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Sample records for metabolic resistance mechanisms

  1. Citric Acid Metabolism in Resistant Hypertension: Underlying Mechanisms and Metabolic Prediction of Treatment Response.

    Martin-Lorenzo, Marta; Martinez, Paula J; Baldan-Martin, Montserrat; Ruiz-Hurtado, Gema; Prado, Jose Carlos; Segura, Julian; de la Cuesta, Fernando; Barderas, Maria G; Vivanco, Fernando; Ruilope, Luis Miguel; Alvarez-Llamas, Gloria

    2017-11-01

    Resistant hypertension (RH) affects 9% to 12% of hypertensive adults. Prolonged exposure to suboptimal blood pressure control results in end-organ damage and cardiovascular risk. Spironolactone is the most effective drug for treatment, but not all patients respond and side effects are not negligible. Little is known on the mechanisms responsible for RH. We aimed to identify metabolic alterations in urine. In addition, a potential capacity of metabolites to predict response to spironolactone was investigated. Urine was collected from 29 patients with RH and from a group of 13 subjects with pseudo-RH. For patients, samples were collected before and after spironolactone administration and were classified in responders (n=19) and nonresponders (n=10). Nuclear magnetic resonance was applied to identify altered metabolites and pathways. Metabolites were confirmed by liquid chromatography-mass spectrometry. Citric acid cycle was the pathway most significantly altered ( P citric acid cycle and deregulation of reactive oxygen species homeostasis control continue its activation after hypertension was developed. A metabolic panel showing alteration before spironolactone treatment and predicting future response of patients is shown. These molecular indicators will contribute optimizing the rate of control of RH patients with spironolactone. © 2017 American Heart Association, Inc.

  2. Insulin Signaling, Resistance, and the Metabolic Syndrome: Insights from Mouse Models to Disease Mechanisms

    Guo, Shaodong

    2014-01-01

    Insulin resistance is a major underlying mechanism for the “metabolic syndrome”, which is also known as insulin resistance syndrome. Metabolic syndrome is increasing at an alarming rate, becoming a major public and clinical problem worldwide. Metabolic syndrome is represented by a group of interrelated disorders, including obesity, hyperglycemia, hyperlipidemia, and hypertension. It is also a significant risk factor for cardiovascular disease and increased morbidity and mortality. Animal studies demonstrate that insulin and its signaling cascade normally control cell growth, metabolism and survival through activation of mitogen-activated protein kinases (MAPKs) and phosphotidylinositide-3-kinase (PI3K), of which activation of PI-3K-associated with insulin receptor substrate-1 and -2 (IRS1, 2) and subsequent Akt→Foxo1 phosphorylation cascade has a central role in control of nutrient homeostasis and organ survival. Inactivation of Akt and activation of Foxo1, through suppression IRS1 and IRS2 in different organs following hyperinsulinemia, metabolic inflammation, and over nutrition may provide the underlying mechanisms for metabolic syndrome in humans. Targeting the IRS→Akt→Foxo1 signaling cascade will likely provide a strategy for therapeutic intervention in the treatment of type 2 diabetes and its complications. This review discusses the basis of insulin signaling, insulin resistance in different mouse models, and how a deficiency of insulin signaling components in different organs contributes to the feature of the metabolic syndrome. Emphasis will be placed on the role of IRS1, IRS2, and associated signaling pathways that couple to Akt and the forkhead/winged helix transcription factor Foxo1. PMID:24281010

  3. Immune and Metabolic Regulation Mechanism of Dangguiliuhuang Decoction against Insulin Resistance and Hepatic Steatosis

    Hui Cao

    2017-07-01

    Full Text Available Dangguiliuhuang decoction (DGLHD is a traditional Chinese medicine (TCM formula, which mainly consists of angelica, radix rehmanniae, radix rehmanniae praeparata, scutellaria baicalensis, coptis chinensis, astragalus membranaceus, and golden cypress, and used for the treatment of diabetes and some autoimmune diseases. In this study, we explored the potential mechanism of DGLHD against insulin resistance and fatty liver in vivo and in vitro. Our data revealed that DGLHD normalized glucose and insulin level, increased the expression of adiponectin, diminished fat accumulation and lipogenesis, and promoted glucose uptake. Metabolomic analysis also demonstrated that DGLHD decreased isoleucine, adenosine, and cholesterol, increased glutamine levels in liver and visceral adipose tissue (VAT of ob/ob mice. Importantly, DGLHD promoted the shift of pro-inflammatory to anti-inflammatory cytokines, suppressed T lymphocytes proliferation, and enhanced regulatory T cells (Tregs differentiation. DGLHD also inhibited dendritic cells (DCs maturation, attenuated DCs-stimulated T cells proliferation and secretion of IL-12p70 cytokine from DCs, and promoted the interaction of DCs with Tregs. Further studies indicated that the changed PI3K/Akt signaling pathway and elevated PPAR-γ expression were not only observed with the ameliorated glucose and lipid metabolism in adipocytes and hepatocytes, but also exhibited in DCs and T cells by DGLHD. Collectively, our results suggest that DGLHD exerts anti-insulin resistant and antisteatotic effects by improving abnormal immune and metabolic homeostasis. And DGLHD may be a novel approach to the treatment of obesity-related insulin resistance and hepatic steatosis.

  4. Metabolic and Target-Site Mechanisms Combine to Confer Strong DDT Resistance in Anopheles gambiae

    Mitchell, Sara N.; Rigden, Daniel J.; Dowd, Andrew J.; Lu, Fang; Wilding, Craig S.; Weetman, David; Dadzie, Samuel; Jenkins, Adam M.; Regna, Kimberly; Boko, Pelagie; Djogbenou, Luc; Muskavitch, Marc A. T.; Ranson, Hilary; Paine, Mark J. I.; Mayans, Olga; Donnelly, Martin J.

    2014-01-01

    The development of resistance to insecticides has become a classic exemplar of evolution occurring within human time scales. In this study we demonstrate how resistance to DDT in the major African malaria vector Anopheles gambiae is a result of both target-site resistance mechanisms that have introgressed between incipient species (the M- and S-molecular forms) and allelic variants in a DDT-detoxifying enzyme. Sequencing of the detoxification enzyme, Gste2, from DDT resistant and susceptible strains of An. gambiae, revealed a non-synonymous polymorphism (I114T), proximal to the DDT binding domain, which segregated with strain phenotype. Recombinant protein expression and DDT metabolism analysis revealed that the proteins from the susceptible strain lost activity at higher DDT concentrations, characteristic of substrate inhibition. The effect of I114T on GSTE2 protein structure was explored through X-ray crystallography. The amino acid exchange in the DDT-resistant strain introduced a hydroxyl group nearby the hydrophobic DDT-binding region. The exchange does not result in structural alterations but is predicted to facilitate local dynamics and enzyme activity. Expression of both wild-type and 114T alleles the allele in Drosophila conferred an increase in DDT tolerance. The 114T mutation was significantly associated with DDT resistance in wild caught M-form populations and acts in concert with target-site mutations in the voltage gated sodium channel (Vgsc-1575Y and Vgsc-1014F) to confer extreme levels of DDT resistance in wild caught An. gambiae. PMID:24675797

