea applying foliarly on all parameters measured were more pronounced in cultivar JD20 than those in ZD958 under drought. It is, therefore, concluded that increases of both BADH activity and choline content possibly resulted in enhancement of GB accumulation. Foliar urea application could provoke better GB accumulation by modulation of GB metabolism, possibly mediating by NO burst as a signal molecule during drought, especially in the drought sensitive maize cultivar. (author)

Dissecting rice polyamine metabolism under controlled long-term drought stress.

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Phuc Thi Do

Full Text Available A selection of 21 rice cultivars (Oryza sativa L. ssp. indica and japonica was characterized under moderate long-term drought stress by comprehensive physiological analyses and determination of the contents of polyamines and selected metabolites directly related to polyamine metabolism. To investigate the potential regulation of polyamine biosynthesis at the transcriptional level, the expression of 21 genes encoding enzymes involved in these pathways were analyzed by qRT-PCR. Analysis of the genomic loci revealed that 11 of these genes were located in drought-related QTL regions, in agreement with a proposed role of polyamine metabolism in rice drought tolerance. The cultivars differed widely in their drought tolerance and parameters such as biomass and photosynthetic quantum yield were significantly affected by drought treatment. Under optimal irrigation free putrescine was the predominant polyamine followed by free spermidine and spermine. When exposed to drought putrescine levels decreased markedly and spermine became predominant in all cultivars. There were no correlations between polyamine contents and drought tolerance. GC-MS analysis revealed drought-induced changes of the levels of ornithine/arginine (substrate, substrates of polyamine synthesis, proline, product of a competing pathway and GABA, a potential degradation product. Gene expression analysis indicated that ADC-dependent polyamine biosynthesis responded much more strongly to drought than the ODC-dependent pathway. Nevertheless the fold change in transcript abundance of ODC1 under drought stress was linearly correlated with the drought tolerance of the cultivars. Combining metabolite and gene expression data, we propose a model of the coordinate adjustment of polyamine biosynthesis for the accumulation of spermine under drought conditions.

Identification of Toxic Pyrrolizidine Alkaloids and Their Common Hepatotoxicity Mechanism

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Xinmiao Yan

2016-03-01

Full Text Available Pyrrolizidine Alkaloids (PAs are currently one of the most important botanical hepatotoxic ingredients. Glutathion (GSH metabolism is the most reported pathway involved in hepatotoxicity mechanism of PAs. We speculate that, for different PAs, there should be a common mechanism underlying their hepatotoxicity in GSH metabolism. Computational methods were adopted to test our hypothesis in consideration of the limitations of current experimental approaches. Firstly, the potential targets of 22 PAs (from three major PA types in GSH metabolism were identified by reverse docking; Secondly, glutathione S-transferase A1 (GSTA1 and glutathione peroxidase 1 (GPX1 targets pattern was found to be a special characteristic of toxic PAs with stepwise multiple linear regressions; Furthermore, the molecular mechanism underlying the interactions within toxic PAs and these two targets was demonstrated with the ligand-protein interaction analysis; Finally, GSTA1 and GPX1 were proved to be significant nodes in GSH metabolism. Overall, toxic PAs could be identified by GSTA1 and GPX1 targets pattern, which suggests their common hepatotoxicity mechanism: the interfering of detoxication in GSH metabolism. In addition, all the strategies developed here could be extended to studies on toxicity mechanism of other toxins.

Identification of Toxic Pyrrolizidine Alkaloids and Their Common Hepatotoxicity Mechanism.

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Yan, Xinmiao; Kang, Hong; Feng, Jun; Yang, Yiyan; Tang, Kailin; Zhu, Ruixin; Yang, Li; Wang, Zhengtao; Cao, Zhiwei

2016-03-07

Pyrrolizidine Alkaloids (PAs) are currently one of the most important botanical hepatotoxic ingredients. Glutathion (GSH) metabolism is the most reported pathway involved in hepatotoxicity mechanism of PAs. We speculate that, for different PAs, there should be a common mechanism underlying their hepatotoxicity in GSH metabolism. Computational methods were adopted to test our hypothesis in consideration of the limitations of current experimental approaches. Firstly, the potential targets of 22 PAs (from three major PA types) in GSH metabolism were identified by reverse docking; Secondly, glutathione S-transferase A1 (GSTA1) and glutathione peroxidase 1 (GPX1) targets pattern was found to be a special characteristic of toxic PAs with stepwise multiple linear regressions; Furthermore, the molecular mechanism underlying the interactions within toxic PAs and these two targets was demonstrated with the ligand-protein interaction analysis; Finally, GSTA1 and GPX1 were proved to be significant nodes in GSH metabolism. Overall, toxic PAs could be identified by GSTA1 and GPX1 targets pattern, which suggests their common hepatotoxicity mechanism: the interfering of detoxication in GSH metabolism. In addition, all the strategies developed here could be extended to studies on toxicity mechanism of other toxins.

Carbon and nitrogen metabolism in arbuscular mycorrhizal maize plants under low-temperature stress

DEFF Research Database (Denmark)

Zhu, Xian-Can; Song, Feng-Bin; Liu, Fulai

2015-01-01

Effects of the arbuscular mycorrhizal (AM) fungus Glomus tortuosum on carbon (C) and nitrogen (N) metabolism of Zea mays L. grown under low-temperature stress was investigated. Maize plants inoculated or not inoculated with AM fungus were grown in a growth chamber at 258C for 4 weeks...... temperature regimes. AM symbiosis modulated C metabolic enzymes, thereby inducing an accumulation of soluble sugars, which may have contributed to an increased tolerance to low temperature, and therefore higher Pn in maize plants....

Identification of Mutations Underlying 20 Inborn Errors of Metabolism in the United Arab Emirates Population

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Ben-Rebeh, Imen; Hertecant, Jozef L.; Al-Jasmi, Fatma A.; Aburawi, Hanan E.; Al-Yahyaee, Said A.; Al-Gazali, Lihadh

2012-01-01

Inborn errors of metabolism (IEM) are frequently encountered by physicians in the United Arab Emirates (UAE). However, the mutations underlying a large number of these disorders have not yet been determined. Therefore, the objective of this study was to identify the mutations underlying a number of IEM disorders among UAE residents from both national and expatriate families. A case series of patients from 34 families attending the metabolic clinic at Tawam Hospital were clinically evaluated, and molecular testing was carried out to determine their causative mutations. The mutation analysis was carried out at molecular genetics diagnostic laboratories. Thirty-eight mutations have been identified as responsible for twenty IEM disorders, including in the metabolism of amino acids, lipids, steroids, metal transport and mitochondrial energy metabolism, and lysosomal storage disorders. Nine of the identified mutations are novel, including two missense mutations, three premature stop codons and four splice site mutations. Mutation analysis of IEM disorders in the UAE population has an important impact on molecular diagnosis and genetic counseling for families affected by these disorders. PMID:22106832

Studies on the mechanism of quinone action on hormonal regulation of metabolism in the rat liver

International Nuclear Information System (INIS)

Cheng, E.Y.

1989-01-01

The mechanism of quinone actions in liver cell metabolism had been investigated using menadione as a model compound. Previous reports suggested that quinones and free radicals could produce perturbations in cellular calcium homeostasis. Since calcium plays an important role in the regulation of cellular metabolic processes, then regulation of cytosolic calcium concentrations, and thus of cellular metabolism, by calcium-mobilizing hormones such as phenylephrine and vasopressin could possibly be modified by quinones such as menadione. Methods used to approach this hypothesis included the assay for activation of glycogen phosphorylase, an indirect index of calcium mobilization; the determination of calcium mobilization with 45 Ca efflux exchange and with fluorescent calcium indicator fura-2; and the measurement of phosphatidylinositides, an important link in the membrane-associated receptor-mediated signal transduction mechanism

Effects of acupuncture on the citrate and glucose metabolism in the liver under various types of stress

International Nuclear Information System (INIS)

Liao, Y.Y.; Seto, K.; Saito, H.; Kawakami, M.

1980-01-01

A study was made of the effect of acupuncture on citrate and glucose metabolism in the liver in terms of incorporation of 14 C-1, 5-citric acid and 14 C-u-glucose in some metabolites. The effect of acupuncture on citrate metabolism in the liver under control conditions was such as to increase production of G and reduce that of KB, FC and FFA. No effect of acupuncture on glucose metabolism in the liver under such conditions was observed. Both citrate and glucose metabolism were affected to a marked extent by immobilization stress or exposure to heat or cold. The deleterious effect of these types of stress was less prominent in animals receiving acupuncture at the Tsu-San-Li locus than in those treated otherwise or receiving no treatment

Effects of acupuncture on the citrate and glucose metabolism in the liver under various types of stress

Energy Technology Data Exchange (ETDEWEB)

Liao, Y.Y.; Seto, K.; Saito, H.; Kawakami, M.

A study was made of the effect of acupuncture on citrate and glucose metabolism in the liver in terms of incorporation of /sup 14/C-1, 5-citric acid and /sup 14/C-u-glucose in some metabolites. The effect of acupuncture on citrate metabolism in the liver under control conditions was such as to increase production of G and reduce that of KB, FC and FFA. No effect of acupuncture on glucose metabolism in the liver under such conditions was observed. Both citrate and glucose metabolism were affected to a marked extent by immobilization stress or exposure to heat or cold. The deleterious effect of these types of stress was less prominent in animals receiving acupuncture at the Tsu-San-Li locus than in those treated otherwise or receiving no treatment.

Connexins, diabetes and the metabolic syndrome.

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Hamelin, Romain; Allagnat, Florent; Haefliger, Jacques-Antoine; Meda, Paolo

2009-02-01

Diabetes and the related metabolic syndrome are multi system disorders that result from improper interactions between various cell types. Even though the underlying mechanism remains to be fully understood, it is most likely that both the long and the short distance range cell interactions, which normally ensure the physiologic functioning of the pancreas, and its relationships with the insulin-targeted organs, are altered. This review focuses on the short-range type of interactions that depend on the contact between adjacent cells and, specifically, on the interactions that are dependent on connexins. The widespread distribution of these membrane proteins, their multiple modes of action, and their interactions with conditions/molecules associated to both the pathogenesis and the treatment of the 2 main forms of diabetes and the metabolic syndrome, make connexins an essential part of the chain of events that leads to metabolic diseases. Here, we review the present state of knowledge about the molecular and cell biology of the connexin genes and proteins, their general mechanisms of action, the roles specific connexin species play in the endocrine pancreas and the major insulin-targeted organs, under physiological and patho-physiological conditions.

Effects of Conservation Tillage on Topsoil Microbial Metabolic Characteristics and Organic Carbon within Aggregates under a Rice (Oryza sativa L.) –Wheat (Triticum aestivum L.) Cropping System in Central China

Science.gov (United States)

Liu, Tian-Qi; Cao, Cou-Gui; Li, Cheng-Fang

2016-01-01

Investigating microbial metabolic characteristics and soil organic carbon (SOC) within aggregates and their relationships under conservation tillage may be useful in revealing the mechanism of SOC sequestration in conservation tillage systems. However, limited studies have been conducted to investigate the relationship between SOC and microbial metabolic characteristics within aggregate fractions under conservation tillage. We hypothesized that close relationships can exist between SOC and microbial metabolic characteristics within aggregates under conservation tillage. In this study, a field experiment was conducted from June 2011 to June 2013 following a split-plot design of a randomized complete block with tillage practices [conventional intensive tillage (CT) and no tillage (NT)] as main plots and straw returning methods [preceding crop residue returning (S, 2100−2500 kg C ha−1) and removal (NS, 0 kg C ha-1)] as subplots with three replications. The objective of this study was to reveal the effects of tillage practices and residue-returning methods on topsoil microbial metabolic characteristics and organic carbon (SOC) fractions within aggregates and their relationships under a rice–wheat cropping system in central China. Microbial metabolic characteristics investigated using the Biolog system was examined within two aggregate fractions (>0.25 and 0.25 aggregate, and 0.25 mm aggregate (11.3%), and 0.25 mm aggregate, and 0.25 mm aggregate, and tillage (NT and S) increased microbial metabolic activities and Shannon index in >0.25 and directly improved SOC by promoting DOC in >0.25 mm aggregate in the upper (0−5 cm) soil layer under conservation tillage systems, as well as directly and indirectly by promoting DOC and MBC in tillage increased SOC in aggregates in the topsoil by improving microbial metabolic activities. PMID:26731654

Metabolic actions of FGF21: molecular mechanisms and therapeutic implications

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Xuan Ge

2012-08-01

Full Text Available Fibroblast growth factor 21 (FGF21 is an atypical member of the FGF family that functions as an endocrine factor. In obese animals, elevation of plasma FGF21 levels by either pharmacological or genetic approaches reduces body weight, decreases hyperglycemia and hyperlipidemia, alleviates fatty liver and increases insulin sensitivity. FGF21 exerts its pleiotropic metabolic effects through its actions on multiple targets, including adipose tissue, liver, brain and pancreas. The expression of FGF21 is under the control of both peroxisome proliferator-activated receptor gamma (PPARγ and peroxisome proliferator-activated receptor alpha (PPARα. A growing body of evidence suggests that the metabolic benefits of these two nuclear receptors are mediated in part by induction of FGF21. In humans, plasma levels of FGF21 are elevated in obese subjects and patients with type 2 diabetes, but are reduced in patients with autoimmune diabetes. This review summarizes recent advances in understanding the physiological roles of FGF21 and the molecular pathways underlying its actions, and also discusses the future prospective of developing FGF21 or its agonists as therapeutic agents for obesity-related medical complications.

MECHANISMS IN ENDOCRINOLOGY

DEFF Research Database (Denmark)

Allin, Kristine H.; Nielsen, Trine; Pedersen, Oluf.

2015-01-01

Perturbations of the composition and function of the gut microbiota have been associated with metabolic disorders including obesity, insulin resistance and type 2 diabetes. Studies on mice have demonstrated several underlying mechanisms including host signalling through bacterial lipopolysacchari...

The effect of maternal chromium status on lipid metabolism in female elderly mice offspring and involved molecular mechanism.

Science.gov (United States)

Zhang, Qian; Sun, Xiaofang; Xiao, Xinhua; Zheng, Jia; Li, Ming; Yu, Miao; Ping, Fan; Wang, Zhixin; Qi, Cuijuan; Wang, Tong; Wang, Xiaojing

2017-04-30

Maternal malnutrition leads to the incidence of metabolic diseases in offspring. The purpose of this project was to examine whether maternal low chromium could disturb normal lipid metabolism in offspring, altering adipose cell differentiation and leading to the incidence of lipid metabolism diseases, including metabolic syndrome and obesity. Female C57BL mice were given a control diet (CD) or a low chromium diet (LCD) during the gestational and lactation periods. After weaning, offspring was fed with CD or LCD. The female offspring were assessed at 32 weeks of age. Fresh adipose samples from CD-CD group and LCD-CD group were collected. Genome mRNA were analysed using Affymetrix GeneChip Mouse Gene 2.0 ST Whole Transcript-based array. Differentially expressed genes (DEGs) were analysed based on gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis database. Maternal low chromium irreversibly increased offspring body weight, fat-pad weight, serum triglyceride (TG) and TNF-α. Eighty five genes increased and 109 genes reduced in the offspring adipose of the maternal low chromium group. According to KEGG pathway and String analyses, the PPAR signalling pathway may be the key controlled pathway related to the effect of maternal low chromium on female offspring. Maternal chromium status have long-term effects of lipid metabolism in female mice offspring. Normalizing offspring diet can not reverse these effects. The potential underlying mechanisms are the disturbance of the PPAR signalling pathway in adipose tissue. © 2017 The Author(s).

Mechanisms of triglyceride metabolism in patients with bile acid diarrhea

Science.gov (United States)

Sagar, Nidhi Midhu; McFarlane, Michael; Nwokolo, Chuka; Bardhan, Karna Dev; Arasaradnam, Ramesh Pulendran

2016-01-01

Bile acids (BAs) are essential for the absorption of lipids. BA synthesis is inhibited through intestinal farnesoid X receptor (FXR) activity. BA sequestration is known to influence BA metabolism and control serum lipid concentrations. Animal data has demonstrated a regulatory role for the FXR in triglyceride metabolism. FXR inhibits hepatic lipogenesis by inhibiting the expression of sterol regulatory element binding protein 1c via small heterodimer primer activity. Conversely, FXR promotes free fatty acids oxidation by inducing the expression of peroxisome proliferator-activated receptor α. FXR can reduce the expression of microsomal triglyceride transfer protein, which regulates the assembly of very low-density lipoproteins (VLDL). FXR activation in turn promotes the clearance of circulating triglycerides by inducing apolipoprotein C-II, very low-density lipoproteins receptor (VLDL-R) and the expression of Syndecan-1 together with the repression of apolipoprotein C-III, which increases lipoprotein lipase activity. There is currently minimal clinical data on triglyceride metabolism in patients with bile acid diarrhoea (BAD). Emerging data suggests that a third of patients with BAD have hypertriglyceridemia. Further research is required to establish the risk of hypertriglyceridaemia in patients with BAD and elicit the mechanisms behind this, allowing for targeted treatment. PMID:27570415

Giant panda׳s tooth enamel: Structure, mechanical behavior and toughening mechanisms under indentation.

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Weng, Z Y; Liu, Z Q; Ritchie, R O; Jiao, D; Li, D S; Wu, H L; Deng, L H; Zhang, Z F

2016-12-01

The giant panda׳s teeth possess remarkable load-bearing capacity and damage resistance for masticating bamboos. In this study, the hierarchical structure and mechanical behavior of the giant panda׳s tooth enamel were investigated under indentation. The effects of loading orientation and location on mechanical properties of the enamel were clarified and the evolution of damage in the enamel under increasing load evaluated. The nature of the damage, both at and beneath the indentation surfaces, and the underlying toughening mechanisms were explored. Indentation cracks invariably were seen to propagate along the internal interfaces, specifically the sheaths between enamel rods, and multiple extrinsic toughening mechanisms, e.g., crack deflection/twisting and uncracked-ligament bridging, were active to shield the tips of cracks from the applied stress. The giant panda׳s tooth enamel is analogous to human enamel in its mechanical properties, yet it has superior hardness and Young׳s modulus but inferior toughness as compared to the bamboo that pandas primarily feed on, highlighting the critical roles of the integration of underlying tissues in the entire tooth and the highly hydrated state of bamboo foods. Our objective is that this study can aid the understanding of the structure-mechanical property relations in the tooth enamel of mammals and further provide some insight on the food habits of the giant pandas. Copyright © 2016 Elsevier Ltd. All rights reserved.

Characterization of γ-aminobutyric acid metabolism and oxidative damage in wheat (Triticum aestivum L.) seedlings under salt and osmotic stress.

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Al-Quraan, Nisreen A; Sartawe, Fatima Al-Batool; Qaryouti, Muien M

2013-07-15

The molecular response of plants to abiotic stresses has been considered a process mainly involved in the modulation of transcriptional activity of stress-related genes. Nevertheless, recent findings have suggested new layers of regulation and complexity. Upstream molecular mechanisms are involved in the plant response to abiotic stress. Plants gain resistance to abiotic stress by reprogramming metabolism and gene expression. GABA is proposed to be a signaling molecule involved in nitrogen metabolism, regulating the cytosolic pH, and protection against oxidative damage in response to various abiotic stresses. The aim of our study was to examine the role of the GABA shunt pathway-specific response in five wheat (Triticum aestivum L.) cultivars (Hurani 75, Sham I, Acsad 65, Um Qayes and Nodsieh) to salt and osmotic stress in terms of seed germination, seedling growth, oxidative damage (malondialdehyde (MDA) accumulation), and characterization of the glutamate decarboxylse gene (GAD) m-RNA level were determined using RT-PCR techniques. Our data showed a marked increase in GABA, MDA and GAD m-RNA levels under salt and osmotic stress in the five wheat cultivars. Um Qayes cultivar showed the highest germination percentage, GABA accumulation, and MDA level under salt and osmotic stresses. The marked increase in GAD gene expression explains the high accumulation of the GABA level under both stresses. Our results indicated that the GABA shunt is a key signaling and metabolic pathway that allows wheat to adapt to salt and osmotic stress. Based on our data, the Um Qayes wheat cultivar is the cultivar most recommended to be grown in soil with high salt and osmotic contents. Copyright © 2013 Elsevier GmbH. All rights reserved.

MECHANISMS IN ENDOCRINOLOGY: Diabetic cardiomyopathy: pathophysiology and potential metabolic interventions state of the art review.

Science.gov (United States)

Levelt, Eylem; Gulsin, Gaurav; Neubauer, Stefan; McCann, Gerry P

2018-04-01

Heart failure is a major cause of morbidity and mortality in type 2 diabetes. Type 2 diabetes contributes to the development of heart failure through a variety of mechanisms, including disease-specific myocardial structural, functional and metabolic changes. This review will focus on the contemporary contributions of state of the art non-invasive technologies to our understanding of diabetic cardiomyopathy, including data on cardiac disease phenotype, cardiac energy metabolism and energetic deficiency, ectopic and visceral adiposity, diabetic liver disease, metabolic modulation strategies and cardiovascular outcomes with new classes of glucose-lowering therapies. © 2018 The authors.

Mechanisms of metabonomic for a gateway drug: nicotine priming enhances behavioral response to cocaine with modification in energy metabolism and neurotransmitter level.

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Hongyu Li

Full Text Available Nicotine, one of the most commonly used drugs, has become a major concern because tobacco serves as a gateway drug and is linked to illicit drug abuse, such as cocaine and marijuana. However, previous studies mainly focused on certain genes or neurotransmitters which have already been known to participate in drug addiction, lacking endogenous metabolic profiling in a global view. To further explore the mechanism by which nicotine modifies the response to cocaine, we developed two conditioned place preference (CPP models in mice. In threshold dose model, mice were pretreated with nicotine, followed by cocaine treatment at the dose of 2 mg/kg, a threshold dose of cocaine to induce CPP in mice. In high-dose model, mice were only treated with 20 mg/kg cocaine, which induced a significant CPP. (1H nuclear magnetic resonance based on metabonomics was used to investigate metabolic profiles of the nucleus accumbens (NAc and striatum. We found that nicotine pretreatment dramatically increased CPP induced by 2 mg/kg cocaine, which was similar to 20 mg/kg cocaine-induced CPP. Interestingly, metabolic profiles showed considerable overlap between these two models. These overlapped metabolites mainly included neurotransmitters as well as the molecules participating in energy homeostasis and cellular metabolism. Our results show that the reinforcing effect of nicotine on behavioral response to cocaine may attribute to the modification of some specific metabolites in NAc and striatum, thus creating a favorable metabolic environment for enhancing conditioned rewarding effect of cocaine. Our findings provide an insight into the effect of cigarette smoking on cocaine dependence and the underlying mechanism.

Optimal decoding and information transmission in Hodgkin-Huxley neurons under metabolic cost constraints.

Science.gov (United States)

Kostal, Lubomir; Kobayashi, Ryota

2015-10-01

Information theory quantifies the ultimate limits on reliable information transfer by means of the channel capacity. However, the channel capacity is known to be an asymptotic quantity, assuming unlimited metabolic cost and computational power. We investigate a single-compartment Hodgkin-Huxley type neuronal model under the spike-rate coding scheme and address how the metabolic cost and the decoding complexity affects the optimal information transmission. We find that the sub-threshold stimulation regime, although attaining the smallest capacity, allows for the most efficient balance between the information transmission and the metabolic cost. Furthermore, we determine post-synaptic firing rate histograms that are optimal from the information-theoretic point of view, which enables the comparison of our results with experimental data. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Water deprivation induces appetite and alters metabolic strategy in Notomys alexis: unique mechanisms for water production in the desert.

Science.gov (United States)

Takei, Yoshio; Bartolo, Ray C; Fujihara, Hiroaki; Ueta, Yoichi; Donald, John A

2012-07-07

Like many desert animals, the spinifex hopping mouse, Notomys alexis, can maintain water balance without drinking water. The role of the kidney in producing a small volume of highly concentrated urine has been well-documented, but little is known about the physiological mechanisms underpinning the metabolic production of water to offset obligatory water loss. In Notomys, we found that water deprivation (WD) induced a sustained high food intake that exceeded the pre-deprivation level, which was driven by parallel changes in plasma leptin and ghrelin and the expression of orexigenic and anorectic neuropeptide genes in the hypothalamus; these changed in a direction that would stimulate appetite. As the period of WD was prolonged, body fat disappeared but body mass increased gradually, which was attributed to hepatic glycogen storage. Switching metabolic strategy from lipids to carbohydrates would enhance metabolic water production per oxygen molecule, thus providing a mechanism to minimize respiratory water loss. The changes observed in appetite control and metabolic strategy in Notomys were absent or less prominent in laboratory mice. This study reveals novel mechanisms for appetite regulation and energy metabolism that could be essential for desert rodents to survive in xeric environments.

Expansion of plants with Crassulacean Acid Metabolism under global environment change

Science.gov (United States)

Yu, K.; D'Odorico, P.; Collins, S. L.; Carr, D.

2016-12-01

The abundance of plants with Crassulacean Acid Metabolism (CAM) has increased in many drylands worldwide. This is hypothesized to occur because CAM plants store water, take up CO2 at night, exhibit photosynthetic plasticity, and have high water use efficiency. The increased dominance of CAM plants, however, also depends on their competitive relationship with other functional groups, an aspect of CAM plant sensitivity to global environmental change that has remained largely understudied. Here, we investigated the response of CAM plants and their competitive relationships with C3 and C4 plants under global environmental change. We focused on two pairs of CAM and non-CAM species, namely Cylindropuntia imbricata (a constitutive CAM species) and Bouteloua eriopoda (C4 grass), which co-occur in desert grasslands in northern Mexico, and invasive Mesembryanthemum crystallinum (a facultative CAM species) and Bromus mollis (a C3 invasive grass), which coexist in California's coastal grasslands. A set of growth chamber experiments under altered CO2 and water conditions show that C. imbricata outcompeted B. eriopoda under drought conditions, while in well-watered conditions B. eriopoda was a stronger competitor for soil water than C. imbricata. Under drought conditions a more positive response to CO2 enrichment by C. imbricata indirectly disfavored B. eriopoda, which suggests that interspecific competition can outweigh the favorable direct effect of CO2 enrichment on plant growth. A set of greenhouse experiments under water, N, and soil salinity manipulations showed that drought, N deposition, and/or increased soil salinity served as important drivers for success of M. crystallinum invasion, while B. mollis exerted strong competitive effects on M. crystallinum for light and soil nutrients in well-watered conditions. M. crystallinum switched from C3 photosynthesis to CAM photosynthesis as an adaptive strategy in response to moderate intensity of competition from B. mollis, in

Peeling mechanism of tomato under infrared heating

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Critical behaviors of peeling tomatoes using infrared heat are thermally induced peel loosening and subsequent cracking. However, the mechanism of peel loosening and cracking due to infrared heating remains unclear. This study aimed at investigating the mechanism of peeling tomatoes under infrared h...

Insight into the metabolic mechanism of scoparone on biomarkers for inhibiting Yanghuang syndrome.

Science.gov (United States)

Fang, Heng; Zhang, Aihua; Yu, Jingbo; Wang, Liang; Liu, Chang; Zhou, Xiaohang; Sun, Hui; Song, Qi; Wang, Xijun

2016-11-21

Scoparone (6,7-dimethoxycoumarin) is the representative ingredient of Yinchenhao (Artemisia capillaris Thunb.) which is a famous Chinese medicinal herb and shows favorable efficacy for all kinds of liver disease, specifically for the treatment of Yanghuang syndrome (YHS). The precise molecular mechanism concerning the action of scoparone on YHS is yet to be fully elucidated. The aim of the present study was to determine the mechanism of scoparone and evaluate its efficacy on metabolite levels. The differential expression of metabolites responsible for the pharmacological effects of scoparone was characterized and the protection effect of scoparone against this disease. Using multivariate statistical analysis, 33 biomarkers were identified using precise MS/MS and play an important role in the regulation of key metabolic pathways associated with liver disease. In addition, pathological results also showed consistent changes in the YHS model group and after treatment with scoparone, both the metabolic profile and histopathology resembled that of normal level, which suggesting favorable efficacy over the observed time period. The present work indicated that a metabolomics platform provided a new insight into understanding the mechanisms of action of natural medicines such as scoparone.

Mechanisms relevant to the enhanced virulence of a dihydroxynaphthalene-melanin metabolically engineered entomopathogen.

Directory of Open Access Journals (Sweden)

Min-Nan Tseng

Full Text Available The entomopathogenic fungus Metarhizium anisopliae MA05-169 is a transformant strain that has been metabolically engineered to express dihydroxynaphthalene-melanin biosynthesis genes. In contrast to the wild type strain, the transformant displays a greater resistance to environmental stress and a higher virulence toward target insect host. However, the underlying mechanisms for these characteristics remain unclear; hence experiments were initiated to explore the possible mechanism(s through physiological and molecular approaches. Although both transformant and wild type strains could infect and share the same insect host range, the former germinated faster and produced more appressoria than the latter, both in vivo and in vitro. The transformant showed a significantly shorter median lethal time (LT50 when infecting the diamondback moth (Plutella xylostella and the striped flea beetle (Phyllotreta striolata, than the wild type. Additionally, the transformant was more tolerant to reactive oxygen species (ROS, produced 40-fold more orthosporin and notably overexpressed the transcripts of the pathogenicity-relevant hydrolytic enzymes (chitinase, protease, and phospholipase genes in vivo. In contrast, appressorium turgor pressure and destruxin A content were slightly decreased compared to the wild type. The transformant's high anti-stress tolerance, its high virulence against five important insect pests (cowpea aphid Aphis craccivora, diamondback moth Pl. xylostella, striped flea beetle Ph. striolata, and silverleaf whitefly Bemisia argentifolii and its capacity to colonize the root system are key properties for its potential bio-control field application.

How does 'metabolic surgery' work its magic? New evidence for gut microbiota.

Science.gov (United States)

Peck, Bailey C E; Seeley, Randy J

2018-04-01

Metabolic surgery is recommended for the treatment of type 2 diabetes for its potent ability to improve glycemic control. However, the mechanisms underlying the beneficial effects of metabolic surgery are still under investigation. We provide an updated review of recent studies into the molecular underpinnings of metabolic surgery, focusing in on what is known about the role of gut microbiota. Over the last 7 years several reports have been published on the topic, however the field is expanding rapidly. Studies have now linked the regulation of glucose and lipid metabolism, neuronal and intestinal adaptations, and hormonal and nutrient signaling pathways to gut microbiota. Given that the composition of gut microbiota is altered by metabolic surgery, investigating the potential mechanism and outcomes of this change are now a priority to the field. As evidence for a role for microbiota builds, we expect future patients may receive microbe-based therapeutics to improve surgical outcomes and perhaps one day preclude the need for surgical therapies all together. In this review and perspective, we evaluate the current state of the field and its future.

Temporal expression-based analysis of metabolism.

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Sara B Collins

Full Text Available Metabolic flux is frequently rerouted through cellular metabolism in response to dynamic changes in the intra- and extra-cellular environment. Capturing the mechanisms underlying these metabolic transitions in quantitative and predictive models is a prominent challenge in systems biology. Progress in this regard has been made by integrating high-throughput gene expression data into genome-scale stoichiometric models of metabolism. Here, we extend previous approaches to perform a Temporal Expression-based Analysis of Metabolism (TEAM. We apply TEAM to understanding the complex metabolic dynamics of the respiratorily versatile bacterium Shewanella oneidensis grown under aerobic, lactate-limited conditions. TEAM predicts temporal metabolic flux distributions using time-series gene expression data. Increased predictive power is achieved by supplementing these data with a large reference compendium of gene expression, which allows us to take into account the unique character of the distribution of expression of each individual gene. We further propose a straightforward method for studying the sensitivity of TEAM to changes in its fundamental free threshold parameter θ, and reveal that discrete zones of distinct metabolic behavior arise as this parameter is changed. By comparing the qualitative characteristics of these zones to additional experimental data, we are able to constrain the range of θ to a small, well-defined interval. In parallel, the sensitivity analysis reveals the inherently difficult nature of dynamic metabolic flux modeling: small errors early in the simulation propagate to relatively large changes later in the simulation. We expect that handling such "history-dependent" sensitivities will be a major challenge in the future development of dynamic metabolic-modeling techniques.

Controlled sumoylation of the mevalonate pathway enzyme HMGS-1 regulates metabolism during aging

NARCIS (Netherlands)

Sapir, Amir; Tsur, Assaf; Koorman, Thijs; Ching, Kaitlin; Mishra, Prashant; Bardenheier, Annabelle; Podolsky, Lisa; Bening-Abu-Shach, Ulrike; Boxem, Mike; Chou, Tsui-Fen; Broday, Limor; Sternberg, Paul W

2014-01-01

Many metabolic pathways are critically regulated during development and aging but little is known about the molecular mechanisms underlying this regulation. One key metabolic cascade in eukaryotes is the mevalonate pathway. It catalyzes the synthesis of sterol and nonsterol isoprenoids, such as

Metabolic profiles of flooding-tolerant mechanism in early-stage soybean responding to initial stress.

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Wang, Xin; Zhu, Wei; Hashiguchi, Akiko; Nishimura, Minoru; Tian, Jingkui; Komatsu, Setsuko

2017-08-01

Metabolomic analysis of flooding-tolerant mutant and abscisic acid-treated soybeans suggests that accumulated fructose might play a role in initial flooding tolerance through regulation of hexokinase and phosphofructokinase. Soybean is sensitive to flooding stress, which markedly reduces plant growth. To explore the mechanism underlying initial-flooding tolerance in soybean, mass spectrometry-based metabolomic analysis was performed using flooding-tolerant mutant and abscisic-acid treated soybeans. Among the commonly-identified metabolites in both flooding-tolerant materials, metabolites involved in carbohydrate and organic acid displayed same profile at initial-flooding stress. Sugar metabolism was highlighted in both flooding-tolerant materials with the decreased and increased accumulation of sucrose and fructose, respectively, compared to flooded soybeans. Gene expression of hexokinase 1 was upregulated in flooded soybean; however, it was downregulated in both flooding-tolerant materials. Metabolites involved in carbohydrate/organic acid and proteins related to glycolysis/tricarboxylic acid cycle were integrated. Increased protein abundance of phosphofructokinase was identified in both flooding-tolerant materials, which was in agreement with its enzyme activity. Furthermore, sugar metabolism was pointed out as the tolerant-responsive process at initial-flooding stress with the integration of metabolomics, proteomics, and transcriptomics. Moreover, application of fructose declined the increased fresh weight of plant induced by flooding stress. These results suggest that fructose might be the critical metabolite through regulation of hexokinase and phosphofructokinase to confer initial-flooding stress in soybean.

Exploring the Metabolic and Perceptual Correlates of Self-Selected Walking Speed under Constrained and Un-Constrained Conditions

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David T Godsiff, Shelly Coe, Charlotte Elsworth-Edelsten, Johnny Collett, Ken Howells, Martyn Morris, Helen Dawes

2018-03-01

Full Text Available Mechanisms underpinning self-selected walking speed (SSWS are poorly understood. The present study investigated the extent to which SSWS is related to metabolism, energy cost, and/or perceptual parameters during both normal and artificially constrained walking. Fourteen participants with no pathology affecting gait were tested under standard conditions. Subjects walked on a motorized treadmill at speeds derived from their SSWS as a continuous protocol. RPE scores (CR10 and expired air to calculate energy cost (J.kg-1.m-1 and carbohydrate (CHO oxidation rate (J.kg-1.min-1 were collected during minutes 3-4 at each speed. Eight individuals were re-tested under the same conditions within one week with a hip and knee-brace to immobilize their right leg. Deflection in RPE scores (CR10 and CHO oxidation rate (J.kg-1.min-1 were not related to SSWS (five and three people had deflections in the defined range of SSWS in constrained and unconstrained conditions, respectively (p > 0.05. Constrained walking elicited a higher energy cost (J.kg-1.m-1 and slower SSWS (p 0.05. SSWS did not occur at a minimum energy cost (J.kg-1.m-1 in either condition, however, the size of the minimum energy cost to SSWS disparity was the same (Froude {Fr} = 0.09 in both conditions (p = 0.36. Perceptions of exertion can modify walking patterns and therefore SSWS and metabolism/ energy cost are not directly related. Strategies which minimize perceived exertion may enable faster walking in people with altered gait as our findings indicate they should self-optimize to the same extent under different conditions.

Muscle-tendon mechanics explain unexpected effects of exoskeleton assistance on metabolic rate during walking.

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Jackson, Rachel W; Dembia, Christopher L; Delp, Scott L; Collins, Steven H

2017-06-01

The goal of this study was to gain insight into how ankle exoskeletons affect the behavior of the plantarflexor muscles during walking. Using data from previous experiments, we performed electromyography-driven simulations of musculoskeletal dynamics to explore how changes in exoskeleton assistance affected plantarflexor muscle-tendon mechanics, particularly for the soleus. We used a model of muscle energy consumption to estimate individual muscle metabolic rate. As average exoskeleton torque was increased, while no net exoskeleton work was provided, a reduction in tendon recoil led to an increase in positive mechanical work performed by the soleus muscle fibers. As net exoskeleton work was increased, both soleus muscle fiber force and positive mechanical work decreased. Trends in the sum of the metabolic rates of the simulated muscles correlated well with trends in experimentally observed whole-body metabolic rate ( R 2 =0.9), providing confidence in our model estimates. Our simulation results suggest that different exoskeleton behaviors can alter the functioning of the muscles and tendons acting at the assisted joint. Furthermore, our results support the idea that the series tendon helps reduce positive work done by the muscle fibers by storing and returning energy elastically. We expect the results from this study to promote the use of electromyography-driven simulations to gain insight into the operation of muscle-tendon units and to guide the design and control of assistive devices. © 2017. Published by The Company of Biologists Ltd.

Targeting Cellular Stress Mechanisms and Metabolic Homeostasis by Chinese Herbal Drugs for Neuroprotection

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Hsiao-Chien Ting

2018-01-01

Full Text Available Traditional Chinese medicine has been practiced for centuries in East Asia. Herbs are used to maintain health and cure disease. Certain Chinese herbs are known to protect and improve the brain, memory, and nervous system. To apply ancient knowledge to modern science, some major natural therapeutic compounds in herbs were extracted and evaluated in recent decades. Emerging studies have shown that herbal compounds have neuroprotective effects or can ameliorate neurodegenerative diseases. To understand the mechanisms of herbal compounds that protect against neurodegenerative diseases, we summarize studies that discovered neuroprotection by herbal compounds and compound-related mechanisms in neurodegenerative disease models. Those compounds discussed herein show neuroprotection through different mechanisms, such as cytokine regulation, autophagy, endoplasmic reticulum (ER stress, glucose metabolism, and synaptic function. The interleukin (IL-1β and tumor necrosis factor (TNF-α signaling pathways are inhibited by some compounds, thus attenuating the inflammatory response and protecting neurons from cell death. As to autophagy regulation, herbal compounds show opposite regulatory effects in different neurodegenerative models. Herbal compounds that inhibit ER stress prevent neuronal death in neurodegenerative diseases. Moreover, there are compounds that protect against neuronal death by affecting glucose metabolism and synaptic function. Since the progression of neurodegenerative diseases is complicated, and compound-related mechanisms for neuroprotection differ, therapeutic strategies may need to involve multiple compounds and consider the type and stage of neurodegenerative diseases.

Bitter melon juice targets molecular mechanisms underlying gemcitabine resistance in pancreatic cancer cells

OpenAIRE

SOMASAGARA, RANGANATHA R.; DEEP, GAGAN; SHROTRIYA, SANGEETA; PATEL, MANISHA; AGARWAL, CHAPLA; AGARWAL, RAJESH

2015-01-01

Pancreatic cancer (PanC) is one of the most lethal malignancies, and resistance towards gemcitabine, the front-line chemotherapy, is the main cause for dismal rate of survival in PanC patients; overcoming this resistance remains a major challenge to treat this deadly malignancy. Whereas several molecular mechanisms are known for gemcitabine resistance in PanC cells, altered metabolism and bioenergetics are not yet studied. Here, we compared metabolic and bioenergetic functions between gemcita...

Deciphering the Cognitive and Neural Mechanisms Underlying ...

International Development Research Centre (IDRC) Digital Library (Canada)

Deciphering the Cognitive and Neural Mechanisms Underlying Auditory Learning. This project seeks to understand the brain mechanisms necessary for people to learn to perceive sounds. Neural circuits and learning. The research team will test people with and without musical training to evaluate their capacity to learn ...

Free fatty acids and their metabolism affect function and survival of podocytes

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Jonas eSieber

2014-10-01

Full Text Available Podocyte injury and loss critically contribute to the pathogenesis of proteinuric kidney diseases including diabetic nephropathy. Deregulated lipid metabolism with disturbed free fatty acid (FFA metabolism is a characteristic of metabolically unhealthy obesity and type 2 diabetes and likely contributes to end-stage kidney disease irrespective of the underlying kidney disease. In the current review we summarize recent findings related to FFAs and altered renal FFA metabolism with a special focus on podocytes. We will outline the opposing effects of saturated and monounsaturated FFAs and a particular emphasis will be given to the underlying molecular mechanisms involving insulin resistance and endoplasmic reticulum homeostasis. Finally, recent data suggesting a critical role of renal FFA metabolism to adapt to an altered lipid environment will be discussed.

Intestinal IRE1 Is Required for Increased Triglyceride Metabolism and Longer Lifespan under Dietary Restriction.

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Luis, Nuno Miguel; Wang, Lifen; Ortega, Mauricio; Deng, Hansong; Katewa, Subhash D; Li, Patrick Wai-Lun; Karpac, Jason; Jasper, Heinrich; Kapahi, Pankaj

2016-10-25

Dietary restriction (DR) is one of the most robust lifespan-extending interventions in animals. The beneficial effects of DR involve a metabolic adaptation toward increased triglyceride usage. The regulatory mechanism and the tissue specificity of this metabolic switch remain unclear. Here, we show that the IRE1/XBP1 endoplasmic reticulum (ER) stress signaling module mediates metabolic adaptation upon DR in flies by promoting triglyceride synthesis and accumulation in enterocytes (ECs) of the Drosophila midgut. Consistently, IRE1/XBP1 function in ECs is required for increased longevity upon DR. We further identify sugarbabe, a Gli-like zinc-finger transcription factor, as a key mediator of the IRE1/XBP1-regulated induction of de novo lipogenesis in ECs. Overexpression of sugarbabe rescues metabolic and lifespan phenotypes of IRE1 loss-of-function conditions. Our study highlights the critical role of metabolic adaptation of the intestinal epithelium for DR-induced lifespan extension and explores the IRE1/XBP1 signaling pathway regulating this adaptation and influencing lifespan. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Shift work and its association with metabolic disorders.

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Brum, Maria Carlota Borba; Filho, Fábio Fernandes Dantas; Schnorr, Claudia Carolina; Bottega, Gustavo Borchardt; Rodrigues, Ticiana C

2015-01-01

Although the health burden of shift work has not been extensively studied, evidence suggests that it may affect the metabolic balance and cause obesity and other metabolic disorders. Sleep deprivation, circadian desynchronization and behavioral changes in diet and physical activity are among the most commonly mentioned factors in studies of the association between night work and metabolic disorders. Individual adaptation to night work depends greatly on personal factors such as family and social life, but occupational interventions may also make a positive contribution to the transition to shift work, such as exposure to bright lights during the night shift, melatonin use, shift regularity and clockwise rotation, and dietary adaptations for the metabolic needs of night workers. The evaluation of the impact of night work on health and of the mechanisms underlying this relationship can serve as a basis for intervention strategies to minimize the health burden of shift work. This review aimed to identify highlights regarding therapeutic implications following the association between night and shift work and metabolic disorders, as well as the mechanisms and pathways responsible for these relationships.

Endocrine and metabolic mechanisms linking postpartum glucose with early embryonic and foetal development in dairy cows.

Science.gov (United States)

Lucy, M C; Butler, S T; Garverick, H A

2014-05-01

Milk and milk solids production per cow is increasing annually in dairy systems. Peak milk production is in early lactation when the uterus and ovary are recovering from the previous pregnancy. The competing processes of milk production and restoration of reproductive function can be at odds, particularly if unique homeorhetic mechanisms that typify early lactation become imbalanced and cows experience metabolic disease. Homeorhesis leads to an increase in the synthesis of glucose that is irreversibly lost to milk lactose. Irreversible loss of glucose during lactation can invoke an endocrine and metabolic state that impinges upon postpartum uterine health, oestrous cyclicity and subsequent establishment of pregnancy. The first 30 days postpartum may be most critical in terms of the impact that metabolites and metabolic hormones have on reproduction. Depressed immune function caused in part by the postpartum metabolic profile leads to a failure in uterine involution and uterine disease. Oestrous cyclicity (interval to first ovulation and subsequent periodicity) is affected by the same hormones and metabolites that control postpartum immune function. Slower growth of the embryo or foetus perhaps explained by the unique metabolic profile during lactation may predispose cows to pregnancy loss. Understanding homeorhetic mechanisms that involve glucose and collectively affect postpartum uterine health, oestrous cyclicity and the establishment of pregnancy should lead to methods to improve postpartum fertility in dairy cows.

Gas Bubble Dynamics under Mechanical Vibrations

Science.gov (United States)

Mohagheghian, Shahrouz; Elbing, Brian

2017-11-01

The scientific community has a limited understanding of the bubble dynamics under mechanical oscillations due to over simplification of Navier-Stockes equation by neglecting the shear stress tensor and not accounting for body forces when calculating the acoustic radiation force. The current work experimental investigates bubble dynamics under mechanical vibration and resulting acoustic field by measuring the bubble size and velocity using high-speed imaging. The experimental setup consists of a custom-designed shaker table, cast acrylic bubble column, compressed air injection manifold and an optical imaging system. The mechanical vibrations resulted in accelerations between 0.25 to 10 times gravitational acceleration corresponding to frequency and amplitude range of 8 - 22Hz and 1 - 10mm respectively. Throughout testing the void fraction was limited to <5%. The bubble size is larger than resonance size and smaller than acoustic wavelength. The amplitude of acoustic pressure wave was estimated using the definition of Bjerknes force in combination with Rayleigh-Plesset equation. Physical behavior of the system was capture and classified. Bubble size, velocity as well as size and spatial distribution will be presented.

Metabolic activation and carcinogenicity of polycyclic hydrocarbons: A new quantum mechanical theory

International Nuclear Information System (INIS)

Mohammad, S.N.

1986-01-01

This investigation aims to describe a quantum mechanical theory of cancer, which, on the basis of certain electronic indices calculated for the parent compound, would give prediction of its P-450 mediated metabolic activation and would provide better representation of its relative carcinogenic potency when activated to its PUM. The author's theory is based on the assumption that electronic charge distribution of activated species resembles at least qualitatively the charge distribution of the parent compound, and a careful analysis of electronic characteristics of the parent compound would suffice to give reasonable estimation of the carcinogenic activities of the metabolic products. The details of the theoretical method is given and the results for some alternant and non-alternant PAHs are presented

Pharmacogenomic and clinical data link non-pharmacokinetic metabolic dysregulation to drug side effect pathogenesis

DEFF Research Database (Denmark)

Zielinski, Daniel C.; Filipp, F. V.; Bordbar, A.

2015-01-01

Drug side effects cause a significant clinical and economic burden. However, mechanisms of drug action underlying side effect pathogenesis remain largely unknown. Here, we integrate pharmacogenomic and clinical data with a human metabolic network and find that non-pharmacokinetic metabolic pathways...

Adenylate kinase I does not affect cellular growth characteristics under normal and metabolic stress conditions.

Science.gov (United States)

de Bruin, Wieke; Oerlemans, Frank; Wieringa, Bé

2004-07-01

Adenylate kinase (AK)-catalyzed phosphotransfer is essential in the maintenance of cellular energetic economy in cells of fully differentiated tissues with highly variable energy demand, such as muscle and brain. To investigate if AK isoenzymes have a comparable function in the energy-demand management of proliferating cells, AK1 and AK1beta were expressed in mouse neuroblastoma N2a cells and in human colon carcinoma SW480 cells. Glucose deprivation, galactose feeding, and metabolic inhibitor tests revealed a differential energy dependency for these two cell lines. N2a cells showed a faster proliferation rate and strongest coupling to mitochondrial activity, SW480 proliferation was more dependent on glycolysis. Despite these differences, ectopic expression of AK1 or AK1beta did not affect their growth characteristics under normal conditions. Also, no differential effects were seen under metabolic stress upon treatment with mitochondrial and glycolytic inhibitors in in vitro culture or in solid tumors grown in vivo. Although many intimate connections have been revealed between cell death and metabolism, our results suggest that AK1- or AK1beta-mediated high-energy phosphoryl transfer is not a modulating factor in the survival of tumor cells during episodes of metabolic crisis.

Sleep and metabolism: role of hypothalamic neuronal circuitry.

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Rolls, Asya; Schaich Borg, Jana; de Lecea, Luis

2010-10-01

Sleep and metabolism are intertwined physiologically and behaviorally, but the neural systems underlying their coordination are still poorly understood. The hypothalamus is likely to play a major role in the regulation sleep, metabolism, and their interaction. And increasing evidence suggests that hypocretin cells in the lateral hypothalamus may provide particularly important contributions. Here we review: 1) direct interactions between biological arousal and metabolic systems in the hypothalamus, and 2) indirect interactions between these two systems mediated by stress or reward, emphasizing the role of hypocretins. An increased understanding of the mechanisms underlying these interactions may provide novel approaches for the treatment of patients with sleep disorders and obesity, as well as suggest new therapeutic strategies for symptoms of aging, stress, or addiction. Copyright © 2010. Published by Elsevier Ltd.

Different routes, same pathways: Molecular mechanisms under silver ion and nanoparticle exposures in the soil sentinel Eisenia fetida

International Nuclear Information System (INIS)

Novo, Marta; Lahive, Elma; Díez-Ortiz, María; Matzke, Marianne; Morgan, Andrew J.; Spurgeon, David J.; Svendsen, Claus; Kille, Peter

2015-01-01

Use of nanotechnology products is increasing; with silver (Ag) nanoparticles particularly widely used. A key uncertainty surrounding the risk assessment of AgNPs is whether their effects are driven through the same mechanism of action that underlies the toxic effects of Ag ions. We present the first full transcriptome study of the effects of Ag ions and NPs in an ecotoxicological model soil invertebrate, the earthworm Eisenia fetida. Gene expression analyses indicated similar mechanisms for both silver forms with toxicity being exerted through pathways related to ribosome function, sugar and protein metabolism, molecular stress, disruption of energy production and histones. The main difference seen between Ag ions and NPs was associated with potential toxicokinetic effects related to cellular internalisation and communication, with pathways related to endocytosis and cilia being significantly enriched. These results point to a common final toxicodynamic response, but initial internalisation driven by different exposure routes and toxicokinetic mechanisms. - Highlights: • Molecular effects underlying Ag ions and NPs exposure were studied in Eisenia fetida. • Full transcriptomic study of a genetically characterised lineage. • NPs and ions presented a similar toxicodynamic response. • Internalisation of the two Ag forms by different toxicokinetic mechanisms. - Transcriptomic analyses after exposure of earthworms to silver NPs or ions showed a final common toxicodynamic response, but internalisation by different toxicokinetic mechanisms

High fructose diet-induced metabolic syndrome: Pathophysiological mechanism and treatment by traditional Chinese medicine.

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Pan, Ying; Kong, Ling-Dong

2018-04-01

Fructose is a natural monosaccharide broadly used in modern society. Over the past few decades, epidemiological studies have demonstrated that high fructose intake is an etiological factor of metabolic syndrome (MetS). This review highlights research advances on fructose-induced MetS, especially the underlying pathophysiological mechanism as well as pharmacotherapy by traditional Chinese medicine (TCM), using the PubMed, Web of science, China National Knowledge Infrastructure, China Science and Technology Journal and Wanfang Data. This review focuses on de novo lipogenesis (DNL) and uric acid (UA) production, two unique features of fructolysis different from glucose glycolysis. High level of DNL and UA production can result in insulin resistance, the key pathological event in developing MetS, mostly through oxidative stress and inflammation. Some other pathologies like the disturbance in brain and gut microbiota in the development of fructose-induced MetS in the past years, are also discussed. In management of MetS, TCM is an excellent representative in alternative and complementary medicine with a complete theory system and substantial herbal remedies. TCMs against MetS or MetS components, including Chinese patent medicines, TCM compound formulas, single TCM herbs and active compounds of TCM herbs, are reviewed on their effects and molecular mechanisms. TCMs with hypouricemic activity, which specially target fructose-induced MetS, are highlighted. And new technologies and strategies (such as high-throughput assay and systems biology) in this field are further discussed. In summary, fructose-induced MetS is a multifactorial disorder with the underlying complex mechanisms. Current clinical and pre-clinical evidence supports the potential of TCMs in management of MetS. Additionally, TCMs may show some advantages against complex MetS as their holistic feature through multiple target actions. However, further work is needed to confirm the effectivity and safety of TCMs

Prediction of lithium-ion battery capacity with metabolic grey model

International Nuclear Information System (INIS)

Chen, Lin; Lin, Weilong; Li, Junzi; Tian, Binbin; Pan, Haihong

2016-01-01

Given the popularity of Lithium-ion batteries in EVs (electric vehicles), predicting the capacity quickly and accurately throughout a battery's full life-time is still a challenging issue for ensuring the reliability of EVs. This paper proposes an approach in predicting the varied capacity with discharge cycles based on metabolic grey theory and consider issues from two perspectives: 1) three metabolic grey models will be presented, including MGM (metabolic grey model), MREGM (metabolic Residual-error grey model), and MMREGM (metabolic Markov-residual-error grey model); 2) the universality of these models will be explored under different conditions (such as various discharge rates and temperatures). Furthermore, the research findings in this paper demonstrate the excellent performance of the prediction depending on the three models; however, the precision of the MREGM model is inferior compared to the others. Therefore, we have obtained the conclusion in which the MGM model and the MMREGM model have excellent performances in predicting the capacity under a variety of load conditions, even using few data points for modeling. Also, the universality of the metabolic grey prediction theory is verified by predicting the capacity of batteries under different discharge rates and different temperatures. - Highlights: • The metabolic mechanism is introduced in a grey system for capacity prediction. • Three metabolic grey models are presented and studied. • The universality of these models under different conditions is assessed. • A few data points are required for predicting the capacity with these models.

Genomic interrogation of mechanism(s) underlying cellular responses to toxicants

International Nuclear Information System (INIS)

Amin, Rupesh P.; Hamadeh, Hisham K.; Bushel, Pierre R.; Bennett, Lee; Afshari, Cynthia A.; Paules, Richard S.

2002-01-01

Assessment of the impact of xenobiotic exposure on human health and disease progression is complex. Knowledge of mode(s) of action, including mechanism(s) contributing to toxicity and disease progression, is valuable for evaluating compounds. Toxicogenomics, the subdiscipline which merges genomics with toxicology, holds the promise to contributing significantly toward the goal of elucidating mechanism(s) by studying genome-wide effects of xenobiotics. Global gene expression profiling, revolutionized by microarray technology and a crucial aspect of a toxicogenomic study, allows measuring transcriptional modulation of thousands of genes following exposure to a xenobiotic. We use our results from previous studies on compounds representing two different classes of xenobiotics (barbiturate and peroxisome proliferator) to discuss the application of computational approaches for analyzing microarray data to elucidate mechanism(s) underlying cellular responses to toxicants. In particular, our laboratory demonstrated that chemical-specific patterns of gene expression can be revealed using cDNA microarrays. Transcript profiling provides discrimination between classes of toxicants, as well as, genome-wide insight into mechanism(s) of toxicity and disease progression. Ultimately, the expectation is that novel approaches for predicting xenobiotic toxicity in humans will emerge from such information

Interplay of drug metabolizing enzymes with cellular transporters.

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Böhmdorfer, Michaela; Maier-Salamon, Alexandra; Riha, Juliane; Brenner, Stefan; Höferl, Martina; Jäger, Walter

2014-11-01

Many endogenous and xenobiotic substances and their metabolites are substrates for drug metabolizing enzymes and cellular transporters. These proteins may not only contribute to bioavailability of molecules but also to uptake into organs and, consequently, to overall elimination. The coordinated action of uptake transporters, metabolizing enzymes, and efflux pumps, therefore, is a precondition for detoxification and elimination of drugs. As the understanding of the underlying mechanisms is important to predict alterations in drug disposal, adverse drug reactions and, finally, drug-drug interactions, this review illustrates the interplay between selected uptake/efflux transporters and phase I/II metabolizing enzymes.

Amino Acid Metabolism and Transport Mechanisms as Potential Antifungal Targets

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Matthew W. McCarthy

2018-03-01

Full Text Available Discovering new drugs for treatment of invasive fungal infections is an enduring challenge. There are only three major classes of antifungal agents, and no new class has been introduced into clinical practice in more than a decade. However, recent advances in our understanding of the fungal life cycle, functional genomics, proteomics, and gene mapping have enabled the identification of new drug targets to treat these potentially deadly infections. In this paper, we examine amino acid transport mechanisms and metabolism as potential drug targets to treat invasive fungal infections, including pathogenic yeasts, such as species of Candida and Cryptococcus, as well as molds, such as Aspergillus fumigatus. We also explore the mechanisms by which amino acids may be exploited to identify novel drug targets and review potential hurdles to bringing this approach into clinical practice.

Modeling phenotypic metabolic adaptations of Mycobacterium tuberculosis H37Rv under hypoxia.

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Xin Fang

Full Text Available The ability to adapt to different conditions is key for Mycobacterium tuberculosis, the causative agent of tuberculosis (TB, to successfully infect human hosts. Adaptations allow the organism to evade the host immune responses during acute infections and persist for an extended period of time during the latent infectious stage. In latently infected individuals, estimated to include one-third of the human population, the organism exists in a variety of metabolic states, which impedes the development of a simple strategy for controlling or eradicating this disease. Direct knowledge of the metabolic states of M. tuberculosis in patients would aid in the management of the disease as well as in forming the basis for developing new drugs and designing more efficacious drug cocktails. Here, we propose an in silico approach to create state-specific models based on readily available gene expression data. The coupling of differential gene expression data with a metabolic network model allowed us to characterize the metabolic adaptations of M. tuberculosis H37Rv to hypoxia. Given the microarray data for the alterations in gene expression, our model predicted reduced oxygen uptake, ATP production changes, and a global change from an oxidative to a reductive tricarboxylic acid (TCA program. Alterations in the biomass composition indicated an increase in the cell wall metabolites required for cell-wall growth, as well as heightened accumulation of triacylglycerol in preparation for a low-nutrient, low metabolic activity life style. In contrast, the gene expression program in the deletion mutant of dosR, which encodes the immediate hypoxic response regulator, failed to adapt to low-oxygen stress. Our predictions were compatible with recent experimental observations of M. tuberculosis activity under hypoxic and anaerobic conditions. Importantly, alterations in the flow and accumulation of a particular metabolite were not necessarily directly linked to

Lower urinary tract symptoms and metabolic disorders: ICI-RS 2014.

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Denys, Marie-Astrid; Anding, Ralf; Tubaro, Andrea; Abrams, Paul; Everaert, Karel

2016-02-01

To investigate the link between lower urinary tract symptoms (LUTS) and metabolic disorders. This report results from presentations and subsequent discussions about LUTS and metabolic disorders at the International Consultation on Incontinence Research Society (ICI-RS) in Bristol, 2014. There are common pathophysiological determinants for the onset of LUTS and the metabolic syndrome (MetS). Both conditions are multifactorial, related to disorders in circadian rhythms and share common risk factors. As in men with erectile dysfunction, these potentially modifiable lifestyle factors may be novel targets to prevent and treat LUTS. The link between LUTS and metabolic disorders is discussed by using sleep, urine production and bladder function as underlying mechanisms that need to be further explored during future research. Recent findings indicate a bidirectional relationship between LUTS and the MetS. Future research has to explore underlying mechanisms to explain this relationship, in order to develop new preventive and therapeutic recommendations, such as weight loss and increasing physical activity. The second stage is to determine the effect of these new treatment approaches on the severity of LUTS and each of the components of the MetS. © 2016 Wiley Periodicals, Inc.

Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation of macrophage

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Kim, Kyoung-Han; Kim, Yun Hye; Son, Joe Eun; Lee, Ju Hee; Kim, Sarah; Choe, Min Seon; Moon, Joon Ho; Zhong, Jian; Fu, Kiya; Lenglin, Florine; Yoo, Jeong-Ah; Bilan, Philip J; Klip, Amira; Nagy, Andras; Kim, Jae-Ryong

2017-01-01

Intermittent fasting (IF), a periodic energy restriction, has been shown to provide health benefits equivalent to prolonged fasting or caloric restriction. However, our understanding of the underlying mechanisms of IF-mediated metabolic benefits is limited. Here we show that isocaloric IF improves metabolic homeostasis against diet-induced obesity and metabolic dysfunction primarily through adipose thermogenesis in mice. IF-induced metabolic benefits require fasting-mediated increases of vasc...

Mechanisms of action for the medium-chain triglyceride ketogenic diet in neurological and metabolic disorders.

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Augustin, Katrin; Khabbush, Aziza; Williams, Sophie; Eaton, Simon; Orford, Michael; Cross, J Helen; Heales, Simon J R; Walker, Matthew C; Williams, Robin S B

2018-01-01

High-fat, low-carbohydrate diets, known as ketogenic diets, have been used as a non-pharmacological treatment for refractory epilepsy. A key mechanism of this treatment is thought to be the generation of ketones, which provide brain cells (neurons and astrocytes) with an energy source that is more efficient than glucose, resulting in beneficial downstream metabolic changes, such as increasing adenosine levels, which might have effects on seizure control. However, some studies have challenged the central role of ketones because medium-chain fatty acids, which are part of a commonly used variation of the diet (the medium-chain triglyceride ketogenic diet), have been shown to directly inhibit AMPA receptors (glutamate receptors), and to change cell energetics through mitochondrial biogenesis. Through these mechanisms, medium-chain fatty acids rather than ketones are likely to block seizure onset and raise seizure threshold. The mechanisms underlying the ketogenic diet might also have roles in other disorders, such as preventing neurodegeneration in Alzheimer's disease, the proliferation and spread of cancer, and insulin resistance in type 2 diabetes. Analysing medium-chain fatty acids in future ketogenic diet studies will provide further insights into their importance in modified forms of the diet. Moreover, the results of these studies could facilitate the development of new pharmacological and dietary therapies for epilepsy and other disorders. Copyright © 2018 Elsevier Ltd. All rights reserved.

Work stress and metabolic and hemostatic risk factors

NARCIS (Netherlands)

Vrijkotte, T. G.; van Doornen, L. J.; de Geus, E. J.

1999-01-01

A high level of work stress has been associated with cardiovascular disease. However, the pathophysiological mechanisms underlying this association remain unclear. This study examined the effect of work stress on a cluster of metabolic and hemostatic risk factors. Blood was collected three times, on

The driving force of the Na+/Ca2+-exchanger during metabolic inhibition

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Baartscheer, Antonius; Schumacher, Cees A.; Coronel, Ruben; Fiolet, Jan W. T.

2011-01-01

Objective: Metabolic inhibition causes a decline in mechanical performance and, if prolonged, myocardial contracture and cell death. The decline in mechanical performance is mainly due to altered intracellular calcium handling, which is under control of the Na+/Ca2+-exchanger (NCX) The driving force

Mitochondrial Dysfunction in Metabolic Syndrome and Asthma

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Mabalirajan, Ulaganathan; Ghosh, Balaram

2013-01-01

Though severe or refractory asthma merely affects less than 10% of asthma population, it consumes significant health resources and contributes significant morbidity and mortality. Severe asthma does not fell in the routine definition of asthma and requires alternative treatment strategies. It has been observed that asthma severity increases with higher body mass index. The obese-asthmatics, in general, have the features of metabolic syndrome and are progressively causing a significant burden for both developed and developing countries thanks to the westernization of the world. As most of the features of metabolic syndrome seem to be originated from central obesity, the underlying mechanisms for metabolic syndrome could help us to understand the pathobiology of obese-asthma condition. While mitochondrial dysfunction is the common factor for most of the risk factors of metabolic syndrome, such as central obesity, dyslipidemia, hypertension, insulin resistance, and type 2 diabetes, the involvement of mitochondria in obese-asthma pathogenesis seems to be important as mitochondrial dysfunction has recently been shown to be involved in airway epithelial injury and asthma pathogenesis. This review discusses current understanding of the overlapping features between metabolic syndrome and asthma in relation to mitochondrial structural and functional alterations with an aim to uncover mechanisms for obese-asthma. PMID:23840225

The ketogenic diet: metabolic influences on brain excitability and epilepsy

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Lutas, Andrew; Yellen, Gary

2012-01-01

A dietary therapy for pediatric epilepsy known as the ketogenic diet has seen a revival in its clinical use in the past decade. Though the diet’s underlying mechanism remains unknown, modern scientific approaches like genetic disruption of glucose metabolism are allowing for more detailed questions to be addressed. Recent work indicates that several mechanisms may exist for the ketogenic diet including disruption of glutamatergic synaptic transmission, inhibition of glycolysis, and activation of ATP-sensitive potassium channels. Here we describe on-going work in these areas that is providing a better understanding of metabolic influences on brain excitability and epilepsy. PMID:23228828

Insulin resistance in obesity as the underlying cause for the metabolic syndrome.

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Gallagher, Emily J; Leroith, Derek; Karnieli, Eddy

2010-01-01

The metabolic syndrome affects more than a third of the US population, predisposing to the development of type 2 diabetes and cardiovascular disease. The 2009 consensus statement from the International Diabetes Federation, American Heart Association, World Heart Federation, International Atherosclerosis Society, International Association for the Study of Obesity, and the National Heart, Lung, and Blood Institute defines the metabolic syndrome as 3 of the following elements: abdominal obesity, elevated blood pressure, elevated triglycerides, low high-density lipoprotein cholesterol, and hyperglycemia. Many factors contribute to this syndrome, including decreased physical activity, genetic predisposition, chronic inflammation, free fatty acids, and mitochondrial dysfunction. Insulin resistance appears to be the common link between these elements, obesity and the metabolic syndrome. In normal circumstances, insulin stimulates glucose uptake into skeletal muscle, inhibits hepatic gluconeogenesis, and decreases adipose-tissue lipolysis and hepatic production of very-low-density lipoproteins. Insulin signaling in the brain decreases appetite and prevents glucose production by the liver through neuronal signals from the hypothalamus. Insulin resistance, in contrast, leads to the release of free fatty acids from adipose tissue, increased hepatic production of very-low-density lipoproteins and decreased high-density lipoproteins. Increased production of free fatty acids, inflammatory cytokines, and adipokines and mitochondrial dysfunction contribute to impaired insulin signaling, decreased skeletal muscle glucose uptake, increased hepatic gluconeogenesis, and β cell dysfunction, leading to hyperglycemia. In addition, insulin resistance leads to the development of hypertension by impairing vasodilation induced by nitric oxide. In this review, we discuss normal insulin signaling and the mechanisms by which insulin resistance contributes to the development of the metabolic

Does sleep disturbance affect the amyloid clearance mechanisms in Alzheimer's disease?

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Yulug, Burak; Hanoglu, Lutfu; Kilic, Ertugrul

2017-10-01

Sleep is an important factor that plays a key role in Alzheimer's disease pathogenesis. However, it is still unclear whether poor-quality sleep may overlap with sleep disturbances in the underlying dysfunctional mechanisms of amyloid beta (Aβ) clearance metabolism. Here, we aimed to evaluate the current evidence on the role of sleep deprivation in Aβ clearance metabolism. To that end, we discuss possible mechanisms underlying the bidirectional interaction between the sleep deprivation and Aβ clearance pathways. © 2017 The Authors. Psychiatry and Clinical Neurosciences © 2017 Japanese Society of Psychiatry and Neurology.

Lipidomics: Novel insight into the biochemical mechanism of lipid metabolism and dysregulation-associated disease.

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Zhao, Ying-Yong; Miao, Hua; Cheng, Xian-Long; Wei, Feng

2015-10-05

The application of lipidomics, after genomics, proteomics and metabolomics, offered largely opportunities to illuminate the entire spectrum of lipidome based on a quantitative or semi-quantitative level in a biological system. When combined with advances in proteomics and metabolomics high-throughput platforms, lipidomics provided the opportunity for analyzing the unique roles of specific lipids in complex cellular processes. Abnormal lipid metabolism was demonstrated to be greatly implicated in many human lifestyle-related diseases. In this review, we focused on lipidomic applications in brain injury disease, cancer, metabolic disease, cardiovascular disease, respiratory disease and infectious disease to discover disease biomarkers and illustrate biochemical metabolic pathways. We also discussed the analytical techniques, future perspectives and potential problems of lipidomic applications. The application of lipidomics in disease biomarker discovery provides the opportunity for gaining novel insights into biochemical mechanism. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Global transcriptomic profiling of aspen trees under elevated [CO2] to identify potential molecular mechanisms responsible for enhanced radial growth.

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Wei, Hairong; Gou, Jiqing; Yordanov, Yordan; Zhang, Huaxin; Thakur, Ramesh; Jones, Wendy; Burton, Andrew

2013-03-01

Aspen (Populus tremuloides) trees growing under elevated [CO(2)] at a free-air CO(2) enrichment (FACE) site produced significantly more biomass than control trees. We investigated the molecular mechanisms underlying the observed increase in biomass by producing transcriptomic profiles of the vascular cambium zone (VCZ) and leaves, and then performed a comparative study to identify significantly changed genes and pathways after 12 years exposure to elevated [CO(2)]. In leaves, elevated [CO(2)] enhanced expression of genes related to Calvin cycle activity and linked pathways. In the VCZ, the pathways involved in cell growth, cell division, hormone metabolism, and secondary cell wall formation were altered while auxin conjugation, ABA synthesis, and cytokinin glucosylation and degradation were inhibited. Similarly, the genes involved in hemicellulose and pectin biosynthesis were enhanced, but some genes that catalyze important steps in lignin biosynthesis pathway were inhibited. Evidence from systemic analysis supported the functioning of multiple molecular mechanisms that underpin the enhanced radial growth in response to elevated [CO(2)].

Epigenetic priming of the metabolic syndrome.

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Bruce, Kimberley D; Cagampang, Felino R

2011-05-01

The metabolic syndrome (MetS) represents a cluster of cardiometabolic risk factors, including central obesity, insulin resistance, glucose intolerance, dyslipidemia, hypertension, hyperinsulinemia and microalbuminuria, and more recently, nonalcoholic fatty liver disease (NAFLD), polycystic ovarian syndrome (PCOS) and atherosclerosis. Although the concept of the MetS is subject to debate due to lack of a unifying underlying mechanism, the prevalence of a metabolic syndrome phenotype is rapidly increasing worldwide. Moreover, it is increasingly prevalent in children and adolescents of obese mothers. Evidence from both epidemiological and experimental animal studies now demonstrates that MetS onset is increasingly likely following exposure to suboptimal nutrition during critical periods of development, as observed in maternal obesity. Thus, the developmental priming of the MetS provides a common origin for this multifactorial disorder. Consequently, the mechanisms leading to this developmental priming have recently been the subject of intensive investigation. This review discusses recent data regarding the epigenetic modifications resulting from nutrition during early development that mediate persistent changes in the expression of key metabolic genes and contribute toward an adult metabolic syndrome phenotype. In addition, this review considers the role of the endogenous molecular circadian clock system, which has the potential to act at the interface between nutrient sensing and epigenetic processing. A continued and greater understanding of these mechanisms will eventually aid in the identification of individuals at high risk of cardiovascular disease (CVD) and type 2 diabetes, and help develop therapeutic interventions, in accordance with current global government strategy.

Metabolic Remodeling of Membrane Glycerolipids in the Microalga Nannochloropsis oceanica under Nitrogen Deprivation

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Danxiang Han

2017-08-01

Full Text Available HIGHLIGHTSAn electrospray ionization mass spectrometry-based lipidomics method was developed and integrated with transcriptomics to elucidate metabolic remodeling and turnover of microalgal membrane lipids by using Nannochloropsis oceanica as a model.The lack of lipidome analytical tools has limited our ability to gain new knowledge about lipid metabolism in microalgae, especially for membrane glycerolipids. An electrospray ionization mass spectrometry-based lipidomics method was developed for Nannochloropsis oceanica IMET1, which resolved 41 membrane glycerolipids molecular species belonging to eight classes. Changes in membrane glycerolipids under nitrogen deprivation and high-light (HL conditions were uncovered. The results showed that the amount of plastidial membrane lipids including monogalactosyldiacylglycerol, phosphatidylglycerol, and the extraplastidic lipids diacylglyceryl-O-4′-(N, N, N,-trimethyl homoserine and phosphatidylcholine decreased drastically under HL and nitrogen deprivation stresses. Algal cells accumulated considerably more digalactosyldiacylglycerol and sulfoquinovosyldiacylglycerols under stresses. The genes encoding enzymes responsible for biosynthesis, modification and degradation of glycerolipids were identified by mining a time-course global RNA-seq data set. It suggested that reduction in lipid contents under nitrogen deprivation is not attributable to the retarded biosynthesis processes, at least at the gene expression level, as most genes involved in their biosynthesis were unaffected by nitrogen supply, yet several genes were significantly up-regulated. Additionally, a conceptual eicosapentaenoic acid (EPA biosynthesis network is proposed based on the lipidomic and transcriptomic data, which underlined import of EPA from cytosolic glycerolipids to the plastid for synthesizing EPA-containing chloroplast membrane lipids.

Chronic treatment with olanzapine increases adiposity by changing fuel substrate and causes desensitization of the acute metabolic side effects

NARCIS (Netherlands)

Girault, Elodie M.; Guigas, Bruno; Alkemade, Anneke; Foppen, Ewout; Ackermans, Mariëtte T.; la Fleur, Susanne E.; Fliers, Eric; Kalsbeek, Andries

2014-01-01

Atypical antipsychotic drugs such as olanzapine induce weight gain and metabolic changes associated with the development of type 2 diabetes. The mechanisms underlying these metabolic side-effects are unknown at the moment. In this study, we investigated the metabolic changes induced by a chronic

Chronic treatment with olanzapine increases adiposity by changing fuel substrate and causes desensitization of the acute metabolic side effects

NARCIS (Netherlands)

Girault, Elodie M; Guigas, Bruno; Alkemade, Anneke; Foppen, Ewout; Ackermans, Mariëtte T; la Fleur, Susanne E; Fliers, Eric; Kalsbeek, A.

Atypical antipsychotic drugs such as olanzapine induce weight gain and metabolic changes associated with the development of type 2 diabetes. The mechanisms underlying these metabolic side-effects are unknown at the moment. In this study, we investigated the metabolic changes induced by a chronic

Widespread Pyrethroid and DDT Resistance in the Major Malaria Vector Anopheles funestus in East Africa Is Driven by Metabolic Resistance Mechanisms

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Mulamba, Charles; Riveron, Jacob M.; Ibrahim, Sulaiman S.; Irving, Helen; Barnes, Kayla G.; Mukwaya, Louis G.; Birungi, Josephine; Wondji, Charles S.

2014-01-01

Background Establishing the extent, geographical distribution and mechanisms of insecticide resistance in malaria vectors is a prerequisite for resistance management. Here, we report a widespread distribution of insecticide resistance in the major malaria vector An. funestus across Uganda and western Kenya under the control of metabolic resistance mechanisms. Methodology/Principal Findings Female An. funestus collected throughout Uganda and western Kenya exhibited a Plasmodium infection rate between 4.2 to 10.4%. Widespread resistance against both type I (permethrin) and II (deltamethrin) pyrethroids and DDT was observed across Uganda and western Kenya. All populations remain highly susceptible to carbamate, organophosphate and dieldrin insecticides. Knockdown resistance plays no role in the pyrethroid and DDT resistance as no kdr mutation associated with resistance was detected despite the presence of a F1021C replacement. Additionally, no signature of selection was observed on the sodium channel gene. Synergist assays and qRT-PCR indicated that metabolic resistance plays a major role notably through elevated expression of cytochrome P450s. DDT resistance mechanisms differ from West Africa as the L119F-GSTe2 mutation only explains a small proportion of the genetic variance to DDT resistance. Conclusion The extensive distribution of pyrethroid and DDT resistance in East African An. funestus populations represents a challenge to the control of this vector. However, the observed carbamate and organophosphate susceptibility offers alternative solutions for resistance management. PMID:25333491

A Mechanism-Based Model for the Prediction of the Metabolic Sites of Steroids Mediated by Cytochrome P450 3A4

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Zi-Ru Dai

2015-06-01

Full Text Available Early prediction of xenobiotic metabolism is essential for drug discovery and development. As the most important human drug-metabolizing enzyme, cytochrome P450 3A4 has a large active cavity and metabolizes a broad spectrum of substrates. The poor substrate specificity of CYP3A4 makes it a huge challenge to predict the metabolic site(s on its substrates. This study aimed to develop a mechanism-based prediction model based on two key parameters, including the binding conformation and the reaction activity of ligands, which could reveal the process of real metabolic reaction(s and the site(s of modification. The newly established model was applied to predict the metabolic site(s of steroids; a class of CYP3A4-preferred substrates. 38 steroids and 12 non-steroids were randomly divided into training and test sets. Two major metabolic reactions, including aliphatic hydroxylation and N-dealkylation, were involved in this study. At least one of the top three predicted metabolic sites was validated by the experimental data. The overall accuracy for the training and test were 82.14% and 86.36%, respectively. In summary, a mechanism-based prediction model was established for the first time, which could be used to predict the metabolic site(s of CYP3A4 on steroids with high predictive accuracy.

Effectiveness of acetazolamide for reversal of metabolic alkalosis in weaning COPD patients from mechanical ventilation.

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Faisy, Christophe; Mokline, Amel; Sanchez, Olivier; Tadié, Jean-Marc; Fagon, Jean-Yves

2010-05-01

To evaluate the effects of a single daily dose of acetazolamide (ACET) on metabolic alkalosis and respiratory parameters in weaning chronic obstructive pulmonary disease (COPD) patients from invasive mechanical ventilation. Case-control study. An 18-bed intensive care unit (ICU) in a university hospital. Twenty-six intubated COPD patients with mixed metabolic alkalosis (serum bicarbonate >26 mmol/l and arterial pH >or=7.38) were compared with a historical control group (n = 26) matched for serum bicarbonate, arterial pH, age, and severity of illness at admission to ICU. ACET administration (500 mg intravenously) was monitored daily according to arterial blood gas analysis from readiness to wean until extubation. ACET was administered 4 (1-11) days throughout the weaning period. Patients with ACET treatment significantly decreased their serum bicarbonate (p = 0.01 versus baseline) and arterial blood pH (p respiratory parameters except PaO(2)/FiO(2) ratio (p = 0.03). ACET patients and their matched controls had similar duration of weaning. Extubation success rate was not significantly different between groups, and causes of reintubation were comparable. ACET used at the dosage of 500 mg per day reduces metabolic alkalosis but has no benefit in terms of improving PaCO(2) or respiratory parameters in weaning COPD patients from mechanical ventilation.

Elucidation of molecular mechanisms of physiological variations between bovine subcutaneous and visceral fat depots under different nutritional regimes.

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Romao, Josue Moura; Jin, Weiwu; He, Maolong; McAllister, Tim; Guan, Le Luo

2013-01-01

Adipose tissue plays a critical role in energy homeostasis and metabolism. There is sparse understanding of the molecular regulation at the protein level of bovine adipose tissues, especially within different fat depots under different nutritional regimes. The objective of this study was to analyze the differences in protein expression between bovine subcutaneous and visceral fat depots in steers fed different diets and to identify the potential regulatory molecular mechanisms of protein expression. Subcutaneous and visceral fat tissues were collected from 16 British-continental steers (15.5 month old) fed a high-fat diet (7.1% fat, n=8) or a control diet (2.7% fat, n=8). Protein expression was profiled using label free quantification LC-MS/MS and expression of selected transcripts was evaluated using qRT-PCR. A total of 682 proteins were characterized and quantified with fat depot having more impact on protein expression, altering the level of 51.0% of the detected proteins, whereas diet affected only 5.3%. Functional analysis revealed that energy production and lipid metabolism were among the main functions associated with differentially expressed proteins between fat depots, with visceral fat being more metabolically active than subcutaneous fat as proteins associated with lipid and energy metabolism were upregulated. The expression of several proteins was significantly correlated to subcutaneous fat thickness and adipocyte size, indicating their potential as adiposity markers. A poor correlation (r=0.245) was observed between mRNA and protein levels for 9 genes, indicating that many proteins may be subjected to post-transcriptional regulation. A total of 8 miRNAs were predicted to regulate more than 20% of lipid metabolism proteins differentially expressed between fat depots, suggesting that miRNAs play a role in adipose tissue regulation. Our results show that proteomic changes support the distinct metabolic and physiological characteristics observed between

Mechanisms of Body Weight Reduction and Metabolic Syndrome Alleviation by Tea

Science.gov (United States)

Yang, Chung S.; Zhang, Jinsong; Zhang, Le; Huang, Jinbao; Wang, Yijun

2016-01-01

Tea, a popular beverage made from leaves of the plant Camellia sinensis, has been shown to reduce body weight, alleviate metabolic syndrome, and prevent diabetes and cardiovascular diseases in animal models and humans. Such beneficial effects have generally been observed in most human studies when the level of tea consumption was 3 to 4 cups (600–900 mg tea catechins) or more per day. Green tea is more effective than black tea. In spite of numerous studies, the fundamental mechanisms for these actions still remain unclear. From a review of the literature, we propose that the two major mechanisms are: 1) decreasing absorption of lipids and proteins by tea constituents in the intestine, thus reducing calorie intake; and 2) activating AMPK by tea polyphenols that are bioavailable in the liver, skeletal muscle, and adipose tissues. The relative importance of these two mechanisms depends on the types of tea and diet consumed by individuals. The activated AMPK would decrease gluconeogenesis and fatty acid synthesis and increase catabolism, leading to body weight reduction and MetS alleviation. Other mechanisms and the health relevance of these beneficial effects of tea consumption remain to be further investigated. PMID:26577614

Metabolomics Approach Reveals Integrated Metabolic Network Associated with Serotonin Deficiency

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Weng, Rui; Shen, Sensen; Tian, Yonglu; Burton, Casey; Xu, Xinyuan; Liu, Yi; Chang, Cuilan; Bai, Yu; Liu, Huwei

2015-07-01

Serotonin is an important neurotransmitter that broadly participates in various biological processes. While serotonin deficiency has been associated with multiple pathological conditions such as depression, schizophrenia, Alzheimer’s disease and Parkinson’s disease, the serotonin-dependent mechanisms remain poorly understood. This study therefore aimed to identify novel biomarkers and metabolic pathways perturbed by serotonin deficiency using metabolomics approach in order to gain new metabolic insights into the serotonin deficiency-related molecular mechanisms. Serotonin deficiency was achieved through pharmacological inhibition of tryptophan hydroxylase (Tph) using p-chlorophenylalanine (pCPA) or genetic knockout of the neuronal specific Tph2 isoform. This dual approach improved specificity for the serotonin deficiency-associated biomarkers while minimizing nonspecific effects of pCPA treatment or Tph2 knockout (Tph2-/-). Non-targeted metabolic profiling and a targeted pCPA dose-response study identified 21 biomarkers in the pCPA-treated mice while 17 metabolites in the Tph2-/- mice were found to be significantly altered compared with the control mice. These newly identified biomarkers were associated with amino acid, energy, purine, lipid and gut microflora metabolisms. Oxidative stress was also found to be significantly increased in the serotonin deficient mice. These new biomarkers and the overall metabolic pathways may provide new understanding for the serotonin deficiency-associated mechanisms under multiple pathological states.

Comparative Transcriptome Analysis of Latex Reveals Molecular Mechanisms Underlying Increased Rubber Yield in Hevea brasiliensis Self-Rooting Juvenile Clones.

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Li, Hui-Liang; Guo, Dong; Zhu, Jia-Hong; Wang, Ying; Chen, Xiong-Ting; Peng, Shi-Qing

2016-01-01

Rubber tree (Hevea brasiliensis) self-rooting juvenile clones (JCs) are promising planting materials for rubber production. In a comparative trial between self-rooting JCs and donor clones (DCs), self-rooting JCs exhibited better performance in rubber yield. To study the molecular mechanism associated with higher rubber yield in self-rooting JCs, we sequenced and comparatively analyzed the latex of rubber tree self-rooting JCs and DCs at the transcriptome level. Total raw reads of 34,632,012 and 35,913,020 bp were obtained from the library of self-rooting JCs and DCs, respectively, by using Illumina HiSeq 2000 sequencing technology. De novo assemblies yielded 54689 unigenes from the library of self-rooting JCs and DCs. Among 54689 genes, 1716 genes were identified as differentially expressed between self-rooting JCs and DCs via comparative transcript profiling. Functional analysis showed that the genes related to the mass of categories were differentially enriched between the two clones. Several genes involved in carbohydrate metabolism, hormone metabolism and reactive oxygen species scavenging were up-regulated in self-rooting JCs, suggesting that the self-rooting JCs provide sufficient molecular basis for the increased rubber yielding, especially in the aspects of improved latex metabolisms and latex flow. Some genes encoding epigenetic modification enzymes were also differentially expressed between self-rooting JCs and DCs. Epigenetic modifications may lead to gene differential expression between self-rooting JCs and DCs. These data will provide new cues to understand the molecular mechanism underlying the improved rubber yield of H. brasiliensis self-rooting clones.

The concept of metabolic syndrome: contribution of visceral fat accumulation and its molecular mechanism.

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Matsuzawa, Yuji; Funahashi, Tohru; Nakamura, Tadashi

2011-01-01

Although abdominal obesity or visceral obesity is considered to be one of the components of metabolic syndrome and to have an important role in a cluster of cardiovascular risks, there is no consensus about the definition and diagnostic criteria for this syndrome, probably because there is considerable disagreement about the location and definition of abdominal obesity or visceral obesity.In this review article, the important role of visceral fat accumulation in the development of a variety of lifestyle-related diseases is shown, including cardiovascular disease based on our clinical studies using CT scans, and the mechanism of these disorders is discussed, focusing on adipocytokines, especially adiponectin.The importance of diagnosing metabolic syndrome, in which visceral fat accumulation plays an essential role in the development of multiple risk factors, should be emphasized because lifestyle modification for the reduction of visceral fat may be very effective for the reduction of risks of this type, namely metabolic syndrome in the narrow sense.

Metabolic Network Topology Reveals Transcriptional Regulatory Signatures of Type 2 Diabetes

DEFF Research Database (Denmark)

Zelezniak, Aleksej; Pers, Tune Hannes; Pinho Soares, Simao Pedro

2010-01-01

mechanisms underlying these transcriptional changes and their impact on the cellular metabolic phenotype is a challenging task due to the complexity of transcriptional regulation and the highly interconnected nature of the metabolic network. In this study we integrate skeletal muscle gene expression datasets...... with human metabolic network reconstructions to identify key metabolic regulatory features of T2DM. These features include reporter metabolites—metabolites with significant collective transcriptional response in the associated enzyme-coding genes, and transcription factors with significant enrichment...... factor regulatory network connecting several parts of metabolism. The identified transcription factors include members of the CREB, NRF1 and PPAR family, among others, and represent regulatory targets for further experimental analysis. Overall, our results provide a holistic picture of key metabolic...

Metabolic Characteristics of a Glucose-Utilizing Shewanella oneidensis Strain Grown under Electrode-Respiring Conditions.

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Gen Nakagawa

Full Text Available In bioelectrochemical systems, the electrode potential is an important parameter affecting the electron flow between electrodes and microbes and microbial metabolic activities. Here, we investigated the metabolic characteristics of a glucose-utilizing strain of engineered Shewanella oneidensis under electrode-respiring conditions in electrochemical reactors for gaining insight into how metabolic pathways in electrochemically active bacteria are affected by the electrode potential. When an electrochemical reactor was operated with its working electrode poised at +0.4 V (vs. an Ag/AgCl reference electrode, the engineered S. oneidensis strain, carrying a plasmid encoding a sugar permease and glucose kinase of Escherichia coli, generated current by oxidizing glucose to acetate and produced D-lactate as an intermediate metabolite. However, D-lactate accumulation was not observed when the engineered strain was grown with a working electrode poised at 0 V. We also found that transcription of genes involved in pyruvate and D-lactate metabolisms was upregulated at a high electrode potential compared with their transcription at a low electrode potential. These results suggest that the carbon catabolic pathway of S. oneidensis can be modified by controlling the potential of a working electrode in an electrochemical bioreactor.

Deciphering Molecular Mechanism Underlying Hypolipidemic Activity of Echinocystic Acid

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Li Han

2014-01-01

Full Text Available Our previous study showed that a triterpene mixture, consisting of echinocystic acid (EA and oleanolic acid (OA at a ratio of 4 : 1, dose-dependently ameliorated the hyperlipidemia and atherosclerosis in rabbits fed with high fat/high cholesterol diets. This study was aimed at exploring the mechanisms underlying antihyperlipidemic effect of EA. Molecular docking simulation of EA was performed using Molegro Virtual Docker (version: 4.3.0 to investigate the potential targets related to lipid metabolism. Based on the molecular docking information, isotope labeling method or spectrophotometry was applied to examine the effect of EA on the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase, acyl-CoA:cholesterol acyltransferase (ACAT, and diacylglycerol acyltransferase (DGAT in rat liver microsomes. Our results revealed a strong affinity of EA towards ACAT and DGAT in molecular docking analysis, while low binding affinity existed between EA and HMG-CoA reductase as well as between EA and cholesteryl ester transfer protein. Consistent with the results of molecular docking, in vitro enzyme activity assays showed that EA inhibited ACAT and DGAT, with IC50 values of 103 and 139 μM, respectively, and exhibited no significant effect on HMG-CoA reductase activity. The present findings suggest that EA may exert hypolipidemic effect by inhibiting the activity of ACAT and DGAT.

Berberine Regulated Lipid Metabolism in the Presence of C75, Compound C, and TOFA in Breast Cancer Cell Line MCF-7.

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Tan, Wen; Zhong, Zhangfeng; Wang, Shengpeng; Suo, Zhanwei; Yang, Xian; Hu, Xiaodong; Wang, Yitao

2015-01-01

Berberine interfering with cancer reprogramming metabolism was confirmed in our previous study. Lipid metabolism and mitochondrial function were also the core parts in reprogramming metabolism. In the presence of some energy-related inhibitors, including C75, compound C, and TOFA, the discrete roles of berberine in lipid metabolism and mitochondrial function were elucidated. An altered lipid metabolism induced by berberine was observed under the inhibition of FASN, AMPK, and ACC in breast cancer cell MCF-7. And the reversion of berberine-induced lipid suppression indicated that ACC inhibition might be involved in that process instead of FASN inhibition. A robust apoptosis induced by berberine even under the inhibition of AMPK and lipid synthesis was also indicated. Finally, mitochondrial function regulation under the inhibition of AMPK and ACC might be in an ACL-independent manner. Undoubtedly, the detailed mechanisms of berberine interfering with lipid metabolism and mitochondrial function combined with energy-related inhibitors need further investigation, including the potential compensatory mechanisms for ATP production and the upregulation of ACL.

Berberine Regulated Lipid Metabolism in the Presence of C75, Compound C, and TOFA in Breast Cancer Cell Line MCF-7

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Wen Tan

2015-01-01

Full Text Available Berberine interfering with cancer reprogramming metabolism was confirmed in our previous study. Lipid metabolism and mitochondrial function were also the core parts in reprogramming metabolism. In the presence of some energy-related inhibitors, including C75, compound C, and TOFA, the discrete roles of berberine in lipid metabolism and mitochondrial function were elucidated. An altered lipid metabolism induced by berberine was observed under the inhibition of FASN, AMPK, and ACC in breast cancer cell MCF-7. And the reversion of berberine-induced lipid suppression indicated that ACC inhibition might be involved in that process instead of FASN inhibition. A robust apoptosis induced by berberine even under the inhibition of AMPK and lipid synthesis was also indicated. Finally, mitochondrial function regulation under the inhibition of AMPK and ACC might be in an ACL-independent manner. Undoubtedly, the detailed mechanisms of berberine interfering with lipid metabolism and mitochondrial function combined with energy-related inhibitors need further investigation, including the potential compensatory mechanisms for ATP production and the upregulation of ACL.

Lipid Metabolism, Apoptosis and Cancer Therapy

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Chunfa Huang

2015-01-01

Full Text Available Lipid metabolism is regulated by multiple signaling pathways, and generates a variety of bioactive lipid molecules. These bioactive lipid molecules known as signaling molecules, such as fatty acid, eicosanoids, diacylglycerol, phosphatidic acid, lysophophatidic acid, ceramide, sphingosine, sphingosine-1-phosphate, phosphatidylinositol-3 phosphate, and cholesterol, are involved in the activation or regulation of different signaling pathways. Lipid metabolism participates in the regulation of many cellular processes such as cell growth, proliferation, differentiation, survival, apoptosis, inflammation, motility, membrane homeostasis, chemotherapy response, and drug resistance. Bioactive lipid molecules promote apoptosis via the intrinsic pathway by modulating mitochondrial membrane permeability and activating different enzymes including caspases. In this review, we discuss recent data in the fields of lipid metabolism, lipid-mediated apoptosis, and cancer therapy. In conclusion, understanding the underlying molecular mechanism of lipid metabolism and the function of different lipid molecules could provide the basis for cancer cell death rationale, discover novel and potential targets, and develop new anticancer drugs for cancer therapy.

Effect of carbon/nitrogen ratio on carbohydrate metabolism and light energy dissipation mechanisms in Arabidopsis thaliana.

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Huarancca Reyes, Thais; Scartazza, Andrea; Lu, Yu; Yamaguchi, Junji; Guglielminetti, Lorenzo

2016-08-01

Carbon (C) and nitrogen (N) nutrient sources are essential elements for metabolism, and their availability must be tightly coordinated for the optimal growth and development in plants. Plants are able to sense and respond to different C/N conditions via specific partitioning of C and N sources and the regulation of a complex cellular metabolic activity. We studied how the interaction between C and N signaling could affect carbohydrate metabolism, soluble sugar levels, photochemical efficiency of photosystem II (PSII) and the ability to drive the excess energy in Arabidopsis seedlings under moderated and disrupted C/N-nutrient conditions. Invertase and sucrose synthase activities were markedly affected by C/N-nutrient status depending on the phosphorylation status, suggesting that these enzymes may necessarily be modulated by their direct phosphorylation or phosphorylation of proteins that form complex with them in response to C/N stress. In addition, the enzymatic activity of these enzymes was also correlated with the amount of sugars, which not only act as substrate but also as signaling compounds. Analysis of chlorophyll fluorescence in plants under disrupted C/N condition suggested a reduction of electron transport rate at PSII level associated with a higher capacity for non-radiative energy dissipation in comparison with plants under moderated C/N condition. In conclusion, the tight coordination between C and N not only affects the carbohydrates metabolism and their concentration within plant tissues, but also the partitioning of the excitation energy at PSII level between radiative (electron transport) and non-radiative (heat) dissipation pathways. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Maternal resveratrol consumption and its programming effects on metabolic health in offspring mechanisms and potential implications.

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Zheng, Sheng; Feng, Qianyun; Cheng, Jing; Zheng, Jia

2018-04-27

A growing body of evidence has clearly demonstrated that maternal nutrition can strongly determine the susceptibility to the development of metabolic diseases in offspring. With the increasing prevalence of maternal overweight, obesity, and gestational diabetes mellitus, it yields enormous burden for individual and public health. Interventions during pregnancy have been proven to be challenging, with limited efficacy and low compliance. Resveratrol, as a natural polyphenolic compound, has a wide-range of beneficial properties, including potent antiobesogenic, antiatherosclerotic, and antidiabetic effects. However, the role of maternal resveratrol intake on metabolic health in offspring has not been extensively investigated. Therefore, the aim of this study was to review the effects of maternal resveratrol supplementation on metabolic health in offspring and its potential mechanisms. © 2018 The Author(s).

Clinical predictors and outcome of metabolic acidosis in under-five children admitted to an urban hospital in Bangladesh with diarrhea and pneumonia.

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Mohammod J Chisti

Full Text Available BACKGROUND: Clinical features of metabolic acidosis and pneumonia frequently overlap in young diarrheal children, resulting in differentiation from each other very difficult. However, there is no published data on the predictors of metabolic acidosis in diarrheal children also having pneumonia. Our objective was to evaluate clinical predictors of metabolic acidosis in under-five diarrheal children with radiological pneumonia, and their outcome. METHODS: We prospectively enrolled all under-five children (n = 164 admitted to the Special Care Ward (SCW of the Dhaka Hospital of icddr, b between September and December 2007 with diarrhea and radiological pneumonia who also had their total serum carbon-dioxide estimated. We compared the clinical features and outcome of children with radiological pneumonia and diarrhea with (n = 98 and without metabolic acidosis (n = 66. RESULTS: Children with metabolic acidosis more often had higher case-fatality (16% vs. 5%, p = 0.039 compared to those without metabolic acidosis on admission. In logistic regression analysis, after adjusting for potential confounders such as age of the patient, fever on admission, and severe wasting, the independent predictors of metabolic acidosis in under-five diarrheal children having pneumonia were clinical dehydration (OR 3.57, 95% CI 1.62-7.89, p = 0.002, and low systolic blood pressure even after full rehydration (OR 1.02, 95% CI 1.01-1.04, p = 0.005. Proportions of children with cough, respiratory rate/minute, lower chest wall indrawing, nasal flaring, head nodding, grunting respiration, and cyanosis were comparable (p>0.05 among the groups. CONCLUSION AND SIGNIFICANCE: Under-five diarrheal children with radiological pneumonia having metabolic acidosis had frequent fatal outcome than those without acidosis. Clinical dehydration and persistent systolic hypotension even after adequate rehydration were independent clinical predictors of metabolic acidosis among the children

Clinical predictors and outcome of metabolic acidosis in under-five children admitted to an urban hospital in Bangladesh with diarrhea and pneumonia.

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Chisti, Mohammod J; Ahmed, Tahmeed; Ashraf, Hasan; Faruque, A S G; Bardhan, Pradip K; Dey, Sanjoy Kumer; Huq, Sayeeda; Das, Sumon Kumar; Salam, Mohammed A

2012-01-01

Clinical features of metabolic acidosis and pneumonia frequently overlap in young diarrheal children, resulting in differentiation from each other very difficult. However, there is no published data on the predictors of metabolic acidosis in diarrheal children also having pneumonia. Our objective was to evaluate clinical predictors of metabolic acidosis in under-five diarrheal children with radiological pneumonia, and their outcome. We prospectively enrolled all under-five children (n = 164) admitted to the Special Care Ward (SCW) of the Dhaka Hospital of icddr, b between September and December 2007 with diarrhea and radiological pneumonia who also had their total serum carbon-dioxide estimated. We compared the clinical features and outcome of children with radiological pneumonia and diarrhea with (n = 98) and without metabolic acidosis (n = 66). Children with metabolic acidosis more often had higher case-fatality (16% vs. 5%, p = 0.039) compared to those without metabolic acidosis on admission. In logistic regression analysis, after adjusting for potential confounders such as age of the patient, fever on admission, and severe wasting, the independent predictors of metabolic acidosis in under-five diarrheal children having pneumonia were clinical dehydration (OR 3.57, 95% CI 1.62-7.89, p = 0.002), and low systolic blood pressure even after full rehydration (OR 1.02, 95% CI 1.01-1.04, p = 0.005). Proportions of children with cough, respiratory rate/minute, lower chest wall indrawing, nasal flaring, head nodding, grunting respiration, and cyanosis were comparable (p>0.05) among the groups. Under-five diarrheal children with radiological pneumonia having metabolic acidosis had frequent fatal outcome than those without acidosis. Clinical dehydration and persistent systolic hypotension even after adequate rehydration were independent clinical predictors of metabolic acidosis among the children. However, metabolic acidosis in young diarrheal children had no impact on the

Diet and cognition: interplay between cell metabolism and neuronal plasticity.