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

    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

  6. Multiple insecticide resistance mechanisms involving metabolic changes and insensitive target sites selected in anopheline vectors of malaria in Sri Lanka

    Karunaratne SHP Parakrama

    2008-08-01

    Full Text Available Abstract Background The current status of insecticide resistance and the underlying resistance mechanisms were studied in the major vector of malaria, Anopheles culicifacies, and the secondary vector, Anopheles subpictus in five districts (Anuradhapura, Kurunegala, Moneragala, Puttalam and Trincomalee of Sri Lanka. Eight other anophelines, Anopheles annularis, Anopheles barbirostris, Anopheles jamesii, Anopheles nigerrimus, Anopheles peditaeniatus, Anopheles tessellatus, Anopheles vagus and Anopheles varuna from Anuradhapura district were also tested. Methods Adult females were exposed to the WHO discriminating dosages of DDT, malathion, fenitrothion, propoxur, λ-cyhalothrin, cyfluthrin, cypermethrin, deltamethrin, permethrin and etofenprox. The presence of metabolic resistance by esterase, glutathione S-transferase (GST and monooxygenase-based mechanisms, and the sensitivity of the acetylcholinesterase target site were assessed using synergists, and biochemical, and metabolic techniques. Results All the anopheline species had high DDT resistance. All An. culicifacies and An. subpictus populations were resistant to malathion, except An. culicifacies from Kurunegala, where there was no malathion carboxylesterase activity. Kurunegala and Puttalam populations of An. culicifacies were susceptible to fenitrothion. All the An. culicifacies populations were susceptible to carbamates. Both species were susceptible to the discriminating dosages of cypermethrin and cyfluthrin, but had different levels of resistance to other pyrethroids. Of the 8 other anophelines, only An. nigerrimus and An. peditaeniatus were resistant to all the insecticides tested, probably due to their high exposure to the insecticides used in agriculture. An. vagus showed some resistance to permethrin. Esterases, GSTs and monooxygenases were elevated in both An. culicifacies and An. subpictus. AChE was most sensitive to insecticides in Kurunegala and Trincomalee An. culicifacies

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

    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.

  8. Metabolic Resistance in Bed Bugs

    Omprakash Mittapalli

    2011-03-01

    Full Text Available Blood-feeding insects have evolved resistance to various insecticides (organochlorines, pyrethroids, carbamates, etc. through gene mutations and increased metabolism. Bed bugs (Cimex lectularius are hematophagous ectoparasites that are poised to become one of the major pests in households throughout the United States. Currently, C. lectularius has attained a high global impact status due to its sudden and rampant resurgence. Resistance to pesticides is one factor implicated in this phenomenon. Although much emphasis has been placed on target sensitivity, little to no knowledge is available on the role of key metabolic players (e.g., cytochrome P450s and glutathione S-transferases towards pesticide resistance in C. lectularius. In this review, we discuss different modes of resistance (target sensitivity, penetration resistance, behavioral resistance, and metabolic resistance with more emphasis on metabolic resistance.

  9. Metabolic Reprogramming During Multidrug Resistance in Leukemias

    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.

  10. Effect of the pacing strategy during half-duration resistance test on the mechanic, metabolic and cardio-respiratory response

    A. Pérez-Guerra

    2017-12-01

    ção. Foram observadas diferenças significativas na eficiência energética durante o 3°-min entre CP vs. KP, RP vs. KP e KP vs. IP. Estas diferenças significativas foram estendidas para o 4°-min na comparação CP vs. IP, CP vs. KP, CP vs. KP, KP vs. RP e KP vs. IP. No último minuto do teste, houve diferenças significativas entre CP vs. KP. Não foram encontradas diferenças significativas em nenhuma das variáveis que avaliam o metabolismo anaeróbico (déficit de oxigênio acumulado, débito de oxigênio, cinética do consumo de oxigênio e lactato no sangue entre ambos os protocolos. Conclusões: Os resultados sugerem que as principais respostas dos sistemas funcionais são afetadas significativamente pela estratégia de corrida usado por indivíduos de nível médio durante a meia-corrida de longa distância. Keywords: Resistance test, Metabolic response, Cardio-respiratory response, Mechanic response, Students, Palabras clave: Test de resistencia, Respuesta metabólica, Respuesta cardiorespiratoria, Respuesta mecánica, Estudiantes, Palavras-chave: Teste de resistência, Resposta metabólica, Resposta cardiorrespiratória, Resposta mecânica, Estudantes

  11. Mechanisms of Antibiotic Resistance

    Munita, Jose M.; Arias, Cesar A.

    2015-01-01

    Emergence of resistance among the most important bacterial pathogens is recognized as a major public health threat affecting humans worldwide. Multidrug-resistant organisms have emerged not only in the hospital environment but are now often identified in community settings, suggesting that reservoirs of antibiotic-resistant bacteria are present outside the hospital. The bacterial response to the antibiotic “attack” is the prime example of bacterial adaptation and the pinnacle of evolution. “Survival of the fittest” is a consequence of an immense genetic plasticity of bacterial pathogens that trigger specific responses that result in mutational adaptations, acquisition of genetic material or alteration of gene expression producing resistance to virtually all antibiotics currently available in clinical practice. Therefore, understanding the biochemical and genetic basis of resistance is of paramount importance to design strategies to curtail the emergence and spread of resistance and devise innovative therapeutic approaches against multidrug-resistant organisms. In this chapter, we will describe in detail the major mechanisms of antibiotic resistance encountered in clinical practice providing specific examples in relevant bacterial pathogens. PMID:27227291

  12. Fructose, insulin resistance, and metabolic dyslipidemia

    Adeli Khosrow

    2005-02-01

    Full Text Available Abstract Obesity and type 2 diabetes are occurring at epidemic rates in the United States and many parts of the world. The "obesity epidemic" appears to have emerged largely from changes in our diet and reduced physical activity. An important but not well-appreciated dietary change has been the substantial increase in the amount of dietary fructose consumption from high intake of sucrose and high fructose corn syrup, a common sweetener used in the food industry. A high flux of fructose to the liver, the main organ capable of metabolizing this simple carbohydrate, perturbs glucose metabolism and glucose uptake pathways, and leads to a significantly enhanced rate of de novo lipogenesis and triglyceride (TG synthesis, driven by the high flux of glycerol and acyl portions of TG molecules from fructose catabolism. These metabolic disturbances appear to underlie the induction of insulin resistance commonly observed with high fructose feeding in both humans and animal models. Fructose-induced insulin resistant states are commonly characterized by a profound metabolic dyslipidemia, which appears to result from hepatic and intestinal overproduction of atherogenic lipoprotein particles. Thus, emerging evidence from recent epidemiological and biochemical studies clearly suggests that the high dietary intake of fructose has rapidly become an important causative factor in the development of the metabolic syndrome. There is an urgent need for increased public awareness of the risks associated with high fructose consumption and greater efforts should be made to curb the supplementation of packaged foods with high fructose additives. The present review will discuss the trends in fructose consumption, the metabolic consequences of increased fructose intake, and the molecular mechanisms leading to fructose-induced lipogenesis, insulin resistance and metabolic dyslipidemia.

  13. PEDF-induced alteration of metabolism leading to insulin resistance.

    Carnagarin, Revathy; Dharmarajan, Arunasalam M; Dass, Crispin R

    2015-02-05

    Pigment epithelium-derived factor (PEDF) is an anti-angiogenic, immunomodulatory, and neurotrophic serine protease inhibitor protein. PEDF is evolving as a novel metabolic regulatory protein that plays a causal role in insulin resistance. Insulin resistance is the central pathogenesis of metabolic disorders such as obesity, type 2 diabetes mellitus, polycystic ovarian disease, and metabolic syndrome, and PEDF is associated with them. The current evidence suggests that PEDF administration to animals induces insulin resistance, whereas neutralisation improves insulin sensitivity. Inflammation, lipolytic free fatty acid mobilisation, and mitochondrial dysfunction are the proposed mechanism of PEDF-mediated insulin resistance. This review summarises the probable mechanisms adopted by PEDF to induce insulin resistance, and identifies PEDF as a potential therapeutic target in ameliorating insulin resistance. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  14. Mechanisms of ouabain resistance

    Schulz, J.T. III.

    1987-01-01

    Experiments were designed to investigate the mechanism of ouabain resistance in two distinct types of transfected cells derived from ouabain-sensitive CV-1 cell parents. The first type of transfectant is the recipient of a gene encoding the alpha subunit of the rodent renal Na,K-ATPase (R-alphal gene); the second type of transfectant is the recipient of the mouse ouabain resistance gene. Measurements of 86 Rb + uptake and Na,K=ATPase activity in R-alphal gene transfectant cells and CV-1 parent cells indicate that the ouabain-resistant phenotype of the transfectants is due to expression of a relatively ouabain-insensitive Na,K=ATPase. CV-1 parent cells express one component of ouabain sensitive 86 Rb + uptake and one component of ouabain-sensitive Na, K-ATPase activity. R-alpha 1 gene transfectants express the parental forms of ouabain-sensitive 86 Rb + uptake and Na,K-ATPase activity, but in addition express new,relatively ouabain-insensitive forms of 86 Rb + uptake activity and Na,K-ATPase activity

  15. Analysis of the Genome and Mobilome of a Dissimilatory Arsenate Reducing Aeromonas sp. O23A Reveals Multiple Mechanisms for Heavy Metal Resistance and Metabolism

    Witold Uhrynowski

    2017-05-01

    Full Text Available Aeromonas spp. are among the most ubiquitous microorganisms, as they have been isolated from different environmental niches including waters, soil, as well as wounds and digestive tracts of poikilothermic animals and humans. Although much attention has been paid to the pathogenicity of Aeromonads, the role of these bacteria in environmentally important processes, such as transformation of heavy metals, remains to be discovered. Therefore, the aim of this study was a detailed genomic characterization of Aeromonas sp. O23A, the first representative of this genus capable of dissimilatory arsenate reduction. The strain was isolated from microbial mats from the Zloty Stok mine (SW Poland, an environment strongly contaminated with arsenic. Previous physiological studies indicated that O23A may be involved in both mobilization and immobilization of this metalloid in the environment. To discover the molecular basis of the mechanisms behind the observed abilities, the genome of O23A (∼5.0 Mbp was sequenced and annotated, and genes for arsenic respiration, heavy metal resistance (hmr and other phenotypic traits, including siderophore production, were identified. The functionality of the indicated gene modules was assessed in a series of minimal inhibitory concentration analyses for various metals and metalloids, as well as mineral dissolution experiments. Interestingly, comparative analyses revealed that O23A is related to a fish pathogen Aeromonas salmonicida subsp. salmonicida A449 which, however, does not carry genes for arsenic respiration. This indicates that the dissimilatory arsenate reduction ability may have been lost during genome reduction in pathogenic strains, or acquired through horizontal gene transfer. Therefore, particular emphasis was placed upon the mobilome of O23A, consisting of four plasmids, a phage, and numerous transposable elements, which may play a role in the dissemination of hmr and arsenic metabolism genes in the

  16. Analysis of the Genome and Mobilome of a Dissimilatory Arsenate Reducing Aeromonas sp. O23A Reveals Multiple Mechanisms for Heavy Metal Resistance and Metabolism.

    Uhrynowski, Witold; Decewicz, Przemyslaw; Dziewit, Lukasz; Radlinska, Monika; Krawczyk, Pawel S; Lipinski, Leszek; Adamska, Dorota; Drewniak, Lukasz

    2017-01-01

    Aeromonas spp. are among the most ubiquitous microorganisms, as they have been isolated from different environmental niches including waters, soil, as well as wounds and digestive tracts of poikilothermic animals and humans. Although much attention has been paid to the pathogenicity of Aeromonads, the role of these bacteria in environmentally important processes, such as transformation of heavy metals, remains to be discovered. Therefore, the aim of this study was a detailed genomic characterization of Aeromonas sp. O23A, the first representative of this genus capable of dissimilatory arsenate reduction. The strain was isolated from microbial mats from the Zloty Stok mine (SW Poland), an environment strongly contaminated with arsenic. Previous physiological studies indicated that O23A may be involved in both mobilization and immobilization of this metalloid in the environment. To discover the molecular basis of the mechanisms behind the observed abilities, the genome of O23A (∼5.0 Mbp) was sequenced and annotated, and genes for arsenic respiration, heavy metal resistance ( hmr ) and other phenotypic traits, including siderophore production, were identified. The functionality of the indicated gene modules was assessed in a series of minimal inhibitory concentration analyses for various metals and metalloids, as well as mineral dissolution experiments. Interestingly, comparative analyses revealed that O23A is related to a fish pathogen Aeromonas salmonicida subsp. salmonicida A449 which, however, does not carry genes for arsenic respiration. This indicates that the dissimilatory arsenate reduction ability may have been lost during genome reduction in pathogenic strains, or acquired through horizontal gene transfer. Therefore, particular emphasis was placed upon the mobilome of O23A, consisting of four plasmids, a phage, and numerous transposable elements, which may play a role in the dissemination of hmr and arsenic metabolism genes in the environment. The obtained

  17. Analysis of the Genome and Mobilome of a Dissimilatory Arsenate Reducing Aeromonas sp. O23A Reveals Multiple Mechanisms for Heavy Metal Resistance and Metabolism

    Uhrynowski, Witold; Decewicz, Przemyslaw; Dziewit, Lukasz; Radlinska, Monika; Krawczyk, Pawel S.; Lipinski, Leszek; Adamska, Dorota; Drewniak, Lukasz