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Gomez-Pinilla, Fernando; Tyagi, Ethika

2013-11-01

To discuss studies in humans and animals revealing the ability of foods to benefit the brain: new information with regards to mechanisms of action and the treatment of neurological and psychiatric disorders. Dietary factors exert their effects on the brain by affecting molecular events related to the management of energy metabolism and synaptic plasticity. Energy metabolism influences neuronal function, neuronal signaling, and synaptic plasticity, ultimately affecting mental health. Epigenetic regulation of neuronal plasticity appears as an important mechanism by which foods can prolong their effects on long-term neuronal plasticity. The prime focus of the discussion is to emphasize the role of cell metabolism as a mediator for the action of foods on the brain. Oxidative stress promotes damage to phospholipids present in the plasma membrane such as the omega-3 fatty acid docosahexenoic acid, disrupting neuronal signaling. Thus, dietary docosahexenoic acid seems crucial for supporting plasma membrane function, interneuronal signaling, and cognition. The dual action of brain-derived neurotrophic factor in neuronal metabolism and synaptic plasticity is crucial for activating signaling cascades under the action of diet and other environmental factors, using mechanisms of epigenetic regulation.

Beneficial Effects of Cinnamon on the Metabolic Syndrome, Inflammation, and Pain, and Mechanisms Underlying These Effects – A Review

Science.gov (United States)

Shen, Yan; Jia, Liu-Nan; Honma, Natsumi; Hosono, Takashi; Ariga, Toyohiko; Seki, Taiichiro

2012-01-01

Cinnamon is one of the most important herbal drugs and has been widely used in Asia for more than 4000 years. As a folk medicine, cinnamon has been traditionally applied to the treatment of inflammatory disorders and gastric diseases. After chemical profiling of cinnamon's components, their biological activities including antimicrobial, antiviral, antioxidant, antitumor, antihypertension, antilipemic, antidiabetes, gastroprotective and immunomodulatory were reported by many investigators. As a result, current studies have been performed mostly focusing on the bioactivity of cinnamon toward the recently generalized metabolic syndrome involving diabetes. In this review article, we provide an overview of the recent literature describing cinnamon's potential for preventing the metabolic syndrome. PMID:24716111

Probing energy metabolism and microviscosity in cancer using FLIM

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Shirmanova, Marina V.; Lukina, Maria M.; Shimolina, Lyubov'E.; Kuimova, Marina K.; Dudenkova, Varvara V.; Shcheslavskiy, Vladislav I.; Zagaynova, Elena V.

2017-07-01

Fluorescence lifetime imaging microscopy (FLIM) is a promising non-invasive highly sensitive technique for probing multiple physiological and physicochemical parameters in living cells and tissues. The present study is focused on the investigation of bioenergetics and microscopic viscosity of cultured cancer cells and animal tumors using FLIM during natural growth and chemotherapy. Fluorescence lifetime measurements of the metabolic cofactor NAD(P)H revealed a decrease of the relative amplitude of free NAD(P)H after cisplatin treatment, indicating a change towards a more oxidative metabolic state. Microviscosity mapping performed with the use of fluorescent molecular rotor BODIPY-2 showed a pronounced increase in the plasma membrane viscosity in cancer cells exposed to cisplatin. Although biochemical mechanisms underlying the metabolic and viscosity alterations during chemotherapy have yet to be clarified, our data suggest that the cisplatin-induced changes in cellular metabolism and membrane viscosity play a role in the cytotoxicity of the drug. The results of the study contribute to an understanding of mechanisms of cisplatin action and will be useful for development new approach for assessing response to a therapy.

Steroidogenic versus Metabolic Programming of Reproductive Neuroendocrine, Ovarian and Metabolic Dysfunctions.

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Cardoso, Rodolfo C; Puttabyatappa, Muraly; Padmanabhan, Vasantha

2015-01-01

The susceptibility of the reproductive system to early exposure to steroid hormones has become a major concern in our modern societies. Human fetuses are at risk of abnormal programming via exposure to endocrine disrupting chemicals, inadvertent use of contraceptive pills during pregnancy, as well as from excess exposure to steroids due to disease states. Animal models provide an unparalleled resource to understand the developmental origin of diseases. In female sheep, prenatal exposure to testosterone excess results in an array of adult reproductive disorders that recapitulate those seen in women with polycystic ovary syndrome (PCOS), including disrupted neuroendocrine feedback mechanisms, increased pituitary sensitivity to gonadotropin-releasing hormone, luteinizing hormone excess, functional hyperandrogenism, and multifollicular ovarian morphology culminating in early reproductive failure. Prenatal testosterone treatment also leads to fetal growth retardation, insulin resistance, and hypertension. Mounting evidence suggests that developmental exposure to an improper steroidal/metabolic environment may mediate the programming of adult disorders in prenatal testosterone-treated females, and these defects are maintained or amplified by the postnatal sex steroid and metabolic milieu. This review addresses the steroidal and metabolic contributions to the development and maintenance of the PCOS phenotype in the prenatal testosterone-treated sheep model, including the effects of prenatal and postnatal treatment with an androgen antagonist or insulin sensitizer as potential strategies to prevent/ameliorate these dysfunctions. Insights obtained from these intervention strategies on the mechanisms underlying these defects are likely to have translational relevance to human PCOS. © 2015 S. Karger AG, Basel.

Obese and anorexic yeasts: experimental models to understand the metabolic syndrome and lipotoxicity.

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Kohlwein, Sepp D

2010-03-01

Lipotoxicity is the pathological consequence of lipid overflow in non-adipose tissue, mediated through reactive lipid moieties which may even lead to lipid-induced cell death (lipoapoptosis). This derailment of cellular and organismal fat homeostasis is the consequence of obesity due to continued over-feeding, and contributes substantially to the pathogenesis of insulin resistance, type 2 diabetes mellitus and cardiovascular disease, which are all components of the metabolic syndrome. Now, does yeast, a single-celled eukaryote, ever suffer from the metabolic syndrome and what can we potentially learn from studies in this organism about the underlying molecular mechanism that lead to lipid-associated pathologies in human cells? In this review I will summarize the remarkably conserved metabolic and regulatory processes relevant to establishing cellular energy and lipid homeostasis, as well as recent findings that provide detailed insights into the molecular mechanisms underlying fat-induced cellular malfunction and cell death, with potential implications also for mammalian cells. Copyright (c) 2010 Elsevier B.V. All rights reserved.

Hypothyroidism in metabolic syndrome

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Sunil Kumar Kota

2012-01-01

Full Text Available Aim: Metabolic syndrome (MetS and hypothyroidism are well established forerunners of atherogenic cardiovascular disease. Considerable overlap occurs in the pathogenic mechanisms of atherosclerotic cardiovascular disease by metabolic syndrome and hypothyroidism. Insulin resistance has been studied as the basic pathogenic mechanism in metabolic syndrome. [1] This cross sectional study intended to assess thyroid function in patients with metabolic syndrome and to investigate the association between hypothyroidism and metabolic syndrome. Materials and Methods: One hundred patients with metabolic syndrome who fulfilled the National Cholesterol Education Program- Adult Treatment Panel (NCEP-ATP III criteria [ 3 out of 5 criteria positive namely blood pressure ≥ 130/85 mm hg or on antihypertensive medications, fasting plasma glucose > 100 mg/dl or on anti-diabetic medications, fasting triglycerides > 150 mg/dl, high density lipoprotein cholesterol (HDL-C 102 cms in men and 88 cms in women] were included in the study group. [2] Fifty patients who had no features of metabolic syndrome (0 out of 5 criteria for metabolic syndrome were included in the control group. Patients with liver disorders, renal disorders, congestive cardiac failure, pregnant women, patients on oral contraceptive pills, statins and other medications that alter thyroid functions and lipid levels and those who are under treatment for any thyroid related disorder were excluded from the study. Acutely ill patients were excluded taking into account sick euthyroid syndrome. Patients were subjected to anthropometry, evaluation of vital parameters, lipid and thyroid profile along with other routine laboratory parameters. Students t-test, Chi square test and linear regression, multiple logistic regression models were used for statistical analysis. P value < 0.05 was considered significant. Results: Of the 100 patients in study group, 55 were females (55% and 45 were males (45%. Of the 50

An extrahepatic receptor-associated protein-sensitive mechanism is involved in the metabolism of triglyceride-rich lipoproteins

NARCIS (Netherlands)

Vlijmen, B.J.M. van; Rohlmann, A.; Page, S.T.; Bensadoun, A.; Bos, I.S.T.; Berkel, T.J.C. van; Havekes, L.M.; Herz, J.

1999-01-01

We have used adenovirus-mediated gene transfer in mice to investigate low density lipoprotein receptor (LDLR) and LDLR-related protein (LRP)- independent mechanisms that control the metabolism of chylomicron and very low density lipoprotein (VLDL) remnants in vivo. Overexpression of receptor-

Gastrointestinal Transit Time, Glucose Homeostasis and Metabolic Health: Modulation by Dietary Fibers.

Science.gov (United States)

Müller, Mattea; Canfora, Emanuel E; Blaak, Ellen E

2018-02-28

Gastrointestinal transit time may be an important determinant of glucose homeostasis and metabolic health through effects on nutrient absorption and microbial composition, among other mechanisms. Modulation of gastrointestinal transit may be one of the mechanisms underlying the beneficial health effects of dietary fibers. These effects include improved glucose homeostasis and a reduced risk of developing metabolic diseases such as obesity and type 2 diabetes mellitus. In this review, we first discuss the regulation of gastric emptying rate, small intestinal transit and colonic transit as well as their relation to glucose homeostasis and metabolic health. Subsequently, we briefly address the reported health effects of different dietary fibers and discuss to what extent the fiber-induced health benefits may be mediated through modulation of gastrointestinal transit.

[Metabolic acidosis].

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Regolisti, Giuseppe; Fani, Filippo; Antoniotti, Riccardo; Castellano, Giuseppe; Cremaschi, Elena; Greco, Paolo; Parenti, Elisabetta; Morabito, Santo; Sabatino, Alice; Fiaccadori, Enrico

2016-01-01

Metabolic acidosis is frequently observed in clinical practice, especially among critically ill patients and/or in the course of renal failure. Complex mechanisms are involved, in most cases identifiable by medical history, pathophysiology-based diagnostic reasoning and measure of some key acid-base parameters that are easily available or calculable. On this basis the bedside differential diagnosis of metabolic acidosis should be started from the identification of the two main subtypes of metabolic acidosis: the high anion gap metabolic acidosis and the normal anion gap (or hyperchloremic) metabolic acidosis. Metabolic acidosis, especially in its acute forms with elevated anion gap such as is the case of lactic acidosis, diabetic and acute intoxications, may significantly affect metabolic body homeostasis and patients hemodynamic status, setting the stage for true medical emergencies. The therapeutic approach should be first aimed at early correction of concurrent clinical problems (e.g. fluids and hemodynamic optimization in case of shock, mechanical ventilation in case of concomitant respiratory failure, hemodialysis for acute intoxications etc.), in parallel to the formulation of a diagnosis. In case of severe acidosis, the administration of alkalizing agents should be carefully evaluated, taking into account the risk of side effects, as well as the potential need of renal replacement therapy.

Sleep Control, GPCRs, and Glucose Metabolism.

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Tsuneki, Hiroshi; Sasaoka, Toshiyasu; Sakurai, Takeshi

2016-09-01

Modern lifestyles prolong daily activities into the nighttime, disrupting circadian rhythms, which may cause sleep disturbances. Sleep disturbances have been implicated in the dysregulation of blood glucose levels and reported to increase the risk of type 2 diabetes (T2D) and diabetic complications. Sleep disorders are treated using anti-insomnia drugs that target ionotropic and G protein-coupled receptors (GPCRs), including γ-aminobutyric acid (GABA) agonists, melatonin agonists, and orexin receptor antagonists. A deeper understanding of the effects of these medications on glucose metabolism and their underlying mechanisms of action is crucial for the treatment of diabetic patients with sleep disorders. In this review we focus on the beneficial impact of sleep on glucose metabolism and suggest a possible strategy for therapeutic intervention against sleep-related metabolic disorders. Copyright © 2016. Published by Elsevier Ltd.

Imaging microbial metal metabolism in situ under conditions of the deep-sea hydrothermal vents

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Oger, P. M.; Daniel, I.; Simionovici, A.; Picard, A.

2006-12-01

High-pressure biotopes are the most widely spread biotopes on Earth. They represent one possible location for the origin of life. They also share striking similarities with extraterrestrial biotopes such as those postulated for Europe or Mars. In absence of light, dissimilatory reduction of metals (DMR) is fueling the ecosystem. Monitoring the metabolism of the deep-sea hydrothermal vent microbial fauna under P, T and chemical conditions relevant to their isolation environment can be difficult because of the confinement and because most spectroscopic probes do not sense metallic ions in solution. We demonstrated the possibility to use Xray spectroscopy to monitor the speciation of metallic species in solution. Experiments were performed at The ESRF using Selenium (Se) detoxification by Agrobacterium tumefaciens as an analog of DMR. The reduction of Se from selenite to the metal was monitored by a combiantion of two Xray spectroscopic techniques (XANES and μXRF). Cells were incubated in the low pressure DAC in growth medium supplemented with 5mM Selenite and incubated under pressures up to 60 Mpa at 30°C for 24h. The evolution of the speciation can be easily monitored and the concentration of each Se species determined from the Xray spectra by linear combinations of standard spectra. Selenite is transformed by the bacterium into a mixture of metal Se and methylated Se after 24 hours. Se detoxification is observed in situ up to at least 25 MPa. The technique, developped for Se can be adapted to monitor other elements more relevant to DMR such as As, Fe or S, which should allow to monitor in situ under controlled pressure and temperature the metabolism of vent organisms. It is also amenable to the monitoring of toxic metals. Xray spectroscopy and the lpDAC are compatible with other spectroscopic techniques, such as Raman, UV or IR spectroscopies, allowing to probe other metabolic activities. Hence, enlarging the range of metabolic information that can be obtained in

Regulation of metabolic networks by small molecule metabolites

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Kanehisa Minoru

2007-03-01

Full Text Available Abstract Background The ability to regulate metabolism is a fundamental process in living systems. We present an analysis of one of the mechanisms by which metabolic regulation occurs: enzyme inhibition and activation by small molecules. We look at the network properties of this regulatory system and the relationship between the chemical properties of regulatory molecules. Results We find that many features of the regulatory network, such as the degree and clustering coefficient, closely match those of the underlying metabolic network. While these global features are conserved across several organisms, we do find local differences between regulation in E. coli and H. sapiens which reflect their different lifestyles. Chemical structure appears to play an important role in determining a compounds suitability for use in regulation. Chemical structure also often determines how groups of similar compounds can regulate sets of enzymes. These groups of compounds and the enzymes they regulate form modules that mirror the modules and pathways of the underlying metabolic network. We also show how knowledge of chemical structure and regulation could be used to predict regulatory interactions for drugs. Conclusion The metabolic regulatory network shares many of the global properties of the metabolic network, but often varies at the level of individual compounds. Chemical structure is a key determinant in deciding how a compound is used in regulation and for defining modules within the regulatory system.

Pediatric Obesity-Related Asthma: The Role of Metabolic Dysregulation.

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Vijayakanthi, Nandini; Greally, John M; Rastogi, Deepa

2016-05-01

The burden of obesity-related asthma among children, particularly among ethnic minorities, necessitates an improved understanding of the underlying disease mechanisms. Although obesity is an independent risk factor for asthma, not all obese children develop asthma. Several recent studies have elucidated mechanisms, including the role of diet, sedentary lifestyle, mechanical fat load, and adiposity-mediated inflammation that may underlie the obese asthma pathophysiology. Here, we review these recent studies and emerging scientific evidence that suggest metabolic dysregulation may play a role in pediatric obesity-related asthma. We also review the genetic and epigenetic factors that may underlie susceptibility to metabolic dysregulation and associated pulmonary morbidity among children. Lastly, we identify knowledge gaps that need further exploration to better define pathways that will allow development of primary preventive strategies for obesity-related asthma in children. Copyright © 2016 by the American Academy of Pediatrics.

Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation of macrophage.

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Kim, Kyoung-Han; Kim, Yun Hye; Son, Joe Eun; Lee, Ju Hee; Kim, Sarah; Choe, Min Seon; Moon, Joon Ho; Zhong, Jian; Fu, Kiya; Lenglin, Florine; Yoo, Jeong-Ah; Bilan, Philip J; Klip, Amira; Nagy, Andras; Kim, Jae-Ryong; Park, Jin Gyoon; Hussein, Samer Mi; Doh, Kyung-Oh; Hui, Chi-Chung; Sung, Hoon-Ki

2017-11-01

Intermittent fasting (IF), a periodic energy restriction, has been shown to provide health benefits equivalent to prolonged fasting or caloric restriction. However, our understanding of the underlying mechanisms of IF-mediated metabolic benefits is limited. Here we show that isocaloric IF improves metabolic homeostasis against diet-induced obesity and metabolic dysfunction primarily through adipose thermogenesis in mice. IF-induced metabolic benefits require fasting-mediated increases of vascular endothelial growth factor (VEGF) expression in white adipose tissue (WAT). Furthermore, periodic adipose-VEGF overexpression could recapitulate the metabolic improvement of IF in non-fasted animals. Importantly, fasting and adipose-VEGF induce alternative activation of adipose macrophage, which is critical for thermogenesis. Human adipose gene analysis further revealed a positive correlation of adipose VEGF-M2 macrophage-WAT browning axis. The present study uncovers the molecular mechanism of IF-mediated metabolic benefit and suggests that isocaloric IF can be a preventive and therapeutic approach against obesity and metabolic disorders.

Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation of macrophage

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Kim, Kyoung-Han; Kim, Yun Hye; Son, Joe Eun; Lee, Ju Hee; Kim, Sarah; Choe, Min Seon; Moon, Joon Ho; Zhong, Jian; Fu, Kiya; Lenglin, Florine; Yoo, Jeong-Ah; Bilan, Philip J; Klip, Amira; Nagy, Andras; Kim, Jae-Ryong; Park, Jin Gyoon; Hussein, Samer MI; Doh, Kyung-Oh; Hui, Chi-chung; Sung, Hoon-Ki

2017-01-01

Intermittent fasting (IF), a periodic energy restriction, has been shown to provide health benefits equivalent to prolonged fasting or caloric restriction. However, our understanding of the underlying mechanisms of IF-mediated metabolic benefits is limited. Here we show that isocaloric IF improves metabolic homeostasis against diet-induced obesity and metabolic dysfunction primarily through adipose thermogenesis in mice. IF-induced metabolic benefits require fasting-mediated increases of vascular endothelial growth factor (VEGF) expression in white adipose tissue (WAT). Furthermore, periodic adipose-VEGF overexpression could recapitulate the metabolic improvement of IF in non-fasted animals. Importantly, fasting and adipose-VEGF induce alternative activation of adipose macrophage, which is critical for thermogenesis. Human adipose gene analysis further revealed a positive correlation of adipose VEGF-M2 macrophage-WAT browning axis. The present study uncovers the molecular mechanism of IF-mediated metabolic benefit and suggests that isocaloric IF can be a preventive and therapeutic approach against obesity and metabolic disorders. PMID:29039412

Late-onset ornithine transcarbamylase deficiency: An under recognized cause of metabolic encephalopathy

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Eric T Rush

2014-07-01

Full Text Available Introduction: Ornithine transcarbamylase deficiency is the most common inherited disorder of the urea cycle, has a variable phenotype, and is caused by mutations in the OTC gene. We report three cases of ornithine transcarbamylase deficiency to illustrate the late-onset presentation of this disorder and provide strategies for diagnosis and treatment. The patients were maternal first cousins, presenting with hyperammonemia and obtundation. Urea cycle disorder was not initially suspected in the first patient, delaying diagnosis. Results: Sequencing of the OTC gene showed a novel missense mutation, c.563G > C (p.G188A. Numerous family members were found to carry this mutation, which shows a trend toward later onset. Each urea cycle disorder has its own unique pattern of biochemical abnormalities, which differ from non-metabolic causes of critical illness. Conclusion: Regardless of age, clinical suspicion of a urea cycle disorder is important in encephalopathic patients to ensure quick diagnosis and definitive treatment of the underlying inborn error of metabolism.

Induction of drug-metabolizing enzymes: mechanisms and consequences

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Okey, A.B.; Roberts, E.A.; Harper, P.A.; Denison, M.S.

1986-04-01

The activity of many enzymes that carry out biotransformation of drugs and environmental chemicals can be substantially increased by prior exposure of humans or animals to a wide variety of foreign chemicals. Increased enzyme activity is due to true enzyme induction mediated by increased synthesis of mRNAs which code for specific drug-metabolizing enzymes. Several species of cytochrome P-450 are inducible as are certain conjugating enzymes such as glutathione S-transferases, glucuronosyl transferases, and epoxide hydrolases. Induction of drug-metabolizing enzymes has been shown in several instances to alter the efficacy of some therapeutic agents. Induction of various species of cytochrome P-450 also is known to increase the rate at which potentially toxic reactive metabolic intermediates are formed from drugs or environmental chemicals. Overall, however, induction of drug-metabolizing enzymes appears to be a beneficial adaptive response for organisms living in a ''chemically-hostile'' world.48 references.

Intracellular metabolite profiling of Saccharomyces cerevisiae evolved under furfural.

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Jung, Young Hoon; Kim, Sooah; Yang, Jungwoo; Seo, Jin-Ho; Kim, Kyoung Heon

2017-03-01

Furfural, one of the most common inhibitors in pre-treatment hydrolysates, reduces the cell growth and ethanol production of yeast. Evolutionary engineering has been used as a selection scheme to obtain yeast strains that exhibit furfural tolerance. However, the response of Saccharomyces cerevisiae to furfural at the metabolite level during evolution remains unknown. In this study, evolutionary engineering and metabolomic analyses were applied to determine the effects of furfural on yeasts and their metabolic response to continuous exposure to furfural. After 50 serial transfers of cultures in the presence of furfural, the evolved strains acquired the ability to stably manage its physiological status under the furfural stress. A total of 98 metabolites were identified, and their abundance profiles implied that yeast metabolism was globally regulated. Under the furfural stress, stress-protective molecules and cofactor-related mechanisms were mainly induced in the parental strain. However, during evolution under the furfural stress, S. cerevisiae underwent global metabolic allocations to quickly overcome the stress, particularly by maintaining higher levels of metabolites related to energy generation, cofactor regeneration and recovery from cellular damage. Mapping the mechanisms of furfural tolerance conferred by evolutionary engineering in the present study will be led to rational design of metabolically engineered yeasts. © 2016 The Authors. Microbial Biotechnology published by John Wiley & Sons Ltd and Society for Applied Microbiology.

The diel imprint of leaf metabolism on the δ13 C signal of soil respiration under control and drought conditions.

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Barthel, Matthias; Hammerle, Albin; Sturm, Patrick; Baur, Thomas; Gentsch, Lydia; Knohl, Alexander

2011-12-01

Recent (13) CO(2) canopy pulse chase labeling studies revealed that photosynthesis influences the carbon isotopic composition of soil respired CO(2) (δ(13) C(SR)) even on a diel timescale. However, the driving mechanisms underlying these short-term responses remain unclear, in particular under drought conditions. The gas exchange of CO(2) isotopes of canopy and soil was monitored in drought/nondrought-stressed beech (Fagus sylvatica) saplings after (13) CO(2) canopy pulse labeling. A combined canopy/soil chamber system with gas-tight separated soil and canopy compartments was coupled to a laser spectrometer measuring mixing ratios and isotopic composition of CO(2) in air at high temporal resolution. The measured δ(13) C(SR) signal was then explained and substantiated by a mechanistic carbon allocation model. Leaf metabolism had a strong imprint on diel cycles in control plants, as a result of an alternating substrate supply switching between sugar and transient starch. By contrast, diel cycles in drought-stressed plants were determined by the relative contributions of autotrophic and heterotrophic respiration throughout the day. Drought reduced the speed of the link between photosynthesis and soil respiration by a factor of c. 2.5, depending on the photosynthetic rate. Drought slows the coupling between photosynthesis and soil respiration and alters the underlying mechanism causing diel variations of δ(13) C(SR). © 2011 The Authors. New Phytologist © 2011 New Phytologist Trust.

Advanced computational workflow for the multi-scale modeling of the bone metabolic processes.

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Dao, Tien Tuan

2017-06-01

Multi-scale modeling of the musculoskeletal system plays an essential role in the deep understanding of complex mechanisms underlying the biological phenomena and processes such as bone metabolic processes. Current multi-scale models suffer from the isolation of sub-models at each anatomical scale. The objective of this present work was to develop a new fully integrated computational workflow for simulating bone metabolic processes at multi-scale levels. Organ-level model employs multi-body dynamics to estimate body boundary and loading conditions from body kinematics. Tissue-level model uses finite element method to estimate the tissue deformation and mechanical loading under body loading conditions. Finally, cell-level model includes bone remodeling mechanism through an agent-based simulation under tissue loading. A case study on the bone remodeling process located on the human jaw was performed and presented. The developed multi-scale model of the human jaw was validated using the literature-based data at each anatomical level. Simulation outcomes fall within the literature-based ranges of values for estimated muscle force, tissue loading and cell dynamics during bone remodeling process. This study opens perspectives for accurately simulating bone metabolic processes using a fully integrated computational workflow leading to a better understanding of the musculoskeletal system function from multiple length scales as well as to provide new informative data for clinical decision support and industrial applications.

Microbial Regulation of Glucose Metabolism and Insulin Resistance

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Silke Crommen

2017-12-01

Full Text Available Type 2 diabetes is a combined disease, resulting from a hyperglycemia and peripheral and hepatic insulin resistance. Recent data suggest that the gut microbiota is involved in diabetes development, altering metabolic processes including glucose and fatty acid metabolism. Thus, type 2 diabetes patients show a microbial dysbiosis, with reduced butyrate-producing bacteria and elevated potential pathogens compared to metabolically healthy individuals. Furthermore, probiotics are a known tool to modulate the microbiota, having a therapeutic potential. Current literature will be discussed to elucidate the complex interaction of gut microbiota, intestinal permeability and inflammation leading to peripheral and hepatic insulin resistance. Therefore, this review aims to generate a deeper understanding of the underlying mechanism of potential microbial strains, which can be used as probiotics.

CCAAT/Enhancer Binding Protein β in relation to ER Stress, Inflammation, and Metabolic Disturbances

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Sophie E. van der Krieken

2015-01-01

Full Text Available The prevalence of the metabolic syndrome and underlying metabolic disturbances increase rapidly in developed countries. Various molecular targets are currently under investigation to unravel the molecular mechanisms that cause these disturbances. This is done in attempt to counter or prevent the negative health consequences of the metabolic disturbances. Here, we reviewed the current knowledge on the role of C/EBP-β in these metabolic disturbances. C/EBP-β deletion in mice resulted in downregulation of hepatic lipogenic genes and increased expression of β-oxidation genes in brown adipose tissue. Furthermore, C/EBP-β is important in the differentiation and maturation of adipocytes and is increased during ER stress and proinflammatory conditions. So far, studies were only conducted in animals and in cell systems. The results found that C/EBP-β is an important transcription factor within the metabolic disturbances of the metabolic system. Therefore, it is interesting to examine the potential role of C/EBP-β at molecular and physiological level in humans.

Interactions between sleep, stress, and metabolism: From physiological to pathological conditions

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Camila Hirotsu

2015-11-01

Full Text Available Poor sleep quality due to sleep disorders and sleep loss is highly prevalent in the modern society. Underlying mechanisms show that stress is involved in the relationship between sleep and metabolism through hypothalamic–pituitary–adrenal (HPA axis activation. Sleep deprivation and sleep disorders are associated with maladaptive changes in the HPA axis, leading to neuroendocrine dysregulation. Excess of glucocorticoids increase glucose and insulin and decrease adiponectin levels. Thus, this review provides overall view of the relationship between sleep, stress, and metabolism from basic physiology to pathological conditions, highlighting effective treatments for metabolic disturbances.

L-arginine:glycine amidinotransferase deficiency protects from metabolic syndrome.

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Choe, Chi-un; Nabuurs, Christine; Stockebrand, Malte C; Neu, Axel; Nunes, Patricia; Morellini, Fabio; Sauter, Kathrin; Schillemeit, Stefan; Hermans-Borgmeyer, Irm; Marescau, Bart; Heerschap, Arend; Isbrandt, Dirk

2013-01-01

Phosphorylated creatine (Cr) serves as an energy buffer for ATP replenishment in organs with highly fluctuating energy demand. The central role of Cr in the brain and muscle is emphasized by severe neurometabolic disorders caused by Cr deficiency. Common symptoms of inborn errors of creatine synthesis or distribution include mental retardation and muscular weakness. Human mutations in l-arginine:glycine amidinotransferase (AGAT), the first enzyme of Cr synthesis, lead to severely reduced Cr and guanidinoacetate (GuA) levels. Here, we report the generation and metabolic characterization of AGAT-deficient mice that are devoid of Cr and its precursor GuA. AGAT-deficient mice exhibited decreased fat deposition, attenuated gluconeogenesis, reduced cholesterol levels and enhanced glucose tolerance. Furthermore, Cr deficiency completely protected from the development of metabolic syndrome caused by diet-induced obesity. Biochemical analyses revealed the chronic Cr-dependent activation of AMP-activated protein kinase (AMPK), which stimulates catabolic pathways in metabolically relevant tissues such as the brain, skeletal muscle, adipose tissue and liver, suggesting a mechanism underlying the metabolic phenotype. In summary, our results show marked metabolic effects of Cr deficiency via the chronic activation of AMPK in a first animal model of AGAT deficiency. In addition to insights into metabolic changes in Cr deficiency syndromes, our genetic model reveals a novel mechanism as a potential treatment option for obesity and type 2 diabetes mellitus.

Linking neuronal brain activity to the glucose metabolism.

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Göbel, Britta; Oltmanns, Kerstin M; Chung, Matthias

2013-08-29

Energy homeostasis ensures the functionality of the entire organism. The human brain as a missing link in the global regulation of the complex whole body energy metabolism is subject to recent investigation. The goal of this study is to gain insight into the influence of neuronal brain activity on cerebral and peripheral energy metabolism. In particular, the tight link between brain energy supply and metabolic responses of the organism is of interest. We aim to identifying regulatory elements of the human brain in the whole body energy homeostasis. First, we introduce a general mathematical model describing the human whole body energy metabolism. It takes into account the two central roles of the brain in terms of energy metabolism. The brain is considered as energy consumer as well as regulatory instance. Secondly, we validate our mathematical model by experimental data. Cerebral high-energy phosphate content and peripheral glucose metabolism are measured in healthy men upon neuronal activation induced by transcranial direct current stimulation versus sham stimulation. By parameter estimation we identify model parameters that provide insight into underlying neurophysiological processes. Identified parameters reveal effects of neuronal activity on regulatory mechanisms of systemic glucose metabolism. Our examinations support the view that the brain increases its glucose supply upon neuronal activation. The results indicate that the brain supplies itself with energy according to its needs, and preeminence of cerebral energy supply is reflected. This mechanism ensures balanced cerebral energy homeostasis. The hypothesis of the central role of the brain in whole body energy homeostasis as active controller is supported.

Genome-Scale Metabolic Model for the Green Alga Chlorella vulgaris UTEX 395 Accurately Predicts Phenotypes under Autotrophic, Heterotrophic, and Mixotrophic Growth Conditions.

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Zuñiga, Cristal; Li, Chien-Ting; Huelsman, Tyler; Levering, Jennifer; Zielinski, Daniel C; McConnell, Brian O; Long, Christopher P; Knoshaug, Eric P; Guarnieri, Michael T; Antoniewicz, Maciek R; Betenbaugh, Michael J; Zengler, Karsten

2016-09-01

The green microalga Chlorella vulgaris has been widely recognized as a promising candidate for biofuel production due to its ability to store high lipid content and its natural metabolic versatility. Compartmentalized genome-scale metabolic models constructed from genome sequences enable quantitative insight into the transport and metabolism of compounds within a target organism. These metabolic models have long been utilized to generate optimized design strategies for an improved production process. Here, we describe the reconstruction, validation, and application of a genome-scale metabolic model for C. vulgaris UTEX 395, iCZ843. The reconstruction represents the most comprehensive model for any eukaryotic photosynthetic organism to date, based on the genome size and number of genes in the reconstruction. The highly curated model accurately predicts phenotypes under photoautotrophic, heterotrophic, and mixotrophic conditions. The model was validated against experimental data and lays the foundation for model-driven strain design and medium alteration to improve yield. Calculated flux distributions under different trophic conditions show that a number of key pathways are affected by nitrogen starvation conditions, including central carbon metabolism and amino acid, nucleotide, and pigment biosynthetic pathways. Furthermore, model prediction of growth rates under various medium compositions and subsequent experimental validation showed an increased growth rate with the addition of tryptophan and methionine. © 2016 American Society of Plant Biologists. All rights reserved.

Metabolic Profile and Inflammatory Responses in Dairy Cows with Left Displaced Abomasum Kept under Small-Scaled Farm Conditions

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Fenja Klevenhusen

2015-10-01

Full Text Available Left displaced abomasum (LDA is a severe metabolic disease of cattle with a strong negative impact on production efficiency of dairy farms. Metabolic and inflammatory alterations associated with this disease have been reported in earlier studies, conducted mostly in large dairy farms. This research aimed to: (1 evaluate metabolic and inflammatory responses in dairy cows affected by LDA in small-scaled dairy farms; and (2 establish an Animals 2015, 5 1022 association between lactation number and milk production with the outcome of metabolic variables. The cows with LDA had lower serum calcium (Ca, but greater concentrations of non-esterified fatty acids (NEFA and beta-hydroxy-butyrate (BHBA, in particular when lactation number was >2. Cows with LDA showed elevated levels of aspartate aminotransferase, glutamate dehydrogenase, and serum amyloid A (SAA, regardless of lactation number. In addition, this study revealed strong associations between milk yield and the alteration of metabolic profile but not with inflammation in the sick cows. Results indicate metabolic alterations, liver damage, and inflammation in LDA cows kept under small-scale farm conditions. Furthermore, the data suggest exacerbation of metabolic profile and Ca metabolism but not of inflammation and liver health with increasing lactation number and milk yield in cows affected by LDA.

Metabolic Profile and Inflammatory Responses in Dairy Cows with Left Displaced Abomasum Kept under Small-Scaled Farm Conditions.

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Klevenhusen, Fenja; Humer, Elke; Metzler-Zebeli, Barbara; Podstatzky-Lichtenstein, Leopold; Wittek, Thomas; Zebeli, Qendrim

2015-10-13

Left displaced abomasum (LDA) is a severe metabolic disease of cattle with a strong negative impact on production efficiency of dairy farms. Metabolic and inflammatory alterations associated with this disease have been reported in earlier studies, conducted mostly in large dairy farms. This research aimed to: (1) evaluate metabolic and inflammatory responses in dairy cows affected by LDA in small-scaled dairy farms; and (2) establish an Animals 2015, 5 1022 association between lactation number and milk production with the outcome of metabolic variables. The cows with LDA had lower serum calcium (Ca), but greater concentrations of non-esterified fatty acids (NEFA) and beta-hydroxy-butyrate (BHBA), in particular when lactation number was >2. Cows with LDA showed elevated levels of aspartate aminotransferase, glutamate dehydrogenase, and serum amyloid A (SAA), regardless of lactation number. In addition, this study revealed strong associations between milk yield and the alteration of metabolic profile but not with inflammation in the sick cows. Results indicate metabolic alterations, liver damage, and inflammation in LDA cows kept under small-scale farm conditions. Furthermore, the data suggest exacerbation of metabolic profile and Ca metabolism but not of inflammation and liver health with increasing lactation number and milk yield in cows affected by LDA.

Effects of nicotinamide N-methyltransferase on PANC-1 cells proliferation, metastatic potential and survival under metabolic stress.

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Yu, Tao; Wang, Yong-Tao; Chen, Pan; Li, Yu-Hua; Chen, Yi-Xin; Zeng, Hang; Yu, Ai-Ming; Huang, Min; Bi, Hui-Chang

2015-01-01

Aberrant expression of Nicotinamide N-methyltransferase (NNMT) has been reported in pancreatic cancer. However, the role of NNMT in pancreatic cancer development remains elusive. Therefore, the present study was to investigate the impact of NNMT on pancreatic cancer cell proliferation, metastatic potential and survival under metabolic stress. Pancreatic cancer cell line PANC-1 was transfected with NNMT expression plasmid or small interfering RNA of NNMT to overexpress or knockdown intracellular NNMT expression, respectively. Rate of cell proliferation was monitored. Transwell migration and matrigel invasion assays were conducted to assess cell migration and invasion capacity. Resistance to glucose deprivation, sensitivity to glycolytic inhibition, mitochondrial inhibtion and resistance to rapamycin were examined to evaluate cell survival under metabolic stress. NNMT silencing markedly reduced cell proliferation, whereas NNMT overexpression promoted cell growth moderately. Knocking down NNMT also significantly suppressed the migration and invasion capacities of PANC-1 cells. Conversely, NNMT upregulation enhanced cell migration and invasion capacities. In addition, NNMT knockdown cells were much less resistant to glucose deprivation and rapamycin as well as glycolytic inhibitor 2-deoxyglucose whereas NNMT-expressing cells showed opposite effects although the effects were not so striking. These data sugguest that NNMT plays an important role in PANC-1 cell proliferation, metastatic potential and survival under metabolic stress. © 2015 S. Karger AG, Basel.

Effects of Nicotinamide N-Methyltransferase on PANC-1 Cells Proliferation, Metastatic Potential and Survival Under Metabolic Stress

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Tao Yu

2015-01-01

Full Text Available Background: Aberrant expression of Nicotinamide N-methyltransferase (NNMT has been reported in pancreatic cancer. However, the role of NNMT in pancreatic cancer development remains elusive. Therefore, the present study was to investigate the impact of NNMT on pancreatic cancer cell proliferation, metastatic potential and survival under metabolic stress. Methods: Pancreatic cancer cell line PANC-1 was transfected with NNMT expression plasmid or small interfering RNA of NNMT to overexpress or knockdown intracellular NNMT expression, respectively. Rate of cell proliferation was monitored. Transwell migration and matrigel invasion assays were conducted to assess cell migration and invasion capacity. Resistance to glucose deprivation, sensitivity to glycolytic inhibition, mitochondrial inhibtion and resistance to rapamycin were examined to evaluate cell survival under metabolic stress. Results: NNMT silencing markedly reduced cell proliferation, whereas NNMT overexpression promoted cell growth moderately. Knocking down NNMT also significantly suppressed the migration and invasion capacities of PANC-1 cells. Conversely, NNMT upregulation enhanced cell migration and invasion capacities. In addition, NNMT knockdown cells were much less resistant to glucose deprivation and rapamycin as well as glycolytic inhibitor 2-deoxyglucose whereas NNMT-expressing cells showed opposite effects although the effects were not so striking. Conclusions: These data sugguest that NNMT plays an important role in PANC-1 cell proliferation, metastatic potential and survival under metabolic stress.

A systems biology-based approach to uncovering the molecular mechanisms underlying the effects of dragon's blood tablet in colitis, involving the integration of chemical analysis, ADME prediction, and network pharmacology.

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Haiyu Xu

Full Text Available Traditional Chinese medicine (TCM is one of the oldest East Asian medical systems. The present study adopted a systems biology-based approach to provide new insights relating to the active constituents and molecular mechanisms underlying the effects of dragon's blood (DB tablets for the treatment of colitis. This study integrated chemical analysis, prediction of absorption, distribution, metabolism, and excretion (ADME, and network pharmacology. Firstly, a rapid, reliable, and accurate ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry method was employed to identify 48 components of DB tablets. In silico prediction of the passive absorption of these compounds, based on Caco-2 cell permeability, and their P450 metabolism enabled the identification of 22 potentially absorbed components and 8 metabolites. Finally, networks were constructed to analyze interactions between these DB components/metabolites absorbed and their putative targets, and between the putative DB targets and known therapeutic targets for colitis. This study provided a great opportunity to deepen the understanding of the complex pharmacological mechanisms underlying the effects of DB in colitis treatment.

[Hypovitaminosis D and metabolic syndrome].

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Miñambres, Inka; de Leiva, Alberto; Pérez, Antonio

2014-12-23

Metabolic syndrome and hypovitaminosis D are 2 diseases with high prevalence that share several risk factors, while epidemiological evidence shows they are associated. Although the mechanisms involved in this association are not well established, hypovitaminosis D is associated with insulin resistance, decreased insulin secretion and activation of the renin-angiotensin system, mechanisms involved in the pathophysiology of metabolic syndrome. However, the apparent ineffectiveness of vitamin D supplementation on metabolic syndrome components, as well as the limited information about the effect of improving metabolic syndrome components on vitamin D concentrations, does not clarify the direction and the mechanisms involved in the causal relationship between these 2 pathologies. Overall, because of the high prevalence and the epidemiological association between both diseases, hypovitaminosis D could be considered a component of the metabolic syndrome. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

Elucidation of molecular mechanisms of physiological variations between bovine subcutaneous and visceral fat depots under different nutritional regimes.

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Josue Moura Romao

Full Text Available Adipose tissue plays a critical role in energy homeostasis and metabolism. There is sparse understanding of the molecular regulation at the protein level of bovine adipose tissues, especially within different fat depots under different nutritional regimes. The objective of this study was to analyze the differences in protein expression between bovine subcutaneous and visceral fat depots in steers fed different diets and to identify the potential regulatory molecular mechanisms of protein expression. Subcutaneous and visceral fat tissues were collected from 16 British-continental steers (15.5 month old fed a high-fat diet (7.1% fat, n=8 or a control diet (2.7% fat, n=8. Protein expression was profiled using label free quantification LC-MS/MS and expression of selected transcripts was evaluated using qRT-PCR. A total of 682 proteins were characterized and quantified with fat depot having more impact on protein expression, altering the level of 51.0% of the detected proteins, whereas diet affected only 5.3%. Functional analysis revealed that energy production and lipid metabolism were among the main functions associated with differentially expressed proteins between fat depots, with visceral fat being more metabolically active than subcutaneous fat as proteins associated with lipid and energy metabolism were upregulated. The expression of several proteins was significantly correlated to subcutaneous fat thickness and adipocyte size, indicating their potential as adiposity markers. A poor correlation (r=0.245 was observed between mRNA and protein levels for 9 genes, indicating that many proteins may be subjected to post-transcriptional regulation. A total of 8 miRNAs were predicted to regulate more than 20% of lipid metabolism proteins differentially expressed between fat depots, suggesting that miRNAs play a role in adipose tissue regulation. Our results show that proteomic changes support the distinct metabolic and physiological characteristics

DNA under Force: Mechanics, Electrostatics, and Hydration

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Jingqiang Li

2015-02-01

Full Text Available Quantifying the basic intra- and inter-molecular forces of DNA has helped us to better understand and further predict the behavior of DNA. Single molecule technique elucidates the mechanics of DNA under applied external forces, sometimes under extreme forces. On the other hand, ensemble studies of DNA molecular force allow us to extend our understanding of DNA molecules under other forces such as electrostatic and hydration forces. Using a variety of techniques, we can have a comprehensive understanding of DNA molecular forces, which is crucial in unraveling the complex DNA functions in living cells as well as in designing a system that utilizes the unique properties of DNA in nanotechnology.

The SWI/SNF chromatin-remodeling factors BAF60a, b, and c in nutrient signaling and metabolic control

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Ruo-Ran Wang

2017-07-01

Full Text Available ABSTRACT Metabolic syndrome has become a global epidemic that adversely affects human health. Both genetic and environmental factors contribute to the pathogenesis of metabolic disorders; however, the mechanisms that integrate these cues to regulate metabolic physiology and the development of metabolic disorders remain incompletely defined. Emerging evidence suggests that SWI/SNF chromatin-remodeling complexes are critical for directing metabolic reprogramming and adaptation in response to nutritional and other physiological signals. The ATP-dependent SWI/SNF chromatin-remodeling complexes comprise up to 11 subunits, among which the BAF60 subunit serves as a key link between the core complexes and specific transcriptional factors. The BAF60 subunit has three members, BAF60a, b, and c. The distinct tissue distribution patterns and regulatory mechanisms of BAF60 proteins confer each isoform with specialized functions in different metabolic cell types. In this review, we summarize the emerging roles and mechanisms of BAF60 proteins in the regulation of nutrient sensing and energy metabolism under physiological and disease conditions.

Exploring the molecular mechanisms underlying the potentiation of exogenous growth hormone on alcohol-induced fatty liver diseases in mice

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Tian Ya-ping

2010-11-01

Full Text Available Abstract Background Growth hormone (GH is an essential regulator of intrahepatic lipid metabolism by activating multiple complex hepatic signaling cascades. Here, we examined whether chronic exogenous GH administration (via gene therapy could ameliorate liver steatosis in animal models of alcoholic fatty liver disease (AFLD and explored the underlying molecular mechanisms. Methods Male C57BL/6J mice were fed either an alcohol or a control liquid diet with or without GH therapy for 6 weeks. Biochemical parameters, liver histology, oxidative stress markers, and serum high molecular weight (HMW adiponectin were measured. Quantitative real-time PCR and western blotting were also conducted to determine the underlying molecular mechanism. Results Serum HMW adiponectin levels were significantly higher in the GH1-treated control group than in the control group (3.98 ± 0.71 μg/mL vs. 3.07 ± 0.55 μg/mL; P P P P P Conclusions GH therapy had positive effects on AFLD and may offer a promising approach to prevent or treat AFLD. These beneficial effects of GH on AFLD were achieved through the activation of the hepatic adiponectin-SIRT1-AMPK and PPARα-AMPK signaling systems.

Genome-Scale Metabolic Model for the Green Alga Chlorella vulgaris UTEX 395 Accurately Predicts Phenotypes under Autotrophic, Heterotrophic, and Mixotrophic Growth Conditions1

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Zuñiga, Cristal; Li, Chien-Ting; Zielinski, Daniel C.; Guarnieri, Michael T.; Antoniewicz, Maciek R.; Zengler, Karsten

2016-01-01

The green microalga Chlorella vulgaris has been widely recognized as a promising candidate for biofuel production due to its ability to store high lipid content and its natural metabolic versatility. Compartmentalized genome-scale metabolic models constructed from genome sequences enable quantitative insight into the transport and metabolism of compounds within a target organism. These metabolic models have long been utilized to generate optimized design strategies for an improved production process. Here, we describe the reconstruction, validation, and application of a genome-scale metabolic model for C. vulgaris UTEX 395, iCZ843. The reconstruction represents the most comprehensive model for any eukaryotic photosynthetic organism to date, based on the genome size and number of genes in the reconstruction. The highly curated model accurately predicts phenotypes under photoautotrophic, heterotrophic, and mixotrophic conditions. The model was validated against experimental data and lays the foundation for model-driven strain design and medium alteration to improve yield. Calculated flux distributions under different trophic conditions show that a number of key pathways are affected by nitrogen starvation conditions, including central carbon metabolism and amino acid, nucleotide, and pigment biosynthetic pathways. Furthermore, model prediction of growth rates under various medium compositions and subsequent experimental validation showed an increased growth rate with the addition of tryptophan and methionine. PMID:27372244

Metabolic Syndrome in Schizophrenia: A Non‑systematic Review

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Marta Nascimento

2012-12-01

Full Text Available Background: The link between mental illness and metabolic disturbances has been recognized since the beginning of the last century. The debate concerning medical morbidity in schizophrenia intensified during the last twenty years, especially after the introduction of atypical antipsychotics. Aims: To highlight some features of the metabolic syndrome in this population, specifically epidemiological data, underlying mechanisms and antipsychotic therapy. Methods: Non‑systematic review of literature. Results and Conclusions: Despite the different criteria used for the definition of metabolic syndrome, it is clear today that the schizophrenic population has the highest rate of metabolic syndrome. Additionally, the prevalence of the metabolic syndrome in this population demonstrates a geographical distribution similar to the general population. Although it hasn’t been recognized for years, schizophrenic patients’ vulnerability to develop metabolic disturbances isn’t entirely related to antipsychotic therapy. Actually, it results from an interaction of multiple factors, including hereditary, genetic, biochemical and environmental ones (which include antipsychotic therapy. Moreover, they are not exclusively explained by weight gain. Metabolic disturbances are one of the main concerns related to general psychopharmacology. The differences between typical and atypical antipsychotics in terms of metabolic syndrome are not completely established. However, clozapine and olanzapine are recognized to have the worst metabolic profile, amongst all atypical antipsychotics.

Metabolic Syndrome in Schizophrenia: A Non‑systematic Review

Directory of Open Access Journals (Sweden)

Marta Nascimento

2013-11-01

Full Text Available Background: The link between mental illness and metabolic disturbances has been recognized since the beginning of the last century. The debate concerning medical morbidity in schizophrenia intensified during the last twenty years, especially after the introduction of atypical antipsychotics. Aims: To highlight some features of the metabolic syndrome in this population, specifically epidemiological data, underlying mechanisms and antipsychotic therapy. Methods: Non‑systematic review of literature. Results and Conclusions: Despite the different criteria used for the definition of metabolic syndrome, it is clear today that the schizophrenic population has the highest rate of metabolic syndrome. Additionally, the prevalence of the metabolic syndrome in this population demonstrates a geographical distribution similar to the general population. Although it hasn’t been recognized for years, schizophrenic patients’ vulnerability to develop metabolic disturbances isn’t entirely related to antipsychotic therapy. Actually, it results from an interaction of multiple factors, including hereditary, genetic, biochemical and environmental ones (which include antipsychotic therapy. Moreover, they are not exclusively explained by weight gain. Metabolic disturbances are one of the main concerns related to general psychopharmacology. The differences between typical and atypical antipsychotics in terms of metabolic syndrome are not completely established. However, clozapine and olanzapine are recognized to have the worst metabolic profile, amongst all atypical antipsychotics.