    2017-01-01

    Aeromonas spp. are among the most ubiquitous microorganisms, as they have been isolated from different environmental niches including waters, soil, as well as wounds and digestive tracts of poikilothermic animals and humans. Although much attention has been paid to the pathogenicity of Aeromonads, the role of these bacteria in environmentally important processes, such as transformation of heavy metals, remains to be discovered. Therefore, the aim of this study was a detailed genomic characterization of Aeromonas sp. O23A, the first representative of this genus capable of dissimilatory arsenate reduction. The strain was isolated from microbial mats from the Zloty Stok mine (SW Poland), an environment strongly contaminated with arsenic. Previous physiological studies indicated that O23A may be involved in both mobilization and immobilization of this metalloid in the environment. To discover the molecular basis of the mechanisms behind the observed abilities, the genome of O23A (∼5.0 Mbp) was sequenced and annotated, and genes for arsenic respiration, heavy metal resistance (hmr) and other phenotypic traits, including siderophore production, were identified. The functionality of the indicated gene modules was assessed in a series of minimal inhibitory concentration analyses for various metals and metalloids, as well as mineral dissolution experiments. Interestingly, comparative analyses revealed that O23A is related to a fish pathogen Aeromonas salmonicida subsp. salmonicida A449 which, however, does not carry genes for arsenic respiration. This indicates that the dissimilatory arsenate reduction ability may have been lost during genome reduction in pathogenic strains, or acquired through horizontal gene transfer. Therefore, particular emphasis was placed upon the mobilome of O23A, consisting of four plasmids, a phage, and numerous transposable elements, which may play a role in the dissemination of hmr and arsenic metabolism genes in the environment. The obtained

  18. Mechanisms of Resistance to Neurotoxins

    Schubert, David

    2002-01-01

    .... During all of these events, some groups of nerve cells are spared relative to others. It is therefore likely that biochemical mechanisms exist which lead to increased resistance to oxidative stress and other forms of cytotoxicity...

  19. RESISTANT HYPERTENSION IN A PATIENT WITH METABOLIC SYNDROME

    O. M. Drapkina; J. S. Sibgatullina

    2016-01-01

    Clinical case of resistant hypertension in a patient with metabolic syndrome is presented. Features of hypertension in metabolic syndrome and features of metabolic syndrome in women of pre- and postmenopausal age are also considered. Understanding the features of metabolic syndrome in women, as well as features of hypertension and metabolic syndrome will improve the results of treatment in patients with resistant hypertension.

  20. Molecular mechanism of insulin resistance

    Free fatty acids are known to play a key role in promoting loss of insulin sensitivity, thereby causing insulin resistance and type 2 diabetes. However, the underlying mechanism involved is still unclear. In searching for the cause of the mechanism, it has been found that palmitate inhibits insulin receptor (IR) gene expression, ...

  1. Microbial Regulation of Glucose Metabolism and Insulin Resistance

    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.

  2. Metabolic consequences of resistive-type exercise

    Dudley, G. A.

    1988-01-01

    This brief review concerns acute and chronic metabolic responses to resistive-type exercise (RTE) (i.e., Olympic/power weight lifting and bodybuilding). Performance of RTE presents power output substantially greater (10-15-fold) than that evident with endurance-type exercise. Accordingly, RTE relies heavily on the anaerobic enzyme machinery of skeletal muscle for energy supply, with alterations in the rate of aerobic metabolism being modest. Hydrolysis of high energy phosphate compounds (PC, ATP), glycogenolysis, and glycolysis are evident during an acute bout of RTE as indicated by metabolic markers in mixed fiber type skeletal muscle samples. The type of RTE probably influences the magnitude of these responses since the increase in blood lactate is much greater during a typical "bodybuilding" than "power lifting" session. The influence of RTE training on acute metabolic responses to RTE has received little attention. An individual's inherent metabolic characteristics are apparently sufficient to meet the energy demands of RTE as training of this type does not increase VO2max or substantially alter the content of marker enzymes in mixed fiber type skeletal muscle. Analyses of pools of fast- vs slow-twitch fibers, however, indicate that RTE-induced changes may be fiber type specific. Future studies should better delineate the metabolic responses to RTE and determine whether these are related to the enhanced performance associated with such training.

  3. Pathophysiological mechanisms of insulin resistance

    Brands, M.

    2013-01-01

    In this thesis we studied pathophysiological mechanisms of insulin resistance in different conditions in humans, i.e. in obesity, during lipid infusions, after hypercaloric feeding, and glucocorticoid treatment. We focused on 3 important hypotheses that are suggested to be implicated in the

  4. Action and resistance mechanisms of antibiotics: A guide for clinicians

    Garima Kapoor

    2017-01-01

    Full Text Available Infections account for a major cause of death throughout the developing world. This is mainly due to the emergence of newer infectious agents and more specifically due to the appearance of antimicrobial resistance. With time, the bacteria have become smarter and along with it, massive imprudent usage of antibiotics in clinical practice has resulted in resistance of bacteria to antimicrobial agents. The antimicrobial resistance is recognized as a major problem in the treatment of microbial infections. The biochemical resistance mechanisms used by bacteria include the following: antibiotic inactivation, target modification, altered permeability, and “bypass” of metabolic pathway. Determination of bacterial resistance to antibiotics of all classes (phenotypes and mutations that are responsible for bacterial resistance to antibiotics (genetic analysis are helpful. Better understanding of the mechanisms of antibiotic resistance will help clinicians regarding usage of antibiotics in different situations. This review discusses the mechanism of action and resistance development in commonly used antimicrobials.

  5. Antimicrobial resistance mechanisms among Campylobacter.

    Wieczorek, Kinga; Osek, Jacek

    2013-01-01

    Campylobacter jejuni and Campylobacter coli are recognized as the most common causative agents of bacterial gastroenteritis in the world. Humans most often become infected by ingesting contaminated food, especially undercooked chicken, but also other sources of bacteria have been described. Campylobacteriosis is normally a self-limiting disease. Antimicrobial treatment is needed only in patients with more severe disease and in those who are immunologically compromised. The most common antimicrobial agents used in the treatment of Campylobacter infections are macrolides, such as erythromycin, and fluoroquinolones, such as ciprofloxacin. Tetracyclines have been suggested as an alternative choice in the treatment of clinical campylobacteriosis but in practice are not often used. However, during the past few decades an increasing number of resistant Campylobacter isolates have developed resistance to fluoroquinolones and other antimicrobials such as macrolides, aminoglycosides, and beta-lactams. Trends in antimicrobial resistance have shown a clear correlation between use of antibiotics in the veterinary medicine and animal production and resistant isolates of Campylobacter in humans. In this review, the patterns of emerging resistance to the antimicrobial agents useful in treatment of the disease are presented and the mechanisms of resistance to these drugs in Campylobacter are discussed.

  6. Concretes with high mechanical resistance

    Mauny, Pierre.

    1973-01-01

    Description is given of a method for manufacturing concretes with high mechanical resistance in compression, obtained by mixing gravels highly resistant to compression, sand and cement in an aqueous medium. Use is made of sands of porous ceramics, such as terra-cotta, of a grain size from 0,1 to 5mm, the pore diameter of which is from 0.5 to 15 microns, chosen so as to be slighty bigger than the crystals of the cement used. This can be applied to the pre-stressed structures used in the nuclear field [fr

  7. Insecticide resistance and resistance mechanisms in bed bugs, Cimex spp. (Hemiptera: Cimicidae).

    Dang, Kai; Doggett, Stephen L; Veera Singham, G; Lee, Chow-Yang

    2017-06-29

    The worldwide resurgence of bed bugs [both Cimex lectularius L. and Cimex hemipterus (F.)] over the past two decades is believed in large part to be due to the development of insecticide resistance. The transcriptomic and genomic studies since 2010, as well as morphological, biochemical and behavioral studies, have helped insecticide resistance research on bed bugs. Multiple resistance mechanisms, including penetration resistance through thickening or remodelling of the cuticle, metabolic resistance by increased activities of detoxification enzymes (e.g. cytochrome P450 monooxygenases and esterases), and knockdown resistance by kdr mutations, have been experimentally identified as conferring insecticide resistance in bed bugs. Other candidate resistance mechanisms, including behavioral resistance, some types of physiological resistance (e.g. increasing activities of esterases by point mutations, glutathione S-transferase, target site insensitivity including altered AChEs, GABA receptor insensitivity and altered nAChRs), symbiont-mediated resistance and other potential, yet undiscovered mechanisms may exist. This article reviews recent studies of resistance mechanisms and the genes governing insecticide resistance, potential candidate resistance mechanisms, and methods of monitoring insecticide resistance in bed bugs. This article provides an insight into the knowledge essential for the development of both insecticide resistance management (IRM) and integrated pest management (IPM) strategies for successful bed bug management.

  8. Mechanism of quinolone action and resistance.

    Aldred, Katie J; Kerns, Robert J; Osheroff, Neil

    2014-03-18

    Quinolones are one of the most commonly prescribed classes of antibacterials in the world and are used to treat a variety of bacterial infections in humans. Because of the wide use (and overuse) of these drugs, the number of quinolone-resistant bacterial strains has been growing steadily since the 1990s. As is the case with other antibacterial agents, the rise in quinolone resistance threatens the clinical utility of this important drug class. Quinolones act by converting their targets, gyrase and topoisomerase IV, into toxic enzymes that fragment the bacterial chromosome. This review describes the development of the quinolones as antibacterials, the structure and function of gyrase and topoisomerase IV, and the mechanistic basis for quinolone action against their enzyme targets. It will then discuss the following three mechanisms that decrease the sensitivity of bacterial cells to quinolones. Target-mediated resistance is the most common and clinically significant form of resistance. It is caused by specific mutations in gyrase and topoisomerase IV that weaken interactions between quinolones and these enzymes. Plasmid-mediated resistance results from extrachromosomal elements that encode proteins that disrupt quinolone-enzyme interactions, alter drug metabolism, or increase quinolone efflux. Chromosome-mediated resistance results from the underexpression of porins or the overexpression of cellular efflux pumps, both of which decrease cellular concentrations of quinolones. Finally, this review will discuss recent advancements in our understanding of how quinolones interact with gyrase and topoisomerase IV and how mutations in these enzymes cause resistance. These last findings suggest approaches to designing new drugs that display improved activity against resistant strains.

  9. The Emerging Role of Branched-Chain Amino Acids in Insulin Resistance and Metabolism

    Yoon, Mee-Sup

    2016-01-01

    Insulin is required for maintenance of glucose homeostasis. Despite the importance of insulin sensitivity to metabolic health, the mechanisms that induce insulin resistance remain unclear. Branched-chain amino acids (BCAAs) belong to the essential amino acids, which are both direct and indirect nutrient signals. Even though BCAAs have been reported to improve metabolic health, an increased BCAA plasma level is associated with a high risk of metabolic disorder and future insulin resistance, or...

  10. Mechanisms of buffer therapy resistance.

    Bailey, Kate M; Wojtkowiak, Jonathan W; Cornnell, Heather H; Ribeiro, Maria C; Balagurunathan, Yoganand; Hashim, Arig Ibrahim; Gillies, Robert J

    2014-04-01

    Many studies have shown that the acidity of solid tumors contributes to local invasion and metastasis. Oral pH buffers can specifically neutralize the acidic pH of tumors and reduce the incidence of local invasion and metastatic formation in multiple murine models. However, this effect is not universal as we have previously observed that metastasis is not inhibited by buffers in some tumor models, regardless of buffer used. B16-F10 (murine melanoma), LL/2 (murine lung) and HCT116 (human colon) tumors are resistant to treatment with lysine buffer therapy, whereas metastasis is potently inhibited by lysine buffers in MDA-MB-231 (human breast) and PC3M (human prostate) tumors. In the current work, we confirmed that sensitive cells utilized a pH-dependent mechanism for successful metastasis supported by a highly glycolytic phenotype that acidifies the local tumor microenvironment resulting in morphological changes. In contrast, buffer-resistant cell lines exhibited a pH-independent metastatic mechanism involving constitutive secretion of matrix degrading proteases without elevated glycolysis. These results have identified two distinct mechanisms of experimental metastasis, one of which is pH-dependent (buffer therapy sensitive cells) and one which is pH-independent (buffer therapy resistant cells). Further characterization of these models has potential for therapeutic benefit. Copyright © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. All rights reserved.

  11. The Characteristic of Metabolic Changes at Insulin Resistance in Children with Primary Hypertension

    N.N. Kaladze

    2013-09-01

    Full Text Available In children with hypertension we identified various metabolic disorders and the role of insulin resistance in their development, as well as compensatory mechanisms of maintaining normoglycemia.

  12. Novel Plasmodium falciparum metabolic network reconstruction identifies shifts associated with clinical antimalarial resistance.

    Carey, Maureen A; Papin, Jason A; Guler, Jennifer L

    2017-07-19

    Malaria remains a major public health burden and resistance has emerged to every antimalarial on the market, including the frontline drug, artemisinin. Our limited understanding of Plasmodium biology hinders the elucidation of resistance mechanisms. In this regard, systems biology approaches can facilitate the integration of existing experimental knowledge and further understanding of these mechanisms. Here, we developed a novel genome-scale metabolic network reconstruction, iPfal17, of the asexual blood-stage P. falciparum parasite to expand our understanding of metabolic changes that support resistance. We identified 11 metabolic tasks to evaluate iPfal17 performance. Flux balance analysis and simulation of gene knockouts and enzyme inhibition predict candidate drug targets unique to resistant parasites. Moreover, integration of clinical parasite transcriptomes into the iPfal17 reconstruction reveals patterns associated with antimalarial resistance. These results predict that artemisinin sensitive and resistant parasites differentially utilize scavenging and biosynthetic pathways for multiple essential metabolites, including folate and polyamines. Our findings are consistent with experimental literature, while generating novel hypotheses about artemisinin resistance and parasite biology. We detect evidence that resistant parasites maintain greater metabolic flexibility, perhaps representing an incomplete transition to the metabolic state most appropriate for nutrient-rich blood. Using this systems biology approach, we identify metabolic shifts that arise with or in support of the resistant phenotype. This perspective allows us to more productively analyze and interpret clinical expression data for the identification of candidate drug targets for the treatment of resistant parasites.