Radiation Changes the Metabolic Profiling of Melanoma Cell Line B16.

Directory of Open Access Journals (Sweden)

Lige Wu

Full Text Available Radiation therapy can be an effective way to kill cancer cells using ionizing radiation, but some tumors are resistant to radiation therapy and the underlying mechanism still remains elusive. It is therefore necessary to establish an appropriate working model to study and monitor radiation-mediated cancer therapy. In response to cellular stress, the metabolome is the integrated profiling of changes in all metabolites in cells, which can be used to investigate radiation tolerance mechanisms and identify targets for cancer radiation sensibilization. In this study, using 1H nuclear magnetic resonance for untargeted metabolic profiling in radiation-tolerant mouse melanoma cell line B16, we comprehensively investigated changes in metabolites and metabolic network in B16 cells in response to radiation. Principal component analysis and partial least squares discriminant analysis indicated the difference in cellular metabolites between the untreated cells and X-ray radiated cells. In radiated cells, the content of alanine, glutamate, glycine and choline was increased, while the content of leucine, lactate, creatine and creatine phosphate was decreased. Enrichment analysis of metabolic pathway showed that the changes in metabolites were related to multiple metabolic pathways including the metabolism of glycine, arginine, taurine, glycolysis, and gluconeogenesis. Taken together, with cellular metabolome study followed by bioinformatic analysis to profile specific metabolic pathways in response to radiation, we deepened our understanding of radiation-resistant mechanisms and radiation sensibilization in cancer, which may further provide a theoretical and practical basis for personalized cancer therapy.

Insecticide Resistance and Metabolic Mechanisms Involved in Larval and Adult Stages of Aedes aegypti Insecticide-Resistant Reference Strains from Cuba.

Science.gov (United States)

Bisset, Juan Andrés; Rodríguez, María Magdalena; French, Leydis; Severson, David W; Gutiérrez, Gladys; Hurtado, Daymi; Fuentes, Ilario

2014-12-01

Studies were conducted to compare levels of insecticide resistance and to determine the metabolic resistance mechanisms in larval and adult stages of Aedes aegypti from Cuba. Three insecticide-resistant reference strains of Ae. aegypti from Cuba were examined. These strains were derived from a Santiago de Cuba strain isolated in 1997; it was previously subjected to a strong selection for resistance to temephos (SAN-F6), deltamethrin (SAN-F12), and propoxur (SAN-F13) and routinely maintained in the laboratory under selection pressure up to the present time, when the study was carried out. In addition, an insecticide-susceptible strain was used for comparison. The insecticide resistance in larvae and adults was determined using standard World Health Organization methodologies. Insecticide resistance mechanisms were determined by biochemical assays. The esterases (α EST and β EST) and mixed function oxidase (MFO) activities were significantly higher in adults than in the larvae of the three resistant strains studied. The association of resistance level with the biochemical mechanism for each insecticide was established for each stage. The observed differences between larval and adult stages of Ae. aegypti in their levels of insecticide resistance and the biochemical mechanisms involved should be included as part of monitoring and surveillance activities in Ae. aegypti vector control programs.

Turing mechanism underlying a branching model for lung morphogenesis.

Science.gov (United States)

Xu, Hui; Sun, Mingzhu; Zhao, Xin

2017-01-01

The mammalian lung develops through branching morphogenesis. Two primary forms of branching, which occur in order, in the lung have been identified: tip bifurcation and side branching. However, the mechanisms of lung branching morphogenesis remain to be explored. In our previous study, a biological mechanism was presented for lung branching pattern formation through a branching model. Here, we provide a mathematical mechanism underlying the branching patterns. By decoupling the branching model, we demonstrated the existence of Turing instability. We performed Turing instability analysis to reveal the mathematical mechanism of the branching patterns. Our simulation results show that the Turing patterns underlying the branching patterns are spot patterns that exhibit high local morphogen concentration. The high local morphogen concentration induces the growth of branching. Furthermore, we found that the sparse spot patterns underlie the tip bifurcation patterns, while the dense spot patterns underlies the side branching patterns. The dispersion relation analysis shows that the Turing wavelength affects the branching structure. As the wavelength decreases, the spot patterns change from sparse to dense, the rate of tip bifurcation decreases and side branching eventually occurs instead. In the process of transformation, there may exists hybrid branching that mixes tip bifurcation and side branching. Since experimental studies have reported that branching mode switching from side branching to tip bifurcation in the lung is under genetic control, our simulation results suggest that genes control the switch of the branching mode by regulating the Turing wavelength. Our results provide a novel insight into and understanding of the formation of branching patterns in the lung and other biological systems.

Photosynthetic limitation and mechanisms of photoprotection under drought and recovery of Calotropis procera, an evergreen C3 from arid regions.

Science.gov (United States)

Rivas, Rebeca; Frosi, Gabriella; Ramos, Diego G; Pereira, Silvia; Benko-Iseppon, Ana M; Santos, Mauro G

2017-09-01

Calotropis procera is a C 3 plant native from arid environmental zones. It is an evergreen, shrubby, non-woody plant with intense photosynthetic metabolism during the dry season. We measured photosynthetic parameters and leaf biochemical traits, such as gas exchange, photochemical parameters, A/C i analysis, organic solutes, and antioxidant enzymes under controlled conditions in potted plants during drought stress, and following recovery conditions to obtain a better insight in the drought stress responses of C. procera. Indeed, different processes contribute to the drought stress resilience of C. procera and to the fast recovery after rehydration. The parameters analyzed showed that C. procera has a high efficiency for energy dissipation. The photosynthetic machinery is protected by a robust antioxidant system and photoprotective mechanisms such as alternative pathways for electrons (photorespiration and day respiration). Under severe drought stress, increased stomatal limitation and decreased biochemical limitation permitted C. procera to maintain maximum rate of Rubisco carboxylation (V c,max ) and photosynthetic rate (A max ). On the other hand, limitation of stomatal or mesophyll CO 2 diffusion did not impair fast recovery, maintaining V c,max , chloroplast CO 2 concentration (C c ) and mesophyll conductance (g m ) unchanged while electron flow used for RuBP carboxylation (J c ) and A max increased. The ability to tolerate drought stress and the fast recovery of this evergreen C 3 species was also due to leaf anti-oxidative stress enzyme activity, and photosynthetic pigments. Thus, these different drought tolerance mechanisms allowed high performance of photosynthetic metabolism by drought stressed plants during the re-watering period. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Mechanical and Metabolic Responses to Traditional and Cluster Set Configurations in the Bench Press Exercise.

Science.gov (United States)

García-Ramos, Amador; González-Hernández, Jorge M; Baños-Pelegrín, Ezequiel; Castaño-Zambudio, Adrián; Capelo-Ramírez, Fernando; Boullosa, Daniel; Haff, Guy G; Jiménez-Reyes, Pedro

2017-10-20

García-Ramos, A, González-Hernández, JM, Baños-Pelegrín, E, Castaño-Zambudio, A, Capelo-Ramírez, F, Boullosa, D, Haff, GG, and Jiménez-Reyes, P. Mechanical and metabolic responses to traditional and cluster set configurations in the bench press exercise. J Strength Cond Res XX(X): 000-000, 2017-This study aimed to compare mechanical and metabolic responses between traditional (TR) and cluster (CL) set configurations in the bench press exercise. In a counterbalanced randomized order, 10 men were tested with the following protocols (sets × repetitions [inter-repetition rest]): TR1: 3 × 10 (0-second), TR2: 6 × 5 (0-second), CL5: 3 × 10 (5-second), CL10: 3 × 10 (10-second), and CL15: 3 × 10 (15-second). The number of repetitions (30), interset rest (5 minutes), and resistance applied (10 repetition maximum) were the same for all set configurations. Movement velocity and blood lactate concentration were used to assess the mechanical and metabolic responses, respectively. The comparison of the first and last set of the training session revealed a significant decrease in movement velocity for TR1 (Effect size [ES]: -0.92), CL10 (ES: -0.85), and CL15 (ES: -1.08) (but not for TR2 [ES: -0.38] and CL5 [ES: -0.37]); while blood lactate concentration was significantly increased for TR1 (ES: 1.11), TR2 (ES: 0.90), and CL5 (ES: 1.12) (but not for CL10 [ES: 0.03] and CL15 [ES: -0.43]). Based on velocity loss, set configurations were ranked as follows: TR1 (-39.3 ± 7.3%) > CL5 (-20.2 ± 14.7%) > CL10 (-12.9 ± 4.9%), TR2 (-10.3 ± 5.3%), and CL15 (-10.0 ± 2.3%). The set configurations were ranked as follows based on the lactate concentration: TR1 (7.9 ± 1.1 mmol·L) > CL5 (5.8 ± 0.9 mmol·L) > TR2 (4.2 ± 0.7 mmol·L) > CL10 (3.5 ± 0.4 mmol·L) and CL15 (3.4 ± 0.7 mmol·L). These results support the use of TR2, CL10, and CL15 for the maintenance of high mechanical outputs, while CL10 and CL15 produce less metabolic stress than TR2.

Enhancement of radiation effect using beta-lapachone and underlying mechanism

International Nuclear Information System (INIS)

Ahn, Ki Jung; Lee, Hyung Sik; Bai, Se Kyung; Song, Chang Won

2013-01-01

Beta-lapachone (β-Lap; 3,4-dihydro-2, 2-dimethyl-2H-naphthol[1, 2-b]pyran-5,6-dione) is a novel anti-cancer drug under phase I/II clinical trials. (β-Lap has been demonstrated to cause apoptotic and necrotic death in a variety of human cancer cells in vitro and in vivo. The mechanisms underlying the (β-Lap toxicity against cancer cells has been controversial. The most recent view is that (β-Lap, which is a quinone compound, undergoes two-electron reduction to hydroquinone form utilizing NAD(P)H or NADH as electron source. This two-electron reduction of (β-Lap is mediated by NAD(P)H:quinone oxidoreductase (NQO1), which is known to mediate the reduction of many quinone compounds. The hydroquinone forms of (β-Lap then spontaneously oxidizes back to the original oxidized (β-Lap, creating futile cycling between the oxidized and reduced forms of (β-Lap. It is proposed that the futile recycling between oxidized and reduced forms of (β-Lap leads to two distinct cell death pathways. First one is that the two-electron reduced (β-Lap is converted first to one-electron reduced (β-Lap, i.e., semiquinone (β-Lap (SQ)- causing production of reactive oxygen species (ROS), which then causes apoptotic cell death. The second mechanism is that severe depletion of NAD(P)H and NADH as a result of futile cycling between the quinone and hydroquinone forms of β- p causes severe disturbance in cellular metabolism leading to apoptosis and necrosis. The relative importance of the aforementioned two mechanisms, i.e., generation of ROS or depletion of NAD(P)H/NADH, may vary depending on cell type and environment. Importantly, the NQO1 level in cancer cells has been found to be higher than that in normal cells indicating that β-Lap may be preferentially toxic to cancer cells relative to non-cancer cells. The cellular level of NQO1 has been found to be significantly increased by divergent physical and chemical stresses including ionizing radiation. Recent reports clearly demonstrated

The metabolic syndrome in hypertension: European society of hypertension position statement

DEFF Research Database (Denmark)

Redon, J.; Cifkova, R.; Laurent, S.

2008-01-01

patients have to develop type 2 diabetes or hypertension. Treatment consists in the opposition to the underlying mechanisms of the metabolic syndrome, adopting lifestyle interventions that effectively reduce visceral obesity with or without the use of drugs that oppose the development of insulin resistance...

Effects and mechanisms of caffeine to improve immunological and metabolic abnormalities in diet-induced obese rats.

Science.gov (United States)

Liu, Chih-Wei; Tsai, Hung-Cheng; Huang, Chia-Chang; Tsai, Chang-Youh; Su, Yen-Bo; Lin, Ming-Wei; Lee, Kuei-Chuan; Hsieh, Yun-Cheng; Li, Tzu-Hao; Huang, Shiang-Fen; Yang, Ying-Ying; Hou, Ming-Chih; Lin, Han-Chieh; Lee, Fa-Yauh; Lee, Shou-Dong

2018-05-01

In obesity, there are no effective therapies for parallel immune and metabolic abnormalities, including systemic/tissue insulin-resistance/inflammation, adiposity and hepatic steatosis. Caffeine has anti-inflammation, antihepatic steatosis, and anti-insulin resistance effects. In this study, we evaluated the effects and molecular mechanisms of 6 wk of caffeine treatment (HFD-caf) on immunological and metabolic abnormalities of high-fat diet (HFD)-induced obese rats. Compared with HFD vehicle (HFD-V) rats, in HFD-caf rats the suppressed circulating immune cell inflammatory [TNFα, MCP-1, IL-6, intercellular adhesion molecule 1 (ICAM-1), and nitrite] profiles were accompanied by decreased liver, white adipose tissue (WAT), and muscle macrophages and their intracellular cytokine levels. Metabolically, the increase in metabolic rates reduced lipid accumulation in various tissues, resulting in reduced adiposity, lower fat mass, decreased body weight, amelioration of hepatic steatosis, and improved systemic/muscle insulin resistance. Further mechanistic approaches revealed an upregulation of tissue lipogenic [(SREBP1c, fatty acid synthase, acetyl-CoA carboxylase)/insulin-sensitizing (GLUT4 and p-IRS1)] markers in HFD-caf rats. Significantly, ex vivo experiments revealed that the cytokine release by the cocultured peripheral blood mononuclear cell (monocyte) and WAT (adipocyte), which are known to stimulate macrophage migration and hepatocyte lipogenesis, were lower in HFD-V groups than HFD-caf groups. Caffeine treatment simultaneously ameliorates immune and metabolic pathogenic signals present in tissue to normalize immunolgical and metabolic abnormalities found in HFD-induced obese rats.

The Arachidonic Acid Metabolome Serves as a Conserved Regulator of Cholesterol Metabolism

NARCIS (Netherlands)

Demetz, Egon; Schroll, Andrea; Auer, Kristina; Heim, Christiane; Patsch, Josef R.; Eller, Philipp; Theurl, Markus; Theurl, Igor; Theurl, Milan; Seifert, Markus; Lener, Daniela; Stanzl, Ursula; Haschka, David; Asshoff, Malte; Dichtl, Stefanie; Nairz, Manfred; Huber, Eva; Stadlinger, Martin; Moschen, Alexander R.; Li, Xiaorong; Pallweber, Petra; Scharnagl, Hubert; Stojakovic, Tatjana; Maerz, Winfried; Kleber, Marcus E.; Garlaschelli, Katia; Uboldi, Patrizia; Catapano, Alberico L.; Stellaard, Frans; Rudling, Mats; Kuba, Keiji; Imai, Yumiko; Arita, Makoto; Schuetz, John D.; Pramstaller, Peter P.; Tietge, Uwe J. F.; Trauner, Michael; Norata, Giuseppe D.; Claudel, Thierry; Hicks, Andrew A.; Weiss, Guenter; Tancevski, Ivan

2014-01-01

Cholesterol metabolism is closely interrelated with cardiovascular disease in humans. Dietary supplementation with omega-6 polyunsaturated fatty acids including arachidonic acid (AA) was shown to favorably affect plasma LDL-C and HDL-C. However, the underlying mechanisms are poorly understood. By

Targeting Adipose Tissue Lipid Metabolism to Improve Glucose Metabolism in Cardiometabolic Disease

Directory of Open Access Journals (Sweden)

Johan W.E. Jocken

2014-10-01

Full Text Available With Type 2 diabetes mellitus and cardiovascular disease prevalence on the rise, there is a growing need for improved strategies to prevent or treat obesity and insulin resistance, both of which are major risk factors for these chronic diseases. Impairments in adipose tissue lipid metabolism seem to play a critical role in these disorders. In the classical picture of intracellular lipid breakdown, cytosolic lipolysis was proposed as the sole mechanism for triacylglycerol hydrolysis in adipocytes. Recent evidence suggests involvement of several hormones, membrane receptors, and intracellular signalling cascades, which has added complexity to the regulation of cytosolic lipolysis. Interestingly, a specific form of autophagy, called lipophagy, has been implicated as alternative lipolytic pathway. Defective regulation of cytosolic lipolysis and lipophagy might have substantial effects on lipid metabolism, thereby contributing to adipose tissue dysfunction, insulin resistance, and related cardiometabolic (cMet diseases. This review will discuss recent advances in our understanding of classical lipolysis and lipophagy in adipocyte lipid metabolism under normal and pathological conditions. Furthermore, the question of whether modulation of adipocyte lipolysis and lipophagy might be a potential therapeutic target to combat cMet disorders will be addressed.

Biological mechanisms discriminating growth rate and adult body weight phenotypes in two Chinese indigenous chicken breeds.

Science.gov (United States)

Dou, Tengfei; Zhao, Sumei; Rong, Hua; Gu, Dahai; Li, Qihua; Huang, Ying; Xu, Zhiqiang; Chu, Xiaohui; Tao, Linli; Liu, Lixian; Ge, Changrong; Te Pas, Marinus F W; Jia, Junjing

2017-06-20

Intensive selection has resulted in increased growth rates and muscularity in broiler chickens, in addition to adverse effects, including delayed organ development, sudden death syndrome, and altered metabolic rates. The biological mechanisms underlying selection responses remain largely unknown. Non-artificially-selected indigenous Chinese chicken breeds display a wide variety of phenotypes, including differential growth rate, body weight, and muscularity. The Wuding chicken breed is a fast growing large chicken breed, and the Daweishan mini chicken breed is a slow growing small chicken breed. Together they form an ideal model system to study the biological mechanisms underlying broiler chicken selection responses in a natural system. The objective of this study was to study the biological mechanisms underlying differential phenotypes between the two breeds in muscle and liver tissues, and relate these to the growth rate and body development phenotypes of the two breeds. The muscle tissue in the Wuding breed showed higher expression of muscle development genes than muscle tissue in the Daweishan chicken breed. This expression was accompanied by higher expression of acute inflammatory response genes in Wuding chicken than in Daweishan chicken. The muscle tissue of the Daweishan mini chicken breed showed higher expression of genes involved in several metabolic mechanisms including endoplasmic reticulum, protein and lipid metabolism, energy metabolism, as well as specific immune traits than in the Wuding chicken. The liver tissue showed fewer differences between the two breeds. Genes displaying higher expression in the Wuding breed than in the Daweishan breed were not associated with a specific gene network or biological mechanism. Genes highly expressed in the Daweishan mini chicken breed compared to the Wuding breed were enriched for protein metabolism, ABC receptors, signal transduction, and IL6-related mechanisms. We conclude that faster growth rates and larger

Mechanisms of vitamin K transport and metabolism in Swiss 3T3 mouse fibroblasts

International Nuclear Information System (INIS)

Canfield, L.M.; Townsend, A.F.; Hibbs, D.B.

1986-01-01

Transport of vitamin K into isolated fibroblasts was followed using 3 H vitamin K 1 . The initial rate is saturable by 5 min. at 25μM vitamin K with a Km(app) of 10μM and V/sub max/ of 50 pmols/min/10 6 cells. Kinetics of uptake are biphasic with a second slower rate ensuing after 10 minutes. Insensitivity of the initial rate of uptake to FCCP or ouabain indicates an ATP-independent transport mechanism. Specificity of transport is shown by competition of uptake of 3 H vitamin K by unlabelled vitamin and strong (>90%) inhibition of the initial rate by equimolar concentrations of the vitamin K analog, Chloro-K. In addition, following uptake, both vitamins K 1 and K 2 are metabolized to their respective epoxides. Vitamin K 1 epoxide is also transported into fibroblasts and metabolized to the parent quinone in a Warfarin-sensitive reaction. Following alkaline hydrolysis of isolated intracellular protein, the vitamin K-dependent amino acid, gamma carboxyglutamic acid (gla) was detected. It is concluded that vitamin K is specifically transported into fibroblasts and metabolized via the classical pathway described in liver with the concomitant production of vitamin K-dependent proteins

[Research advance in nitrogen metabolism of plant and its environmental regulation].

Science.gov (United States)

Xu, Zhenzhu; Zhou, Guangsheng

2004-03-01

Nitrogen metabolism is not only one of the basic processes of plant physiology, but also one of the important parts of global chemical cycle. Plant nitrogen assimilation directly takes part in the synthesis and conversion of amino acid through the reduction of nitrate. During this stage, some key enzymes, e.g., nitrate reductase (NR), glutamine synthetase (GS), glutamate dehydrogenase (GDH), glutamine synthase (GOGAT), aspargine synthetase (AS), and asparate aminotransferase (AspAT) participate these processes. The protein is assimilated in plant cell through amino acid, and becomes a part of plant organism through modifying, classifying, transporting and storing processes, etc. The nitrogen metabolism is associated with carbonic metabolism through key enzyme regulations and the conversion of products, which consists of basic life process. Among these amino acids in plant cell, glutamic acid (Glu), glutamine (Gln), aspartic acid (Asp) and asparagines (Asn), etc., play a key role, which regulates their conversion each other and their contents in the plant cell through regulating formation and activity of those key enzymes. Environmental factors also affect the conversion and recycle of the key amino acids through regulating gene expression of the key enzymes and their activities. Nitrate and light intensity positively regulate the gene transcription of NR, but ammonium ions and Glu, Gln do the negative way. Water deficit is a very serious constraint on N2 fixation rate and soybean (Glycine max Merr.) grain yield, in which, ureide accumulation and degradation under water deficit appear to be the key issues of feedback mechanism on nitrogen fixation. Water stress decreases NR activity, but increases proteinase activity, and thus, they regulate plant nitrogen metabolism, although there are some different effects among species and cultivars. Water stress also decreases plant tissue protein content, ratio of protein and amino acid, and reduces the absorption of amino

Metabolic Syndrome and Antipsychotics: The Role of Mitochondrial Fission/Fusion Imbalance

Directory of Open Access Journals (Sweden)

Andrea del Campo

2018-04-01

Full Text Available Second-generation antipsychotics (SGAs are known to increase cardiovascular risk through several physiological mechanisms, including insulin resistance, hepatic steatosis, hyperphagia, and accelerated weight gain. There are limited prophylactic interventions to prevent these side effects of SGAs, in part because the molecular mechanisms underlying SGAs toxicity are not yet completely elucidated. In this perspective article, we introduce an innovative approach to study the metabolic side effects of antipsychotics through the alterations of the mitochondrial dynamics, which leads to an imbalance in mitochondrial fusion/fission ratio and to an inefficient mitochondrial phenotype of muscle cells. We believe that this approach may offer a valuable path to explain SGAs-induced alterations in metabolic homeostasis.

Regional cerebral glucose metabolic changes in oculopalatal myoclonus: implication for neural pathways, underlying the disorder

Energy Technology Data Exchange (ETDEWEB)

Cho, Sang Soo; Moon, So Young; Kim, Ji Soo; Kim, Sang Eun [College of Medicine, Seoul National University, Seoul (Korea, Republic of)

2004-07-01

Palatal myoclonus (PM) is characterized by rhythmic involuntary jerky movements of the soft palate of the throat. When associated with eye movements, it is called oculopalatal myoclonus (OPM). Ordinary PM is characterized by hypertrophic olivary degeneration, a trans-synaptic degeneration following loss of neuronal input to the inferior olivary nucleus due to an interruption of the Guillain-Mollaret triangle usually by a hemorrhage. However, the neural pathways underlying the disorder are uncertain. In an attempt to understand the pathologic neural pathways, we examined the metabolic correlates of this tremulous condition. Brain FDG PET scans were acquired in 8 patients with OPM (age, 49.9{+-}4.6 y: all males: 7 with pontine hemorrhage, 1 with diffuse brainstem infarction) and age-matched 50 healthy males (age, 50.7{+-} 9.0) and the regional glucose metabolism compared using SPM99. For group analysis, the hemispheres containing lesions were assigned to the right side of the brain. Patients with OPM had significant hypometabolism in the ipsilateral (to the lesion) brainstem and superior temporal and parahippocampal gyri (P < 0.05 corrected, k = 100). By contrast, there was significant hypermetabolism in the contralateral middle and inferior temporal gyri, thalamus, middle frontal gyrus and precuneus (P < 0.05 corrected, k=l00). Our data demonstrate the distinct metabolic changes between several ipsilateral and contralateral brain regions (hypometabolism vs. hypermetabolism) in patients with OPM. This may provide clues for understanding the neural pathways underlying the disorder.

Regional cerebral glucose metabolic changes in oculopalatal myoclonus: implication for neural pathways, underlying the disorder

International Nuclear Information System (INIS)

Cho, Sang Soo; Moon, So Young; Kim, Ji Soo; Kim, Sang Eun

2004-01-01

Palatal myoclonus (PM) is characterized by rhythmic involuntary jerky movements of the soft palate of the throat. When associated with eye movements, it is called oculopalatal myoclonus (OPM). Ordinary PM is characterized by hypertrophic olivary degeneration, a trans-synaptic degeneration following loss of neuronal input to the inferior olivary nucleus due to an interruption of the Guillain-Mollaret triangle usually by a hemorrhage. However, the neural pathways underlying the disorder are uncertain. In an attempt to understand the pathologic neural pathways, we examined the metabolic correlates of this tremulous condition. Brain FDG PET scans were acquired in 8 patients with OPM (age, 49.9±4.6 y: all males: 7 with pontine hemorrhage, 1 with diffuse brainstem infarction) and age-matched 50 healthy males (age, 50.7± 9.0) and the regional glucose metabolism compared using SPM99. For group analysis, the hemispheres containing lesions were assigned to the right side of the brain. Patients with OPM had significant hypometabolism in the ipsilateral (to the lesion) brainstem and superior temporal and parahippocampal gyri (P < 0.05 corrected, k = 100). By contrast, there was significant hypermetabolism in the contralateral middle and inferior temporal gyri, thalamus, middle frontal gyrus and precuneus (P < 0.05 corrected, k=l00). Our data demonstrate the distinct metabolic changes between several ipsilateral and contralateral brain regions (hypometabolism vs. hypermetabolism) in patients with OPM. This may provide clues for understanding the neural pathways underlying the disorder

Gait Dynamics and Locomotor Metabolism

Science.gov (United States)

2014-12-01

26 47. Taylor CR, Heglund NC, Maloiy GMO . Energetics and mechanics of terrestrial locomotion. I. Metabolic energy consumption as a function of...San Diego, CA: Academic Press, 1994. 110 47. Taylor CR, Heglund NC, Maloiy GMO . Energetics and mechanics of terrestrial locomotion. I. Metabolic

Metabolomic applications to decipher gut microbial metabolic influence in health and disease

Directory of Open Access Journals (Sweden)

Francois-Pierre eMartin

2012-04-01

Full Text Available Dietary preferences and nutrients composition have been shown to influence human and gut microbial metabolism, which ultimately has specific effects on health and diseases’ risk. Increasingly, results from molecular biology and microbiology demonstrate the key role of the gut microbiota metabolic interface to the overall mammalian host’s health status. There is therefore raising interest in nutrition research to characterize the molecular foundations of the gut microbial mammalian cross-talk at both physiological and biochemical pathway levels. Tackling these challenges can be achieved through systems biology approaches, such as metabolomics, to underpin the highly complex metabolic exchanges between diverse biological compartments, including organs, systemic biofluids and microbial symbionts. By the development of specific biomarkers for prediction of health and disease, metabolomics is increasingly used in clinical applications as regard to disease aetiology, diagnostic stratification and potentially mechanism of action of therapeutical and nutraceutical solutions. Surprisingly, an increasing number of metabolomics investigations in pre-clinical and clinical studies based on proton nuclear magnetic resonance (1H NMR spectroscopy and mass spectrometry (MS provided compelling evidence that system wide and organ-specific biochemical processes are under the influence of gut microbial metabolism. This review aims at describing recent applications of metabolomics in clinical fields where main objective is to discern the biochemical mechanisms under the influence of the gut microbiota, with insight into gastrointestinal health and diseases diagnostics and improvement of homeostasis metabolic regulation.

Biofilm Formation Mechanisms of Pseudomonas aeruginosa Predicted via Genome-Scale Kinetic Models of Bacterial Metabolism

Science.gov (United States)

2016-03-15

RESEARCH ARTICLE Biofilm Formation Mechanisms of Pseudomonas aeruginosa Predicted via Genome-Scale Kinetic Models of Bacterial Metabolism Francisco G...jaques.reifman.civ@mail.mil Abstract A hallmark of Pseudomonas aeruginosa is its ability to establish biofilm -based infections that are difficult to...eradicate. Biofilms are less susceptible to host inflammatory and immune responses and have higher antibiotic tolerance than free-living planktonic

Amount of fear extinction changes its underlying mechanisms.

Science.gov (United States)

An, Bobae; Kim, Jihye; Park, Kyungjoon; Lee, Sukwon; Song, Sukwoon; Choi, Sukwoo

2017-07-03

There has been a longstanding debate on whether original fear memory is inhibited or erased after extinction. One possibility that reconciles this uncertainty is that the inhibition and erasure mechanisms are engaged in different phases (early or late) of extinction. In this study, using single-session extinction training and its repetition (multiple-session extinction training), we investigated the inhibition and erasure mechanisms in the prefrontal cortex and amygdala of rats, where neural circuits underlying extinction reside. The inhibition mechanism was prevalent with single-session extinction training but faded when single-session extinction training was repeated. In contrast, the erasure mechanism became prevalent when single-session extinction training was repeated. Moreover, ablating the intercalated neurons of amygdala, which are responsible for maintaining extinction-induced inhibition, was no longer effective in multiple-session extinction training. We propose that the inhibition mechanism operates primarily in the early phase of extinction training, and the erasure mechanism takes over after that.

Metabolic Regulation of a Bacterial Cell System with Emphasis on Escherichia coli Metabolism

Science.gov (United States)

Shimizu, Kazuyuki

2013-01-01

It is quite important to understand the overall metabolic regulation mechanism of bacterial cells such as Escherichia coli from both science (such as biochemistry) and engineering (such as metabolic engineering) points of view. Here, an attempt was made to clarify the overall metabolic regulation mechanism by focusing on the roles of global regulators which detect the culture or growth condition and manipulate a set of metabolic pathways by modulating the related gene expressions. For this, it was considered how the cell responds to a variety of culture environments such as carbon (catabolite regulation), nitrogen, and phosphate limitations, as well as the effects of oxygen level, pH (acid shock), temperature (heat shock), and nutrient starvation. PMID:25937963

Sulfosys (Sulfolobus Systems Biology): towards a silicon cell model for the central carbohydrate metabolism of the archaeon Sulfolobus solfataricus under temperature variation.

NARCIS (Netherlands)

Albers, S.V.; Birkeland, N.K.; Driessen, A.J.; Gertig, S.; Haferkamp, P.; Klenk, H.P.; Kouril, T.; Manica, A.; Pham, T.K.; Ruoff, P.; Schleper, C.; Schomburg, D.; Sharkey, K.J.; Siebers, B.; Sierocinski, P.; Steuer, R.; van der Oost, J.; Westerhoff, H.V.; Wieloch, P.; Wright, P.C.; Zaparty, M.

2009-01-01

SulfoSYS (Sulfolobus Systems Biology) focuses on the study of the CCM (central carbohydrate metabolism) of Sulfolobus solfataricus and its regulation under temperature variation at the systems level. In Archaea, carbohydrates are metabolized by modifications of the classical pathways known from

Overfeeding-Induced Obesity in Rats : Insulin Sensitivity and Autonomic Regulation of Metabolism

NARCIS (Netherlands)

Balkan, B; Strubbe, J.H.; Bruggink, J.E.; Steffens, A.B.

1993-01-01

The metabolic consequences of the development of obesity and the underlying mechanisms were investigated. For this purpose, male rats were overfed for 5 weeks through long-term gastric catheters. Permanent cardiac cannulas implanted before the overfeeding period allowed frequent blood sampling and

Control of a perturbed under-actuated mechanical system

KAUST Repository

Zayane, Chadia; Laleg-Kirati, Taous-Meriem; Chemori, Ahmed

2015-01-01

In this work, the trajectory tracking problem for an under-actuated mechanical system in presence of unknown input disturbances is addressed. The studied inertia wheel inverted pendulum falls in the class of non minimum phase systems. The proposed

Arctigenin preferentially induces tumor cell death under glucose deprivation by inhibiting cellular energy metabolism.

Science.gov (United States)

Gu, Yuan; Qi, Chunting; Sun, Xiaoxiao; Ma, Xiuquan; Zhang, Haohao; Hu, Lihong; Yuan, Junying; Yu, Qiang

2012-08-15

Selectively eradicating cancer cells with minimum adverse effects on normal cells is a major challenge in the development of anticancer therapy. We hypothesize that nutrient-limiting conditions frequently encountered by cancer cells in poorly vascularized solid tumors might provide an opportunity for developing selective therapy. In this study, we investigated the function and molecular mechanisms of a natural compound, arctigenin, in regulating tumor cell growth. We demonstrated that arctigenin selectively promoted glucose-starved A549 tumor cells to undergo necrosis by inhibiting mitochondrial respiration. In doing so, arctigenin elevated cellular level of reactive oxygen species (ROS) and blocked cellular energy metabolism in the glucose-starved tumor cells. We also demonstrated that cellular ROS generation was caused by intracellular ATP depletion and played an essential role in the arctigenin-induced tumor cell death under the glucose-limiting condition. Furthermore, we combined arctigenin with the glucose analogue 2-deoxyglucose (2DG) and examined their effects on tumor cell growth. Interestingly, this combination displayed preferential cell-death inducing activity against tumor cells compared to normal cells. Hence, we propose that the combination of arctigenin and 2DG may represent a promising new cancer therapy with minimal normal tissue toxicity. Crown Copyright © 2012. Published by Elsevier Inc. All rights reserved.

Exploration of mechanisms underlying the strain-rate-dependent mechanical property of single chondrocytes

Energy Technology Data Exchange (ETDEWEB)

Nguyen, Trung Dung; Gu, YuanTong, E-mail: yuantong.gu@qut.edu.au [School of Chemistry, Physics and Mechanical Engineering, Queensland University of Technology, Brisbane, Queensland (Australia)

2014-05-05

Based on the characterization by Atomic Force Microscopy, we report that the mechanical property of single chondrocytes has dependency on the strain-rates. By comparing the mechanical deformation responses and the Young's moduli of living and fixed chondrocytes at four different strain-rates, we explore the deformation mechanisms underlying this dependency property. We found that the strain-rate-dependent mechanical property of living cells is governed by both of the cellular cytoskeleton and the intracellular fluid when the fixed chondrocytes are mainly governed by their intracellular fluid, which is called the consolidation-dependent deformation behavior. Finally, we report that the porohyperelastic constitutive material model which can capture the consolidation-dependent behavior of both living and fixed chondrocytes is a potential candidature to study living cell biomechanics.

Offspring neuroimmune consequences of maternal malnutrition: Potential mechanism for behavioral impairments that underlie metabolic and neurodevelopmental disorders.

Science.gov (United States)

Smith, B L; Reyes, T M

2017-10-01

Maternal malnutrition significantly increases offspring risk for both metabolic and neurodevelopmental disorders. Animal models of maternal malnutrition have identified behavioral changes in the adult offspring related to executive function and reward processing. Together, these changes in executive and reward-based behaviors likely contribute to the etiology of both metabolic and neurodevelopmental disorders associated with maternal malnutrition. Concomitant with the behavioral effects, maternal malnutrition alters offspring expression of reward-related molecules and inflammatory signals in brain pathways that control executive function and reward. Neuroimmune pathways and microglial interactions in these specific brain circuits, either in early development or later in adulthood, could directly contribute to the maternal malnutrition-induced behavioral phenotypes. Understanding these mechanisms will help advance treatment strategies for metabolic and neurodevelopmental disorders, especially noninvasive dietary supplementation interventions. Copyright © 2017 Elsevier Inc. All rights reserved.

Predicting the Metabolic Sites by Flavin-Containing Monooxygenase on Drug Molecules Using SVM Classification on Computed Quantum Mechanics and Circular Fingerprints Molecular Descriptors.

Directory of Open Access Journals (Sweden)

Chien-Wei Fu

Full Text Available As an important enzyme in Phase I drug metabolism, the flavin-containing monooxygenase (FMO also metabolizes some xenobiotics with soft nucleophiles. The site of metabolism (SOM on a molecule is the site where the metabolic reaction is exerted by an enzyme. Accurate prediction of SOMs on drug molecules will assist the search for drug leads during the optimization process. Here, some quantum mechanics features such as the condensed Fukui function and attributes from circular fingerprints (called Molprint2D are computed and classified using the support vector machine (SVM for predicting some potential SOMs on a series of drugs that can be metabolized by FMO enzymes. The condensed Fukui function fA- representing the nucleophilicity of central atom A and the attributes from circular fingerprints accounting the influence of neighbors on the central atom. The total number of FMO substrates and non-substrates collected in the study is 85 and they are equally divided into the training and test sets with each carrying roughly the same number of potential SOMs. However, only N-oxidation and S-oxidation features were considered in the prediction since the available C-oxidation data was scarce. In the training process, the LibSVM package of WEKA package and the option of 10-fold cross validation are employed. The prediction performance on the test set evaluated by accuracy, Matthews correlation coefficient and area under ROC curve computed are 0.829, 0.659, and 0.877 respectively. This work reveals that the SVM model built can accurately predict the potential SOMs for drug molecules that are metabolizable by the FMO enzymes.

Acute fatal metabolic complications in alkaptonuria.

Science.gov (United States)

Davison, A S; Milan, A M; Gallagher, J A; Ranganath, L R

2016-03-01

Alkaptonuria (AKU) is a rare inherited metabolic disorder of tyrosine metabolism that results from a defect in an enzyme called homogentisate 1,2-dioxygenase. The result of this is that homogentisic acid (HGA) accumulates in the body. HGA is central to the pathophysiology of this disease and the consequences observed; these include spondyloarthropathy, rupture of ligaments/muscle/tendons, valvular heart disease including aortic stenosis and renal stones. While AKU is considered to be a chronic progressive disorder, it is clear from published case reports that fatal acute metabolic complications can also occur. These include oxidative haemolysis and methaemoglobinaemia. The exact mechanisms underlying the latter are not clear, but it is proposed that disordered metabolism within the red blood cell is responsible for favouring a pro-oxidant environment that leads to the life threatening complications observed. Herein the role of red blood cell in maintaining the redox state of the body is reviewed in the context of AKU. In addition previously reported therapeutic strategies are discussed, specifically with respect to why reported treatments had little therapeutic effect. The potential use of nitisinone for the management of patients suffering from the acute metabolic decompensation in AKU is proposed as an alternative strategy.

Deformation Mechanisms of Gum Metals Under Nanoindentation

Science.gov (United States)

Sankaran, Rohini Priya

defect structures to applied loading, we perform ex-situ nanoindentation. Nanoindentation is a convenient method as the plastic deformation is localized and probes a nominally defect free volume of the material. We subsequently characterize the defect structures in these alloys with both conventional TEM and advanced techniques such as HAADF HRSTEM and nanoprobe diffraction. These advanced techniques allow for a more thorough understanding of the observed deformation features. The main findings from this investigation are as follows. As expected we observe that a non-equilibrium phase, o, is present in the leaner beta-stabilized alloy, ST Ref-1. We do not find any direct evidence of secondary phases in STGM, and we find the beta phase in CWGM, along with lath microstructure with subgrain structure consisting of dislocation cell networks. Upon nanoindentation, we find twinning accompanied by beta nucleation on the twin boundary in ST Ref-1 samples. This result is consistent with previous findings and is reasonable considering the alloy is unstable with respect to beta transformation. We find deformation nanotwinning in cold worked gum metals under nanoindentation, which is initially surprising. We argue that when viewed as a nanocrystalline material, such a deformation mechanism is consistent with previous work, and furthermore, a deformation nanotwinned structure does not preclude an ideal shear mechanism from operating in the alloy. Lastly, we observe continuous lattice rotations in STGM under nanoindentation via nanoprobe diffraction. With this technique, for the first time we can demonstrate that the lattice rotations are truly continuous at the nanoscale. We can quantify this lattice rotation, and find that even though the rotation is large, it may be mediated by a reasonable geometrically necessary dislocation density, and note that similar rotations are typically observed in other materials under nanoindentation. HRSTEM and conventional TEM data confirm the

Targeting energy metabolism in brain cancer with calorically restricted ketogenic diets.

Science.gov (United States)

Seyfried, Thomas N; Kiebish, Michael; Mukherjee, Purna; Marsh, Jeremy

2008-11-01

Information is presented on the calorically restricted ketogenic diet (CRKD) as an alternative therapy for brain cancer. In contrast to normal neurons and glia, which evolved to metabolize ketone bodies as an alternative fuel to glucose under energy-restricted conditions, brain tumor cells are largely glycolytic due to mitochondrial defects and have a reduced ability to metabolize ketone bodies. The CRKD is effective in managing brain tumor growth in animal models and in patients, and appears to act through antiangiogenic, anti-inflammatory, and proapoptotic mechanisms.

Proteomics approach reveals mechanism underlying susceptibility of loquat fruit to sunburn during color changing period.

Science.gov (United States)

Jiang, Ji-Mou; Lin, Yong-Xiang; Chen, Yi-Yong; Deng, Chao-Jun; Gong, Hui-Wen; Xu, Qi-Zhi; Zheng, Shao-Quan; Chen, Wei

2015-06-01

The objective of this work was to investigate why loquat fruit peels are more sensitive to high temperature and strong sunlight, making them highly susceptible to sunburn, during the color changing period (CCP). Two dimensional gel electrophoresis (2-DE) of the fruit peel proteins was performed over three developmental periods, namely green fruit period (GFP), color changing period and yellow ripening period (YRP). Fifty-five protein spots with at least 2-fold differences in abundance were successfully identified by MALDI-TOF-TOF/MS. The identified proteins were divided into categories related to heat-shock response, stress response and defense, energy metabolism, photosynthesis and protein biosynthesis. The results showed that expression of proteins related to anaerobic respiration and photorespiration were increased while the proteins related to ROS scavenging, polyamine biosynthesis, defense pathogens and photosynthesis were decreased during CCP under heat stress. Our findings provide new insights into the molecular mechanism of loquat fruit susceptible to sunburn during CCP. Copyright © 2014 Elsevier Ltd. All rights reserved.

Flux Balance Analysis of Escherichia coli under Temperature and pH Stress Conditions

KAUST Repository

Xu, Xiaopeng

2015-05-12

An interesting discovery in biology is that most genes in an organism are dispensable. That means these genes have minor effects on survival of the organism in standard laboratory conditions. One explanation of this discovery is that some genes play important roles in specific conditions and are essential genes under those conditions. E. coli is a model organism, which is widely used. It can adapt to many stress conditions, including temperature, pH, osmotic, antibiotic, etc. Underlying mechanisms and associated genes of each stress condition responses are usually different. In our analysis, we combined protein abundance data and mutant conditional fitness data into E. coli constraint-based metabolic models to study conditionally essential metabolic genes under temperature and pH stress conditions. Flux Balance Analysis was employed as the modeling method to analysis these data. We discovered lists of metabolic genes, which are E. coli dispensable genes, but conditionally essential under some stress conditions. Among these conditionally essential genes, atpA in low pH stress and nhaA in high pH stress found experimental evidences from previous studies. Our study provides new conditionally essential gene candidates for biologists to explore stress condition mechanisms.

Sleep and metabolic function.

Science.gov (United States)

Morselli, Lisa L; Guyon, Aurore; Spiegel, Karine

2012-01-01

Evidence for the role of sleep on metabolic and endocrine function has been reported more than four decades ago. In the past 30 years, the prevalence of obesity and diabetes has greatly increased in industrialized countries, and self-imposed sleep curtailment, now very common, is starting to be recognized as a contributing factor, alongside with increased caloric intake and decreased physical activity. Furthermore, obstructive sleep apnea, a chronic condition characterized by recurrent upper airway obstruction leading to intermittent hypoxemia and sleep fragmentation, has also become highly prevalent as a consequence of the epidemic of obesity and has been shown to contribute, in a vicious circle, to the metabolic disturbances observed in obese patients. In this article, we summarize the current data supporting the role of sleep in the regulation of glucose homeostasis and the hormones involved in the regulation of appetite. We also review the results of the epidemiologic and laboratory studies that investigated the impact of sleep duration and quality on the risk of developing diabetes and obesity, as well as the mechanisms underlying this increased risk. Finally, we discuss how obstructive sleep apnea affects glucose metabolism and the beneficial impact of its treatment, the continuous positive airway pressure. In conclusion, the data available in the literature highlight the importance of getting enough good sleep for metabolic health.

Title: Potassium application regulates nitrogen metabolism and osmotic adjustment in cotton (Gossypium hirsutum L.) functional leaf under drought stress.

Science.gov (United States)

Zahoor, Rizwan; Zhao, Wenqing; Abid, Muhammad; Dong, Haoran; Zhou, Zhiguo

2017-08-01

To evaluate the role of potassium (K) in maintaining nitrogen metabolism and osmotic adjustment development of cotton functional leaves to sustain growth under soil drought and rewatering conditions, the plants of two cotton cultivars Siza 3 (low-K sensitive) and Simian 3 (low-K tolerant), were grown under three different K rates (K0, K1, and K2; 0, 150, and 300kgK 2 Oha -1 , respectively) and exposed to drought stress with 40±5% soil relative water content (SRWC). The drought stress was applied at flowering stage by withholding water for eight days followed by rewatering to a well-watered level (75±5% SRWC). The results showed that drought-stressed plants of both cultivars showed a decrease in leaf relative water content (RWC) and osmotic potential in the functional leaves and developed osmotic adjustment with an increase in the contents of free amino acids, soluble sugars, inorganic K, and nitrate as compared to well-watered plants. In drought-stressed plants, nitrogen-metabolizing enzyme activities of nitrogen reductase (NR), glutamine synthetase (GS), and glutamate synthase (GOGAT) were diminished significantly (P≤0.05) along with decreased chlorophyll content and soluble proteins. However, drought-stressed plants under K application not only exhibited higher osmotic adjustment with greater accumulation of osmolytes but also regulated nitrogen metabolism by maintaining higher enzyme activities, soluble proteins, and chlorophyll content in functional leaves as compared to the plants without K application. Siza 3 showed better stability in enzyme activities and resulted in 89% higher seed cotton yield under K2 as compared to K0 in drought-stressed plants, whereas this increase was 53% in the case of Simian 3. The results of the study suggested that K application enhances cotton plants' potential for sustaining high nitrogen-metabolizing enzyme activities and related components to supplement osmotic adjustment under soil drought conditions. Copyright © 2017

Individuals with Metabolically Healthy Overweight/Obesity Have Higher Fat Utilization than Metabolically Unhealthy Individuals

Directory of Open Access Journals (Sweden)

Arturo Pujia

2016-01-01

Full Text Available The mechanisms underlying the change in phenotype from metabolically healthy to metabolically unhealthy obesity are still unclear. The aim of this study is to investigate whether a difference in fasting fat utilization exists between overweight/obese individuals with a favorable cardiovascular risk profile and those with Metabolic Syndrome and Type 2 diabetes. Furthermore, we sought to explore whether there is an association between fasting fat utilization and insulin resistance. In this cross-sectional study, 172 overweight/obese individuals underwent a nutritional assessment. Those with fasting glucose ≥126 mg/dL or antidiabetic treatment were considered to be diabetics. If at least three of the NCEP criteria were present, they had Metabolic Syndrome, while those with less criteria were considered to be healthy overweight/obese. An indirect calorimetry was performed to estimate Respiratory Quotient, an index of nutrient utilization. A lower Respiratory Quotient (i.e., higher fat utilization was found in healthy overweight/obese individuals than in those with Metabolic Syndrome and Type 2 diabetes (0.85 ± 0.05; 0.87 ± 0.06; 0.88 ± 0.05 respectively, p = 0.04. The univariate and multivariable analysis showed a positive association between the Respiratory Quotient and HOMA-IR (slope in statistic (B = 0.004; β = 0.42; p = 0.005; 95% Confidence interval = 0.001–0.006. In this study, we find, for the first time, that the fasting Respiratory Quotient is significantly lower (fat utilization is higher in individuals who are metabolically healthy overweight/obese than in those with metabolically unhealthy obesity. In addition, we demonstrated the association between fat utilization and HOMA-IR, an insulin resistance index.

Cell-Nonautonomous Mechanisms Underlying Cellular and Organismal Aging.

Science.gov (United States)

Medkour, Younes; Svistkova, Veronika; Titorenko, Vladimir I

2016-01-01

Cell-autonomous mechanisms underlying cellular and organismal aging in evolutionarily distant eukaryotes have been established; these mechanisms regulate longevity-defining processes within a single eukaryotic cell. Recent findings have provided valuable insight into cell-nonautonomous mechanisms modulating cellular and organismal aging in eukaryotes across phyla; these mechanisms involve a transmission of various longevity factors between different cells, tissues, and organisms. Herein, we review such cell-nonautonomous mechanisms of aging in eukaryotes. We discuss the following: (1) how low molecular weight transmissible longevity factors modulate aging and define longevity of cells in yeast populations cultured in liquid media or on solid surfaces, (2) how communications between proteostasis stress networks operating in neurons and nonneuronal somatic tissues define longevity of the nematode Caenorhabditis elegans by modulating the rates of aging in different tissues, and (3) how different bacterial species colonizing the gut lumen of C. elegans define nematode longevity by modulating the rate of organismal aging. Copyright © 2016. Published by Elsevier Inc.