  13. Mechanism of resistance of noncycling mammalian cells to 4'-(9-acridinylamino)methanesulfon-m-anisidide: comparison of uptake, metabolism, and DNA breakage in log- and plateau-phase Chinese hamster fibroblast cell cultures

    Robbie, M.A.; Baguley, B.C.; Denny, W.A.; Gavin, J.B.; Wilson, W.R.

    1988-01-01

    Resistance of noncycling cells to amsacrine (m-AMSA) has been widely reported and may limit the activity of this drug against solid tumors. The biochemical mechanism(s) for this resistance have been investigated using spontaneously transformed Chinese hamster fibroblasts (AA8 cells, a subline of Chinese hamster ovary-cells) in log- and plateau-phase spinner cultures. In early plateau phase most cells entered a growth-arrested state with a G1-G0 DNA content and showed a marked decrease in sensitivity to cytotoxicity induced by a 1-h exposure to m-AMSA or to its solid tumor-active analogue, CI-921. Studies with radiolabeled m-AMSA established that similar levels of drug were accumulated by log- and plateau-phase cells and that there was no significant drug metabolism in either of these cultures after 1 h. However, marked differences in sensitivity to m-AMSA-induced DNA breakage were observed using a fluorescence assay for DNA unwinding. Changes in sensitivity to DNA breakage occurred in parallel with changes in sensitivity to m-AMSA-induced cell killing. DNA breaks disappeared rapidly after drug removal (half-time approximately 4 min), suggesting that these lesions were probably mediated by DNA topoisomerase II. Resistance to m-AMSA may therefore be associated with changes in topoisomerase II activity in noncycling cells

  14. Resistance to Antiangiogenic Therapies by Metabolic Symbiosis in Renal Cell Carcinoma PDX Models and Patients

    Gabriela Jiménez-Valerio

    2016-05-01

    Full Text Available Antiangiogenic drugs are used clinically for treatment of renal cell carcinoma (RCC as a standard first-line treatment. Nevertheless, these agents primarily serve to stabilize disease, and resistance eventually develops concomitant with progression. Here, we implicate metabolic symbiosis between tumor cells distal and proximal to remaining vessels as a mechanism of resistance to antiangiogenic therapies in patient-derived RCC orthoxenograft (PDX models and in clinical samples. This metabolic patterning is regulated by the mTOR pathway, and its inhibition effectively blocks metabolic symbiosis in PDX models. Clinically, patients treated with antiangiogenics consistently present with histologic signatures of metabolic symbiosis that are exacerbated in resistant tumors. Furthermore, the mTOR pathway is also associated in clinical samples, and its inhibition eliminates symbiotic patterning in patient samples. Overall, these data support a mechanism of resistance to antiangiogenics involving metabolic compartmentalization of tumor cells that can be inhibited by mTOR-targeted drugs.

  15. Metabolic Mechanisms in Obesity and Type 2 Diabetes: Insights from Bariatric/Metabolic Surgery

    Adriana Florinela Cătoi

    2015-11-01

    Full Text Available Obesity and the related diabetes epidemics represent a real concern worldwide. Bariatric/metabolic surgery emerged in last years as a valuable therapeutic option for obesity and related diseases, including type 2 diabetes mellitus (T2DM. The complicated network of mechanisms involved in obesity and T2DM have not completely defined yet. There is still a debate on which would be the first metabolic defect leading to metabolic deterioration: insulin resistance or hyperinsulinemia? Insight into the metabolic effects of bariatric/metabolic surgery has revealed that, beyond weight loss and food restriction, other mechanisms can be activated by the rearrangements of the gastrointestinal tract, such as the incretinic/anti-incretinic system, changes in bile acid composition and flow, and modifications of gut microbiota; all of them possibly involved in the remission of T2DM. The complete elucidation of these mechanisms will lead to a better understanding of the pathogenesis of this disease. Our aim was to review some of the metabolic mechanisms involved in the development of T2DM in obese patients as well as in the remission of this condition in patients submitted to bariatric/metabolic surgery.

  16. Molecular Mechanisms of Insulin Resistance in Chronic Kidney Disease

    Thomas, Sandhya S.; Zhang, Liping; Mitch, William E.

    2015-01-01

    Insulin resistance refers to reduced sensitivity of organs to insulin-initiated biologic processes that result in metabolic defects. Insulin resistance is common in patients with end-stage renal disease but also occurs in patients with chronic kidney disease (CKD), even when the serum creatinine is minimally increased. Following insulin binding to its receptor, auto-phosphorylation of the insulin receptor is followed by kinase reactions that phosphorylate insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3-kinase (PI3K) and Akt. In fact, low levels of Akt phosphorylation (p-Akt) identifies the presence of the insulin resistance that leads to metabolic defects in insulin-initiated metabolism of glucose, lipids and muscle proteins. Besides CKD, other complex conditions (e.g., inflammation, oxidative stress, metabolic acidosis, aging and excess angiotensin II) reduce p-Akt resulting in insulin resistance. Insulin resistance in each of these conditions is due to activation of different, E3 ubiquitin ligases which specifically conjugate ubiquitin to IRS-1 marking it for degradation in the ubiquitin-proteasome system (UPS). Consequently, IRS-1 degradation suppresses insulin-induced intracellular signaling, causing insulin resistance. Understanding mechanisms of insulin resistance could lead to therapeutic strategies that improve the metabolism of patients with CKD. PMID:26444029

  17. Characterisation of glufosinate resistance mechanisms in Eleusine indica.

    Jalaludin, Adam; Yu, Qin; Zoellner, Peter; Beffa, Roland; Powles, Stephen B

    2017-06-01

    An Eleusine indica population has evolved resistance to glufosinate, a major post-emergence herbicide of global agriculture. This population was analysed for target-site (glutamine synthetase) and non-target-site (glufosinate uptake, translocation and metabolism) resistance mechanisms. Glutamine synthetase (GS) activity extracted from susceptible (S) and resistant (R*) plants was equally sensitive to glufosinate inhibition, with IC 50 values of 0.85 mm and 0.99 mm, respectively. The extractable GS activity was also similar in S and R* samples. Foliar uptake of [ 14 C]-glufosinate did not differ in S and R* plants, nor did glufosinate net uptake in leaf discs. Translocation of [ 14 C]-glufosinate into untreated shoots and roots was also similar in both populations, with 44% to 47% of the herbicide translocated out from the treated leaf 24 h after treatment. The HPLC and LC-MS analysis of glufosinate metabolism revealed no major metabolites in S or R* leaf tissue. Glufosinate resistance in this resistant population is not due to an insensitive GS, or increased activity, or altered glufosinate uptake and translocation, or enhanced glufosinate metabolism. Thus, target-site resistance is likely excluded and the exact resistance mechanism(s) remain to be determined. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

  18. Metabolic Profiles in Obese Children and Adolescents with Insulin Resistance

    Marko Kostovski

    2018-03-01

    CONCLUSION: Higher percentage of insulin-resistant participants was of female gender and was adolescents. In general, insulin resistant obese children and adolescents tend to have a worse metabolic profile in comparison to individuals without insulin resistance. It is of note that the highest insulin resistance was also linked with the highest concentrations of triglycerides.

  19. Exploring the iron metabolism in multidrug resistant tuberculosis ...

    The iron metabolism plays a key role in the progression of active Tuberculosis. Several studies have shown a link between iron metabolism disorders an active tuberculosis. The aim of this study was to explore the iron metabolism of 100 patients with multidrug-resistant tuberculosis. (MDR-TB) treated with second ...

  20. Exploring the iron metabolism in multidrug resistant tuberculosis ...

    The iron metabolism plays a key role in the progression of active Tuberculosis. Several studies have shown a link between iron metabolism disorders an active tuberculosis. The aim of this study was to explore the iron metabolism of 100 patients with multidrug-resistant tuberculosis (MDR-TB) treated with second generation ...

  1. Molecular Mechanisms of Insulin Resistance Development

    Vsevolod Arsen'evich Tkachuk

    2014-05-01

    Full Text Available Insulin resistance (IR is a phenomenon associated with an impaired ability of insulin to stimulate glucose uptake by target cells and to reduce the blood glucose level. A response increase in insulin secretion by the pancreas and hyperinsulinemia are compensatory reactions of the body. The development of IR leads to the inability of target cells to respond to insulin that results in developing type 2 diabetes mellitus (T2DM and metabolic syndrome. For this reason, the metabolic syndrome is defined in practice as a combination of IR with one or more pathologies such as T2DM, arterial hypertension, dyslipidemia, abdominal obesity, non-alcoholic fatty liver disease, and some others. However, a combination of high blood glucose and insulin levels always serves as its physiological criterion.IR should be considered as a systemic failure of the endocrine regulation in the body. Physiological causes of IR are diverse. The main ones are nutritional overload and accumulation of certain lipids and their metabolites in cells, low physical activity, chronic inflammation and stress of various nature, including oxidative and endoplasmic reticulum stress (impairment of damaged protein degradation in the cell. Recent studies have demonstrated that these physiological mechanisms likely act through a single intracellular scenario. This is the impairment of signal transduction from the insulin receptor to its targets via the negative feedback mechanism in intracellular insulin-dependent signaling cascades.This review describes the physiological and intracellular mechanisms of insulin action and focuses on their abnormalities upon IR development. Finally, feasible trends in early molecular diagnosis and therapy of IR are discussed.

  2. Cross-resistance and biochemical mechanisms of resistance to indoxacarb in the diamondback moth, Plutella xylostella.

    Zhang, Shuzhen; Zhang, Xiaolei; Shen, Jun; Li, Dongyang; Wan, Hu; You, Hong; Li, Jianhong

    2017-08-01

    Indoxacarb belongs to a class of insecticides known as oxadiazines and is the first commercialized pyrazoline-type voltage-dependent sodium channel blocker. A moderate level of resistance to indoxacarb has evolved in field populations of Plutella xylostella from Central China. In the present study, cross-resistance, resistance stability and metabolic mechanisms of indoxacarb resistance were investigated in this moth species. A P. xylostella strain with a high level of resistance to indoxacarb was obtained through continuous selection in the laboratory. The strain showed cross-resistance to metaflumizone, beta-cypermethrin and chlorfenapyr, but no resistance to cyantraniliprole, chlorantraniliprole, abamectin, chlorfluazuron, spinosad and diafenthiuron compared with the susceptible strain. Synergism tests revealed that piperonyl butoxide (PBO) (synergistic ratio, SR=7.8) and diethyl maleate (DEF) (SR=3.5) had considerable synergistic effects on indoxacarb toxicity in the resistant strain (F 58 ). Enzyme activity data showed there was an approximate 5.8-fold different in glutathione S-transferase (GST) and a 6.8-fold different in cytochrome P450 monooxygenase between the resistant strain (F 58 ) and susceptible strain, suggesting that the increased activity of these two enzymes is likely the main detoxification mechanism responsible for the species' resistance to indoxacarb. These results will be helpful for insecticide resistance management strategies to delay the development of indoxacarb resistance in fields. Copyright © 2017. Published by Elsevier Inc.

  3. Metabolic syndrome and insulin resistance in obese adolescents

    Amanda Oliva Gobato

    2014-03-01

    Full Text Available Objective: To verify the prevalence of metabolic syndrome and insulin resistance in obese adolescents and its relationship with different body composition indicators. Methods: A cross-sectional study comprising 79 adolescents aged ten to 18 years old. The assessed body composition indicators were: body mass index (BMI, body fat percentage, abdominal circumference, and subcutaneous fat. The metabolic syndrome was diagnosed according to the criteria proposed by Cook et al. The insulin resistance was determined by the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR index for values above 3.16. The analysis of ROC curves was used to assess the BMI and the abdominal circumference, aiming to identify the subjects with metabolic syndrome and insulin resistance. The cutoff point corresponded to the percentage above the reference value used to diagnose obesity. Results: The metabolic syndrome was diagnosed in 45.5% of the patients and insulin resistance, in 29.1%. Insulin resistance showed association with HDL-cholesterol (p=0.032 and with metabolic syndrome (p=0.006. All body composition indicators were correlated with insulin resistance (p<0.01. In relation to the cutoff point evaluation, the values of 23.5 and 36.3% above the BMI reference point allowed the identification of insulin resistance and metabolic syndrome. The best cutoff point for abdominal circumference to identify insulin resistance was 40%. Conclusions: All body composition indicators, HDL-cholesterol and metabolic syndrome showed correlation with insulin resistance. The BMI was the most effective anthropometric indicator to identify insulin resistance.

  4. Quantum Mechanics/Molecular Mechanics Modeling of Drug Metabolism

    Lonsdale, Richard; Fort, Rachel M; Rydberg, Patrik

    2016-01-01

    )-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......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...... 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...

  5. Carboxylesterase-mediated insecticide resistance: Quantitative increase induces broader metabolic resistance than qualitative change.