Crack assessment of pipe under combined thermal and mechanical load

International Nuclear Information System (INIS)

Song, Tae Kwang; Kim, Yun Jae

2009-01-01

In this paper, J-integral and transient C(t)-integral, which were key parameters in low temperature and high temperature fracture mechanics, under combined thermal and mechanical load were estimated via 3-dimensional finite element analyses. Various type of thermal and mechanical load, material hardening were considered to decrease conservatism in existing solutions. As a results, V-factor and redistribution time for combined thermal and mechanical load were proposed to calculate J-integral and C(t)-integral, respectively.

Predicting growth of the healthy infant using a genome scale metabolic model.

Science.gov (United States)

Nilsson, Avlant; Mardinoglu, Adil; Nielsen, Jens

2017-01-01

An estimated 165 million children globally have stunted growth, and extensive growth data are available. Genome scale metabolic models allow the simulation of molecular flux over each metabolic enzyme, and are well adapted to analyze biological systems. We used a human genome scale metabolic model to simulate the mechanisms of growth and integrate data about breast-milk intake and composition with the infant's biomass and energy expenditure of major organs. The model predicted daily metabolic fluxes from birth to age 6 months, and accurately reproduced standard growth curves and changes in body composition. The model corroborates the finding that essential amino and fatty acids do not limit growth, but that energy is the main growth limiting factor. Disruptions to the supply and demand of energy markedly affected the predicted growth, indicating that elevated energy expenditure may be detrimental. The model was used to simulate the metabolic effect of mineral deficiencies, and showed the greatest growth reduction for deficiencies in copper, iron, and magnesium ions which affect energy production through oxidative phosphorylation. The model and simulation method were integrated to a platform and shared with the research community. The growth model constitutes another step towards the complete representation of human metabolism, and may further help improve the understanding of the mechanisms underlying stunting.

Olfaction Under Metabolic Influences

Science.gov (United States)

2012-01-01

Recently published work and emerging research efforts have suggested that the olfactory system is intimately linked with the endocrine systems that regulate or modify energy balance. Although much attention has been focused on the parallels between taste transduction and neuroendocrine controls of digestion due to the novel discovery of taste receptors and molecular components shared by the tongue and gut, the equivalent body of knowledge that has accumulated for the olfactory system, has largely been overlooked. During regular cycles of food intake or disorders of endocrine function, olfaction is modulated in response to changing levels of various molecules, such as ghrelin, orexins, neuropeptide Y, insulin, leptin, and cholecystokinin. In view of the worldwide health concern regarding the rising incidence of diabetes, obesity, and related metabolic disorders, we present a comprehensive review that addresses the current knowledge of hormonal modulation of olfactory perception and how disruption of hormonal signaling in the olfactory system can affect energy homeostasis. PMID:22832483

Transcriptome and metabolome responses of Shewanella oneidensis MR-1 to methyl orange under microaerophilic and aerobic conditions.

Science.gov (United States)

Cao, Xinhua; Qi, Yueling; Xu, Chen; Yang, Yuyi; Wang, Jun

2017-04-01

Shewanella oneidensis MR-1 degrades various azo dyes under microaerophilic and anaerobic conditions, but this process is inhibited under aerobic conditions. The mechanisms underlying azo dye biodegradation and inhibition remain unknown. Therefore, we investigated metabolic and transcriptional changes in strain MR-1, which was cultured under different conditions, to elucidate these mechanisms. At the transcriptional level, genes involved in certain metabolic processes, particularly the tricarboxylic acid (TCA) cycle, amino acid biodegradation, and the electron transfer system, were significantly altered (M ≧ 2, p > 0.8 ) in the presence of methyl orange (MO). Moreover, a high concentration of dissolved oxygen heavily impacted the expression levels of genes involved in fatty acid biodegradation. Metabolome analysis revealed significant alteration (p < 0.05) in the concentrations of nine metabolites when strain MR-1 was cultured under aerobic conditions; the majority of these metabolites were closely associated with amino acid metabolism and DNA replication. Accordingly, we propose a possible pathway for MO biodegradation and discuss the most likely causes of biodegradation inhibition due to dissolved oxygen.

Integrative Analysis of Metabolic Models – from Structure to Dynamics

Energy Technology Data Exchange (ETDEWEB)

Hartmann, Anja, E-mail: hartmann@ipk-gatersleben.de [Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben (Germany); Schreiber, Falk [Monash University, Melbourne, VIC (Australia); Martin-Luther-University Halle-Wittenberg, Halle (Germany)

2015-01-26

The characterization of biological systems with respect to their behavior and functionality based on versatile biochemical interactions is a major challenge. To understand these complex mechanisms at systems level modeling approaches are investigated. Different modeling formalisms allow metabolic models to be analyzed depending on the question to be solved, the biochemical knowledge and the availability of experimental data. Here, we describe a method for an integrative analysis of the structure and dynamics represented by qualitative and quantitative metabolic models. Using various formalisms, the metabolic model is analyzed from different perspectives. Determined structural and dynamic properties are visualized in the context of the metabolic model. Interaction techniques allow the exploration and visual analysis thereby leading to a broader understanding of the behavior and functionality of the underlying biological system. The System Biology Metabolic Model Framework (SBM{sup 2} – Framework) implements the developed method and, as an example, is applied for the integrative analysis of the crop plant potato.

Ketogenic diet and astrocyte/neuron metabolic interactions

OpenAIRE

Vamecq Joseph; Maurois Pierre; Bac Pierre; Delplanque Bernadette; Pages Nicole

2007-01-01

The ketogenic diet is an anticonvulsant diet enriched in fat. It provides the body with a minimal protein requirement and a restricted carbohydrate supply, the vast majority of calories (more than 80-90%) being given by fat. Though anticonvulsant activity of ketogenic diet has been well documented by a large number of experimental and clinical studies, underlying mechanisms still remain partially unclear. Astrocyte-neuron interactions, among which metabolic shuttles, may influence synaptic ac...

Skeletal muscle action of estrogen receptor α is critical for the maintenance of mitochondrial function and metabolic homeostasis in females

DEFF Research Database (Denmark)

Ribas, Vicent; Drew, Brian G; Zhou, Zhenqi

2016-01-01

Impaired estrogen receptor α (ERα) action promotes obesity and metabolic dysfunction in humans and mice; however, the mechanisms underlying these phenotypes remain unknown. Considering that skeletal muscle is a primary tissue responsible for glucose disposal and oxidative metabolism, we establish...... of dysfunctional mitochondria in MERKO muscle and implicate ERα in the preservation of mitochondrial health and insulin sensitivity as a defense against metabolic disease in women....

SulfoSYS (Sulfolobus Systems Biology) : towards a silicon cell model for the central carbohydrate metabolism of the archaeon Sulfolobus solfataricus under temperature variation

NARCIS (Netherlands)

Albers, Sonja-Verena; Birkeland, Nils-Kare; Driessen, Arnold J. M.; Gertig, Susanne; Haferkamp, Patrick; Klenk, Hans-Peter; Kouril, Theresa; Manica, Andrea; Pham, Trong K.; Ruoff, Peter; Schleper, Christa; Schomburg, Dietmar; Sharkey, Kieran J.; Siebers, Bettina; Sierocinski, Pawel; Steuer, Ralf; van der Oost, John; Westerhoff, Hans V.; Wieloch, Patricia; Wright, Phillip C.; Zaparty, Melanie; Birkeland, Nils-Kåre

SulfoSYS (Sulfolobus Systems Biology) focuses on the study of the CCM (central carbohydrate metabolism) of Sulfolobus solfataricus and its regulation under temperature variation at the systems level. in Archaea, carbohydrates are metabolized by modifications of the classical pathways known from

SulfoSYS (Sulfolobus Systems Biology): towards a silicon cell model for the central carbohydrate metabolism of the archaeon Sulfolobus solfataricus under temperature variation

NARCIS (Netherlands)

Albers, S.V.; Birkeland, N.K.; Driessen, A.J.M.; Gertig, S.; Haferkamp, P.; Klenk, H.P.; Kouril, T.; Manica, A.; Pham, T.K.; Ruoff, P.; Schleper, C.; Schomburg, D.; Sharkey, K.; Siebers, B.; Sierocinski, P.; Steur, R.; Oost, van der J.; Westerhoff, H.V.; Wieloch, P.; Wright, P.C.; Zaparty, M.

2009-01-01

SulfoSYS (Sulfolobus Systems Biology) focuses on the study of the CCM (central carbohydrate metabolism) of Sulfolobus solfataricus and its regulation under temperature variation at the systems level. In Archaea, carbohydrates are metabolized by modifications of the classical pathways known from

Maternal health issues and cardio-metabolic outcomes in the offspring: a focus on Indigenous populations.

Science.gov (United States)

Wicklow, Brandy A; Sellers, Elizabeth A C

2015-01-01

Non-communicable diseases (NCDs) including diabetes, obesity and cardiovascular disease are the leading causes of death worldwide. Indigenous populations are disproportionally affected. In an effort to halt the increasing disease burden, the mechanisms underlying the increasing rate of NCDs are an important area of study. Recent evidence has focused on the perinatal period as an influential period impacting the future cardio-metabolic health of the offspring. This concept has been defined as metabolic foetal programming and supports the importance of the developmental origins of health and disease in research and clinical practice, specifically in prevention efforts to protect future generations from NCDs. An understanding of the underlying mechanisms involved is not clear as of yet. However, an understanding of these mechanisms is imperative in order to plan effective intervention strategies. As much of the discussion below is gleaned from large epidemiological studies and animal studies, further research with prospective cohorts is necessary. Copyright © 2014. Published by Elsevier Ltd.

Metabolic Model-Based Integration of Microbiome Taxonomic and Metabolomic Profiles Elucidates Mechanistic Links between Ecological and Metabolic Variation

Energy Technology Data Exchange (ETDEWEB)

Noecker, Cecilia; Eng, Alexander; Srinivasan, Sujatha; Theriot, Casey M.; Young, Vincent B.; Jansson, Janet K.; Fredricks, David N.; Borenstein, Elhanan; Sanchez, Laura M.

2015-12-22

health and disease.

IMPORTANCEStudies characterizing both the taxonomic composition and metabolic profile of various microbial communities are becoming increasingly common, yet new computational methods are needed to integrate and interpret these data in terms of known biological mechanisms. Here, we introduce an analytical framework to link species composition and metabolite measurements, using a simple model to predict the effects of community ecology on metabolite concentrations and evaluating whether these predictions agree with measured metabolomic profiles. We find that a surprisingly large proportion of metabolite variation in the vaginal microbiome can be predicted based on species composition (including dramatic shifts associated with disease), identify putative mechanisms underlying these predictions, and evaluate the roles of individual bacterial species and genes. Analysis of gut microbiome data using this framework recovers similar community metabolic trends. This framework lays the foundation for model-based multi-omic integrative studies, ultimately improving our understanding of microbial community metabolism.

Comprehensive Evaluation of Altered Systemic Metabolism and Pancreatic Cancer Risk

Science.gov (United States)

2016-10-01

information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing...individuals provide extensive data on metabolic phenotypes, such as obesity and diabetes, and banked plasma samples for interrogation . The potential...banked plasma samples for interrogation . The potential impact of understanding the mechanisms underlying early pancreatic cancer growth is

Mechanisms of metabolic dysfunction in cancer-associated cachexia

Science.gov (United States)

Petruzzelli, Michele; Wagner, Erwin F.

2016-01-01

Metabolic dysfunction contributes to the clinical deterioration observed in advanced cancer patients and is characterized by weight loss, skeletal muscle wasting, and atrophy of the adipose tissue. This systemic syndrome, termed cancer-associated cachexia (CAC), is a major cause of morbidity and mortality. While once attributed solely to decreased food intake, the present description of cancer cachexia is a disorder of multiorgan energy imbalance. Here we review the molecules and pathways responsible for metabolic dysfunction in CAC and the ideas that led to the current understanding. PMID:26944676

Metabolic immune restraints: implications for anticancer vaccines.

Science.gov (United States)

Mocellin, Simone

2010-01-01

Metabolic immune restraints belong to a highly complex network of molecular mechanisms underlying the failure of naturally occurring and therapeutically induced immune responses against cancer. In the light of the disappointing results yielded so far with anticancer vaccines in the clinical setting, the dissection of the cascade of molecular events leading to tumor immune escape appears the most promising way to develop more effective immunotherapeutic strategies. Here we review the significant advances recently made in the understanding of the tumor-specific metabolic features that contribute to keep malignant cells from being recognized and destroyed by immune effectors. These mechanistic insights are fostering the development of rationally designed therapeutics aimed to revert the immunosuppressive circuits and thus to enhance the effectiveness of anticancer vaccines.

Modeling Inborn Errors of Hepatic Metabolism Using Induced Pluripotent Stem Cells.

Science.gov (United States)

Pournasr, Behshad; Duncan, Stephen A

2017-11-01

Inborn errors of hepatic metabolism are because of deficiencies commonly within a single enzyme as a consequence of heritable mutations in the genome. Individually such diseases are rare, but collectively they are common. Advances in genome-wide association studies and DNA sequencing have helped researchers identify the underlying genetic basis of such diseases. Unfortunately, cellular and animal models that accurately recapitulate these inborn errors of hepatic metabolism in the laboratory have been lacking. Recently, investigators have exploited molecular techniques to generate induced pluripotent stem cells from patients' somatic cells. Induced pluripotent stem cells can differentiate into a wide variety of cell types, including hepatocytes, thereby offering an innovative approach to unravel the mechanisms underlying inborn errors of hepatic metabolism. Moreover, such cell models could potentially provide a platform for the discovery of therapeutics. In this mini-review, we present a brief overview of the state-of-the-art in using pluripotent stem cells for such studies. © 2017 American Heart Association, Inc.

1H NMR Metabolic Profiling of Biofluids from Rats with Gastric Mucosal Lesion and Electroacupuncture Treatment

Directory of Open Access Journals (Sweden)

Jingjing Xu

2015-01-01

Full Text Available Gastric mucosal lesion (GML is a common gastrointestinal disorder with multiple pathogenic mechanisms in clinical practice. In traditional Chinese medicine (TCM, electroacupuncture (EA treatment has been proven as an effective therapy for GML, although the underlying healing mechanism is not yet clear. Here, we used proton nuclear magnetic resonance- (1H NMR- based metabolomic method to investigate the metabolic perturbation induced by GML and the therapeutic effect of EA treatment on stomach meridian (SM acupoints. Clear metabolic differences were observed between GML and control groups, and related metabolic pathways were discussed by means of online metabolic network analysis toolbox. By comparing the endogenous metabolites from GML and GML-SM groups, the disturbed pathways were partly recovered towards healthy state via EA treated on SM acupoints. Further comparison of the metabolic variations induced by EA stimulated on SM and the control gallbladder meridian (GM acupoints showed a quite similar metabolite composition except for increased phenylacetylglycine, 3,4-dihydroxymandelate, and meta-hydroxyphenylacetate and decreased N-methylnicotinamide in urine from rats with EA treated on SM acupoints. The current study showed the potential application of metabolomics in providing further insight into the molecular mechanism of acupuncture.

Mechanism of crack initiation and crack growth under thermal and mechanical fatigue loading

Energy Technology Data Exchange (ETDEWEB)

Utz, S.; Soppa, E.; Silcher, H.; Kohler, C. [Stuttgart Univ. (Germany). Materials Testing Inst.

2013-07-01

The present contribution is focused on the experimental investigations and numerical simulations of the deformation behaviour and crack development in the austenitic stainless steel X6CrNiNb18-10 under thermal and mechanical cyclic loading in HCF and LCF regimes. The main objective of this research is the understanding of the basic mechanisms of fatigue damage and the development of simulation methods, which can be applied further in safety evaluations of nuclear power plant components. In this context the modelling of crack initiation and crack growth inside the material structure induced by varying thermal or mechanical loads are of particular interest. The mechanisms of crack initiation depend among other things on the type of loading, microstructure, material properties and temperature. The Nb-stabilized austenitic stainless steel in the solution-annealed condition was chosen for the investigations. Experiments with two kinds of cyclic loading - pure thermal and pure mechanical - were carried out and simulated. The fatigue behaviour of the steel X6CrNiNb18-10 under thermal loading was studied within the framework of the joint research project [4]. Interrupted thermal cyclic tests in the temperature range of 150 C to 300 C combined with non-destructive residual stress measurements (XRD) and various microscopic investigations, e.g. in SEM (Scanning Electron Microscope), were used to study the effects of thermal cyclic loading on the material. This thermal cyclic loading leads to thermal induced stresses and strains. As a result intrusions and extrusions appear inside the grains (at the surface), at which microcracks arise and evolve to a dominant crack. Finally, these microcracks cause a continuous and significant decrease of residual stresses. The fatigue behaviour of the steel X6CrNiNb18-10 under mechanical loading at room temperature was studied within the framework of the research project [5], [8]. With a combination of interrupted LCF tests and EBSD

Mechanism of crack initiation and crack growth under thermal and mechanical fatigue loading

International Nuclear Information System (INIS)

Utz, S.; Soppa, E.; Silcher, H.; Kohler, C.

2013-01-01

The present contribution is focused on the experimental investigations and numerical simulations of the deformation behaviour and crack development in the austenitic stainless steel X6CrNiNb18-10 under thermal and mechanical cyclic loading in HCF and LCF regimes. The main objective of this research is the understanding of the basic mechanisms of fatigue damage and the development of simulation methods, which can be applied further in safety evaluations of nuclear power plant components. In this context the modelling of crack initiation and crack growth inside the material structure induced by varying thermal or mechanical loads are of particular interest. The mechanisms of crack initiation depend among other things on the type of loading, microstructure, material properties and temperature. The Nb-stabilized austenitic stainless steel in the solution-annealed condition was chosen for the investigations. Experiments with two kinds of cyclic loading - pure thermal and pure mechanical - were carried out and simulated. The fatigue behaviour of the steel X6CrNiNb18-10 under thermal loading was studied within the framework of the joint research project [4]. Interrupted thermal cyclic tests in the temperature range of 150 C to 300 C combined with non-destructive residual stress measurements (XRD) and various microscopic investigations, e.g. in SEM (Scanning Electron Microscope), were used to study the effects of thermal cyclic loading on the material. This thermal cyclic loading leads to thermal induced stresses and strains. As a result intrusions and extrusions appear inside the grains (at the surface), at which microcracks arise and evolve to a dominant crack. Finally, these microcracks cause a continuous and significant decrease of residual stresses. The fatigue behaviour of the steel X6CrNiNb18-10 under mechanical loading at room temperature was studied within the framework of the research project [5], [8]. With a combination of interrupted LCF tests and EBSD

Energy metabolism in astrocytes and neurons treated with manganese: relation among cell-specific energy failure, glucose metabolism, and intercellular trafficking using multinuclear NMR-spectroscopic analysis.

Science.gov (United States)

Zwingmann, Claudia; Leibfritz, Dieter; Hazell, Alan S

2003-06-01

A central question in manganese neurotoxicity concerns mitochondrial dysfunction leading to cerebral energy failure. To obtain insight into the underlying mechanism(s), the authors investigated cell-specific pathways of [1-13C]glucose metabolism by high-resolution multinuclear NMR-spectroscopy. Five-day treatment of neurons with 100-micro mol/L MnCl(2) led to 50% and 70% decreases of ATP/ADP and phosphocreatine-creatine ratios, respectively. An impaired flux of [1-13C]glucose through pyruvate dehydrogenase, which was associated with Krebs cycle inhibition and hence depletion of [4-13C]glutamate, [2-13C]GABA, and [13C]glutathione, hindered the ability of neurons to compensate for mitochondrial dysfunction by oxidative glucose metabolism and further aggravated neuronal energy failure. Stimulated glycolysis and oxidative glucose metabolism protected astrocytes against energy failure and oxidative stress, leading to twofold increased de novo synthesis of [3-13C]lactate and fourfold elevated [4-13C]glutamate and [13C]glutathione levels. Manganese, however, inhibited the synthesis and release of glutamine. Comparative NMR data obtained from cocultures showed disturbed astrocytic function and a failure of astrocytes to provide neurons with substrates for energy and neurotransmitter metabolism, leading to deterioration of neuronal antioxidant capacity (decreased glutathione levels) and energy metabolism. The results suggest that, concomitant to impaired neuronal glucose oxidation, changes in astrocytic metabolism may cause a loss of intercellular homeostatic equilibrium, contributing to neuronal dysfunction in manganese neurotoxicity.

Lipotoxicity in macrophages: evidence from diseases associated with the metabolic syndrome.

Science.gov (United States)

Prieur, Xavier; Roszer, Tamás; Ricote, Mercedes

2010-03-01

Accumulation of lipid metabolites within non-adipose tissues can induce chronic inflammation by promoting macrophage infiltration and activation. Oxidized and glycated lipoproteins, free fatty acids, free cholesterol, triacylglycerols, diacylglycerols and ceramides have long been known to induce cellular dysfunction through their pro-inflammatory and pro-apoptotic properties. Emerging evidence suggests that macrophage activation by lipid metabolites and further modulation by lipid signaling represents a common pathogenic mechanism underlying lipotoxicity in atherosclerosis, obesity-associated insulin resistance and inflammatory diseases related to metabolic syndrome such as liver steatosis and chronic kidney disease. In this review, we discuss the latest discoveries that support the role of lipids in modulating the macrophage phenotype in different metabolic diseases. We describe the common mechanisms by which lipid derivatives, through modulation of macrophage function, promote plaque instability in the arterial wall, impair insulin responsiveness and contribute to inflammatory liver, muscle and kidney disease. We discuss the molecular mechanism of lipid activation of pro-inflammatory pathways (JNK, NFkappaB) and the key roles played by the PPAR and LXR nuclear receptors-lipid sensors that link lipid metabolism and inflammation. Copyright (c) 2009 Elsevier B.V. All rights reserved.

Gender Differences in Adipocyte Metabolism and Liver Cancer Progression

Directory of Open Access Journals (Sweden)

Otto Ka-Wing Cheung

2016-09-01

Full Text Available Liver cancer is the third most common cancer type and the second leading cause of deaths in men. Large population studies have demonstrated remarkable gender disparities in the incidence and the cumulative risk of liver cancer. A number of emerging risk factors regarding metabolic alterations associated with obesity, diabetes and dyslipidemia have been ascribed to the progression of non-alcoholic fatty liver diseases (NAFLD and ultimately liver cancer. The deregulation of fat metabolism derived from excessive insulin, glucose and lipid promotes cancer-causing inflammatory signaling and oxidative stress, which eventually triggers the uncontrolled hepatocellular proliferation. This review presents the current standing on the gender differences in body fat compositions and their mechanistic linkage with the development of NAFLD-related liver cancer, with an emphasis on genetic, epigenetic and microRNA control. The potential roles of sex hormones in instructing adipocyte metabolic programs may help unravel the mechanisms underlying gender dimorphism in liver cancer and identify the metabolic targets for disease management.

STAT3 Activities and Energy Metabolism: Dangerous Liaisons

Energy Technology Data Exchange (ETDEWEB)

Camporeale, Annalisa, E-mail: annalisa.camporeale@unito.it [Molecular Biotechnology Center and Department of Molecular Biotechnology and Life Sciences, University of Turin, Via Nizza 52, Turin 10126 (Italy); Demaria, Marco [Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA 94945 (United States); Monteleone, Emanuele [Molecular Biotechnology Center and Department of Molecular Biotechnology and Life Sciences, University of Turin, Via Nizza 52, Turin 10126 (Italy); Giorgi, Carlotta [Department of Experimental and Diagnostic Medicine, Section of General Pathology, Laboratory for Technologies of Advances Therapies (LTTA), University of Ferrara, Via Fossato di Mortara 70, Ferrara 44121 (Italy); Wieckowski, Mariusz R. [Nencki Institute of Experimental Biology, Department of Biochemistry, Pasteur Str. 3, Warsaw 02-093 (Poland); Pinton, Paolo [Department of Experimental and Diagnostic Medicine, Section of General Pathology, Laboratory for Technologies of Advances Therapies (LTTA), University of Ferrara, Via Fossato di Mortara 70, Ferrara 44121 (Italy); Poli, Valeria, E-mail: annalisa.camporeale@unito.it [Molecular Biotechnology Center and Department of Molecular Biotechnology and Life Sciences, University of Turin, Via Nizza 52, Turin 10126 (Italy)

2014-07-31

STAT3 mediates cytokine and growth factor receptor signalling, becoming transcriptionally active upon tyrosine 705 phosphorylation (Y-P). Constitutively Y-P STAT3 is observed in many tumors that become addicted to its activity, and STAT3 transcriptional activation is required for tumor transformation downstream of several oncogenes. We have recently demonstrated that constitutively active STAT3 drives a metabolic switch towards aerobic glycolysis through the transcriptional induction of Hif-1α and the down-regulation of mitochondrial activity, in both MEF cells expressing constitutively active STAT3 (Stat3{sup C/C}) and STAT3-addicted tumor cells. This novel metabolic function is likely involved in mediating pre-oncogenic features in the primary Stat3{sup C/C} MEFs such as resistance to apoptosis and senescence and rapid proliferation. Moreover, it strongly contributes to the ability of primary Stat3{sup C/C} MEFs to undergo malignant transformation upon spontaneous immortalization, a feature that may explain the well known causative link between STAT3 constitutive activity and tumor transformation under chronic inflammatory conditions. Taken together with the recently uncovered role of STAT3 in regulating energy metabolism from within the mitochondrion when phosphorylated on Ser 727, these data place STAT3 at the center of a hub regulating energy metabolism under different conditions, in most cases promoting cell survival, proliferation and malignant transformation even though with distinct mechanisms.

STAT3 Activities and Energy Metabolism: Dangerous Liaisons

International Nuclear Information System (INIS)

Camporeale, Annalisa; Demaria, Marco; Monteleone, Emanuele; Giorgi, Carlotta; Wieckowski, Mariusz R.; Pinton, Paolo; Poli, Valeria

2014-01-01

STAT3 mediates cytokine and growth factor receptor signalling, becoming transcriptionally active upon tyrosine 705 phosphorylation (Y-P). Constitutively Y-P STAT3 is observed in many tumors that become addicted to its activity, and STAT3 transcriptional activation is required for tumor transformation downstream of several oncogenes. We have recently demonstrated that constitutively active STAT3 drives a metabolic switch towards aerobic glycolysis through the transcriptional induction of Hif-1α and the down-regulation of mitochondrial activity, in both MEF cells expressing constitutively active STAT3 (Stat3 C/C ) and STAT3-addicted tumor cells. This novel metabolic function is likely involved in mediating pre-oncogenic features in the primary Stat3 C/C MEFs such as resistance to apoptosis and senescence and rapid proliferation. Moreover, it strongly contributes to the ability of primary Stat3 C/C MEFs to undergo malignant transformation upon spontaneous immortalization, a feature that may explain the well known causative link between STAT3 constitutive activity and tumor transformation under chronic inflammatory conditions. Taken together with the recently uncovered role of STAT3 in regulating energy metabolism from within the mitochondrion when phosphorylated on Ser 727, these data place STAT3 at the center of a hub regulating energy metabolism under different conditions, in most cases promoting cell survival, proliferation and malignant transformation even though with distinct mechanisms

ATP-Citrate Lyase Controls a Glucose-to-Acetate Metabolic Switch

Directory of Open Access Journals (Sweden)

Steven Zhao

2016-10-01

Full Text Available Mechanisms of metabolic flexibility enable cells to survive under stressful conditions and can thwart therapeutic responses. Acetyl-coenzyme A (CoA plays central roles in energy production, lipid metabolism, and epigenomic modifications. Here, we show that, upon genetic deletion of Acly, the gene coding for ATP-citrate lyase (ACLY, cells remain viable and proliferate, although at an impaired rate. In the absence of ACLY, cells upregulate ACSS2 and utilize exogenous acetate to provide acetyl-CoA for de novo lipogenesis (DNL and histone acetylation. A physiological level of acetate is sufficient for cell viability and abundant acetyl-CoA production, although histone acetylation levels remain low in ACLY-deficient cells unless supplemented with high levels of acetate. ACLY-deficient adipocytes accumulate lipid in vivo, exhibit increased acetyl-CoA and malonyl-CoA production from acetate, and display some differences in fatty acid content and synthesis. Together, these data indicate that engagement of acetate metabolism is a crucial, although partial, mechanism of compensation for ACLY deficiency.

ATP-Citrate Lyase Controls a Glucose-to-Acetate Metabolic Switch.

Science.gov (United States)

Zhao, Steven; Torres, AnnMarie; Henry, Ryan A; Trefely, Sophie; Wallace, Martina; Lee, Joyce V; Carrer, Alessandro; Sengupta, Arjun; Campbell, Sydney L; Kuo, Yin-Ming; Frey, Alexander J; Meurs, Noah; Viola, John M; Blair, Ian A; Weljie, Aalim M; Metallo, Christian M; Snyder, Nathaniel W; Andrews, Andrew J; Wellen, Kathryn E

2016-10-18

Mechanisms of metabolic flexibility enable cells to survive under stressful conditions and can thwart therapeutic responses. Acetyl-coenzyme A (CoA) plays central roles in energy production, lipid metabolism, and epigenomic modifications. Here, we show that, upon genetic deletion of Acly, the gene coding for ATP-citrate lyase (ACLY), cells remain viable and proliferate, although at an impaired rate. In the absence of ACLY, cells upregulate ACSS2 and utilize exogenous acetate to provide acetyl-CoA for de novo lipogenesis (DNL) and histone acetylation. A physiological level of acetate is sufficient for cell viability and abundant acetyl-CoA production, although histone acetylation levels remain low in ACLY-deficient cells unless supplemented with high levels of acetate. ACLY-deficient adipocytes accumulate lipid in vivo, exhibit increased acetyl-CoA and malonyl-CoA production from acetate, and display some differences in fatty acid content and synthesis. Together, these data indicate that engagement of acetate metabolism is a crucial, although partial, mechanism of compensation for ACLY deficiency. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Convergent Metabolic Specialization through Distinct Evolutionary Paths in Pseudomonas aeruginosa.

Science.gov (United States)

La Rosa, Ruggero; Johansen, Helle Krogh; Molin, Søren

2018-04-10

Evolution by natural selection under complex and dynamic environmental conditions occurs through intricate and often counterintuitive trajectories affecting many genes and metabolic solutions. To study short- and long-term evolution of bacteria in vivo , we used the natural model system of cystic fibrosis (CF) infection. In this work, we investigated how and through which trajectories evolution of Pseudomonas aeruginosa occurs when migrating from the environment to the airways of CF patients, and specifically, we determined reduction of growth rate and metabolic specialization as signatures of adaptive evolution. We show that central metabolic pathways of three distinct Pseudomonas aeruginosa lineages coevolving within the same environment become restructured at the cost of versatility during long-term colonization. Cell physiology changes from naive to adapted phenotypes resulted in (i) alteration of growth potential that particularly converged to a slow-growth phenotype, (ii) alteration of nutritional requirements due to auxotrophy, (iii) tailored preference for carbon source assimilation from CF sputum, (iv) reduced arginine and pyruvate fermentation processes, and (v) increased oxygen requirements. Interestingly, although convergence was evidenced at the phenotypic level of metabolic specialization, comparative genomics disclosed diverse mutational patterns underlying the different evolutionary trajectories. Therefore, distinct combinations of genetic and regulatory changes converge to common metabolic adaptive trajectories leading to within-host metabolic specialization. This study gives new insight into bacterial metabolic evolution during long-term colonization of a new environmental niche. IMPORTANCE Only a few examples of real-time evolutionary investigations in environments outside the laboratory are described in the scientific literature. Remembering that biological evolution, as it has progressed in nature, has not taken place in test tubes, it is not

Obesity and psychotic disorders: uncovering common mechanisms through metabolomics

Directory of Open Access Journals (Sweden)

Matej Orešič

2012-09-01

Full Text Available Primary obesity and psychotic disorders are similar with respect to the associated changes in energy balance and co-morbidities, including metabolic syndrome. Such similarities do not necessarily demonstrate causal links, but instead suggest that specific causes of and metabolic disturbances associated with obesity play a pathogenic role in the development of co-morbid disorders, potentially even before obesity develops. Metabolomics – the systematic study of metabolites, which are small molecules generated by the process of metabolism – has been important in elucidating the pathways underlying obesity-associated co-morbidities. This review covers how recent metabolomic studies have advanced biomarker discovery and the elucidation of mechanisms underlying obesity and its co-morbidities, with a specific focus on metabolic syndrome and psychotic disorders. The importance of identifying metabolic markers of disease-associated intermediate phenotypes – traits modulated but not encoded by the DNA sequence – is emphasized. Such markers would be applicable as diagnostic tools in a personalized healthcare setting and might also open up novel therapeutic avenues.

Mitochondrial translocation of Nur77 induced by ROS contributed to cardiomyocyte apoptosis in metabolic syndrome

Energy Technology Data Exchange (ETDEWEB)

Xu, Aibin; Liu, Jingyi [Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi’an (China); Institute of Cardiovascular Disease, General Hospital of Beijing Command, PLA, Beijing (China); Liu, Peilin; Jia, Min; Wang, Han [Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi’an (China); Tao, Ling, E-mail: lingtao2006@gmail.com [Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi’an (China)

2014-04-18

Highlights: • Metabolic syndrome exacerbated MI/R induced injury accompanied by decreased Nur77. • ROS led to Nur77 translocation in metabolic syndrome. • Inhibiting relocation of Nur77 to mitochondria reduced ROS-induced cardiomyocyte injury in metabolic syndrome. - Abstract: Metabolic syndrome is a major risk factor for cardiovascular diseases, and increased cardiomyocyte apoptosis which contributes to cardiac dysfunction after myocardial ischemia/reperfusion (MI/R) injury. Nur77, a nuclear orphan receptor, is involved in such various cellular events as apoptosis, proliferation, and glucose and lipid metabolism in several cell types. Apoptosis is positively correlated with mitochondrial translocation of Nur77 in the cancer cells. However, the roles of Nur77 on cardiac myocytes in patients with metabolic syndrome remain unclear. The objective of this study was to determine whether Nur77 may contribute to cardiac apoptosis in patients with metabolic syndrome after I/R injury, and, if so, to identify the underlying molecular mechanisms responsible. We used leptin-deficient (ob/ob) mice to make metabolic syndrome models. In this report, we observed that, accompanied by the substantial decline in apoptosis inducer Nur77, MI/R induced cardiac dysfunction was manifested as cardiomyopathy and increased ROS. Using the neonatal rat cardiac myocytes cultured in a high-glucose and high-fat medium, we found that excessive H{sub 2}O{sub 2} led to the significant alteration in mitochondrial membrane potential and translocation of Nur77 from the nucleus to the mitochondria. However, inhibition of the relocation of Nur77 to mitochondria via Cyclosporin A reversed the changes in membrane potential mediated by H{sub 2}O{sub 2} and reduced myocardial cell injury. Therefore, these data provide a potential underlying mechanism for cardiac dysfunction in metabolic syndrome and the suppression of Nur77 translocation may provide an effective approach to reduce cardiac injury in the

Mitochondrial translocation of Nur77 induced by ROS contributed to cardiomyocyte apoptosis in metabolic syndrome

International Nuclear Information System (INIS)

Xu, Aibin; Liu, Jingyi; Liu, Peilin; Jia, Min; Wang, Han; Tao, Ling

2014-01-01

Highlights: • Metabolic syndrome exacerbated MI/R induced injury accompanied by decreased Nur77. • ROS led to Nur77 translocation in metabolic syndrome. • Inhibiting relocation of Nur77 to mitochondria reduced ROS-induced cardiomyocyte injury in metabolic syndrome. - Abstract: Metabolic syndrome is a major risk factor for cardiovascular diseases, and increased cardiomyocyte apoptosis which contributes to cardiac dysfunction after myocardial ischemia/reperfusion (MI/R) injury. Nur77, a nuclear orphan receptor, is involved in such various cellular events as apoptosis, proliferation, and glucose and lipid metabolism in several cell types. Apoptosis is positively correlated with mitochondrial translocation of Nur77 in the cancer cells. However, the roles of Nur77 on cardiac myocytes in patients with metabolic syndrome remain unclear. The objective of this study was to determine whether Nur77 may contribute to cardiac apoptosis in patients with metabolic syndrome after I/R injury, and, if so, to identify the underlying molecular mechanisms responsible. We used leptin-deficient (ob/ob) mice to make metabolic syndrome models. In this report, we observed that, accompanied by the substantial decline in apoptosis inducer Nur77, MI/R induced cardiac dysfunction was manifested as cardiomyopathy and increased ROS. Using the neonatal rat cardiac myocytes cultured in a high-glucose and high-fat medium, we found that excessive H 2 O 2 led to the significant alteration in mitochondrial membrane potential and translocation of Nur77 from the nucleus to the mitochondria. However, inhibition of the relocation of Nur77 to mitochondria via Cyclosporin A reversed the changes in membrane potential mediated by H 2 O 2 and reduced myocardial cell injury. Therefore, these data provide a potential underlying mechanism for cardiac dysfunction in metabolic syndrome and the suppression of Nur77 translocation may provide an effective approach to reduce cardiac injury in the process

Serum metabolic profiling of human gastric cancer based on gas chromatography/mass spectrometry

International Nuclear Information System (INIS)

Song, Hu; Peng, Jun-Sheng; Yao, Dong-Sheng; Yang, Zu-Li; Liu, Huan-Liang; Zeng, Yi-Ke; Shi, Xian-Ping; Lu, Bi-Yan

2011-01-01

Research on molecular mechanisms of carcinogenesis plays an important role in diagnosing and treating gastric cancer. Metabolic profiling may offer the opportunity to understand the molecular mechanism of carcinogenesis and help to non-invasively identify the potential biomarkers for the early diagnosis of human gastric cancer. The aims of this study were to explore the underlying metabolic mechanisms of gastric cancer and to identify biomarkers associated with morbidity. Gas chromatography/mass spectrometry (GC/MS) was used to analyze the serum metabolites of 30 Chinese gastric cancer patients and 30 healthy controls. Diagnostic models for gastric cancer were constructed using orthogonal partial least squares discriminant analysis (OPLS-DA). Acquired metabolomic data were analyzed by the nonparametric Wilcoxon test to find serum metabolic biomarkers for gastric cancer. The OPLS-DA model showed adequate discrimination between cancer and non-cancer cohorts while the model failed to discriminate different pathological stages (I-IV) of gastric cancer patients. A total of 44 endogenous metabolites such as amino acids, organic acids, carbohydrates, fatty acids, and steroids were detected, of which 18 differential metabolites were identified with significant differences. A total of 13 variables were obtained for their greatest contribution in the discriminating OPLS-DA model [variable importance in the projection (VIP) value >1.0], among which 11 metabolites were identified using both VIP values (VIP >1) and the Wilcoxon test. These metabolites potentially revealed perturbations of glycolysis and of amino acid, fatty acid, cholesterol, and nucleotide metabolism of gastric cancer patients. These results suggest that gastric cancer serum metabolic profiling has great potential in detecting this disease and helping to understand its metabolic mechanisms

Fracture mechanics of hydroxyapatite single crystals under geometric confinement.

Science.gov (United States)

Libonati, Flavia; Nair, Arun K; Vergani, Laura; Buehler, Markus J

2013-04-01

Geometric confinement to the nanoscale, a concept that refers to the characteristic dimensions of structural features of materials at this length scale, has been shown to control the mechanical behavior of many biological materials or their building blocks, and such effects have also been suggested to play a crucial role in enhancing the strength and toughness of bone. Here we study the effect of geometric confinement on the fracture mechanism of hydroxyapatite (HAP) crystals that form the mineralized phase in bone. We report a series of molecular simulations of HAP crystals with an edge crack on the (001) plane under tensile loading, and we systematically vary the sample height whilst keeping the sample and the crack length constant. We find that by decreasing the sample height the stress concentration at the tip of the crack disappears for samples with a height smaller than 4.15nm, below which the material shows a different failure mode characterized by a more ductile mechanism with much larger failure strains, and the strength approaching that of a flaw-less crystal. This study directly confirms an earlier suggestion of a flaw-tolerant state that appears under geometric confinement and may explain the mechanical stability of the reinforcing HAP platelets in bone. Copyright © 2012 Elsevier Ltd. All rights reserved.

Using a Genome-Scale Metabolic Network Model to Elucidate the Mechanism of Chloroquine Action in Plasmodium falciparum

Science.gov (United States)

2017-03-22

The transcriptome data of P. falciparum obtained under different stress conditions (e.g., drug exposure, genetic mutation , etc.) contain information...Linking high-resolution metabolic flux phenotypes and transcriptional regulation in yeast modulated by the global regulator Gcn4p. Proc. Natl. Acad

Metabolic syndrome as a risk factor for neurological disorders.

Science.gov (United States)

Farooqui, Akhlaq A; Farooqui, Tahira; Panza, Francesco; Frisardi, Vincenza

2012-03-01

The metabolic syndrome is a cluster of common pathologies: abdominal obesity linked to an excess of visceral fat, insulin resistance, dyslipidemia and hypertension. At the molecular level, metabolic syndrome is accompanied not only by dysregulation in the expression of adipokines (cytokines and chemokines), but also by alterations in levels of leptin, a peptide hormone released by white adipose tissue. These changes modulate immune response and inflammation that lead to alterations in the hypothalamic 'bodyweight/appetite/satiety set point,' resulting in the initiation and development of metabolic syndrome. Metabolic syndrome is a risk factor for neurological disorders such as stroke, depression and Alzheimer's disease. The molecular mechanism underlying the mirror relationship between metabolic syndrome and neurological disorders is not fully understood. However, it is becoming increasingly evident that all cellular and biochemical alterations observed in metabolic syndrome like impairment of endothelial cell function, abnormality in essential fatty acid metabolism and alterations in lipid mediators along with abnormal insulin/leptin signaling may represent a pathological bridge between metabolic syndrome and neurological disorders such as stroke, Alzheimer's disease and depression. The purpose of this review is not only to describe the involvement of brain in the pathogenesis of metabolic syndrome, but also to link the pathogenesis of metabolic syndrome with neurochemical changes in stroke, Alzheimer's disease and depression to a wider audience of neuroscientists with the hope that this discussion will initiate more studies on the relationship between metabolic syndrome and neurological disorders. © Springer Basel AG 2011

Human longevity is characterised by high thyroid stimulating hormone secretion without altered energy metabolism

DEFF Research Database (Denmark)

Jansen, S W; Akintola, A A; Roelfsema, F

2015-01-01

hormone (TH) in an inverse relationship. Greater longevity has been associated with higher TSH and lower TH levels, but mechanisms underlying TSH/TH differences and longevity remain unknown. The HPT axis plays a pivotal role in growth, development and energy metabolism. We report that offspring...... of nonagenarians with at least one nonagenarian sibling have increased TSH secretion but similar bioactivity of TSH and similar TH levels compared to controls. Healthy offspring and spousal controls had similar resting metabolic rate and core body temperature. We propose that pleiotropic effects of the HPT axis...... may favour longevity without altering energy metabolism....

Believing versus interacting: Behavioural and neural mechanisms underlying interpersonal coordination

DEFF Research Database (Denmark)

Konvalinka, Ivana; Bauer, Markus; Kilner, James

When two people engage in a bidirectional interaction with each other, they use both bottom-up sensorimotor mechanisms such as monitoring and adapting to the behaviour of the other, as well as top-down cognitive processes, modulating their beliefs and allowing them to make decisions. Most research...... in joint action has investigated only one of these mechanisms at a time – low-level processes underlying joint coordination, or high-level cognitive mechanisms that give insight into how people think about another. In real interactions, interplay between these two mechanisms modulates how we interact...

PCSK9 and triglyceride-rich lipoprotein metabolism.

Science.gov (United States)

Druce, I; Abujrad, H; Ooi, T C

2015-07-20

Pro-protein convertase subtilisin-kexin 9 (PCSK9) is known to affect low-density lipoprotein (LDL) metabolism, but there are indications from several lines of research that it may also influence the metabolism of other lipoproteins, especially triglyceride-rich lipoproteins (TRL). This review summarizes the current data on this possible role of PCSK9. A link between PCSK9 and TRL has been suggested through the demonstration of (1) a correlation between plasma PCSK9 and triglyceride (TG) levels in health and disease, (2) a correlation between plasma PCSK9 and markers of carbohydrate metabolism, which is closely related to TG metabolism, (3) an effect of TG-lowering fibrate therapy on plasma PCSK9 levels, (4) an effect of PCSK9 on postprandial lipemia, (5) an effect of PCSK9 on adipose tissue biology, (6) an effect of PCSK9 on apolipoprotein B production from the liver and intestines, (7) an effect of PCSK9 on receptors other than low density lipoprotein receptor (LDLR) that are involved in TRL metabolism, and (8) an effect of anti-PCSK9 therapy on serum TG levels. The underlying mechanisms are unclear but starting to emerge. © 2015 the Journal of Biomedical Research. All rights reserved.

Endothelial dysfunction in metabolic and vascular disorders.

Science.gov (United States)

Polovina, Marija M; Potpara, Tatjana S

2014-03-01

Vascular endothelium has important regulatory functions in the cardiovascular system and a pivotal role in the maintenance of vascular health and metabolic homeostasis. It has long been recognized that endothelial dysfunction participates in the pathogenesis of atherosclerosis from early, preclinical lesions to advanced, thrombotic complications. In addition, endothelial dysfunction has been recently implicated in the development of insulin resistance and type 2 diabetes mellitus (T2DM). Considering that states of insulin resistance (eg, metabolic syndrome, impaired fasting glucose, impaired glucose tolerance, and T2DM) represent the most prevalent metabolic disorders and risk factors for atherosclerosis, it is of considerable scientific and clinical interest that both metabolic and vascular disorders have endothelial dysfunction as a common background. Importantly, endothelial dysfunction has been associated with adverse outcomes in patients with established cardiovascular disease, and a growing body of evidence indicates that endothelial dysfunction also imparts adverse prognosis in states of insulin resistance. In this review, we discuss the association of insulin resistance and T2DM with endothelial dysfunction and vascular disease, with a focus on the underlying mechanisms and prognostic implications of the endothelial dysfunction in metabolic and vascular disorders. We also address current therapeutic strategies for the improvement of endothelial dysfunction.

Human longevity is characterised by high thyroid stimulating hormone secretion without altered energy metabolism.

Science.gov (United States)

Jansen, S W; Akintola, A A; Roelfsema, F; van der Spoel, E; Cobbaert, C M; Ballieux, B E; Egri, P; Kvarta-Papp, Z; Gereben, B; Fekete, C; Slagboom, P E; van der Grond, J; Demeneix, B A; Pijl, H; Westendorp, R G J; van Heemst, D

2015-06-19

Few studies have included subjects with the propensity to reach old age in good health, with the aim to disentangle mechanisms contributing to staying healthier for longer. The hypothalamic-pituitary-thyroid (HPT) axis maintains circulating levels of thyroid stimulating hormone (TSH) and thyroid hormone (TH) in an inverse relationship. Greater longevity has been associated with higher TSH and lower TH levels, but mechanisms underlying TSH/TH differences and longevity remain unknown. The HPT axis plays a pivotal role in growth, development and energy metabolism. We report that offspring of nonagenarians with at least one nonagenarian sibling have increased TSH secretion but similar bioactivity of TSH and similar TH levels compared to controls. Healthy offspring and spousal controls had similar resting metabolic rate and core body temperature. We propose that pleiotropic effects of the HPT axis may favour longevity without altering energy metabolism.

Mechanical behavior of silicon carbide nanoparticles under uniaxial compression

Energy Technology Data Exchange (ETDEWEB)

He, Qiuxiang; Fei, Jing; Tang, Chao; Zhong, Jianxin; Meng, Lijun, E-mail: ljmeng@xtu.edu.cn [Xiangtan University, Hunan Key Laboratory for Micro-Nano Energy Materials and Devices, Faculty of School of Physics and Optoelectronics (China)

2016-03-15

The mechanical behavior of SiC nanoparticles under uniaxial compression was investigated using an atomic-level compression simulation technique. The results revealed that the mechanical deformation of SiC nanocrystals is highly dependent on compression orientation, particle size, and temperature. A structural transformation from the original zinc-blende to a rock-salt phase is identified for SiC nanoparticles compressed along the [001] direction at low temperature. However, the rock-salt phase is not observed for SiC nanoparticles compressed along the [110] and [111] directions irrespective of size and temperature. The high-pressure-generated rock-salt phase strongly affects the mechanical behavior of the nanoparticles, including their hardness and deformation process. The hardness of [001]-compressed nanoparticles decreases monotonically as their size increases, different from that of [110] and [111]-compressed nanoparticles, which reaches a maximal value at a critical size and then decreases. Additionally, a temperature-dependent mechanical response was observed for all simulated SiC nanoparticles regardless of compression orientation and size. Interestingly, the hardness of SiC nanocrystals with a diameter of 8 nm compressed in [001]-orientation undergoes a steep decrease at 0.1–200 K and then a gradual decline from 250 to 1500 K. This trend can be attributed to different deformation mechanisms related to phase transformation and dislocations. Our results will be useful for practical applications of SiC nanoparticles under high pressure.

Mitochondrial Metabolism in Aging Heart

Science.gov (United States)

Lesnefsky, Edward J.; Chen, Qun; Hoppel, Charles L.

2016-01-01

Altered mitochondrial metabolism is the underlying basis for the increased sensitivity in the aged heart to stress. The aged heart exhibits impaired metabolic flexibility, with a decreased capacity to oxidize fatty acids and enhanced dependence on glucose metabolism. Aging impairs mitochondrial oxidative phosphorylation, with a greater role played by the mitochondria located between the myofibrils, the interfibrillar mitochondria. With aging, there is a decrease in activity of complexes III and IV, which account for the decrease in respiration. Furthermore, aging decreases mitochondrial content among the myofibrils. The end result is that in the interfibrillar area there is an approximate 50% decrease in mitochondrial function, affecting all substrates. The defective mitochondria persist in the aged heart, leading to enhanced oxidant production and oxidative injury and the activation of oxidant signaling for cell death. Aging defects in mitochondria represent new therapeutic targets, whether by manipulation of the mitochondrial proteome, modulation of electron transport, activation of biogenesis or mitophagy, or the regulation of mitochondrial fission and fusion. These mechanisms provide new ways to attenuate cardiac disease in elders by preemptive treatment of age-related defects, in contrast to the treatment of disease-induced dysfunction. PMID:27174952

Determinants of maternal pregnancy one-carbon metabolism and newborn human DNA methylation profiles

NARCIS (Netherlands)

N.H. van Mil (Nina); M.I. Bouwl-Both (Marieke I.); L. Stolk (Lisette); M.M.P.J. Verbiest (Michael); A. Hofman (Albert); V.W.V. Jaddoe (Vincent); F.C. Verhulst (Frank); P.H.C. Eilers (Paul); A.G. Uitterlinden (André); E.A.P. Steegers (Eric); H.W. Tiemeier (Henning); R.P.M. Steegers-Theunissen (Régine)

2014-01-01

textabstractMaternal one-carbon (1-C) metabolism provides methylgroups for fetal development and programing by DNA methylation as one of the underlying epigenetic mechanisms. We aimed to investigate maternal 1-C biomarkers, folic acid supplement use, and MTHFR C677T genotype as determinants of 1-C

Nonlinear Mechanics of MEMS Rectangular Microplates under Electrostatic Actuation

KAUST Repository

Saghir, Shahid

2016-01-01

The first objective of the dissertation is to develop a suitable reduced order model capable of investigating the nonlinear mechanical behavior of von-Karman plates under electrostatic actuation. The second objective is to investigate the nonlinear

Endothermy in birds: underlying molecular mechanisms.

Science.gov (United States)

Walter, Isabel; Seebacher, Frank

2009-08-01

Endothermy is significant in vertebrate evolution because it changes the relations between animals and their environment. How endothermy has evolved in archosaurs (birds, crocodiles and dinosaurs) is controversial especially because birds do not possess brown adipose tissue, the specialized endothermic tissue of mammals. Internal heat production is facilitated by increased oxidative metabolic capacity, accompanied by the uncoupling of aerobic metabolism from energy (ATP) production. Here we show that the transition from an ectothermic to an endothermic metabolic state in developing chicken embryos occurs by the interaction between increased basal ATP demand (Na(+)/K(+)-ATPase activity and gene expression), increased oxidative capacity and increased uncoupling of mitochondria; this process is controlled by thyroid hormone via its effect on PGC1alpha and adenine nucleotide translocase (ANT) gene expression. Mitochondria become more uncoupled during development, but unlike in mammals, avian uncoupling protein (avUCP) does not uncouple electron transport from oxidative phosphorylation and therefore plays no role in heat production. Instead, ANT is the principal uncoupling protein in birds. The relationship between oxidative capacity and uncoupling indicates that there is a continuum of phenotypes that fall between the extremes of selection for increased heat production and increased aerobic activity, whereas increased cellular ATP demand is a prerequisite for increased oxidative capacity.

Metabolic Dysfunction in Parkinson's Disease: Bioenergetics, Redox Homeostasis and Central Carbon Metabolism.

Science.gov (United States)

Anandhan, Annadurai; Jacome, Maria S; Lei, Shulei; Hernandez-Franco, Pablo; Pappa, Aglaia; Panayiotidis, Mihalis I; Powers, Robert; Franco, Rodrigo

2017-07-01

The loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of protein inclusions (Lewy bodies) are the pathological hallmarks of Parkinson's disease (PD). PD is triggered by genetic alterations, environmental/occupational exposures and aging. However, the exact molecular mechanisms linking these PD risk factors to neuronal dysfunction are still unclear. Alterations in redox homeostasis and bioenergetics (energy failure) are thought to be central components of neurodegeneration that contribute to the impairment of important homeostatic processes in dopaminergic cells such as protein quality control mechanisms, neurotransmitter release/metabolism, axonal transport of vesicles and cell survival. Importantly, both bioenergetics and redox homeostasis are coupled to neuro-glial central carbon metabolism. We and others have recently established a link between the alterations in central carbon metabolism induced by PD risk factors, redox homeostasis and bioenergetics and their contribution to the survival/death of dopaminergic cells. In this review, we focus on the link between metabolic dysfunction, energy failure and redox imbalance in PD, making an emphasis in the contribution of central carbon (glucose) metabolism. The evidence summarized here strongly supports the consideration of PD as a disorder of cell metabolism. Copyright © 2017 Elsevier Inc. All rights reserved.

Peripheral Receptor Mechanisms Underlying Orofacial Muscle Pain and Hyperalgesia

Science.gov (United States)

Saloman, Jami L.

Musculoskeletal pain conditions, particularly those associated with temporomandibular joint and muscle disorders (TMD) are severely debilitating and affect approximately 12% of the population. Identifying peripheral nociceptive mechanisms underlying mechanical hyperalgesia, a prominent feature of persistent muscle pain, could contribute to the development of new treatment strategies for the management of TMD and other muscle pain conditions. This study provides evidence of functional interactions between ligand-gated channels, P2X3 and TRPV1/TRPA1, in trigeminal sensory neurons, and proposes that these interactions underlie the development of mechanical hyperalgesia. In the masseter muscle, direct P2X3 activation, via the selective agonist αβmeATP, induced a dose- and time-dependent hyperalgesia. Importantly, the αβmeATP-induced hyperalgesia was prevented by pretreatment of the muscle with a TRPV1 antagonist, AMG9810, or the TRPA1 antagonist, AP18. P2X3 was co-expressed with both TRPV1 and TRPA1 in masseter muscle afferents confirming the possibility for intracellular interactions. Moreover, in a subpopulation of P2X3 /TRPV1 positive neurons, capsaicin-induced Ca2+ transients were significantly potentiated following P2X3 activation. Inhibition of Ca2+-dependent kinases, PKC and CaMKII, prevented P2X3-mechanical hyperalgesia whereas blockade of Ca2+-independent PKA did not. Finally, activation of P2X3 induced phosphorylation of serine, but not threonine, residues in TRPV1 in trigeminal sensory neurons. Significant phosphorylation was observed at 15 minutes, the time point at which behavioral hyperalgesia was prominent. Similar data were obtained regarding another nonselective cation channel, the NMDA receptor (NMDAR). Our data propose P2X3 and NMDARs interact with TRPV1 in a facilitatory manner, which could contribute to the peripheral sensitization underlying masseter hyperalgesia. This study offers novel mechanisms by which individual pro-nociceptive ligand

Drug metabolizing enzyme systems and their relationship to toxic mechanisms

International Nuclear Information System (INIS)

Boyd, M.R.; Ravindranath, V.; Burka, L.T.

1983-01-01

The metabolism and toxicity of 3-methylfuran (3-MF) are described. The major product of metabolic activation of 3-MF appears to be disemicarbazones. Cursory description of toxic effects of 3-MF on lung and kidneys are provided. 18 refs

Effects of grafting with pumpkin rootstock on carbohydrate metabolism in cucumber seedlings under Ca(NO3)2 stress.

Science.gov (United States)

Xing, Wen-wen; Li, Lin; Gao, Pan; Li, He; Shao, Qiao-sai; Shu, Sheng; Sun, Jin; Guo, Shi-rong

2015-02-01

This study investigated the effects of grafting on the carbohydrate status and the enzymes of carbohydrate metabolism in self-grafted and grafted cucumber seedlings using the salt-tolerant pumpkin rootstock 'Qingzhen 1' (Cucurbita maxima × Cucurbita moschata) under 80 mM Ca(NO3)2 stress for 6 d. The growth of self-grafted seedlings was significantly inhibited after the treatment of Ca(NO3)2 stress, whereas the inhibition of growth was alleviated in pumpkin rootstock-grafted seedlings. Ca(NO3)2 stress increased the contents of the total soluble sugar, sucrose and fructose, but decreased the starch content in rootstock-grafted leaves. However, compared with self-grafted plants, rootstock-grafted seedlings were observed with a higher content of sucrose and total soluble sugar (TSS) under salt stress. Rootstock-grafted seedlings exhibited higher activities of acid invertase (AI), neutral invertase (NI) and phosphate sucrose synthase (SPS) of sucrose metabolism in leaves than that of self-grafted seedlings under salinity. Moreover, the activities of fructokinase (FK), hexokinase (HK), phosphofructokinase (PFK) and pyruvate kinase (PK) of glycolysis were maintained at a higher level in leaves of rootstock-grafted seedlings after Ca(NO3)2 stress. Additionally, rootstock-grafting decrease the high percentage enhancement of key enzymes gene expression in glycolysis in the scion leaves of cucumber seedlings induced by salt stress. These results suggest that the rootstock-grafting improved salt tolerance, which might play a role in elevated sucrose metabolism and a glycolytic pathway regulated by the pumpkin rootstock. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Neuronal Calcium Signaling in Metabolic Regulation and Adaptation to Nutrient Stress.

Science.gov (United States)

Jayakumar, Siddharth; Hasan, Gaiti

2018-01-01

All organisms can respond physiologically and behaviorally to environmental fluxes in nutrient levels. Different nutrient sensing pathways exist for specific metabolites, and their inputs ultimately define appropriate nutrient uptake and metabolic homeostasis. Nutrient sensing mechanisms at the cellular level require pathways such as insulin and target of rapamycin (TOR) signaling that integrates information from different organ systems like the fat body and the gut. Such integration is essential for coordinating growth with development. Here we review the role of a newly identified set of integrative interneurons and the role of intracellular calcium signaling within these neurons, in regulating nutrient sensing under conditions of nutrient stress. A comparison of the identified Drosophila circuit and cellular mechanisms employed in this circuit, with vertebrate systems, suggests that the identified cell signaling mechanisms may be conserved for neural circuit function related to nutrient sensing by central neurons. The ideas proposed are potentially relevant for understanding the molecular basis of metabolic disorders, because these are frequently linked to nutritional stress.

Effect of dietary boron on growth performance, calcium and phosphorus metabolism, and bone mechanical properties in growing barrows.

Science.gov (United States)

Armstrong, T A; Spears, J W

2001-12-01

An experiment was conducted to evaluate the effects of dietary boron (B) on growth performance, bone mechanical properties, and calcium (Ca) and phosphorus (P) metabolism in pigs. Thirty-six barrows were weaned at approximately 21 d of age and randomly assigned to receive one of three dietary treatments. Treatments consisted of 1) low-B basal diet (control), 2) basal + 5 mg B/kg diet, and 3) basal + 15 mg B/kg diet. Boron was supplemented as sodium borate. Barrows remained on their respective experimental diets throughout the nursery (35 d) and growing (30 d) phases of production. Blood samples were obtained from each barrow at the end of each phase. Following the 30-d growing period, eight barrows per treatment were transferred to stainless steel metabolism crates. Barrows had an adjustment period of 7 d, followed by a 7-d total collection of urine and feces. All barrows were fed at 90% of the previous ad libitum grower intake of the control animals during the adjustment and collection periods. At the end of the 7-d collection period, barrows were killed and femurs and fibulas were harvested for the assessment of bone mechanical properties. During the nursery phase, ADG and ADFI were increased (P 0.05) by dietary B. These data indicate that B supplementation to pigs can increase growth and bone strength without greatly affecting Ca and P metabolism.

Developmental plasticity and epigenetic mechanisms underpinning metabolic and cardiovascular diseases.

Science.gov (United States)

Low, Felicia M; Gluckman, Peter D; Hanson, Mark A

2011-06-01

The importance of developmental factors in influencing the risk of later-life disease has a strong evidence base derived from multiple epidemiological, clinical and experimental studies in animals and humans. During early life, an organism is able to adjust its phenotypic development in response to environmental cues. Such developmentally plastic responses evolved as a fitness-maximizing strategy to cope with variable environments. There are now increasing data that these responses are, at least partially, underpinned by epigenetic mechanisms. A mismatch between the early and later-life environments may lead to inappropriate early life-course epigenomic changes that manifest in later life as increased vulnerability to disease. There is also growing evidence for the transgenerational transmission of epigenetic marks. This article reviews the evidence that susceptibility to metabolic and cardiovascular disease in humans is linked to changes in epigenetic marks induced by early-life environmental cues, and discusses the clinical, public health and therapeutic implications that arise.

Underlying mechanisms of improving physical activity behavior after rehabilitation

NARCIS (Netherlands)

van der Ploeg, H.P.; Streppel, K.R.; van der Beek, A.J.; van der Woude, L.H.V.; van Harten, W.H.; van Mechelen, W.

2008-01-01

Background: Regular physical activity is beneficial for the health and functioning of people with a disability. Effective components of successful physical activity promotion interventions should be identified and disseminated. Purpose: To study the underlying mechanisms of the combined sport

Underlying Mechanisms of Improving Physical Activity Behavior after Rehabilitation

NARCIS (Netherlands)

van der Ploeg, Hidde P.; Streppel, Kitty R.M.; van der Beek, Allard J.; Woude, Luc H.V.; van Harten, Willem H.; Vollenbroek-Hutten, Miriam Marie Rosé; van Mechelen, Willem

2008-01-01

Background: Regular physical activity is beneficial for the health and functioning of people with a disability. Effective components of successful physical activity promotion interventions should be identified and disseminated. Purpose: To study the underlying mechanisms of the combined sport

On the dynamic mechanical property and deformation mechanism of as-extruded Mg-Sn-Ca alloys under tension

International Nuclear Information System (INIS)

Huang, Qiuyan; Pan, Hucheng; Tang, Aitao; Ren, Yuping; Song, Bo; Qin, Gaowu; Zhang, Mingxing; Pan, Fusheng

2016-01-01

To further understand the deformation mechanism of magnesium alloys and expand their applications under dynamic conditions, the newly developed Mg-2Sn-1Ca alloy (TX21) is selected as the representative sample and tested under wide loading rate ranging from quasi-static to dynamic level (10"−"3–500/s). Both ultimate tensile strength and elongation of the as-extruded TX21 alloys increase with strain rate. Although twinning is accompanied due to the enhanced activity at higher strain rate, the preferential activation of dislocations is readily clarified and confirmed as the dominant deformation modes. Active interactions of pyramidal dislocations result in the higher strain hardening ability and could be correlated to the obviously positive strain-rate sensitivity for mechanical properties. Moreover, it is observed that the larger grain size and higher content of solute atoms dissolved in matrix would lead to the more active dislocations and twinning formations. The present results would provide insight into further understanding the deformation mechanism under dynamic rate loading and designing Mg alloy suitable for impact conditions.

On the dynamic mechanical property and deformation mechanism of as-extruded Mg-Sn-Ca alloys under tension

Energy Technology Data Exchange (ETDEWEB)

Huang, Qiuyan [National Engineering Research Center for Magnesium Alloys, Chongqing University, Chongqing 400044 (China); Pan, Hucheng [Key Laboratory for Anisotropy and Texture of Materials (Ministry of Education), Northeastern University, Shenyang 110819 (China); Tang, Aitao, E-mail: tat@cqu.edu.cn [National Engineering Research Center for Magnesium Alloys, Chongqing University, Chongqing 400044 (China); Ren, Yuping [Key Laboratory for Anisotropy and Texture of Materials (Ministry of Education), Northeastern University, Shenyang 110819 (China); Song, Bo [Faculty of Materials and Energy, Southwest University, Chongqing 400715 (China); Qin, Gaowu, E-mail: qingw@smm.neu.edu.cn [Key Laboratory for Anisotropy and Texture of Materials (Ministry of Education), Northeastern University, Shenyang 110819 (China); Zhang, Mingxing [School of Mechanical and Mining Engineering, University of Queensland, St Lucia, QLD 4072 (Australia); Pan, Fusheng [National Engineering Research Center for Magnesium Alloys, Chongqing University, Chongqing 400044 (China)

2016-05-10

To further understand the deformation mechanism of magnesium alloys and expand their applications under dynamic conditions, the newly developed Mg-2Sn-1Ca alloy (TX21) is selected as the representative sample and tested under wide loading rate ranging from quasi-static to dynamic level (10{sup −3}–500/s). Both ultimate tensile strength and elongation of the as-extruded TX21 alloys increase with strain rate. Although twinning is accompanied due to the enhanced activity at higher strain rate, the preferential activation of dislocations is readily clarified and confirmed as the dominant deformation modes. Active interactions of pyramidal dislocations result in the higher strain hardening ability and could be correlated to the obviously positive strain-rate sensitivity for mechanical properties. Moreover, it is observed that the larger grain size and higher content of solute atoms dissolved in matrix would lead to the more active dislocations and twinning formations. The present results would provide insight into further understanding the deformation mechanism under dynamic rate loading and designing Mg alloy suitable for impact conditions.

[FETAL PROGRAMMING OF METABOLIC DISORDERS].

Science.gov (United States)

Varadinova, M R; Metodieva, R; Boyadzhieva, N

2015-01-01

Our knowledge of fetal programming has developed notably over the years and recent data suggest that an unbalanced diet prior and during pregnancy can have early-onset and long-lasting consequences on the health of the offspring. Specific negative influences of high dietary glucose and lipid consumption, as well as undernutrition, are associated with development of metabolic syndrome, insulin resistance and diabetes in the offspring. The mechanisms underlying the effects of maternal hyperglycemia on the fetus may involve structural, metabolic and epigenetic changes. The aim of this review is to illustrate how adverse intrauterine environment may influence molecular modifications in the fetus and cause epigenetic alterations in particular. It has been demonstrated that prenatal epigenetic modifications may be linked to the pathogenesis and progression of the adult chronic disorders. Studies on epigenetic alterations will contribute to a better understanding of the long-term effects of in utero exposure and may open new perspectives for disease prevention and treatment.

Animal behavior models of the mechanisms underlying antipsychotic atypicality.

NARCIS (Netherlands)

Geyer, M.A.; Ellenbroek, B.A.

2003-01-01

This review describes the animal behavior models that provide insight into the mechanisms underlying the critical differences between the actions of typical vs. atypical antipsychotic drugs. Although many of these models are capable of differentiating between antipsychotic and other psychotropic

Metabolic Flux Analysis of Shewanella spp. Reveals Evolutionary Robustness in Central Carbon Metabolism

Energy Technology Data Exchange (ETDEWEB)

Tang, Yinjie J.; Martin, Hector Garcia; Dehal, Paramvir S.; Deutschbauer, Adam; Llora, Xavier; Meadows, Adam; Arkin, Adam; Keasling, Jay D.

2009-08-19

Shewanella spp. are a group of facultative anaerobic bacteria widely distributed in marine and fresh-water environments. In this study, we profiled the central metabolic fluxes of eight recently sequenced Shewanella species grown under the same condition in minimal med-ium with [3-13C] lactate. Although the tested Shewanella species had slightly different growth rates (0.23-0.29 h31) and produced different amounts of acetate and pyruvate during early exponential growth (pseudo-steady state), the relative intracellular metabolic flux distributions were remarkably similar. This result indicates that Shewanella species share similar regulation in regard to central carbon metabolic fluxes under steady growth conditions: the maintenance of metabolic robustness is not only evident in a single species under genetic perturbations (Fischer and Sauer, 2005; Nat Genet 37(6):636-640), but also observed through evolutionary related microbial species. This remarkable conservation of relative flux profiles through phylogenetic differences prompts us to introduce the concept of metabotype as an alternative scheme to classify microbial fluxomics. On the other hand, Shewanella spp. display flexibility in the relative flux profiles when switching their metabolism from consuming lactate to consuming pyruvate and acetate.

The Metabolic Role of Gut Microbiota in the Development of Nonalcoholic Fatty Liver Disease and Cardiovascular Disease

Directory of Open Access Journals (Sweden)

Marco Sanduzzi Zamparelli

2016-07-01

Full Text Available The prevalence of metabolic disorders, such as type 2 diabetes (T2D, obesity, and non-alcoholic fatty liver disease (NAFLD, which are common risk factors for cardiovascular disease (CVD, has dramatically increased worldwide over the last decades. Although dietary habit is the main etiologic factor, there is an imperfect correlation between dietary habits and the development of metabolic disease. Recently, research has focused on the role of the microbiome in the development of these disorders. Indeed, gut microbiota is implicated in many metabolic functions and an altered gut microbiota is reported in metabolic disorders. Here we provide evidence linking gut microbiota and metabolic diseases, focusing on the pathogenetic mechanisms underlying this association.

Integration of Environmental and Developmental (or Metabolic) Control of Seed Mass by Sugar and Ethylene Metabolisms in Arabidopsis.

Science.gov (United States)

Meng, Lai-Sheng; Xu, Meng-Ke; Wan, Wen; Wang, Jing-Yi

2018-04-04

In higher plants, seed mass is an important to evolutionary fitness. In this context, seedling establishment positively correlates with seed mass under conditions of environmental stress. Thus, seed mass constitutes an important agricultural trait. Here, we show loss-of-function of YODA (YDA), a MAPKK Kinase, and decreased seed mass, which leads to susceptibility to drought. Furthermore, we demonstrate that yda disrupts sugar metabolisms but not the gaseous plant hormone, ethylene. Our data suggest that the transcription factor EIN3 (ETHYLENE-INSENSITIVE3), integral to both sugar and ethylene metabolisms, physically interacts with YDA. Further, ein3-1 mutants exhibited increased seed mass. Genetic analysis indicated that YDA and EIN3 were integral to a sugar-mediated metabolism cascade which regulates seed mass by maternally controlling embryo size. It is well established that ethylene metabolism leads to the suppression of drought tolerance by the EIN3 mediated inhibition of CBF1, a transcription factor required for the expression genes of abiotic stress. Our findings help guide the synthesis of a model predicting how sugar/ethylene metabolisms and environmental stress are integrated at EIN3 to control both the establishment of drought tolerance and the production of seed mass. Collectively, these insights into the molecular mechanism underpinning the regulation of plant seed size may aid prospective breeding or design strategies to increase crop yield.

Mechanisms underlying the ameliorative property of lisinopril in progressive mesangioproliferative nephritis.

Science.gov (United States)

Shinosaki, Toshihiro; Miyai, Ikuko; Nomura, Yasuharu; Kobayashi, Tatsuo; Sunagawa, Norio; Kurihara, Hidetake

2002-08-01

The present study was performed to clarify the mechanism underlying the beneficial effects of lisinopril on chronic glomerulonephritis. Chronic glomerulonephritis was induced by a single injection of E30 monoclonal antibody (E30) recognizing Thy-1.1 antigen to unilaterally nephrectomized rats. E30 injection resulted in persistent massive proteinuria with a decrease in anionic charge sites on the glomerular basement membrane (GBM) at 8 weeks. Also, renal tissue from rats treated with E30 showed typical glomerulosclerosis and tubulointerstitial fibrosis. Lisinopril exerted a potent antiproteinuric effect and suppressed the progression of both glomerulosclerosis and tubulointerstitial fibrosis. Lisinopril recovered the reduced number of anionic charge sites on GBM, accounting for the positive action against massive proteinuria. Immunostaining for desmin revealed that lisinopril treatment prevented the injury of glomerular epithelial cells (GECs) occurring in the chronic nephritic stage. Also, the level of gene expression of transforming growth factor-beta (TGF-beta) and plasminogen activator inhibitor-1 (PAI-1) in the renal cortex were reduced, suggesting that lisinopril improved extracellular matrix (ECM) metabolism. These results indicated that proteinuria in Thy-1.1 antibody-induced chronic nephritis is associated with a decrease in anionic charge sites on GBM, and that the antiproteinuric effect of lisinopril is attributable to protection against GEC damage. Suppression of TGF-beta and PAI-1 expression contributed to the preventive effect of lisinopril on ECM deposition in renal tissue. Copyright 2002 S. Karger AG, Basel

Nutritional links to plausible mechanisms underlying pancreatic cancer: a conference report.

Science.gov (United States)

Hine, R Jean; Srivastava, Sudhir; Milner, John A; Ross, Sharon A

2003-11-01

Adenocarcinoma of the pancreas is one of most catastrophic and least understood of cancers. Evidence from clinical studies indicates that the development of pancreas cancer progresses over many years before symptoms appear. Most people with pancreatic cancer die within six months of diagnosis. The lack of early disease markers, the paucity of direct subject/patient interview data and limited availability of high quality biological samples have slowed progress toward identifying environmental and genetic disease risk factors. Much remains to be learned about the development of pancreatic cancer and about potential interventions for disease prevention. Epidemiological and mechanistic studies examining risk factors for pancreatic cancer supply little consistent or strong evidence to provide a cohesive prevention strategy for this cancer, but offer clues for future research concerning the prevention and early detection of this devastating disease. This Executive Summary provides background discussion on pancreatic cancer and summaries of each of the topics discussed at the workshop, including 1) Molecular aspects, 2) Dietary and other risk factors for pancreatic cancer, 3) The metabolic hypothesis for pancreatic cancer, 4) Preclinical studies on pancreatic cancer, 5) Methylation, 6) Oxidative stress and 7) Biomarker Profiling. This document also contains a compilation of recommendations for future research, concluding remarks, a list of speakers and participants attending the workshop, and a selection of key references to aid future research into nutritional links to mechanisms underlying pancreas cancer. The recommendations section suggests gaps in current knowledge and articulates future directions for this area of investigation.

Molecular mechanisms underlying the emergence of bacterial pathogens: an ecological perspective.

Science.gov (United States)

Bartoli, Claudia; Roux, Fabrice; Lamichhane, Jay Ram

2016-02-01

The rapid emergence of new bacterial diseases negatively affects both human health and agricultural productivity. Although the molecular mechanisms underlying these disease emergences are shared between human- and plant-pathogenic bacteria, not much effort has been made to date to understand disease emergences caused by plant-pathogenic bacteria. In particular, there is a paucity of information in the literature on the role of environmental habitats in which plant-pathogenic bacteria evolve and on the stress factors to which these microbes are unceasingly exposed. In this microreview, we focus on three molecular mechanisms underlying pathogenicity in bacteria, namely mutations, genomic rearrangements and the acquisition of new DNA sequences through horizontal gene transfer (HGT). We briefly discuss the role of these mechanisms in bacterial disease emergence and elucidate how the environment can influence the occurrence and regulation of these molecular mechanisms by directly impacting disease emergence. The understanding of such molecular evolutionary mechanisms and their environmental drivers will represent an important step towards predicting bacterial disease emergence and developing sustainable management strategies for crops. © 2015 BSPP AND JOHN WILEY & SONS LTD.

Myostatin induces mitochondrial metabolic alteration and typical apoptosis in cancer cells

Science.gov (United States)

Liu, Y; Cheng, H; Zhou, Y; Zhu, Y; Bian, R; Chen, Y; Li, C; Ma, Q; Zheng, Q; Zhang, Y; Jin, H; Wang, X; Chen, Q; Zhu, D

2013-01-01

Myostatin, a member of the transforming growth factor-β superfamily, regulates the glucose metabolism of muscle cells, while dysregulated myostatin activity is associated with a number of metabolic disorders, including muscle cachexia, obesity and type II diabetes. We observed that myostatin induced significant mitochondrial metabolic alterations and prolonged exposure of myostatin induced mitochondria-dependent apoptosis in cancer cells addicted to glycolysis. To address the underlying mechanism, we found that the protein levels of Hexokinase II (HKII) and voltage-dependent anion channel 1 (VDAC1), two key regulators of glucose metabolisms as well as metabolic stress-induced apoptosis, were negatively correlated. In particular, VDAC1 was dramatically upregulated in cells that are sensitive to myostatin treatment whereas HKII was downregulated and dissociated from mitochondria. Myostatin promoted the translocation of Bax from cytosol to mitochondria, and knockdown of VDAC1 inhibited myostatin-induced Bax translocation and apoptosis. These apoptotic changes can be partially rescued by repletion of ATP, or by ectopic expression of HKII, suggesting that perturbation of mitochondrial metabolism is causally linked with subsequent apoptosis. Our findings reveal novel function of myostatin in regulating mitochondrial metabolism and apoptosis in cancer cells. PMID:23412387

Metabolic phenotyping of various tea (Camellia sinensis L.) cultivars and understanding of their intrinsic metabolism.

Science.gov (United States)

Ji, Hyang-Gi; Lee, Yeong-Ran; Lee, Min-Seuk; Hwang, Kyeong Hwan; Kim, Eun-Hee; Park, Jun Seong; Hong, Young-Shick

2017-10-15

Recently, we selected three tea (Camellia sinensis) cultivars that are rich in taste, epigallocatechin-3-O-gallate (EGCG) and epigallocatechin-3-O-(3-O-methyl)-gallate (EGCG3″Me) and then cultivated them through asexual propagation by cutting in the same region. In the present study, proton nuclear magnetic resonance ( 1 H NMR)-based metabolomics was applied to characterize the metabotype and to understand the metabolic mechanism of these tea cultivars including wild type tea. Of the tea leaf metabolite variations, reverse associations of amino acid metabolism with catechin compound metabolism were found in the rich-taste, and EGCG- and EGCG3″Me-rich tea cultivars. Indeed, the metabolism of individual catechin compounds in the EGCG3″Me-rich cultivar differed from those of other tea cultivars. The current study highlights the distinct metabolism of various tea cultivars newly selected for cultivation and the important role of metabolomics in understanding the metabolic mechanism. Thus, comprehensive metabotyping is a useful method to assess and then develop a new plant cultivar. Copyright © 2017 Elsevier Ltd. All rights reserved.

Mechanisms by Which Metabolic Reprogramming in GSD1 Liver Generates a Favorable Tumorigenic Environment

Directory of Open Access Journals (Sweden)

Monika Gjorgjieva PhD Student

2016-11-01

Full Text Available Glycogen storage disease type 1 (GSD1 is an inherited disorder caused by impaired glucose 6-phosphatase activity. This impairment translates into the inhibition of endogenous glucose production and the subsequent accumulation of cellular glucose 6-phosphate. Excess glucose 6-phosphate enhances glycolysis, increases the production of fatty acids, uric acid, and lactate, causes hepatomegaly due to glycogen and lipid accumulation, and finally results in liver tumor development. Although the exact mechanisms of tumorigenesis in patients with GSD1 remain unclear, GSD1 hepatocytes undergo a Warburg-like metabolic switch. The consequent hyperactivation of specific metabolic pathways renders GSD1 hepatocytes susceptible to tumor development, presumably by providing the building blocks and energy required for cell proliferation. In addition to this, enhanced apoptosis in GSD1 may promote mitotic activity and hence result in DNA replication errors, thereby contributing to tumorigenesis. Increased carbohydrate responsive element-binding protein (ChREBP and mammalian target of rapamycin (mTOR activity and impaired AMP-activated protein kinase (AMPK function likely play key roles in these pro-oncogenic processes.

Proteomic Characterization of Armillaria mellea Reveals Oxidative Stress Response Mechanisms and Altered Secondary Metabolism Profiles

Directory of Open Access Journals (Sweden)

Cassandra Collins

2017-09-01

Full Text Available Armillaria mellea is a major plant pathogen. Yet, the strategies the organism uses to infect susceptible species, degrade lignocellulose and other plant material and protect itself against plant defences and its own glycodegradative arsenal are largely unknown. Here, we use a combination of gel and MS-based proteomics to profile A. mellea under conditions of oxidative stress and changes in growth matrix. 2-DE and LC-MS/MS were used to investigate the response of A. mellea to H2O2 and menadione/FeCl3 exposure, respectively. Several proteins were detected with altered abundance in response to H2O2, but not menadione/FeCl3 (i.e., valosin-containing protein, indicating distinct responses to these different forms of oxidative stress. One protein, cobalamin-independent methionine synthase, demonstrated a common response in both conditions, which may be a marker for a more general stress response mechanism. Further changes to the A. mellea proteome were investigated using MS-based proteomics, which identified changes to putative secondary metabolism (SM enzymes upon growth in agar compared to liquid cultures. Metabolomic analyses revealed distinct profiles, highlighting the effect of growth matrix on SM production. This establishes robust methods by which to utilize comparative proteomics to characterize this important phytopathogen.

Tuning of redox regulatory mechanisms, reactive oxygen species and redox homeostasis under salinity stress

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Hossain eSazzad

2016-05-01

Full Text Available Soil salinity is a crucial environmental constraint which limits biomass production at many sites on a global scale. Saline growth conditions cause osmotic and ionic imbalances, oxidative stress and perturb metabolism, e.g. the photosynthetic electron flow. The plant ability to tolerate salinity is determined by multiple biochemical and physiological mechanisms protecting cell functions, in particular by regulating proper water relations and maintaining ion homeostasis. Redox homeostasis is a fundamental cell property. Its regulation includes control of reactive oxygen species (ROS generation, sensing deviation from and readjustment of the cellular redox state. All these redox related functions have been recognized as decisive factors in salinity acclimation and adaptation. This review focuses on the core response of plants to overcome the challenges of salinity stress through regulation of ROS generation and detoxification systems and to maintain redox homeostasis. Emphasis is given to the role of NADH oxidase (RBOH, alternative oxidase (AOX, the plastid terminal oxidase (PTOX and the malate valve with the malate dehydrogenase isoforms under salt stress. Overwhelming evidence assigns an essential auxiliary function of ROS and redox homeostasis to salinity acclimation of plants.

β-Hydroxybutyrate Boosts Mitochondrial and Neuronal Metabolism but is not Preferred Over Glucose Under Activated Conditions.

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Achanta, Lavanya B; Rowlands, Benjamin D; Thomas, Donald S; Housley, Gary D; Rae, Caroline D

2017-06-01

The ketone body, β-hydroxybutyrate (βOHB), is metabolised by the brain alongside the mandatory brain fuel glucose. To examine the extent and circumstances by which βOHB can supplement glucose metabolism, we studied guinea pig cortical brain slices using increasing concentrations of [U- 13 C]D-βOHB in conjunction with [1- 13 C]D-glucose under conditions of normo- and hypoglycaemia, as well as under high potassium (40 mmol/L K + ) depolarization in normo- and hypoglycaemic conditions. The contribution of βOHB to synthesis of GABA was also probed by inhibiting the synthesis of glutamine, a GABA precursor, with methionine sulfoximine (MSO). [U- 13 C]D-βOHB at lower concentrations (0.25 and 1.25 mmol/L) stimulated mitochondrial metabolism, producing greater total incorporation of label into glutamate and GABA but did not have a similar effect in the cytosolic compartment where labelling of glutamine was reduced at 1.25 mmol/L [U- 13 C]D-βOHB. At higher concentrations (2.5 mmol/L) [U- 13 C]D-βOHB inhibited metabolism of [1- 13 C]D-glucose, and reduced total label incorporation and total metabolite pools. When glucose levels were reduced, βOHB was able to partially restore the loss of glutamate and GABA caused by hypoglycaemia, but was not able to supplement levels of lactate, glutamine or alanine or to prevent the increase in aspartate. Under depolarizing conditions glucose was the preferred substrate over βOHB, even in hypoglycaemic conditions where comparatively less βOHB was incorporated except into aspartate isotopomers. Inhibition of glutamine synthesis with MSO had no significant effect on incorporation of label from [U- 13 C]D-βOHB into GABA C2,1 indicating that the majority of this GABA was synthesized in GABAergic neurons from [U- 13 C]D-βOHB rather than from Gln C4,5 imported from astrocytes.

The metabolic impact of methamphetamine on the systemic metabolism of rats and potential markers of methamphetamine abuse.

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Zheng, Tian; Liu, Linsheng; Shi, Jian; Yu, Xiaoyi; Xiao, Wenjing; Sun, Runbing; Zhou, Yahong; Aa, Jiye; Wang, Guangji

2014-07-01

Although the stimulating and psychotropic effects of methamphetamine (METH) on the nervous system are well documented, the impact of METH abuse on biological metabolism and the turnover of peripheral transmitters are poorly understood. Metabolomics has the potential to reveal the effect of METH abuse on systemic metabolism and potential markers suggesting the underlying mechanism of toxicity. In this study, male Sprague Dawley rats were intraperitoneally injected with METH at escalating doses of mg kg(-1) for 5 consecutive days and then were withdrawn for 2 days. The metabolites in the serum and urine were profiled and the systemic effects of METH on metabolic pathways were evaluated. Multivariate statistical analysis showed that METH caused distinct deviations, whereas the withdrawal of METH restored the metabolic patterns towards baseline. METH administration elevated energy metabolism, which was manifested by the distinct depletion of branched-chain amino acids, accelerated tricarboxylic-acid cycle and lipid metabolism, reduced serum glycerol-3-phosphate, and elevated serum and urinary 3-hydroxybutyrate and urinary glycerol. In addition to the increased serum levels of the excitatory amino acids glutamate and aspartate (the inhibitory neurotransmitters in the brain), a marked decline in serum alanine and glycine after METH treatment suggested the activation and decreased inhibition of the nervous system and hence elevated nervous activity. Withdrawal of METH for 2 days efficiently restored all but a few metabolites to baseline, including serum creatinine, citrate, 2-ketoglutarate, and urinary lactate. Therefore, these metabolites are potential markers of METH use, and they may be used to facilitate the diagnosis of METH abuse.

Studies on the utility and mechanism of the V-79 cell metabolic cooperation assay for tumor promoters

International Nuclear Information System (INIS)

Hartman, T.G.

1985-01-01

Cigarette smoke condensate and its fractions were tested for activity in the V-79 Metabolic Cooperation Assay to determine the usefulness of the assay for analysis of a complex mixture and to compare the results obtained with previously conducted in vivo promoter assays. The whole condensate and several of its fractions were positive in the assay. In general, the Metabolic Cooperation Assay results were comparable to previously published results obtained on mouse skin. The effect of cell density, phorbol 12-myrystate-13-acetate (PMA) exposure time, concentration, pre-exposure and binding activity on the recovery of mutant V-79 Chinese hamster lung fibroblasts in the Metabolic Cooperation Assay was determined. A PMA exposure interval of only 1 minute resulted in maximum recovery of mutant cells. PMA began to inhibit metabolic cooperation at an exposure concentration of 0.1 ng/ml. Pre-exposure of cells to PMA increased the recovery of both post-PMA-treated and non-treated mutant cells in a dose-dependent manner. 3 H-PMA was rapidly bound to or taken up by the V-79 cells under assay conditions. The effect of calcium antagonists and representative compounds from several classes of anti-promoters including anti-inflammatory sterols, protease inhibitors, retinoids and cyclic nucleotides on metabolic determined. Each compound was tested for its effect on metabolic cooperation and also for its ability to reverse or modify the inhibitory properties of PMA on inter-cellular communication. Of all the compounds tested only cyclic adenosine monophosphate (cAMP) was able to antagonize the inhibitory effect of PMA

Leptin and the central nervous system control of glucose metabolism.

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Morton, Gregory J; Schwartz, Michael W

2011-04-01

The regulation of body fat stores and blood glucose levels is critical for survival. This review highlights growing evidence that leptin action in the central nervous system plays a key role in both processes. Investigation into underlying mechanisms has begun to clarify the physiological role of leptin in the control of glucose metabolism and raises interesting new possibilities for the treatment of diabetes and related disorders.

A role of the transcriptional regulator LldR (NCgl2814) in glutamate metabolism under biotin-limited conditions in Corynebacterium glutamicum.

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Supkulsutra, Tanyanut; Maeda, Tomoya; Kumagai, Kosuke; Wachi, Masaaki

2013-01-01

Corynebacterium glutamicum is a Gram-positive, rod-shaped, aerobic bacterium used for the fermentative production of L-glutamate. LldR (NCgl2814) is known as a repressor for ldhA and lldD encoding lactate dehydrogenases. LdhA is responsible for production of L-lactate, while LldD is for its assimilation. Since L-lactate production was observed as a by-product of glutamate production under biotin-limited conditions, LldR might play a regulatory role in the glutamate metabolism. Here for the first time, we investigated effects of overproduction or deletion of LldR on the glutamate metabolism under biotin-limited conditions in C. glutamicum. It was found that glutamate production under biotin-limited conditions was decreased by overproduction of LldR. In the wild-type cells, L-lactate was produced in the first 24 h and it was re-consumed thereafter. On the other hand, in the overproduced cells, L-lactate was produced like the wild type, but it was not re-consumed. This means that L-lactate assimilation, which is catalyzed by LldD, was suppressed by the overproduction of LldR, but L-lactate production, which is catalyzed by LdhA, was not affected, indicating that LldR mainly controls the expression of lldD but not of ldhA under biotin-limited conditions. This was confirmed by quantitative real-time RT-PCR. From these results, it is suggested that L-lactate metabolism, which is controlled by LldR, has a buffering function of the pyruvate pool for glutamate production.

Metabolic pathway analysis of Scheffersomyces (Pichia) stipitis: effect of oxygen availability on ethanol synthesis and flux distributions.

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Unrean, Pornkamol; Nguyen, Nhung H A

2012-06-01

Elementary mode analysis (EMA) identifies all possible metabolic states of the cell metabolic network. Investigation of these states can provide a detailed insight into the underlying metabolism in the cell. In this study, the flux states of Scheffersomyces (Pichia) stipitis metabolism were examined. It was shown that increasing oxygen levels led to a decrease of ethanol synthesis. This trend was confirmed by experimental evaluation of S. stipitis in glucose-xylose fermentation. The oxygen transfer rate for an optimal ethanol production was 1.8 mmol/l/h, which gave the ethanol yield of 0.40 g/g and the ethanol productivity of 0.25 g/l/h. For a better understanding of the cell's regulatory mechanism in response to oxygenation levels, EMA was used to examine metabolic flux patterns under different oxygen levels. Up- and downregulation of enzymes in the network during the change of culturing condition from oxygen limitation to oxygen sufficiency were identified. The results indicated the flexibility of S. stipitis metabolism to cope with oxygen availability. In addition, relevant genetic targets towards improved ethanol-producing strains under all oxygenation levels were identified. These targeted genes limited the metabolic functionality of the cell to function according to the most efficient ethanol synthesis pathways. The presented approach is promising and can contribute to the development of culture optimization and strain engineers for improved lignocellulosic ethanol production by S. stipitis.

Effect of alternate energy substrates on mammalian brain metabolism during ischemic events.

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Koppaka, S S; Puchowicz; LaManna, J C; Gatica, J E

2008-01-01

Regulation of brain metabolism and cerebral blood flow involves complex control systems with several interacting variables at both cellular and organ levels. Quantitative understanding of the spatially and temporally heterogeneous brain control mechanisms during internal and external stimuli requires the development and validation of a computational (mathematical) model of metabolic processes in brain. This paper describes a computational model of cellular metabolism in blood-perfused brain tissue, which considers the astrocyte-neuron lactate-shuttle (ANLS) hypothesis. The model structure consists of neurons, astrocytes, extra-cellular space, and a surrounding capillary network. Each cell is further compartmentalized into cytosol and mitochondria. Inter-compartment interaction is accounted in the form of passive and carrier-mediated transport. Our model was validated against experimental data reported by Crumrine and LaManna, who studied the effect of ischemia and its recovery on various intra-cellular tissue substrates under standard diet conditions. The effect of ketone bodies on brain metabolism was also examined under ischemic conditions following cardiac resuscitation through our model simulations. The influence of ketone bodies on lactate dynamics on mammalian brain following ischemia is studied incorporating experimental data.

translin Is Required for Metabolic Regulation of Sleep.

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Murakami, Kazuma; Yurgel, Maria E; Stahl, Bethany A; Masek, Pavel; Mehta, Aradhana; Heidker, Rebecca; Bollinger, Wesley; Gingras, Robert M; Kim, Young-Joon; Ja, William W; Suter, Beat; DiAngelo, Justin R; Keene, Alex C

2016-04-04

Dysregulation of sleep or feeding has enormous health consequences. In humans, acute sleep loss is associated with increased appetite and insulin insensitivity, while chronically sleep-deprived individuals are more likely to develop obesity, metabolic syndrome, type II diabetes, and cardiovascular disease. Conversely, metabolic state potently modulates sleep and circadian behavior; yet, the molecular basis for sleep-metabolism interactions remains poorly understood. Here, we describe the identification of translin (trsn), a highly conserved RNA/DNA binding protein, as essential for starvation-induced sleep suppression. Strikingly, trsn does not appear to regulate energy stores, free glucose levels, or feeding behavior suggesting the sleep phenotype of trsn mutant flies is not a consequence of general metabolic dysfunction or blunted response to starvation. While broadly expressed in all neurons, trsn is transcriptionally upregulated in the heads of flies in response to starvation. Spatially restricted rescue or targeted knockdown localizes trsn function to neurons that produce the tachykinin family neuropeptide Leucokinin. Manipulation of neural activity in Leucokinin neurons revealed these neurons to be required for starvation-induced sleep suppression. Taken together, these findings establish trsn as an essential integrator of sleep and metabolic state, with implications for understanding the neural mechanism underlying sleep disruption in response to environmental perturbation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Metabolic state alters economic decision making under risk in humans.

OpenAIRE

Mkael Symmonds; Julian J Emmanuel; Megan E Drew; Rachel L Batterham; Raymond J Dolan

2010-01-01

Background Animals' attitudes to risk are profoundly influenced by metabolic state (hunger and baseline energy stores). Specifically, animals often express a preference for risky (more variable) food sources when below a metabolic reference point (hungry), and safe (less variable) food sources when sated. Circulating hormones report the status of energy reserves and acute nutrient intake to widespread targets in the central nervous system that regulate feeding behaviour, including brain regio...

Potential mechanisms underlying response to effects of the fungicide pyrimethanil from gene expression profiling in Saccharomyces cerevisiae.

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Gil, Fátima N; Becker, Jörg D; Viegas, Cristina A

2014-06-11

Pyrimethanil is a fungicide mostly applied in vineyards. When misused, residue levels detected in grape must or in the environment may be of concern. The present work aimed to analyze mechanisms underlying response to deleterious effects of pyrimethanil in the eukaryotic model Saccharomyces cerevisiae. Pyrimethanil concentration-dependent effects at phenotypic (inhibition of growth) and transcriptomic levels were examined. For transcriptional profiling, analysis focused on two sublethal exposure conditions that inhibited yeast growth by 20% or 50% compared with control cells not exposed to the fungicide. Gene expression modifications increased with the magnitude of growth inhibition, in numbers and fold-change of differentially expressed genes and in diversity of over-represented functional categories. These included mostly biosynthesis of arginine and sulfur amino acids metabolism, as well as energy conservation, antioxidant response, and multidrug transport. Several pyrimethanil-responsive genes encoded proteins sharing significant homology with proteins from phytopathogenic fungi and ecologically relevant higher eukaryotes.

Metabolic Syndrome Is Associated with Atrial Electrical and Mechanical Dysfunction

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Yilmaz, Hale; Özcan, Kazım Serhan; Sayar, Nurten; Kemaloglu, Tugba; Gungor, Baris; Erer, Betul; Yilmaz, Mehmet; Gurkan, Ufuk; Cakmak, Nazmiye; Oz, Dilaver; Calik, Ali Nazmi; Bolca, Osman

2015-01-01

Objective In this study, we aimed to investigate the left atrial (LA) electrical and mechanical functions in patients with metabolic syndrome (MetS). Subjects and Methods The study population consisted of 87 patients with MetS and 67 controls. Intra-atrial and interatrial electromechanical delays (EDs) were measured with tissue Doppler imaging. P-wave dispersion (Pd) was calculated from the 12-lead electrocardiograms. LA volumes were measured echocardiographically by the biplane area-length method. Results Intra-atrial and interatrial EDs and Pd were significantly higher in patients with MetS (10.3 ± 6.3, 21.0 ± 11.5 and 41.7 ± 10.8) than in controls (7.4 ± 5.5, 12.3 ± 10.4 and 29.2 ± 7.4; p = 0.003, p < 0.001 and p < 0.001, respectively). The LA preatrial contraction volume and active emptying volumes were higher in this population, but the LA passive emptying fraction was lower. In the multivariate linear regression analysis, the presence of MetS, LA active emptying volume and left ventricular early diastolic (E) wave velocity/late diastolic (A) wave velocity (E/A) ratios were independent correlates of interatrial ED (p = 0.002, p = 0.001 and p = 0.025, respectively). Conclusions This study showed that intra-atrial and interatrial EDs and Pd were prolonged and LA mechanical functions were impaired in patients with MetS. PMID:25592764

MECHANISMS IN ENDOCRINOLOGY: The sexually dimorphic role of androgens in human metabolic disease.

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Schiffer, Lina; Kempegowda, Punith; Arlt, Wiebke; O'Reilly, Michael W

2017-09-01

Female androgen excess and male androgen deficiency manifest with an overlapping adverse metabolic phenotype, including abdominal obesity, insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver disease and an increased risk of cardiovascular disease. Here, we review the impact of androgens on metabolic target tissues in an attempt to unravel the complex mechanistic links with metabolic dysfunction; we also evaluate clinical studies examining the associations between metabolic disease and disorders of androgen metabolism in men and women. We conceptualise that an equilibrium between androgen effects on adipose tissue and skeletal muscle underpins the metabolic phenotype observed in female androgen excess and male androgen deficiency. Androgens induce adipose tissue dysfunction, with effects on lipid metabolism, insulin resistance and fat mass expansion, while anabolic effects on skeletal muscle may confer metabolic benefits. We hypothesise that serum androgen concentrations observed in female androgen excess and male hypogonadism are metabolically disadvantageous, promoting adipose and liver lipid accumulation, central fat mass expansion and insulin resistance. © 2017 The authors.

Systematic Sensitivity Analysis of Metabolic Controllers During Reductions in Skeletal Muscle Blood Flow

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Radhakrishnan, Krishnan; Cabrera, Marco

2000-01-01

An acute reduction in oxygen delivery to skeletal muscle is generally associated with profound derangements in substrate metabolism. Given the complexity of the human bioenergetic system and its components, it is difficult to quantify the interaction of cellular metabolic processes to maintain ATP homeostasis during stress (e.g., hypoxia, ischemia, and exercise). Of special interest is the determination of mechanisms relating tissue oxygenation to observed metabolic responses at the tissue, organ, and whole body levels and the quantification of how changes in oxygen availability affect the pathways of ATP synthesis and their regulation. In this study, we apply a previously developed mathematical model of human bioenergetics to study effects of ischemia during periods of increased ATP turnover (e.g., exercise). By using systematic sensitivity analysis the oxidative phosphorylation rate was found to be the most important rate parameter affecting lactate production during ischemia under resting conditions. Here we examine whether mild exercise under ischemic conditions alters the relative importance of pathways and parameters previously obtained.

Analysis of rabbit intervertebral disc physiology based on water metabolism. II. Changes in normal intervertebral discs under axial vibratory load

International Nuclear Information System (INIS)

Hirano, N.; Tsuji, H.; Ohshima, H.; Kitano, S.; Itoh, T.; Sano, A.

1988-01-01

Metabolic changes induced by axial vibratory load to the spine were investigated based on water metabolism in normal intervertebral discs of rabbits with or without pentobarbital anesthesia. Tritiated water concentration in the intervertebral discs of unanesthetized rabbits was reduced remarkably by axial vibration for 30 minutes using the vibration machine developed for this study. Repeated vibratory load for 18 and 42 hours duration showed the recovery of 3 H 2 O concentration of the intervertebral disc without anesthesia. Computer simulation suggested a reduction of blood flow surrounding the intervertebral disc following the vibration stress. However, no reduction of the 3 H 2 O concentration in the intervertebral disc was noted under anesthesia. Emotional stress cannot be excluded as a factor in water metabolism in the intervertebral disc

A potential mechanism of energy-metabolism oscillation in an aerobic chemostat culture of the yeast Saccharomyces cerevisiae.

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Xu, Zhaojun; Tsurugi, Kunio

2006-04-01

The energy-metabolism oscillation in aerobic chemostat cultures of yeast is a periodic change of the respiro-fermentative and respiratory phase. In the respiro-fermentative phase, the NADH level was kept high and respiration was suppressed, and glucose was anabolized into trehalose and glycogen at a rate comparable to that of catabolism. On the transition to the respiratory phase, cAMP levels increased triggering the breakdown of storage carbohydrates and the increased influx of glucose into the glycolytic pathway activated production of glycerol and ethanol consuming NADH. The resulting increase in the NAD(+)/NADH ratio stimulated respiration in combination with a decrease in the level of ATP, which was consumed mainly in the formation of biomass accompanying budding, and the accumulated ethanol and glycerol were gradually degraded by respiration via NAD(+)-dependent oxidation to acetate and the respiratory phase ceased after the recovery of NADH and ATP levels. However, the mRNA levels of both synthetic and degradative enzymes of storage carbohydrates were increased around the early respiro-fermentative phase, when storage carbohydrates are being synthesized, suggesting that the synthetic enzymes were expressed directly as active forms while the degradative enzymes were activated late by cAMP. In summary, the energy-metabolism oscillation is basically regulated by a feedback loop of oxido-reductive reactions of energy metabolism mediated by metabolites like NADH and ATP, and is modulated by metabolism of storage carbohydrates in combination of post-translational and transcriptional regulation of the related enzymes. A potential mechanism of energy-metabolism oscillation is proposed.

Quantitative Raman Spectroscopy to monitor microbial metabolism in situ under pressure

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Picard, A.; Daniel, I.; Oger, P.

2006-12-01

Although high hydrostatic pressure (HHP) biotopes are ubiquitous on Earth, little is known about the metabolism of piezophile organisms. Cell culture under HHP can be technically challenging, and equipment- dependent. In addition, the depressurization step required for analysis can lead to erroneous data. Therefore, to understand how piezophile organisms react to pressure, it is crucial to be able to monitor their activity in situ under HHP. We developed the use of Quantitative Raman Spectroscopy (QRS, 1) to monitor in situ the metabolism of organic molecules. This technique is based on the specific spectral signature of an analyte from which its concentration can be deduced. An application of this technique to the monitoring of alcoholic fermentation by the piezotolerant micro-eucaryote Saccharomyces cerevisiae is presented. Ethanol fermentation from glucose was monitored during 24h from ambient P up to 100 MPa in the low- pressure Diamond Anvil Cell (lpDAC, 2). The experimental compression chamber consisted in a 300 μm-thick Ni gasket in which a 500 μm-diameter hole was drilled. Early-stationnary yeast cells were inoculated into fresh low-fluorescence medium containing 0.15 M of glucose. Ethanol concentration was determined in situ by QRS using the symmetric C-C stretching mode of ethanol at 878 cm-1 normalizing the data to the intensity of the sulfate S-O stretching mode at 980 cm-1. In our setup, the detection limit of ethanol is lower than 0.05 mM with a precision below 1%. At ambient P, ethanol production in the lpDAC and in control experiments proceeds with the same kinetics. Thus, yeast is not affected by its confinement. This is further confirmed by its ability to bud with a generation time similar to control experiments performed in glass tubes at ambient pressure inside the lpDAC. Ethanol production by yeast occurs to at least 65 MPa (3). At 10 MPa, fermentation proceeds 3 times faster than at ambient P. Fermentation rates decrease linearly from 20 to

Using a genome-scale metabolic network model to elucidate the mechanism of chloroquine action in Plasmodium falciparum

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Shivendra G. Tewari

2017-08-01

Full Text Available Chloroquine, long the default first-line treatment against malaria, is now abandoned in large parts of the world because of widespread drug-resistance in Plasmodium falciparum. In spite of its importance as a cost-effective and efficient drug, a coherent understanding of the cellular mechanisms affected by chloroquine and how they influence the fitness and survival of the parasite remains elusive. Here, we used a systems biology approach to integrate genome-scale transcriptomics to map out the effects of chloroquine, identify targeted metabolic pathways, and translate these findings into mechanistic insights. Specifically, we first developed a method that integrates transcriptomic and metabolomic data, which we independently validated against a recently published set of such data for Krebs-cycle mutants of P. falciparum. We then used the method to calculate the effect of chloroquine treatment on the metabolic flux profiles of P. falciparum during the intraerythrocytic developmental cycle. The model predicted dose-dependent inhibition of DNA replication, in agreement with earlier experimental results for both drug-sensitive and drug-resistant P. falciparum strains. Our simulations also corroborated experimental findings that suggest differences in chloroquine sensitivity between ring- and schizont-stage P. falciparum. Our analysis also suggests that metabolic fluxes that govern reduced thioredoxin and phosphoenolpyruvate synthesis are significantly decreased and are pivotal to chloroquine-based inhibition of P. falciparum DNA replication. The consequences of impaired phosphoenolpyruvate synthesis and redox metabolism are reduced carbon fixation and increased oxidative stress, respectively, both of which eventually facilitate killing of the parasite. Our analysis suggests that a combination of chloroquine (or an analogue and another drug, which inhibits carbon fixation and/or increases oxidative stress, should increase the clearance of P

Mechanisms underlying UV-induced immune suppression

International Nuclear Information System (INIS)

Ullrich, Stephen E.

2005-01-01

Skin cancer is the most prevalent form of human neoplasia. Estimates suggest that in excess of one million new cases of skin cancer will be diagnosed this year alone in the United States (www.cancer.org/statistics). Fortunately, because of their highly visible location, skin cancers are more rapidly diagnosed and more easily treated than other types of cancer. Be that as it may, approximately 10,000 Americans a year die from skin cancer. The cost of treating non-melanoma skin cancer is estimated to be in excess of US$ 650 million a year [J.G. Chen, A.B. Fleischer, E.D. Smith, C. Kancler, N.D. Goldman, P.M. Williford, S.R. Feldman, Cost of non-melanoma skin cancer treatment in the United States, Dermatol. Surg. 27 (2001) 1035-1038], and when melanoma is included, the estimated cost of treating skin cancer in the United States is estimated to rise to US$ 2.9 billion annually (www.cancer.org/statistics). Because the morbidity and mortality associated with skin cancer is a major public health problem, it is important to understand the mechanisms underlying skin cancer development. The primary cause of skin cancer is the ultraviolet (UV) radiation found in sunlight. In addition to its carcinogenic potential, UV radiation is also immune suppressive. In fact, data from studies with both experimental animals and biopsy proven skin cancer patients suggest that there is an association between the immune suppressive effects of UV radiation and its carcinogenic potential. The focus of this manuscript will be to review the mechanisms underlying the induction of immune suppression following UV exposure. Particular attention will be directed to the role of soluble mediators in activating immune suppression

Mitochondrial translocation of Nur77 induced by ROS contributed to cardiomyocyte apoptosis in metabolic syndrome.

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Xu, Aibin; Liu, Jingyi; Liu, Peilin; Jia, Min; Wang, Han; Tao, Ling

2014-04-18

Metabolic syndrome is a major risk factor for cardiovascular diseases, and increased cardiomyocyte apoptosis which contributes to cardiac dysfunction after myocardial ischemia/reperfusion (MI/R) injury. Nur77, a nuclear orphan receptor, is involved in such various cellular events as apoptosis, proliferation, and glucose and lipid metabolism in several cell types. Apoptosis is positively correlated with mitochondrial translocation of Nur77 in the cancer cells. However, the roles of Nur77 on cardiac myocytes in patients with metabolic syndrome remain unclear. The objective of this study was to determine whether Nur77 may contribute to cardiac apoptosis in patients with metabolic syndrome after I/R injury, and, if so, to identify the underlying molecular mechanisms responsible. We used leptin-deficient (ob/ob) mice to make metabolic syndrome models. In this report, we observed that, accompanied by the substantial decline in apoptosis inducer Nur77, MI/R induced cardiac dysfunction was manifested as cardiomyopathy and increased ROS. Using the neonatal rat cardiac myocytes cultured in a high-glucose and high-fat medium, we found that excessive H2O2 led to the significant alteration in mitochondrial membrane potential and translocation of Nur77 from the nucleus to the mitochondria. However, inhibition of the relocation of Nur77 to mitochondria via Cyclosporin A reversed the changes in membrane potential mediated by H2O2 and reduced myocardial cell injury. Therefore, these data provide a potential underlying mechanism for cardiac dysfunction in metabolic syndrome and the suppression of Nur77 translocation may provide an effective approach to reduce cardiac injury in the process. Copyright © 2014 Elsevier Inc. All rights reserved.

Mechanisms Underlying Stress Fracture and the Influence of Sex and Race/Ethnicity

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2017-10-01

AWARD NUMBER: W81XWH-16-1-0652 TITLE: Mechanisms Underlying Stress Fracture and the Influence of Sex and Race/Ethnicity PRINCIPAL INVESTIGATOR...5a. CONTRACT NUMBER W81XWH-16-1-0652 Mechanisms Underlying Stress Fracture and the Influence of Sex and Race/Ethnicity 5b. GRANT NUMBER W81XWH...to stress fracture risk. In particular, in Study 1, we will perform advanced skeletal imaging along with gait-assessments in subjects with history of

Transcriptome Analysis of Three Sheep Intestinal Regions reveals Key Pathways and Hub Regulatory Genes of Large Intestinal Lipid Metabolism.

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Chao, Tianle; Wang, Guizhi; Ji, Zhibin; Liu, Zhaohua; Hou, Lei; Wang, Jin; Wang, Jianmin

2017-07-13

The large intestine, also known as the hindgut, is an important part of the animal digestive system. Recent studies on digestive system development in ruminants have focused on the rumen and the small intestine, but the molecular mechanisms underlying sheep large intestine metabolism remain poorly understood. To identify genes related to intestinal metabolism and to reveal molecular regulation mechanisms, we sequenced and compared the transcriptomes of mucosal epithelial tissues among the cecum, proximal colon and duodenum. A total of 4,221 transcripts from 3,254 genes were identified as differentially expressed transcripts. Between the large intestine and duodenum, differentially expressed transcripts were found to be significantly enriched in 6 metabolism-related pathways, among which PPAR signaling was identified as a key pathway. Three genes, CPT1A, LPL and PCK1, were identified as higher expression hub genes in the large intestine. Between the cecum and colon, differentially expressed transcripts were significantly enriched in 5 lipid metabolism related pathways, and CEPT1 and MBOAT1 were identified as hub genes. This study provides important information regarding the molecular mechanisms of intestinal metabolism in sheep and may provide a basis for further study.

Overexpression of the human DEK oncogene reprograms cellular metabolism and promotes glycolysis

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Watanabe, Miki; Muraleedharan, Ranjithmenon; Lambert, Paul F.; Lane, Andrew N.; Romick-Rosendale, Lindsey E.; Wells, Susanne I.

2017-01-01

The DEK oncogene is overexpressed in many human malignancies including at early tumor stages. Our reported in vitro and in vivo models of squamous cell carcinoma have demonstrated that DEK contributes functionally to cellular and tumor survival and to proliferation. However, the underlying molecular mechanisms remain poorly understood. Based on recent RNA sequencing experiments, DEK expression was necessary for the transcription of several metabolic enzymes involved in anabolic pathways. This identified a possible mechanism whereby DEK may drive cellular metabolism to enable cell proliferation. Functional metabolic Seahorse analysis demonstrated increased baseline and maximum extracellular acidification rates, a readout of glycolysis, in DEK-overexpressing keratinocytes and squamous cell carcinoma cells. DEK overexpression also increased the maximum rate of oxygen consumption and therefore increased the potential for oxidative phosphorylation (OxPhos). To detect small metabolites that participate in glycolysis and the tricarboxylic acid cycle (TCA) that supplies substrate for OxPhos, we carried out NMR-based metabolomics studies. We found that high levels of DEK significantly reprogrammed cellular metabolism and altered the abundances of amino acids, TCA cycle intermediates and the glycolytic end products lactate, alanine and NAD+. Taken together, these data support a scenario whereby overexpression of the human DEK oncogene reprograms keratinocyte metabolism to fulfill energy and macromolecule demands required to enable and sustain cancer cell growth. PMID:28558019

Overexpression of the human DEK oncogene reprograms cellular metabolism and promotes glycolysis.

Directory of Open Access Journals (Sweden)

Marie C Matrka

Full Text Available The DEK oncogene is overexpressed in many human malignancies including at early tumor stages. Our reported in vitro and in vivo models of squamous cell carcinoma have demonstrated that DEK contributes functionally to cellular and tumor survival and to proliferation. However, the underlying molecular mechanisms remain poorly understood. Based on recent RNA sequencing experiments, DEK expression was necessary for the transcription of several metabolic enzymes involved in anabolic pathways. This identified a possible mechanism whereby DEK may drive cellular metabolism to enable cell proliferation. Functional metabolic Seahorse analysis demonstrated increased baseline and maximum extracellular acidification rates, a readout of glycolysis, in DEK-overexpressing keratinocytes and squamous cell carcinoma cells. DEK overexpression also increased the maximum rate of oxygen consumption and therefore increased the potential for oxidative phosphorylation (OxPhos. To detect small metabolites that participate in glycolysis and the tricarboxylic acid cycle (TCA that supplies substrate for OxPhos, we carried out NMR-based metabolomics studies. We found that high levels of DEK significantly reprogrammed cellular metabolism and altered the abundances of amino acids, TCA cycle intermediates and the glycolytic end products lactate, alanine and NAD+. Taken together, these data support a scenario whereby overexpression of the human DEK oncogene reprograms keratinocyte metabolism to fulfill energy and macromolecule demands required to enable and sustain cancer cell growth.

Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training

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Roberts, Christian K.; Hevener, Andrea L.; Barnard, R. James

2014-01-01

Metabolic syndrome (MS) is a collection of cardiometabolic risk factors that includes obesity, insulin resistance, hypertension, and dyslipidemia. Although there has been significant debate regarding the criteria and concept of the syndrome, this clustering of risk factors is unequivocally linked to an increased risk of developing type 2 diabetes and cardiovascular disease. Regardless of the true definition, based on current population estimates, nearly 100 million have MS. It is often characterized by insulin resistance, which some have suggested is a major underpinning link between physical inactivity and MS. The purpose of this review is to: (i) provide an overview of the history, causes and clinical aspects of MS, (ii) review the molecular mechanisms of insulin action and the causes of insulin resistance, and (iii) discuss the epidemiological and intervention data on the effects of exercise on MS and insulin sensitivity. PMID:23720280

Intestinal glutathione: determinant of mucosal peroxide transport, metabolism, and oxidative susceptibility

International Nuclear Information System (INIS)

Aw, Tak Yee

2005-01-01

The intestine is a primary site of nutrient absorption and a critical defense barrier against dietary-derived mutagens, carcinogens, and oxidants. Accumulation of oxidants like peroxidized lipids in the gut lumen can contribute to impairment of mucosal metabolic pathways, enterocyte dysfunction independent of cell injury, and development of gut pathologies, such as inflammation and cancer. Despite this recognition, we know little of the pathways of intestinal transport, metabolism, and luminal disposition of dietary peroxides in vivo or of the underlying mechanisms of lipid peroxide-induced genesis of intestinal disease processes. This chapter summarizes our current understanding of the determinants of intestinal absorption and metabolism of peroxidized lipids. I will review experimental evidence from our laboratory and others (Table 1) supporting the pivotal role that glutathione (GSH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH) play in mucosal transport and metabolism of lipid hydroperoxides and how reductant availability can be compromised under chronic stress such as hypoxia, and the influence of GSH on oxidative susceptibility, and redox contribution to genesis of gut disorders. The discussion is pertinent to understanding dietary lipid peroxides and GSH redox balance in intestinal physiology and pathophysiology and the significance of luminal GSH in preserving the integrity of the intestinal epithelium

Nonstructural leaf carbohydrates dynamics of Pinus edulis during drought-induced tree mortality reveal role for carbon metabolism in mortality mechanism

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Adams, Henry D.; Germino, Matthew J.; Breshears, David D.; Barron-Gafford, Greg A.; Guardiola-Claramonte, Maite; Zou, Chris B.; Huxman, Travis E.

2013-01-01

* Vegetation change is expected with global climate change, potentially altering ecosystem function and climate feedbacks. However, causes of plant mortality, which are central to vegetation change, are understudied, and physiological mechanisms remain unclear, particularly the roles of carbon metabolism and xylem function.

Failure Mechanisms of Brittle Rocks under Uniaxial Compression

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Liu, Taoying; Cao, Ping

2017-09-01

The behaviour of a rock mass is determined not only by the properties of the rock matrix, but mostly by the presence and properties of discontinuities or fractures within the mass. The compression test on rock-like specimens with two prefabricated transfixion fissures, made by pulling out the embedded metal inserts in the pre-cured period was carried out on the servo control uniaxial loading tester. The influence of the geometry of pre-existing cracks on the cracking processes was analysed with reference to the experimental observation of crack initiation and propagation from pre-existing flaws. Based on the rock fracture mechanics and the stress-strain curves, the evolution failure mechanism of the fissure body was also analyzed on the basis of exploring the law of the compression-shear crack initiation, wing crack growth and rock bridge connection. Meanwhile, damage fracture mechanical models of a compression-shear rock mass are established when the rock bridge axial transfixion failure, tension-shear combined failure, or wing crack shear connection failure occurs on the specimen under axial compression. This research was of significance in studying the failure mechanism of fractured rock mass.

Approaches in modulating proline metabolism in plants for salt and drought stress tolerance: Phytohormones, mineral nutrients and transgenics.

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Per, Tasir S; Khan, Nafees A; Reddy, Palakolanu Sudhakar; Masood, Asim; Hasanuzzaman, Mirza; Khan, M Iqbal R; Anjum, Naser A

2017-06-01

Major abiotic stress factors such as salt and drought adversely affect important physiological processes and biochemical mechanisms and cause severe loss in crop productivity worldwide. Plants develop various strategies to stand healthy against these stress factors. The accumulation of proline (Pro) is one of the striking metabolic responses of plants to salt and drought stress. Pro biosynthesis and signalling contribute to the redox balance of cell under normal and stressful conditions. However, literature is meager on the sustainable strategies potentially fit for modulating Pro biosynthesis and production in stressed plants. Considering the recent literature, this paper in its first part overviews Pro biosynthesis and transport in plants and also briefly highlights the significance of Pro in plant responses to salt and drought stress. Secondly, this paper discusses mechanisms underlying the regulation of Pro metabolism in salt and drought-exposed plant via phytohormones, mineral nutrients and transgenic approaches. The outcome of the studies may give new opportunities in modulating Pro metabolism for improving plant tolerance to salt and drought stress and benefit sustainable agriculture. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Photosystem II excitation pressure and photosynthetic carbon metabolism in Chlorella vulgaris

International Nuclear Information System (INIS)

Savitch, L.V.; Maxwell, D.P.; Huner, N.P.A.

1996-01-01

Chlorella vulgaris grown at 5 degrees C/150 micromoles m -2 s -1 mimics cells grown under high irradiance (27 degrees C/2200 micromoles m -2 s -1 ). This has been rationalized through the suggestion that both populations of cells were exposed to comparable photosystem II (PSII) excitation pressures measured as the chlorophyll a fluorescence quenching parameter, 1 - qP (D.P. Maxwell, S. Falk, N.P.A. Huner [1995] Plant Physiol 107: 687-694). To assess the possible role(s) of feedback mechanisms on PSII excitation pressure, stromal and cytosolic carbon metabolism were examined. Sucrose phosphate synthase and fructose-1,6-bisphosphatase activities as well as the ratios of fructose-1,6-bisphosphate/fructose-6 phosphate and sucrose/starch indicated that cells grown at 27 degrees C/2200 micromoles m -2 s -1 appeared to exhibit a restriction in starch metabolism. In contrast, cells grown at 5 degrees C/150 micromoles-1 m -2 s -1 appeared to exhibit a restriction in the sucrose metabolism based on decreased cytosolic fructose-1,6-bisphosphatase and sucrose phosphate synthase activities as well as a low sucrose/starch ratio. These metabolic restrictions may feedback on photosynthetic electron transport and, thus, contribute to the observed PSII excitation pressure. We conclude that, although PSII excitation pressure may reflect redox regulation of photosynthetic acclimation to light and temperature in C. vulgaris, it cannot be considered the primary redox signal. Alternative metabolic sensing/signaling mechanisms are discussed

Metabolic and behavioral responses to high-fat feeding in mice selectively bred for high wheel-running activity

NARCIS (Netherlands)

Vaanholt, L. M.; Jonas, I.; Doornbos, M.; Schubert, K. A.; Nyakas, C.; Garland, T.; Visser, G. H.; van Dijk, G.; Garland Jr., T.

2008-01-01

Objective: Increased dietary fat intake is a precipitating factor for the development of obesity and associated metabolic disturbances. Physically active individuals generally have a reduced risk of developing these unhealthy states, but the underlying mechanisms are poorly understood. In the

Metaflammation, NLRP3 Inflammasome Obesity and Metabolic Disease

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Anna Meiliana

2011-12-01

Full Text Available BACKGROUND: Increasing prevalence of obesity gives rise to many problems associated with multiple morbidities, such as diabetes, hypertension, heart disease, sleep apnea and cancer. The mechanism of obesity is very complex, thus its link to various disease is poorly understood. This review highlights important concepts in our understanding of the pathogenesis of obesity and related complications. CONTENT: Many studies have tried to explore the exciting and puzzling links between metabolic homeostasis and inflammatory responses. A form of subclinical, low-grade systemic inflammation is known to be associated with both obesity and chronic disease. This, later called as "metaflammation", refers to metabolically triggered inflammation. The nutrient-sensing pathway and the immune response coordination are facilitated by these molecular sites in order to maintain homeostasis under diverse metabolic and immune conditions. Recent studies have found that the NLRP3 inflammasome during metabolic stress forms a tie linking TXNIP, oxidative stress, and IL-1β production. This provides new opportunities for research and therapy for the disease often described as the next global pandemic: type 2 diabetes mellitus (T2DM. SUMMARY: The crucial role of metaflammation in many complications of obesity shown by the unexpected overlap between inflammatory and metabolic sensors and their downstream tissue responses. Then great interest arose to explore the pathways that integrate nutrient and pathogen sensing, give more understanding in the mechanisms of insulin resistance type 2 diabetes, and other chronic metabolic pathologies. A family of intracellular sensors called NLR family is a critical component of the innate immune system. They can form multiprotein complexes, called inflammasome which is capable of responding to a wide range of stimuli including both microbial and self molecules by activating the cysteine protease caspase-1, leading to processing and

The metabolic regulator CodY links L. monocytogenes metabolism to virulence by directly activating the virulence regulatory gene, prfA

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Lobel, Lior; Sigal, Nadejda; Borovok, Ilya; Belitsky, Boris R.; Sonenshein, Abraham L.; Herskovits, Anat A.

2015-01-01

Summary Metabolic adaptations are critical to the ability of bacterial pathogens to grow within host cells and are normally preceded by sensing of host-specific metabolic signals, which in turn can influence the pathogen's virulence state. Previously, we reported that the intracellular bacterial pathogen Listeria monocytogenes responds to low availability of branched-chain amino acids (BCAA) within mammalian cells by up-regulating both BCAA biosynthesis and virulence genes. The induction of virulence genes required the BCAA-responsive transcription regulator, CodY, but the molecular mechanism governing this mode of regulation was unclear. In this report, we demonstrate that CodY directly binds the coding sequence of the L. monocytogenes master virulence activator gene, prfA, 15 nt downstream of its start codon, and that this binding results in up-regulation of prfA transcription specifically under low concentrations of BCAA. Mutating this site abolished CodY binding and reduced prfA transcription in macrophages, and attenuated bacterial virulence in mice. Notably, the mutated binding site did not alter prfA transcription or PrfA activity under other conditions that are known to activate PrfA, such as during growth in the presence of glucose-1-phosphate. This study highlights the tight crosstalk between L. monocytogenes metabolism and virulence' while revealing novel features of CodY-mediated regulation. PMID:25430920

The Role of Maternal Dietary Proteins in Development of Metabolic Syndrome in Offspring

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Alireza Jahan-Mihan

2015-11-01

Full Text Available The prevalence of metabolic syndrome and obesity has been increasing. Pre-natal environment has been suggested as a factor influencing the risk of metabolic syndrome in adulthood. Both observational and experimental studies showed that maternal diet is a major modifier of the development of regulatory systems in the offspring in utero and post-natally. Both protein content and source in maternal diet influence pre- and early post-natal development. High and low protein dams’ diets have detrimental effect on body weight, blood pressure191 and metabolic and intake regulatory systems in the offspring. Moreover, the role of the source of protein in a nutritionally adequate maternal diet in programming of food intake regulatory system, body weight, glucose metabolism and blood pressure in offspring is studied. However, underlying mechanisms are still elusive. The purpose of this review is to examine the current literature related to the role of proteins in maternal diets in development of characteristics of the metabolic syndrome in offspring.

NADPH oxidases differentially regulate ROS metabolism and nutrient uptake under cadmium toxicity.

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Gupta, D K; Pena, L B; Romero-Puertas, M C; Hernández, A; Inouhe, M; Sandalio, L M

2017-04-01

The role of NADPH oxidases under cadmium (Cd) toxicity was studied using Arabidopsis thaliana mutants AtrbohC, AtrbohD and AtrbohF, which were grown under hydroponic conditions with 25 and 100 μM Cd for 1 and 5 days. Cadmium reduced the growth of leaves in WT, AtrbohC and D, but not in AtrbohF. A time-dependent increase in H 2 O 2 and lipid peroxidation was observed in all genotypes, with AtrbohC showing the smallest increase. An opposite behaviour was observed with NO accumulation. Cadmium increased catalase activity in WT plants and decreased it in Atrboh mutants, while glutathione reductase and glycolate oxidase activities increased in Atrboh mutants, and superoxide dismutases were down-regulated in AtrbohC. The GSH/GSSG and ASA/DHA couples were also affected by the treatment, principally in AtrbohC and AtrbohF, respectively. Cadmium translocation to the leaves was severely reduced in Atrboh mutants after 1 day of treatment and even after 5 days in AtrbohF. Similar results were observed for S, P, Ca, Zn and Fe accumulation, while an opposite trend was observed for K accumulation, except in AtrbohF. Thus, under Cd stress, RBOHs differentially regulate ROS metabolism, redox homeostasis and nutrient balance and could be of potential interest in biotechnology for the phytoremediation of polluted soils. © 2016 John Wiley & Sons Ltd.

Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism.

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Zhao, Hongyun; Yang, Lifeng; Baddour, Joelle; Achreja, Abhinav; Bernard, Vincent; Moss, Tyler; Marini, Juan C; Tudawe, Thavisha; Seviour, Elena G; San Lucas, F Anthony; Alvarez, Hector; Gupta, Sonal; Maiti, Sourindra N; Cooper, Laurence; Peehl, Donna; Ram, Prahlad T; Maitra, Anirban; Nagrath, Deepak

2016-02-27

Cancer-associated fibroblasts (CAFs) are a major cellular component of tumor microenvironment in most solid cancers. Altered cellular metabolism is a hallmark of cancer, and much of the published literature has focused on neoplastic cell-autonomous processes for these adaptations. We demonstrate that exosomes secreted by patient-derived CAFs can strikingly reprogram the metabolic machinery following their uptake by cancer cells. We find that CAF-derived exosomes (CDEs) inhibit mitochondrial oxidative phosphorylation, thereby increasing glycolysis and glutamine-dependent reductive carboxylation in cancer cells. Through 13C-labeled isotope labeling experiments we elucidate that exosomes supply amino acids to nutrient-deprived cancer cells in a mechanism similar to macropinocytosis, albeit without the previously described dependence on oncogenic-Kras signaling. Using intra-exosomal metabolomics, we provide compelling evidence that CDEs contain intact metabolites, including amino acids, lipids, and TCA-cycle intermediates that are avidly utilized by cancer cells for central carbon metabolism and promoting tumor growth under nutrient deprivation or nutrient stressed conditions.

The Xenopus oocyte: a model for studying the metabolic regulation of cancer cell death.

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Nutt, Leta K

2012-06-01

Abnormal metabolism and the evasion of apoptosis are both considered hallmarks of cancer. A remarkable biochemical model system, the Xenopus laevis oocyte, exhibits altered metabolism coupled to its apoptotic machinery in a similar fashion to cancer cells. This review considers the theory that these two hallmarks of cancer are coupled in tumor cells and provides strong proof that the Xenopus laevis oocyte system is an appropriate model in which to dissect the biochemical events underlying the connection between the two hallmarks. By further elucidating the mechanisms through which metabolism suppresses apoptotic machinery, we may gain a better understanding about how normal cells transform into cancer cells. Copyright © 2012 Elsevier Ltd. All rights reserved.

Metabolic Reprogramming During Multidrug Resistance in Leukemias

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Raphael Silveira Vidal

2018-04-01

Full Text Available Cancer outcome has improved since introduction of target therapy. However, treatment success is still impaired by the same drug resistance mechanism of classical chemotherapy, known as multidrug resistance (MDR phenotype. This phenotype promotes resistance to drugs with different structures and mechanism of action. Recent reports have shown that resistance acquisition is coupled to metabolic reprogramming. High-gene expression, increase of active transport, and conservation of redox status are one of the few examples that increase energy and substrate demands. It is not clear if the role of this metabolic shift in the MDR phenotype is related to its maintenance or to its induction. Apart from the nature of this relation, the metabolism may represent a new target to avoid or to block the mechanism that has been impairing treatment success. In this mini-review, we discuss the relation between metabolism and MDR resistance focusing on the multiple non-metabolic functions that enzymes of the glycolytic pathway are known to display, with emphasis with the diverse activities of glyceraldehyde-3-phosphate dehydrogenase.

Systematic Understanding of Mechanisms of a Chinese Herbal Formula in Treatment of Metabolic Syndrome by an Integrated Pharmacology Approach.

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Chen, Meimei; Yang, Fafu; Yang, Xuemei; Lai, Xinmei; Gao, Yuxing

2016-12-16

Metabolic syndrome (MS) is becoming a worldwide health problem. Wendan decoction (WDD)-a famous traditional Chinese medicine formula-has been extensively employed to relieve syndromes related to MS in clinical practice in China. However, its pharmacological mechanisms still remain vague. In this study, a comprehensive approach that integrated chemomics, principal component analysis, molecular docking simulation, and network analysis was established to elucidate the multi-component and multi-target mechanism of action of WDD in treatment of MS. The compounds in WDD were found to possess chemical diversity, complexity and drug-likeness compared to MS drugs. Six nuclear receptors were obtained to have strong binding affinity with 217 compounds of five herbs in WDD. The importance roles of targets and herbs were also identified due to network parameters. Five compounds from Radix Glycyrrhizae Preparata can hit all six targets, which can assist in screening new MS drugs. The pathway network analysis demonstrated that the main pharmacological effects of WDD might lie in maintaining lipid and glucose metabolisms and anticancer activities as well as immunomodulatory and hepatoprotective effects. This study provided a comprehensive system approach for understanding the multi-component, multi-target and multi-pathway mechanisms of WDD during the treatment of MS.

Systematic Understanding of Mechanisms of a Chinese Herbal Formula in Treatment of Metabolic Syndrome by an Integrated Pharmacology Approach

Directory of Open Access Journals (Sweden)

Meimei Chen

2016-12-01

Full Text Available Metabolic syndrome (MS is becoming a worldwide health problem. Wendan decoction (WDD—a famous traditional Chinese medicine formula—has been extensively employed to relieve syndromes related to MS in clinical practice in China. However, its pharmacological mechanisms still remain vague. In this study, a comprehensive approach that integrated chemomics, principal component analysis, molecular docking simulation, and network analysis was established to elucidate the multi-component and multi-target mechanism of action of WDD in treatment of MS. The compounds in WDD were found to possess chemical diversity, complexity and drug-likeness compared to MS drugs. Six nuclear receptors were obtained to have strong binding affinity with 217 compounds of five herbs in WDD. The importance roles of targets and herbs were also identified due to network parameters. Five compounds from Radix Glycyrrhizae Preparata can hit all six targets, which can assist in screening new MS drugs. The pathway network analysis demonstrated that the main pharmacological effects of WDD might lie in maintaining lipid and glucose metabolisms and anticancer activities as well as immunomodulatory and hepatoprotective effects. This study provided a comprehensive system approach for understanding the multi-component, multi-target and multi-pathway mechanisms of WDD during the treatment of MS.

Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to Δ9-THC: Mechanism underlying greater toxicity?

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Fantegrossi, William E.; Moran, Jeffery H.; Radominska-Pandya, Anna; Prather, Paul L.

2013-01-01

K2 or Spice products are emerging drugs of abuse that contain synthetic cannabinoids (SCBs). Although assumed by many teens and first time drug users to be a “safe” and “legal” alternative to marijuana, many recent reports indicate that SCBs present in K2 produce toxicity not associated with the primary psychoactive component of marijuana, Δ9-tetrahydrocannabinol (Δ9-THC). This mini-review will summarize recent evidence that use of K2 products poses greater health risks relative to marijuana, and suggest that distinct pharmacological properties and metabolism of SCBs relative to Δ9-THC may contribute to the observed toxicity. Studies reviewed will indicate that in contrast to partial agonist properties of Δ9-THC typically observed in vitro, SCBs in K2 products act as full cannabinoid receptor type 1 (CB1R) and type 2 (CB2R) agonists in both cellular assays and animal studies. Furthermore, unlike Δ9-THC metabolism, several SCB metabolites retain high affinity for, and exhibit a range of intrinsic activities at, CB1 and CB2Rs. Finally, several reports indicate that although quasi-legal SCBs initially evaded detection and legal consequences, these presumed “advantages” have been limited by new legislation and development of product and human testing capabilities. Collectively, evidence reported in this mini-review suggests that K2 products are neither safe nor legal alternatives to marijuana. Instead, enhanced toxicity of K2 products relative to marijuana, perhaps resulting from the combined actions of a complex mixture of different SCBs present and their active metabolites that retain high affinity for CB1 and CB2Rs, highlights the inherent danger that may accompany use of these substances. PMID:24084047

Distinct pharmacology and metabolism of K2 synthetic cannabinoids compared to Δ(9)-THC: mechanism underlying greater toxicity?

Science.gov (United States)

Fantegrossi, William E; Moran, Jeffery H; Radominska-Pandya, Anna; Prather, Paul L

2014-02-27

K2 or Spice products are emerging drugs of abuse that contain synthetic cannabinoids (SCBs). Although assumed by many teens and first time drug users to be a "safe" and "legal" alternative to marijuana, many recent reports indicate that SCBs present in K2 produce toxicity not associated with the primary psychoactive component of marijuana, ∆(9)-tetrahydrocannabinol (Δ(9)-THC). This mini-review will summarize recent evidence that use of K2 products poses greater health risks relative to marijuana, and suggest that distinct pharmacological properties and metabolism of SCBs relative to Δ(9)-THC may contribute to the observed toxicity. Studies reviewed will indicate that in contrast to partial agonist properties of Δ(9)-THC typically observed in vitro, SCBs in K2 products act as full cannabinoid receptor type 1 (CB1R) and type 2 (CB2R) agonists in both cellular assays and animal studies. Furthermore, unlike Δ(9)-THC metabolism, several SCB metabolites retain high affinity for, and exhibit a range of intrinsic activities at, CB1 and CB2Rs. Finally, several reports indicate that although quasi-legal SCBs initially evaded detection and legal consequences, these presumed "advantages" have been limited by new legislation and development of product and human testing capabilities. Collectively, evidence reported in this mini-review suggests that K2 products are neither safe nor legal alternatives to marijuana. Instead, enhanced toxicity of K2 products relative to marijuana, perhaps resulting from the combined actions of a complex mixture of different SCBs present and their active metabolites that retain high affinity for CB1 and CB2Rs, highlights the inherent danger that may accompany use of these substances. © 2013.

Mycobacterium tuberculosis Metabolism

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Warner, Digby F.

2015-01-01

Metabolism underpins the physiology and pathogenesis of Mycobacterium tuberculosis. However, although experimental mycobacteriology has provided key insights into the metabolic pathways that are essential for survival and pathogenesis, determining the metabolic status of bacilli during different stages of infection and in different cellular compartments remains challenging. Recent advances—in particular, the development of systems biology tools such as metabolomics—have enabled key insights into the biochemical state of M. tuberculosis in experimental models of infection. In addition, their use to elucidate mechanisms of action of new and existing antituberculosis drugs is critical for the development of improved interventions to counter tuberculosis. This review provides a broad summary of mycobacterial metabolism, highlighting the adaptation of M. tuberculosis as specialist human pathogen, and discusses recent insights into the strategies used by the host and infecting bacillus to influence the outcomes of the host–pathogen interaction through modulation of metabolic functions. PMID:25502746

Molecular Mechanisms in Amyotrophic Lateral Sclerosis: The Role of Angiogenin, a Secreted RNase

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Isabela M. Aparicio-Erriu

2012-11-01

Full Text Available Amyotrophic lateral sclerosis is a fatal neurodegenerative disease caused by the loss of motoneurons. The precise molecular and cellular basis for neuronal death is not yet well established, but the contemporary view is that it is a culmination of multiple aberrant biological processes. Among the proposed mechanisms of motoneuron degeneration, alterations in the homeostasis of RNA binding proteins (RBP and the consequent changes in RNA metabolism have received attention recently.The ribonuclease, angiogenin was one of the first RBPs associated with familial and sporadic ALS. It is enriched in motoneurons under physiological conditions, and is required for motoneuron survival under stress conditions. Furthermore, delivery of angiogenin protects cultured motoneurons against stress-induced injury, and significantly increases the survival of motoneurons in SODG93A mice. In this overview on the role of angiogenin in RNA metabolism and in the control of motoneuron survival, we discuss potential pathogenic mechanisms of angiogenin dysfunction relevant to ALS and other neurodegenerative disorders. We also discuss recent evidence demonstrating that angiogenin secreted from stressed motoneurons may alter RNA metabolism in astrocytes.

The use of cultured hepatocytes to investigate the metabolism of drugs and mechanisms of drug hepatotoxicity.

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Gómez-Lechón, M J; Ponsoda, X; Bort, R; Castell, J V

2001-01-01

Hepatotoxins can be classified as intrinsic when they exert their effects on all individuals in a dose-dependent manner, and as idiosyncratic when their effects are the consequence of an abnormal metabolism of the drug by susceptible individuals (metabolic idiosyncrasy) or of an immune-mediated injury to hepatocytes (allergic hepatitis). Some xenobiotics are electrophilic, and others are biotransformed by the liver into highly reactive metabolites that are usually more toxic than the parent compound. This activation process is the key to many hepatotoxic phenomena. Mitochondria are a frequent target of hepatotoxic drugs, and the alteration of their function has immediate effects on the energy balance of cells (depletion of ATP). Lipid peroxidation, oxidative stress, alteration of Ca(2+) homeostasis, and covalent binding to cell macromolecules are the molecular mechanisms that are frequently involved in the toxicity of xenobiotics. Against these potential hazards, cells have their own defence mechanisms (for example, glutathione, DNA repair, suicide inactivation). Ultimately, toxicity is the balance between bioactivation and detoxification, which determines whether a reactive metabolite elicits a toxic effect. The ultimate goal of in vitro experiments is to generate the type of scientific information needed to identify compounds that are potentially toxic to man. For this purpose, both the design of the experiments and the interpretation of the results are critical.

Hyperferritinemia and iron metabolism in Gaucher disease: Potential pathophysiological implications.

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Regenboog, Martine; van Kuilenburg, André B P; Verheij, Joanne; Swinkels, Dorine W; Hollak, Carla E M

2016-11-01

Gaucher disease (GD) is characterized by large amounts of lipid-storing macrophages and is associated with accumulation of iron. High levels of ferritin are a hallmark of the disease. The precise mechanism underlying the changes in iron metabolism has not been elucidated. A systematic search was conducted to summarize available evidence from the literature on iron metabolism in GD and its potential pathophysiological implications. We conclude that in GD, a chronic low grade inflammation state can lead to high ferritin levels and increased hepcidin transcription with subsequent trapping of ferritin in macrophages. Extensive GD manifestations with severe anemia or extreme splenomegaly can lead to a situation of iron-overload resembling hemochromatosis. We hypothesize that specifically this latter situation carries a risk for the occurrence of associated conditions such as the increased cancer risk, metabolic syndrome and neurodegeneration. Copyright © 2016 Elsevier Ltd. All rights reserved.

Metabolic learning and memory formation by the brain influence systemic metabolic homeostasis

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Zhang, Yumin; Liu, Gang; Yan, Jingqi; Zhang, Yalin; Li, Bo; Cai, Dongsheng

2015-01-01

Metabolic homeostasis is regulated by the brain, whether this regulation involves learning and memory of metabolic information remains unexplored. Here we use a calorie-based, taste-independent learning/memory paradigm to show that Drosophila form metabolic memories that help balancing food choice with caloric intake; however, this metabolic learning or memory is lost under chronic high-calorie feeding. We show that loss of individual learning/memory-regulating genes causes a metabolic learning defect, leading to elevated trehalose and lipids levels. Importantly, this function of metabolic learning requires not only the mushroom body but the hypothalamus-like pars intercerebralis, while NF-κB activation in the pars intercerebralis mimics chronic overnutrition in that it causes metabolic learning impairment and disorders. Finally, we evaluate this concept of metabolic learning/memory in mice, suggesting the hypothalamus is involved in a form of nutritional learning and memory, which is critical for determining resistance or susceptibility to obesity. In conclusion, our data indicate the brain, and potentially the hypothalamus, direct metabolic learning and the formation of memories, which contribute to the control of systemic metabolic homeostasis. PMID:25848677

Defects in mitophagy promote redox-driven metabolic syndrome in the absence of TP53INP1.

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Seillier, Marion; Pouyet, Laurent; N'Guessan, Prudence; Nollet, Marie; Capo, Florence; Guillaumond, Fabienne; Peyta, Laure; Dumas, Jean-François; Varrault, Annie; Bertrand, Gyslaine; Bonnafous, Stéphanie; Tran, Albert; Meur, Gargi; Marchetti, Piero; Ravier, Magalie A; Dalle, Stéphane; Gual, Philippe; Muller, Dany; Rutter, Guy A; Servais, Stéphane; Iovanna, Juan L; Carrier, Alice

2015-06-01

The metabolic syndrome covers metabolic abnormalities including obesity and type 2 diabetes (T2D). T2D is characterized by insulin resistance resulting from both environmental and genetic factors. A genome-wide association study (GWAS) published in 2010 identified TP53INP1 as a new T2D susceptibility locus, but a pathological mechanism was not identified. In this work, we show that mice lacking TP53INP1 are prone to redox-driven obesity and insulin resistance. Furthermore, we demonstrate that the reactive oxygen species increase in TP53INP1-deficient cells results from accumulation of defective mitochondria associated with impaired PINK/PARKIN mitophagy. This chronic oxidative stress also favors accumulation of lipid droplets. Taken together, our data provide evidence that the GWAS-identified TP53INP1 gene prevents metabolic syndrome, through a mechanism involving prevention of oxidative stress by mitochondrial homeostasis regulation. In conclusion, this study highlights TP53INP1 as a molecular regulator of redox-driven metabolic syndrome and provides a new preclinical mouse model for metabolic syndrome clinical research. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.

Mechanisms Underlying the Antidepressant Response and Treatment Resistance

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Marjorie Rose Levinstein

2014-06-01

Full Text Available Depression is a complex and heterogeneous disorder affecting millions of Americans. There are several different medications and other treatments that are available and effective for many patients with depression. However, a substantial percentage of patients fail to achieve remission with these currently available interventions, and relapse rates are high. Therefore, it is necessary to determine both the mechanisms underlying the antidepressant response and the differences between responders and non-responders to treatment. Delineation of these mechanisms largely relies on experiments that utilize animal models. Therefore, this review provides an overview of the various mouse models that are currently used to assess the antidepressant response, such as chronic mild stress, social defeat, and chronic corticosterone. We discuss how these mouse models can be used to advance our understanding of the differences between responders and non-responders to antidepressant treatment. We also provide an overview of experimental treatment modalities that are used for treatment-resistant depression, such as deep brain stimulation and ketamine administration. We will then review the various genetic polymorphisms and transgenic mice that display resistance to antidepressant treatment. Finally, we synthesize the published data to describe a potential neural circuit underlying the antidepressant response and treatment resistance.

Human mesenchymal stromal cell-secreted lactate induces M2-macrophage differentiation by metabolic reprogramming

OpenAIRE

Selleri, Silvia; Bifsha, Panojot; Civini, Sara; Pacelli, Consiglia; Dieng, Mame Massar; Lemieux, William; Jin, Ping; Bazin, Ren?e; Patey, Natacha; Marincola, Francesco M.; Moldovan, Florina; Zaouter, Charlotte; Trudeau, Louis-Eric; Benabdhalla, Basma; Louis, Isabelle

2016-01-01

Human mesenchymal stromal cells (MSC) have been shown to dampen immune response and promote tissue repair, but the underlying mechanisms are still under investigation. Herein, we demonstrate that umbilical cord-derived MSC (UC-MSC) alter the phenotype and function of monocyte-derived dendritic cells (DC) through lactate-mediated metabolic reprogramming. UC-MSC can secrete large quantities of lactate and, when present during monocyte-to-DC differentiation, induce instead the acquisition of M2-...

Substrate metabolism in the metabolic response to injury

NARCIS (Netherlands)

Romijn, J. A.

2000-01-01

In healthy subjects the metabolic response to starvation invokes regulatory mechanisms aimed at conservation of protein mass. This response is characterized by a decrease in energy expenditure and a progressive decrease in urinary N excretion. Many non-endocrine diseases induce anorexia and a

Characterization of the Pivotal Carbon Metabolism of Streptococcus suis Serotype 2 under ex Vivo and Chemically Defined in Vitro Conditions by Isotopologue Profiling*

Science.gov (United States)

Willenborg, Jörg; Huber, Claudia; Koczula, Anna; Lange, Birgit; Eisenreich, Wolfgang; Valentin-Weigand, Peter; Goethe, Ralph

2015-01-01

Streptococcus suis is a neglected zoonotic pathogen that has to adapt to the nutritional requirements in the different host niches encountered during infection and establishment of invasive diseases. To dissect the central metabolic activity of S. suis under different conditions of nutrient availability, we performed labeling experiments starting from [13C]glucose specimens and analyzed the resulting isotopologue patterns in amino acids of S. suis grown under in vitro and ex vivo conditions. In combination with classical growth experiments, we found that S. suis is auxotrophic for Arg, Gln/Glu, His, Leu, and Trp in chemically defined medium. De novo biosynthesis was shown for Ala, Asp, Ser, and Thr at high rates and for Gly, Lys, Phe, Tyr, and Val at moderate or low rates, respectively. Glucose degradation occurred mainly by glycolysis and to a minor extent by the pentose phosphate pathway. Furthermore, the exclusive formation of oxaloacetate by phosphoenolpyruvate (PEP) carboxylation became evident from the patterns in de novo synthesized amino acids. Labeling experiments with S. suis grown ex vivo in blood or cerebrospinal fluid reflected the metabolic adaptation to these host niches with different nutrient availability; however, similar key metabolic activities were identified under these conditions. This points at the robustness of the core metabolic pathways in S. suis during the infection process. The crucial role of PEP carboxylation for growth of S. suis in the host was supported by experiments with a PEP carboxylase-deficient mutant strain in blood and cerebrospinal fluid. PMID:25575595

Depression and Chronic Liver Diseases: Are There Shared Underlying Mechanisms?

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Xiaoqin Huang

2017-05-01

Full Text Available The occurrence of depression is higher in patients with chronic liver disease (CLD than that in the general population. The mechanism described in previous studies mainly focused on inflammation and stress, which not only exists in CLD, but also emerges in common chronic diseases, leaving the specific mechanism unknown. This review was to summarize the prevalence and risk factors of depression in CLD including chronic hepatitis B, chronic hepatitis, alcoholic liver disease, and non-alcoholic fatty liver disease, and to point out the possible underlying mechanism of this potential link. Clarifying the origins of this common comorbidity (depression and CLD may provide more information to understand both diseases.

Natural Compounds as Regulators of the Cancer Cell Metabolism

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Claudia Cerella

2013-01-01

Full Text Available Even though altered metabolism is an “old” physiological mechanism, only recently its targeting became a therapeutically interesting strategy and by now it is considered an emerging hallmark of cancer. Nevertheless, a very poor number of compounds are under investigation as potential modulators of cell metabolism. Candidate agents should display selectivity of action towards cancer cells without side effects. This ideal favorable profile would perfectly overlap the requisites of new anticancer therapies and chemopreventive strategies as well. Nature represents a still largely unexplored source of bioactive molecules with a therapeutic potential. Many of these compounds have already been characterized for their multiple anticancer activities. Many of them are absorbed with the diet and therefore possess a known profile in terms of tolerability and bioavailability compared to newly synthetized chemical compounds. The discovery of important cross-talks between mediators of the most therapeutically targeted aberrancies in cancer (i.e., cell proliferation, survival, and migration and the metabolic machinery allows to predict the possibility that many anticancer activities ascribed to a number of natural compounds may be due, in part, to their ability of modulating metabolic pathways. In this review, we attempt an overview of what is currently known about the potential of natural compounds as modulators of cancer cell metabolism.

Human drug metabolism: an introduction

National Research Council Canada - National Science Library

Coleman, Michael D

2010-01-01

..., both under drug pressure and during inhibition. Factors affecting drug metabolism, such as genetic polymorphisms, age and diet are discussed and how metabolism can lead to toxicity is explained. The book concludes with the role of drug metabolism in the commercial development of therapeutic agents as well as the pharmacology of some illicit drugs.

Hepatic diseases related to triglyceride metabolism.

Science.gov (United States)

Aguilera-Méndez, Asdrubal; Álvarez-Delgado, Carolina; Hernández-Godinez, Daniel; Fernandez-Mejia, Cristina

2013-10-01

Triglycerides participate in key metabolic functions such as energy storage, thermal insulation and as deposit for essential and non-essential fatty acids that can be used as precursors for the synthesis of structural and functional phospholipids. The liver is a central organ in the regulation of triglyceride metabolism, and it participates in triglyceride synthesis, export, uptake and oxidation. The metabolic syndrome and associated diseases are among the main concerns of public health worldwide. One of the metabolic syndrome components is impaired triglyceride metabolism. Diseases associated with the metabolic syndrome promote the appearance of hepatic alterations e.g., non-alcoholic steatosis, steatohepatitis, fibrosis, cirrhosis and cancer. In this article, we review the molecular actions involved in impaired triglyceride metabolism and its association with hepatic diseases. We discuss mechanisms that reconcile the chronic inflammation and insulin resistance, and new concepts on the role of intestinal micro-flora permeability and proliferation in fatty liver etiology. We also describe the participation of oxidative stress in the progression of events leading from steatosis to steatohepatitis and fibrosis. Finally, we provide information regarding the mechanisms that link fatty acid accumulation during steatosis with changes in growth factors and cytokines that lead to the development of neoplastic cells. One of the main medical concerns vis-a-vis hepatic diseases is the lack of symptoms at the onset of the illness and, as result, its late diagnosis. The understandings of the molecular mechanisms that underlie hepatic diseases could help design strategies towards establishing markers for their accurate and timely diagnosis.

Mechanical Behavior of Shale Rock under Uniaxial Cyclic Loading and Unloading Condition

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Baoyun Zhao

2018-01-01

Full Text Available In order to investigate the mechanical behavior of shale rock under cyclic loading and unloading condition, two kinds of incremental cyclic loading tests were conducted. Based on the result of the short-term uniaxial incremental cyclic loading test, the permanent residual strain, modulus, and damage evolution were analyzed firstly. Results showed that the relationship between the residual strains and the cycle number can be expressed by an exponential function. The deformation modulus E50 and elastic modulus ES first increased and then decreased with the peak stress under the loading condition, and both of them increased approximately linearly with the peak stress under the unloading condition. On the basis of the energy dissipation, the damage variables showed an exponential increasing with the strain at peak stress. The creep behavior of the shale rock was also analyzed. Results showed that there are obvious instantaneous strain, decay creep, and steady creep under each stress level and the specimen appears the accelerated creep stage under the 4th stress of 51.16 MPa. Based on the characteristics of the Burgers creep model, a viscoelastic-plastic creep model was proposed through viscoplastic mechanics, which agrees very well with the experimental results and can better describe the creep behavior of shale rock better than the Burgers creep model. Results can provide some mechanics reference evidence for shale gas development.

Citrus Flavonoids as Regulators of Lipoprotein Metabolism and Atherosclerosis.

Science.gov (United States)

Mulvihill, Erin E; Burke, Amy C; Huff, Murray W

2016-07-17

Citrus flavonoids are polyphenolic compounds with significant biological properties. This review summarizes recent advances in understanding the ability of citrus flavonoids to modulate lipid metabolism, other metabolic parameters related to the metabolic syndrome, and atherosclerosis. Citrus flavonoids, including naringenin, hesperitin, nobiletin, and tangeretin, have emerged as potential therapeutics for the treatment of metabolic dysregulation. Epidemiological studies reveal an association between the intake of citrus flavonoid-containing foods and a decreased incidence of cardiovascular disease. Studies in cell culture and animal models, as well as a limited number of clinical studies, reveal the lipid-lowering, insulin-sensitizing, antihypertensive, and anti-inflammatory properties of citrus flavonoids. In animal models, supplementation of rodent diets with citrus flavonoids prevents hepatic steatosis, dyslipidemia, and insulin resistance primarily through inhibition of hepatic fatty acid synthesis and increased fatty acid oxidation. Citrus flavonoids blunt the inflammatory response in metabolically important tissues including liver, adipose, kidney, and the aorta. The mechanisms underlying flavonoid-induced metabolic regulation have not been completely established, although several potential targets have been identified. In mouse models, citrus flavonoids show marked suppression of atherogenesis through improved metabolic parameters as well as through direct impact on the vessel wall. Recent studies support a role for citrus flavonoids in the treatment of dyslipidemia, insulin resistance, hepatic steatosis, obesity, and atherosclerosis. Larger human studies examining dose, bioavailability, efficacy, and safety are required to promote the development of these promising therapeutic agents.

Vascular mechanisms underlying the hypotensive effect of Rumex acetosa.

Science.gov (United States)

Qamar, Hafiz Misbah-Ud-Din; Qayyum, Rahila; Salma, Umme; Khan, Shamim; Khan, Taous; Shah, Abdul Jabbar

2018-12-01

Rumex acetosa L. (Polygonaceae) is well known in traditional medicine for its therapeutic efficacy as an antihypertensive. The study investigates antihypertensive potential of crude methanol extract (Ra.Cr) and fractions of Rumex acetosa in normotensive and hypertensive rat models and probes the underlying vascular mechanisms. Ra.Cr and its fractions were tested in vivo on normotensive and hypertensive Sprague-Dawley rats under anaesthesia for blood pressure lowering effect. In vitro experiments on rat and Oryctolagus cuniculus rabbit aortae were employed to probe the underlying vasorelaxant mechanism. In normotensive rats under anaesthesia, Ra.Cr caused fall in MAP (40 mmHg) at 50 mg/kg with % fall of 27.88 ± 4.55. Among the fractions tested, aqueous fraction was more potent at the dose of 50 mg/kg with % fall of 45.63 ± 2.84. In hypertensive rats under similar conditions, extract and fractions showed antihypertensive effect at same doses while aqueous fraction being more potent, exhibited 68.53 ± 4.45% fall in MAP (70 mmHg). In isolated rat aortic rings precontracted with phenylephrine (PE), Ra.Cr and fractions induced endothelium-dependent vasorelaxation, which was partially blocked in presence of l-NAME, indomethacin and atropine. In isolated rabbit aortic rings pre-contracted with PE and K + -(80 mM), Ra.Cr induced vasorelaxation and shifted Ca 2+ concentration-response curves to the right and suppressed PE peak formation, similar to verapamil, in Ca 2+ -free medium. The data indicate that l-NAME and atropine-sensitive endothelial-derived NO and COX enzyme inhibitors and Ca 2+ entry blocking-mediated vasodilator effect of the extract explain its antihypertensive potential.

Utilization of dietary glucose in the metabolic syndrome

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Alemany Marià

2011-10-01

Full Text Available Abstract This review is focused on the fate of dietary glucose under conditions of chronically high energy (largely fat intake, evolving into the metabolic syndrome. We are adapted to carbohydrate-rich diets similar to those of our ancestors. Glucose is the main energy staple, but fats are our main energy reserves. Starvation drastically reduces glucose availability, forcing the body to shift to fatty acids as main energy substrate, sparing glucose and amino acids. We are not prepared for excess dietary energy, our main defenses being decreased food intake and increased energy expenditure, largely enhanced metabolic activity and thermogenesis. High lipid availability is a powerful factor decreasing glucose and amino acid oxidation. Present-day diets are often hyperenergetic, high on lipids, with abundant protein and limited amounts of starchy carbohydrates. Dietary lipids favor their metabolic processing, saving glucose, which additionally spares amino acids. The glucose excess elicits hyperinsulinemia, which may derive, in the end, into insulin resistance. The available systems of energy disposal could not cope with the excess of substrates, since they are geared for saving not for spendthrift, which results in an unbearable overload of the storage mechanisms. Adipose tissue is the last energy sink, it has to store the energy that cannot be used otherwise. However, adipose tissue growth also has limits, and the excess of energy induces inflammation, helped by the ineffective intervention of the immune system. However, even under this acute situation, the excess of glucose remains, favoring its final conversion to fat. The sum of inflammatory signals and deranged substrate handling induce most of the metabolic syndrome traits: insulin resistance, obesity, diabetes, liver steatosis, hyperlipidemia and their compounded combined effects. Thus, a maintained excess of energy in the diet may result in difficulties in the disposal of glucose, eliciting

Plasma metabolic profiling analysis of toxicity induced by brodifacoum using metabonomics coupled with multivariate data analysis.

Science.gov (United States)

Yan, Hui; Qiao, Zheng; Shen, Baohua; Xiang, Ping; Shen, Min

2016-10-01

Brodifacoum is one of the most widely used rodenticides for rodent control and eradication; however, human and animal poisoning due to primary and secondary exposure has been reported since its development. Although numerous studies have described brodifacoum induced toxicity, the precise mechanism still needs to be explored. Gas chromatography mass spectrometry (GC-MS) coupled with an ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was applied to characterize the metabolic profile of brodifacoum induced toxicity and discover potential biomarkers in rat plasma. The toxicity of brodifacoum was dose-dependent, and the high-dose group obviously manifested toxicity with subcutaneous hemorrhage. The blood brodifacoum concentration showed a positive relation to the ingestion dose in toxicological analysis. Significant changes of twenty-four metabolites were identified and considered as potential toxicity biomarkers, primarily involving glucose metabolism, lipid metabolism and amino acid metabolism associated with anticoagulant activity, nephrotoxicity and hepatic damage. MS-based metabonomics analysis in plasma samples is helpful to search for potential poisoning biomarkers and to understand the underlying mechanisms of brodifacoum induced toxicity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Thermodynamic Aspects and Reprogramming Cellular Energy Metabolism during the Fibrosis Process

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Alexandre Vallée

2017-11-01

Full Text Available Fibrosis is characterized by fibroblast proliferation and fibroblast differentiation into myofibroblasts, which generate a relaxation-free contraction mechanism associated with excessive collagen synthesis in the extracellular matrix, which promotes irreversible tissue retraction evolving towards fibrosis. From a thermodynamic point of view, the mechanisms leading to fibrosis are irreversible processes that can occur through changing the entropy production rate. The thermodynamic behaviors of metabolic enzymes involved in fibrosis are modified by the dysregulation of both transforming growth factor β (TGF-β signaling and the canonical WNT/β-catenin pathway, leading to aerobic glycolysis, called the Warburg effect. Molecular signaling pathways leading to fibrosis are considered dissipative structures that exchange energy or matter with their environment far from the thermodynamic equilibrium. The myofibroblastic cells arise from exergonic processes by switching the core metabolism from oxidative phosphorylation to glycolysis, which generates energy and reprograms cellular energy metabolism to induce the process of myofibroblast differentiation. Circadian rhythms are far-from-equilibrium thermodynamic processes. They directly participate in regulating the TGF-β and WNT/β-catenin pathways involved in energetic dysregulation and enabling fibrosis. The present review focusses on the thermodynamic implications of the reprogramming of cellular energy metabolism, leading to fibroblast differentiation into myofibroblasts through the positive interplay between TGF-β and WNT/β-catenin pathways underlying in fibrosis.

Neuroinflammatory basis of metabolic syndrome.

Science.gov (United States)

Purkayastha, Sudarshana; Cai, Dongsheng

2013-10-05

Inflammatory reaction is a fundamental defense mechanism against threat towards normal integrity and physiology. On the other hand, chronic diseases such as obesity, type 2 diabetes, hypertension and atherosclerosis, have been causally linked to chronic, low-grade inflammation in various metabolic tissues. Recent cross-disciplinary research has led to identification of hypothalamic inflammatory changes that are triggered by overnutrition, orchestrated by hypothalamic immune system, and sustained through metabolic syndrome-associated pathophysiology. While continuing research is actively trying to underpin the identity and mechanisms of these inflammatory stimuli and actions involved in metabolic syndrome disorders and related diseases, proinflammatory IκB kinase-β (IKKβ), the downstream nuclear transcription factor NF-κB and some related molecules in the hypothalamus were discovered to be pathogenically significant. This article is to summarize recent progresses in the field of neuroendocrine research addressing the central integrative role of neuroinflammation in metabolic syndrome components ranging from obesity, glucose intolerance to cardiovascular dysfunctions.

Physiological mechanisms underlying animal social behaviour.

Science.gov (United States)

Seebacher, Frank; Krause, Jens

2017-08-19

Many species of animal live in groups, and the group represents the organizational level within which ecological and evolutionary processes occur. Understanding these processes, therefore, relies on knowledge of the mechanisms that permit or constrain group formation. We suggest that physiological capacities and differences in physiology between individuals modify fission-fusion dynamics. Differences between individuals in locomotor capacity and metabolism may lead to fission of groups and sorting of individuals into groups with similar physiological phenotypes. Environmental impacts such as hypoxia can influence maximum group sizes and structure in fish schools by altering access to oxygenated water. The nutritional environment determines group cohesion, and the increase in information collected by the group means that individuals should rely more on social information and form more cohesive groups in uncertain environments. Changing environmental contexts require rapid responses by individuals to maintain group coordination, which are mediated by neuroendocrine signalling systems such as nonapeptides and steroid hormones. Brain processing capacity may constrain social complexity by limiting information processing. Failure to evaluate socially relevant information correctly limits social interactions, which is seen, for example, in autism. Hence, functioning of a group relies to a large extent on the perception and appropriate processing of signals from conspecifics. Many if not all physiological systems are mechanistically linked, and therefore have synergistic effects on social behaviour. A challenge for the future lies in understanding these interactive effects, which will improve understanding of group dynamics, particularly in changing environments.This article is part of the themed issue 'Physiological determinants of social behaviour in animals'. © 2017 The Author(s).

Quantitative estimation of cholinesterase-specific drug metabolism of carbamate inhibitors provided by the analysis of the area under the inhibition-time curve.

Science.gov (United States)

Zhou, Huimin; Xiao, Qiaoling; Tan, Wen; Zhan, Yiyi; Pistolozzi, Marco

2017-09-10

Several molecules containing carbamate groups are metabolized by cholinesterases. This metabolism includes a time-dependent catalytic step which temporary inhibits the enzymes. In this paper we demonstrate that the analysis of the area under the inhibition versus time curve (AUIC) can be used to obtain a quantitative estimation of the amount of carbamate metabolized by the enzyme. (R)-bambuterol monocarbamate and plasma butyrylcholinesterase were used as model carbamate-cholinesterase system. The inhibition of different concentrations of the enzyme was monitored for 5h upon incubation with different concentrations of carbamate and the resulting AUICs were analyzed. The amount of carbamate metabolized could be estimated with cholinesterases in a selected compartment in which the cholinesterase is confined (e.g. in vitro solutions, tissues or body fluids), either in vitro or in vivo. Copyright © 2017 Elsevier B.V. All rights reserved.

A possible realization of Einstein's causal theory underlying quantum mechanics

International Nuclear Information System (INIS)

Yussouff, M.

1979-06-01

It is shown that a new microscopic mechanics formulated earlier can be looked upon as a possible causal theory underlying quantum mechanics, which removes Einstein's famous objections against quantum theory. This approach is free from objections raised against Bohm's hidden variable theory and leads to a clear physical picture in terms of familiar concepts, if self interactions are held responsible for deviations from classical behaviour. The new level of physics unfolded by this approach may reveal novel frontiers in high-energy physics. (author)

Molecular phenotyping of multiple mouse strains under metabolic challenge uncovers a role for Elovl2 in glucose-induced insulin secretion

Directory of Open Access Journals (Sweden)

Céline Cruciani-Guglielmacci

2017-04-01

Conclusion: Our results suggest a role for Elovl2 in ensuring normal insulin secretory responses to glucose. Moreover, the large comprehensive dataset and integrative network-based approach provides a new resource to dissect the molecular etiology of β cell failure under metabolic stress.

Nanoscale copper in the soil–plant system – toxicity and underlying potential mechanisms

Energy Technology Data Exchange (ETDEWEB)

Anjum, Naser A., E-mail: anjum@ua.pt [CESAM-Centre for Environmental and Marine Studies & Department of Chemistry, University of Aveiro, 3810-193 Aveiro (Portugal); Adam, Vojtech [Department of Chemistry and Biochemistry, Faculty of Agronomy, Mendel University in Brno, Zemedelska 1, CZ-613 00 Brno (Czech Republic); Central European Institute of Technology, Brno University of Technology, Technicka 3058/10, CZ-616 00 Brno (Czech Republic); Kizek, Rene [Central European Institute of Technology, Brno University of Technology, Technicka 3058/10, CZ-616 00 Brno (Czech Republic); Duarte, Armando C.; Pereira, Eduarda [CESAM-Centre for Environmental and Marine Studies & Department of Chemistry, University of Aveiro, 3810-193 Aveiro (Portugal); Iqbal, Muhammad [Department of Botany, Faculty of Science, Hamdard University, New Delhi 110062 (India); Lukatkin, Alexander S. [Department of Botany, Plant Physiology and Ecology, N.P. Ogarev Mordovia State University, Bolshevistskaja Str., 68. Saransk 430005 (Russian Federation); Ahmad, Iqbal, E-mail: ahmadr@ua.pt [CESAM-Centre for Environmental and Marine Studies & Department of Chemistry, University of Aveiro, 3810-193 Aveiro (Portugal); CESAM-Centre for Environmental and Marine Studies & Department of Biology, University of Aveiro, 3810-193 Aveiro (Portugal)

2015-04-15

Nanoscale copper particles (nano-Cu) are used in many antimicrobial formulations and products for their antimicrobial activity. They may enter deliberately and/or accidentally into terrestrial environments including soils. Being the major ‘eco-receptors’ of nanoscale particles in the terrestrial ecosystem, soil–microbiota and plants (the soil–plant system) have been used as a model to dissect the potential impact of these particles on the environmental and human health. In the soil–plant system, the plant can be an indirect non-target organism of the soil-associated nano-Cu that may in turn affect plant-based products and their consumers. By all accounts, information pertaining to nano-Cu toxicity and the underlying potential mechanisms in the soil–plant system remains scanty, deficient and little discussed. Therefore, based on some recent reports from (bio)chemical, molecular and genetic studies of nano-Cu versus soil–plant system, this article: (i) overviews the status, chemistry and toxicity of nano-Cu in soil and plants, (ii) discusses critically the poorly understood potential mechanisms of nano-Cu toxicity and tolerance both in soil–microbiota and plants, and (iii) proposes future research directions. It appears from studies hitherto made that the uncontrolled generation and inefficient metabolism of reactive oxygen species through different reactions are the major factors underpinning the overall nano-Cu consequences in both the systems. However, it is not clear whether the nano-Cu or the ion released from it is the cause of the toxicity. We advocate to intensify the multi-approach studies focused at a complete characterization of the nano-Cu, its toxicity (during life cycles of the least-explored soil–microbiota and plants), and behavior in an environmentally relevant terrestrial exposure setting. Such studies may help to obtain a deeper insight into nano-Cu actions and address adequately the nano-Cu-associated safety concerns in the �

Nanoscale copper in the soil–plant system – toxicity and underlying potential mechanisms

International Nuclear Information System (INIS)

Anjum, Naser A.; Adam, Vojtech; Kizek, Rene; Duarte, Armando C.; Pereira, Eduarda; Iqbal, Muhammad; Lukatkin, Alexander S.; Ahmad, Iqbal

2015-01-01

Nanoscale copper particles (nano-Cu) are used in many antimicrobial formulations and products for their antimicrobial activity. They may enter deliberately and/or accidentally into terrestrial environments including soils. Being the major ‘eco-receptors’ of nanoscale particles in the terrestrial ecosystem, soil–microbiota and plants (the soil–plant system) have been used as a model to dissect the potential impact of these particles on the environmental and human health. In the soil–plant system, the plant can be an indirect non-target organism of the soil-associated nano-Cu that may in turn affect plant-based products and their consumers. By all accounts, information pertaining to nano-Cu toxicity and the underlying potential mechanisms in the soil–plant system remains scanty, deficient and little discussed. Therefore, based on some recent reports from (bio)chemical, molecular and genetic studies of nano-Cu versus soil–plant system, this article: (i) overviews the status, chemistry and toxicity of nano-Cu in soil and plants, (ii) discusses critically the poorly understood potential mechanisms of nano-Cu toxicity and tolerance both in soil–microbiota and plants, and (iii) proposes future research directions. It appears from studies hitherto made that the uncontrolled generation and inefficient metabolism of reactive oxygen species through different reactions are the major factors underpinning the overall nano-Cu consequences in both the systems. However, it is not clear whether the nano-Cu or the ion released from it is the cause of the toxicity. We advocate to intensify the multi-approach studies focused at a complete characterization of the nano-Cu, its toxicity (during life cycles of the least-explored soil–microbiota and plants), and behavior in an environmentally relevant terrestrial exposure setting. Such studies may help to obtain a deeper insight into nano-Cu actions and address adequately the nano-Cu-associated safety concerns in the �

Role of the placenta in fetal programming: underlying mechanisms and potential interventional approaches.

Science.gov (United States)

Jansson, Thomas; Powell, Theresa L

2007-07-01

Adverse influences during fetal life alter the structure and function of distinct cells, organ systems or homoeostatic pathways, thereby 'programming' the individual for an increased risk of developing cardiovascular disease and diabetes in adult life. Fetal programming can be caused by a number of different perturbations in the maternal compartment, such as altered maternal nutrition and reduced utero-placental blood flow; however, the underlying mechanisms remain to be fully established. Perturbations in the maternal environment must be transmitted across the placenta in order to affect the fetus. Here, we review recent insights into how the placenta responds to changes in the maternal environment and discuss possible mechanisms by which the placenta mediates fetal programming. In IUGR (intrauterine growth restriction) pregnancies, the increased placental vascular resistance subjects the fetal heart to increased work load, representing a possible direct link between altered placental structure and fetal programming of cardiovascular disease. A decreased activity of placental 11beta-HSD-2 (type 2 isoform of 11beta-hydroxysteroid dehydrogenase) activity can increase fetal exposure to maternal cortisol, which programmes the fetus for later hypertension and metabolic disease. The placenta appears to function as a nutrient sensor regulating nutrient transport according to the ability of the maternal supply line to deliver nutrients. By directly regulating fetal nutrient supply and fetal growth, the placenta plays a central role in fetal programming. Furthermore, perturbations in the maternal compartment may affect the methylation status of placental genes and increase placental oxidative/nitrative stress, resulting in changes in placental function. Intervention strategies targeting the placenta in order to prevent or alleviate altered fetal growth and/or fetal programming include altering placental growth and nutrient transport by maternally administered IGFs (insulin

Cognitive mechanisms underlying disorganization of thought in a genetic syndrome (47,XXY)

NARCIS (Netherlands)

Van Rijn, Sophie; Aleman, Andre; De Sonneville, Leo; Swaab, Hanna

Because of the risk for development of psychopathology such as psychotic symptoms, it has been suggested that studying men with the XXY karyotype may help in the search for underlying cognitive, neural and genetic mechanisms. The aim of this study was to identify cognitive mechanisms that may

First-principles investigation of mechanical and electronic properties of tetragonal NbAl3 under tension

Science.gov (United States)

Jiao, Zhen; Liu, Qi-Jun; Liu, Fu-Sheng; Tang, Bin

2018-06-01

Using the density functional theory calculations, the mechanical and electronic properties of NbAl3 under different tensile loads were investigated. The calculated lattice parameters, elastic constants and mechanical properties (bulk modulus, shear modulus, Young's modulus, Poisson's ratio, Pugh's criterion and Cauchy's pressure) indicated that our results were in agreement with the published experimental and theoretical data at zero tension. With respect to NbAl3 under tension in this paper, the crystal structure was changed from tetragonal to orthorhombic under tension along the [100] and [101] directions. The NbAl3 crystal has been classified as brittle material under tension from 0 to 20 GPa. The obtained Young's modulus and Debye temperature monotonically decreased with increasing tension stress. Combining with mechanical and electronic properties in detail, the decreased mechanical properties were mainly due to the weakening of covalency.

Green tea polyphenols alter lipid metabolism in the livers of broiler chickens through increased phosphorylation of AMP-activated protein kinase.

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Jinbao Huang

Full Text Available Our previous results showed that green tea polyphenols (GTPs significantly altered the expression of lipid-metabolizing genes in the liver of chickens. However, the underlying mechanism was not elucidated. In this study, we further characterized how GTPs influence AMP-activated protein kinase (AMPK in the regulation of hepatic fat metabolism. Thirty-six male chickens were fed GTPs at a daily dose of 0, 80 or 160 mg/kg of body weight for 4 weeks. The results demonstrated that oral administration of GTPs significantly reduced hepatic lipid content and abdominal fat mass, enhanced the phosphorylation levels of AMPKα and ACACA, and altered the mRNA levels and enzymatic activities of lipid-metabolizing enzymes in the liver. These results suggested that the activation of AMPK is a potential mechanism by which GTPs regulate hepatic lipid metabolism in such a way that lipid synthesis is reduced and fat oxidation is stimulated.

Metabolic syndrome in Tunisian bipolar I patients | Ezzaher | African ...

African Journals Online (AJOL)

Gender, age, illness episode and treatment were not significantly associated with metabolic syndrome, while patients under lithium had higher prevalence of metabolic syndrome than those under valproic acid, carbamazepine or antipsychotics. Patients with metabolic syndrome had significant higher levels of HOMA-IR and ...

MetaFluxNet: the management of metabolic reaction information and quantitative metabolic flux analysis.

Science.gov (United States)

Lee, Dong-Yup; Yun, Hongsoek; Park, Sunwon; Lee, Sang Yup

2003-11-01

MetaFluxNet is a program package for managing information on the metabolic reaction network and for quantitatively analyzing metabolic fluxes in an interactive and customized way. It allows users to interpret and examine metabolic behavior in response to genetic and/or environmental modifications. As a result, quantitative in silico simulations of metabolic pathways can be carried out to understand the metabolic status and to design the metabolic engineering strategies. The main features of the program include a well-developed model construction environment, user-friendly interface for metabolic flux analysis (MFA), comparative MFA of strains having different genotypes under various environmental conditions, and automated pathway layout creation. http://mbel.kaist.ac.kr/ A manual for MetaFluxNet is available as PDF file.

Nonstructural leaf carbohydrate dynamics of Pinus edulis during drought-induced tree mortality reveal role for carbon metabolism in mortality mechanism.

Science.gov (United States)

Adams, Henry D; Germino, Matthew J; Breshears, David D; Barron-Gafford, Greg A; Guardiola-Claramonte, Maite; Zou, Chris B; Huxman, Travis E

2013-03-01

Vegetation change is expected with global climate change, potentially altering ecosystem function and climate feedbacks. However, causes of plant mortality, which are central to vegetation change, are understudied, and physiological mechanisms remain unclear, particularly the roles of carbon metabolism and xylem function. We report analysis of foliar nonstructural carbohydrates (NSCs) and associated physiology from a previous experiment where earlier drought-induced mortality of Pinus edulis at elevated temperatures was associated with greater cumulative respiration. Here, we predicted faster NSC decline for warmed trees than for ambient-temperature trees. Foliar NSC in droughted trees declined by 30% through mortality and was lower than in watered controls. NSC decline resulted primarily from decreased sugar concentrations. Starch initially declined, and then increased above pre-drought concentrations before mortality. Although temperature did not affect NSC and sugar, starch concentrations ceased declining and increased earlier with higher temperatures. Reduced foliar NSC during lethal drought indicates a carbon metabolism role in mortality mechanism. Although carbohydrates were not completely exhausted at mortality, temperature differences in starch accumulation timing suggest that carbon metabolism changes are associated with time to death. Drought mortality appears to be related to temperature-dependent carbon dynamics concurrent with increasing hydraulic stress in P. edulis and potentially other similar species. © 2013 The Authors. New Phytologist © 2013 New Phytologist Trust.

Kinetic theory approach to modeling of cellular repair mechanisms under genome stress.

Directory of Open Access Journals (Sweden)

Jinpeng Qi

Full Text Available Under acute perturbations from outer environment, a normal cell can trigger cellular self-defense mechanism in response to genome stress. To investigate the kinetics of cellular self-repair process at single cell level further, a model of DNA damage generating and repair is proposed under acute Ion Radiation (IR by using mathematical framework of kinetic theory of active particles (KTAP. Firstly, we focus on illustrating the profile of Cellular Repair System (CRS instituted by two sub-populations, each of which is made up of the active particles with different discrete states. Then, we implement the mathematical framework of cellular self-repair mechanism, and illustrate the dynamic processes of Double Strand Breaks (DSBs and Repair Protein (RP generating, DSB-protein complexes (DSBCs synthesizing, and toxins accumulating. Finally, we roughly analyze the capability of cellular self-repair mechanism, cellular activity of transferring DNA damage, and genome stability, especially the different fates of a certain cell before and after the time thresholds of IR perturbations that a cell can tolerate maximally under different IR perturbation circumstances.

Kinetic theory approach to modeling of cellular repair mechanisms under genome stress.

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Qi, Jinpeng; Ding, Yongsheng; Zhu, Ying; Wu, Yizhi

2011-01-01

Under acute perturbations from outer environment, a normal cell can trigger cellular self-defense mechanism in response to genome stress. To investigate the kinetics of cellular self-repair process at single cell level further, a model of DNA damage generating and repair is proposed under acute Ion Radiation (IR) by using mathematical framework of kinetic theory of active particles (KTAP). Firstly, we focus on illustrating the profile of Cellular Repair System (CRS) instituted by two sub-populations, each of which is made up of the active particles with different discrete states. Then, we implement the mathematical framework of cellular self-repair mechanism, and illustrate the dynamic processes of Double Strand Breaks (DSBs) and Repair Protein (RP) generating, DSB-protein complexes (DSBCs) synthesizing, and toxins accumulating. Finally, we roughly analyze the capability of cellular self-repair mechanism, cellular activity of transferring DNA damage, and genome stability, especially the different fates of a certain cell before and after the time thresholds of IR perturbations that a cell can tolerate maximally under different IR perturbation circumstances.

Control of a perturbed under-actuated mechanical system

KAUST Repository

Zayane, Chadia

2015-11-05

In this work, the trajectory tracking problem for an under-actuated mechanical system in presence of unknown input disturbances is addressed. The studied inertia wheel inverted pendulum falls in the class of non minimum phase systems. The proposed high order sliding mode control architecture including a controller and differentiator allows to track accurately the predefined trajectory and to stabilize the internal dynamics. The robustness of the proposed approach is illustrated through different perturbation and output noise configurations.

Myocardial metabolism of 123I-BMIPP under low-dose dobutamine infusion: implications for clinical SPECT imaging of ischemic heart disease

International Nuclear Information System (INIS)

Hosokawa, Ryohei; Fujita, Masatoshi; Kambara, Naoshige; Ohba, Muneo; Tadamura, Eiji; Kimura, Takeshi; Kita, Toru; Nohara, Ryuji; Hirai, Taku; Fujibayashi, Yasuhisa

2005-01-01

123 I-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid ( 123 I-BMIPP) is a fatty acid analog for single-photon emission computed tomography (SPECT) imaging that is mainly stored in the triglyceride pool. Low-dose dobutamine infusion has been reported to improve BMIPP uptake in the stunned myocardium, but the mechanism underlying this effect remains unclear. The purpose of this study was therefore to investigate the myocardial metabolism of 123 I-BMIPP in the stunned myocardium under low-dose dobutamine infusion, and to elucidate the mechanism by which dobutamine improves BMIPP uptake. Using open-chest dogs, stunned myocardium was induced by occlusion of the left anterior descending artery (LAD) for 30 min, with subsequent reperfusion (ischemia group, n=6). After direct injection of BMIPP into the LAD, myocardial extraction and retention were examined and metabolites evaluated (using high-performance liquid chromatography) during dobutamine infusion. The results in the ischemia group were compared with findings obtained in a control group under dobutamine infusion (n=6). Dobutamine infusion significantly increased both the rapid extraction (within 30 s) of BMIPP into the myocardium (control vs ischemia group: 48±19% vs 66±14%, p<0.05) and its subsequent retention (73±13% vs 85±8%, p<0.05). The metabolites from the myocardium consisted of back diffusion of nonmetabolized BMIPP, the alpha-oxidation metabolite, intermediate metabolites, and the full-oxidation metabolite. Among these metabolites, the full-oxidation metabolite decreased significantly (from 34.0±20.0% to 15.8±9.3%, p<0.05) in the stunned regions, though back diffusion of nonmetabolized BMIPP increased (from 51.3±21.9% to 71.3±10.1%, p<0.05). These results indicate that increased uptake of BMIPP in stunned myocardium is mainly due to decreased beta-oxidation in tissue and increased shunt retention of BMIPP in the triglyceride pool, and thereby provide further insight into the pathophysiology of

Mechanisms underlying astringency: introduction to an oral tribology approach

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Upadhyay, Rutuja; Brossard, Natalia; Chen, Jianshe

2016-03-01

Astringency is one of the predominant factors in the sensory experience of many foods and beverages ranging from wine to nuts. The scientific community is discussing mechanisms that explain this complex phenomenon, since there are no conclusive results which correlate well with sensory astringency. Therefore, the mechanisms and perceptual characteristics of astringency warrant further discussion and investigation. This paper gives a brief introduction of the fundamentals of oral tribology forming a basis of the astringency mechanism. It discusses the current state of the literature on mechanisms underlying astringency describing the existing astringency models. The review discusses the crucial role of saliva and its physiology which contributes significantly in astringency perception in the mouth. It also provides an overview of research concerned with the physiological and psychophysical factors that mediate the perception of this sensation, establishing the ground for future research. Thus, the overall aim of the review is to establish the critical roles of oral friction (thin-film lubrication) in the sensation of astringency and possibly of some other specific sensory features.

Elsevier Trophoblast Research Award lecture: Molecular mechanisms underlying estrogen functions in trophoblastic cells--focus on leptin expression.

Science.gov (United States)

Gambino, Y P; Maymó, J L; Pérez Pérez, A; Calvo, J C; Sánchez-Margalet, V; Varone, C L

2012-02-01

The steroid hormone 17β-estradiol is an estrogen that influences multiple aspects of placental function and fetal development in humans. During early pregnancy it plays a role in the regulation of blastocyst implantation, trophoblast differentiation and invasiveness, remodeling of uterine arteries, immunology and trophoblast production of hormones such as leptin. Estradiol exerts some effects through the action of classical estrogen receptors ERα and ERβ, which act as ligand-activated transcription factors and regulate gene expression. In addition, estradiol can elicit rapid responses from membrane-associated receptors, like activation of protein-kinase pathways. Thus, the cellular effects of estradiol will depend on the specific receptors expressed and the integration of their signaling events. Leptin, the 16,000MW protein product of the obese gene, was originally considered an adipocyte-derived signaling molecule for the central control of metabolism. However, pleiotropic effects of leptin have been identified in reproduction and pregnancy. The leptin gene is expressed in placenta, where leptin promotes proliferation and survival of trophoblastic cells. Expression of leptin in placenta is highly regulated by key pregnancy molecules as hCG and estradiol. The aim of this paper is to review the molecular mechanisms underlying estrogen functions in trophoblastic cells; focusing on mechanisms involved in estradiol regulation of placental leptin expression. Copyright © 2012 Elsevier Ltd. All rights reserved.

Tumor Metabolism of Malignant Gliomas

Energy Technology Data Exchange (ETDEWEB)

Ru, Peng; Williams, Terence M.; Chakravarti, Arnab; Guo, Deliang, E-mail: deliang.guo@osumc.edu [Department of Radiation Oncology, Ohio State University Comprehensive Cancer Center & Arthur G James Cancer Hospital, Columbus, OH 43012 (United States)

2013-11-08

Constitutively activated oncogenic signaling via genetic mutations such as in the EGFR/PI3K/Akt and Ras/RAF/MEK pathways has been recognized as a major driver for tumorigenesis in most cancers. Recent insights into tumor metabolism have further revealed that oncogenic signaling pathways directly promote metabolic reprogramming to upregulate biosynthesis of lipids, carbohydrates, protein, DNA and RNA, leading to enhanced growth of human tumors. Therefore, targeting cell metabolism has become a novel direction for drug development in oncology. In malignant gliomas, metabolism pathways of glucose, glutamine and lipid are significantly reprogrammed. Moreover, molecular mechanisms causing these metabolic changes are just starting to be unraveled. In this review, we will summarize recent studies revealing critical gene alterations that lead to metabolic changes in malignant gliomas, and also discuss promising therapeutic strategies via targeting the key players in metabolic regulation.

Tumor Metabolism of Malignant Gliomas

International Nuclear Information System (INIS)

Ru, Peng; Williams, Terence M.; Chakravarti, Arnab; Guo, Deliang

2013-01-01

Constitutively activated oncogenic signaling via genetic mutations such as in the EGFR/PI3K/Akt and Ras/RAF/MEK pathways has been recognized as a major driver for tumorigenesis in most cancers. Recent insights into tumor metabolism have further revealed that oncogenic signaling pathways directly promote metabolic reprogramming to upregulate biosynthesis of lipids, carbohydrates, protein, DNA and RNA, leading to enhanced growth of human tumors. Therefore, targeting cell metabolism has become a novel direction for drug development in oncology. In malignant gliomas, metabolism pathways of glucose, glutamine and lipid are significantly reprogrammed. Moreover, molecular mechanisms causing these metabolic changes are just starting to be unraveled. In this review, we will summarize recent studies revealing critical gene alterations that lead to metabolic changes in malignant gliomas, and also discuss promising therapeutic strategies via targeting the key players in metabolic regulation

Study on Mechanical Properties of Barite Concrete under Impact Load

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Chen, Z. F.; Cheng, K.; Wu, D.; Gan, Y. C.; Tao, Q. W.

2018-03-01

In order to research the mechanical properties of Barite concrete under impact load, a group of concrete compression tests was carried out under the impact load by using the drop test machine. A high-speed camera was used to record the failure process of the specimen during the impact process. The test results show that:with the increase of drop height, the loading rate, the peak load, the strain under peak load, the strain rate and the dynamic increase factor (DIF) all increase gradually. The ultimate tensile strain is close to each other, and the time of impact force decreases significantly, showing significant strain rate effect.

Early-life adversity programs emotional functions and the neuroendocrine stress system: the contribution of nutrition, metabolic hormones and epigenetic mechanisms.

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Yam, Kit-Yi; Naninck, Eva F G; Schmidt, Mathias V; Lucassen, Paul J; Korosi, Aniko

2015-01-01

Clinical and pre-clinical studies have shown that early-life adversities, such as abuse or neglect, can increase the vulnerability to develop psychopathologies and cognitive decline later in life. Remarkably, the lasting consequences of stress during this sensitive period on the hypothalamic-pituitary-adrenal axis and emotional function closely resemble the long-term effects of early malnutrition and suggest a possible common pathway mediating these effects. During early-life, brain development is affected by both exogenous factors, like nutrition and maternal care as well as by endogenous modulators including stress hormones. These elements, while mostly considered for their independent actions, clearly do not act alone but rather in a synergistic manner. In order to better understand how the programming by early-life stress takes place, it is important to gain further insight into the exact interplay of these key elements, the possible common pathways as well as the underlying molecular mechanisms that mediate their effects. We here review evidence that exposure to both early-life stress and early-life under-/malnutrition similarly lead to life-long alterations on the neuroendocrine stress system and modify emotional functions. We further discuss how the different key elements of the early-life environment interact and affect one another and next suggest a possible role for the early-life adversity induced alterations in metabolic hormones and nutrient availability in shaping later stress responses and emotional function throughout life, possibly via epigenetic mechanisms. Such knowledge will help to develop intervention strategies, which gives the advantage of viewing the synergistic action of a more complete set of changes induced by early-life adversity.

Metabolic profiling of hypoxic cells revealed a catabolic signature required for cell survival.

Directory of Open Access Journals (Sweden)

Christian Frezza

Full Text Available Hypoxia is one of the features of poorly vascularised areas of solid tumours but cancer cells can survive in these areas despite the low oxygen tension. The adaptation to hypoxia requires both biochemical and genetic responses that culminate in a metabolic rearrangement to counter-balance the decrease in energy supply from mitochondrial respiration. The understanding of metabolic adaptations under hypoxia could reveal novel pathways that, if targeted, would lead to specific death of hypoxic regions. In this study, we developed biochemical and metabolomic analyses to assess the effects of hypoxia on cellular metabolism of HCT116 cancer cell line. We utilized an oxygen fluorescent probe in anaerobic cuvettes to study oxygen consumption rates under hypoxic conditions without the need to re-oxygenate the cells and demonstrated that hypoxic cells can maintain active, though diminished, oxidative phosphorylation even at 1% oxygen. These results were further supported by in situ microscopy analysis of mitochondrial NADH oxidation under hypoxia. We then used metabolomic methodologies, utilizing liquid chromatography-mass spectrometry (LC-MS, to determine the metabolic profile of hypoxic cells. This approach revealed the importance of synchronized and regulated catabolism as a mechanism of adaptation to bioenergetic stress. We then confirmed the presence of autophagy under hypoxic conditions and demonstrated that the inhibition of this catabolic process dramatically reduced the ATP levels in hypoxic cells and stimulated hypoxia-induced cell death. These results suggest that under hypoxia, autophagy is required to support ATP production, in addition to glycolysis, and that the inhibition of autophagy might be used to selectively target hypoxic regions of tumours, the most notoriously resistant areas of solid tumours.

Metabolic learning and memory formation by the brain influence systemic metabolic homeostasis.

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Zhang, Yumin; Liu, Gang; Yan, Jingqi; Zhang, Yalin; Li, Bo; Cai, Dongsheng

2015-04-07

Metabolic homeostasis is regulated by the brain, but whether this regulation involves learning and memory of metabolic information remains unexplored. Here we use a calorie-based, taste-independent learning/memory paradigm to show that Drosophila form metabolic memories that help in balancing food choice with caloric intake; however, this metabolic learning or memory is lost under chronic high-calorie feeding. We show that loss of individual learning/memory-regulating genes causes a metabolic learning defect, leading to elevated trehalose and lipid levels. Importantly, this function of metabolic learning requires not only the mushroom body but also the hypothalamus-like pars intercerebralis, while NF-κB activation in the pars intercerebralis mimics chronic overnutrition in that it causes metabolic learning impairment and disorders. Finally, we evaluate this concept of metabolic learning/memory in mice, suggesting that the hypothalamus is involved in a form of nutritional learning and memory, which is critical for determining resistance or susceptibility to obesity. In conclusion, our data indicate that the brain, and potentially the hypothalamus, direct metabolic learning and the formation of memories, which contribute to the control of systemic metabolic homeostasis.

Phase I to II cross-induction of xenobiotic metabolizing enzymes: A feedforward control mechanism for potential hormetic responses

International Nuclear Information System (INIS)

Zhang Qiang; Pi Jingbo; Woods, Courtney G.; Andersen, Melvin E.

2009-01-01

Hormetic responses to xenobiotic exposure likely occur as a result of overcompensation by the homeostatic control systems operating in biological organisms. However, the mechanisms underlying overcompensation that leads to hormesis are still unclear. A well-known homeostatic circuit in the cell is the gene induction network comprising phase I, II and III metabolizing enzymes, which are responsible for xenobiotic detoxification, and in many cases, bioactivation. By formulating a differential equation-based computational model, we investigated in this study whether hormesis can arise from the operation of this gene/enzyme network. The model consists of two feedback and one feedforward controls. With the phase I negative feedback control, xenobiotic X activates nuclear receptors to induce cytochrome P450 enzyme, which bioactivates X into a reactive metabolite X'. With the phase II negative feedback control, X' activates transcription factor Nrf2 to induce phase II enzymes such as glutathione S-transferase and glutamate cysteine ligase, etc., which participate in a set of reactions that lead to the metabolism of X' into a less toxic conjugate X''. The feedforward control involves phase I to II cross-induction, in which the parent chemical X can also induce phase II enzymes directly through the nuclear receptor and indirectly through transcriptionally upregulating Nrf2. As a result of the active feedforward control, a steady-state hormetic relationship readily arises between the concentrations of the reactive metabolite X' and the extracellular parent chemical X to which the cell is exposed. The shape of dose-response evolves over time from initially monotonically increasing to J-shaped at the final steady state-a temporal sequence consistent with adaptation-mediated hormesis. The magnitude of the hormetic response is enhanced by increases in the feedforward gain, but attenuated by increases in the bioactivation or phase II feedback loop gains. Our study suggests a

Phase I to II cross-induction of xenobiotic metabolizing enzymes: a feedforward control mechanism for potential hormetic responses.

Science.gov (United States)

Zhang, Qiang; Pi, Jingbo; Woods, Courtney G; Andersen, Melvin E

2009-06-15

Hormetic responses to xenobiotic exposure likely occur as a result of overcompensation by the homeostatic control systems operating in biological organisms. However, the mechanisms underlying overcompensation that leads to hormesis are still unclear. A well-known homeostatic circuit in the cell is the gene induction network comprising phase I, II and III metabolizing enzymes, which are responsible for xenobiotic detoxification, and in many cases, bioactivation. By formulating a differential equation-based computational model, we investigated in this study whether hormesis can arise from the operation of this gene/enzyme network. The model consists of two feedback and one feedforward controls. With the phase I negative feedback control, xenobiotic X activates nuclear receptors to induce cytochrome P450 enzyme, which bioactivates X into a reactive metabolite X'. With the phase II negative feedback control, X' activates transcription factor Nrf2 to induce phase II enzymes such as glutathione S-transferase and glutamate cysteine ligase, etc., which participate in a set of reactions that lead to the metabolism of X' into a less toxic conjugate X''. The feedforward control involves phase I to II cross-induction, in which the parent chemical X can also induce phase II enzymes directly through the nuclear receptor and indirectly through transcriptionally upregulating Nrf2. As a result of the active feedforward control, a steady-state hormetic relationship readily arises between the concentrations of the reactive metabolite X' and the extracellular parent chemical X to which the cell is exposed. The shape of dose-response evolves over time from initially monotonically increasing to J-shaped at the final steady state-a temporal sequence consistent with adaptation-mediated hormesis. The magnitude of the hormetic response is enhanced by increases in the feedforward gain, but attenuated by increases in the bioactivation or phase II feedback loop gains. Our study suggests a

micro-mechanical experimental investigation and modelling of strain and damage of argillaceous rocks under combined hydric and mechanical loads

International Nuclear Information System (INIS)

Wang, L.

2012-01-01

The hydro-mechanical behavior of argillaceous rocks, which are possible host rocks for underground radioactive nuclear waste storage, is investigated by means of micro-mechanical experimental investigations and modellings. Strain fields at the micrometric scale of the composite structure of this rock, are measured by the combination of environmental scanning electron microscopy, in situ testing and digital image correlation technique. The evolution of argillaceous rocks under pure hydric loading is first investigated. The strain field is strongly heterogeneous and manifests anisotropy. The observed nonlinear deformation at high relative humidity (RH) is related not only to damage, but also to the nonlinear swelling of the clay mineral itself, controlled by different local mechanisms depending on RH. Irreversible deformations are observed during hydric cycles, as well as a network of microcracks located in the bulk of the clay matrix and/or at the inclusion-matrix interface. Second, the local deformation field of the material under combined hydric and mechanical loadings is quantified. Three types of deformation bands are evidenced under mechanical loading, either normal to stress direction (compaction), parallel (microcracking) or inclined (shear). Moreover, they are strongly controlled by the water content of the material: shear bands are in particular prone to appear at high RH states. In view of understanding the mechanical interactions a local scale, the material is modeled as a composite made of non-swelling elastic inclusions embedded in an elastic swelling clay matrix. The internal stress field induced by swelling strain incompatibilities between inclusions and matrix, as well as the overall deformation, is numerically computed at equilibrium but also during the transient stage associated with a moisture gradient. An analytical micro-mechanical model based on Eshelby's solution is proposed. In addition, 2D finite element computations are performed. Results

Progressive damage analysis of carbon/epoxy laminates under couple laser and mechanical loading

Directory of Open Access Journals (Sweden)

Wanlei Liu

Full Text Available A multiscale model based bridge theory is proposed for the progressive damage analysis of carbon/epoxy laminates under couple laser and mechanical loading. The ablation model is adopted to calculate ablation temperature changing and ablation surface degradation. The polynomial strengthening model of matrix is used to improve bridging model for reducing parameter input. Stiffness degradation methods of bridging model are also improved in order to analyze the stress redistribution more accurately when the damage occurs. Thermal-mechanical analyses of the composite plate are performed using the ABAQUS/Explicit program with the developed model implemented in the VUMAT. The simulation results show that this model can be used to proclaim the mesoscale damage mechanism of composite laminates under coupled loading. Keywords: Laser irradiation, Multiscale analysis, Bridge model, Thermal-mechanical

An NMDA Receptor-Dependent Mechanism Underlies Inhibitory Synapse Development