    Cui, Feng; Li, Mei-Xia; Chang, Hai-Jing; Mao, Yun; Zhang, Han-Ying; Lu, Li-Xia; Yan, Shuai-Guo; Lang, Ming-Lin; Liu, Li; Qiao, Chuan-Ling

    2015-06-01

    Carboxylesterases are mainly involved in the mediation of metabolic resistance of many insects to organophosphate (OP) insecticides. Carboxylesterases underwent two divergent evolutionary events: (1) quantitative mechanism characterized by the overproduction of carboxylesterase protein; and (2) qualitative mechanism caused by changes in enzymatic properties because of mutation from glycine/alanine to aspartate at the 151 site (G/A151D) or from tryptophan to leucine at the 271 site (W271L), following the numbering of Drosophila melanogaster AChE. Qualitative mechanism has been observed in few species. However, whether this carboxylesterase mutation mechanism is prevalent in insects remains unclear. In this study, wild-type, G/A151D and W271L mutant carboxylesterases from Culex pipiens and Aphis gossypii were subjected to germline transformation and then transferred to D. melanogaster. These germlines were ubiquitously expressed as induced by tub-Gal4. In carboxylesterase activity assay, the introduced mutant carboxylesterase did not enhance the overall carboxylesterase activity of flies. This result indicated that G/A151D or W271L mutation disrupted the original activities of the enzyme. Less than 1.5-fold OP resistance was only observed in flies expressing A. gossypii mutant carboxylesterases compared with those expressing A. gossypii wild-type carboxylesterase. However, transgenic flies universally showed low resistance to OP insecticides compared with non-transgenic flies. The flies expressing A. gossypii W271L mutant esterase exhibited 1.5-fold resistance to deltamethrin, a pyrethroid insecticide compared with non-transgenic flies. The present transgenic Drosophila system potentially showed that a quantitative increase in carboxylesterases induced broader resistance of insects to insecticides than a qualitative change. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Molecular mechanism of insulin resistance

    PRAKASH

    incidence of insulin resistance and type 2 diabetes is ..... 10% SDS-PAGE and then subjected to Western blot analysis with anti-pPDK1, pAkt/Akt or anti-pPKCε antibodies (1:1000). ... in humans, where qualitative and quantitative abnormalities.

  7. Bedaquiline resistance: Its emergence, mechanism and prevention.

    Nguyen, Thi Van Anh; Anthony, Richard M; Bañuls, Anne-Laure; Vu, Dinh Hoa; Alffenaar, Jan-Willem C

    2017-11-08

    Bedaquiline, a new anti-tuberculosis drug, has already been used in more than 50 countries. The emergence of bedaquiline resistance is alarming, as it may result in the rapid loss of this new drug. This paper aims to review currently identified mechanisms of resistance, the emergence of bedaquiline resistance, and discuss strategies to delay the resistance acquisition. In vitro and clinical studies as well as reports from the compassionate use have identified the threat of bedaquiline resistance and cross-resistance with clofazimine, emphasizing the crucial need for the systematic surveillance of resistance. Currently known mechanisms of resistance include mutations within the atpE, Rv0678 and pepQ genes. The development of standardized drug susceptibility testing (DST) for bedaquiline is urgently needed.Understanding any target and non-target based mechanisms is essential to minimize the resistance development and treatment failure, help to develop appropriate DST for bedaquiline and genetic based resistance screening. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  8. Pool of resistance mechanisms to glyphosate in Digitaria insularis.

    de Carvalho, Leonardo Bianco; Alves, Pedro Luis da Costa Aguiar; González-Torralva, Fidel; Cruz-Hipolito, Hugo Enrique; Rojano-Delgado, Antonia María; De Prado, Rafael; Gil-Humanes, Javier; Barro, Francisco; de Castro, María Dolores Luque

    2012-01-18

    Digitaria insularis biotypes resistant to glyphosate have been detected in Brazil. Studies were carried out in controlled conditions to determine the role of absorption, translocation, metabolism, and gene mutation as mechanisms of glyphosate resistance in D. insularis. The susceptible biotype absorbed at least 12% more (14)C-glyphosate up to 48 h after treatment (HAT) than resistant biotypes. High differential (14)C-glyphosate translocation was observed at 12 HAT, so that >70% of the absorbed herbicide remained in the treated leaf in resistant biotypes, whereas 42% remained in the susceptible biotype at 96 HAT. Glyphosate was degraded to aminomethylphosphonic acid (AMPA), glyoxylate, and sarcosine by >90% in resistant biotypes, whereas a small amount of herbicide (up to 11%) was degraded by the susceptible biotype up to 168 HAT. Two amino acid changes were found at positions 182 and 310 in EPSPS, consisting of a proline to threonine and a tyrosine to cysteine substitution, respectively, in resistant biotypes. Therefore, absorption, translocation, metabolism, and gene mutation play an important role in the D. insularis glyphosate resistance.

  9. Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance.

    Højlund, Kurt

    2014-07-01

    synthesis was at least equally strong. Moreover, we found a correlation between plasma adiponectin and insulin activation of GS. This result is supported by a number of recent studies of animal models and muscle cell lines, which have shown that adiponectin augments insulin action on enzymes in the insulin signaling cascade. In contrast, we observed no differences in the abundance or activity of AMPK in obesity, type 2 diabetes, PCOS or inherited insulin resistance. This indicates that reduced insulin sensitivity in these conditions is not mediated via abnormal AMPK activity. The results from these studies demonstrate that the well-established abnormalities in insulin action on glucose uptake and glycogen synthesis are reflected by defects in insulin signaling to these cellular processes in type 2 diabetes, obesity, and PCOS, and as expected also in inherited insulin resistance caused by a mutation in INSR. In common metabolic disorders, low plasma adiponectin may contribute to insulin resistance and defects in insulin signaling, whereas in inherited insulin resistance a normal plasma adiponectin and reduced insulin clearance could contribute to maintain a sufficient activation of the insulin signaling cascade. The insight gained from these studies have improved our understanding of the molecular mechanisms underlying insulin resistance in skeletal muscle of humans, and can form the basis for further studies, which can lead to the development of treatment that more directly targets insulin resistance, and hence reduce the risk of type 2 diabetes and cardiovascular disease.

  10. Resistance Mechanisms of Anopheles stephensi (Diptera: Culicidae to Temephos

    Aboozar Soltani

    2015-10-01

    Full Text Available Background: Anopheles stephensi is a sub-tropical species and has been considered as one of the most important vector of human malaria throughout the Middle East and South Asian region including the malarious areas of southern Iran. Current reports confirmed An. stephensi resistance to temephos in Oman and India. However, there is no comprehensive research on mechanisms of temephos resistance in An. stephensi in the literature. This study was designed in order to clarify the enzymatic and molecular mechanisms of temephos resistance in this species.Methods: Profile activities of α- and ß-esterases, mixed function oxidase (MFO, glutathione-S-transferase (GST, insensitive acetylcholinesterase, and para-nitrophenyl acetate (PNPA-esterase enzymes were tested for An. stephensi strain with resistance ratio of 15.82 to temephos in comparison with susceptible strain.Results: Results showed that the mean activity of α-EST, GST and AChE enzymes were classified as altered indicating metabolic mechanisms have considerable role in resistance of An. stephensi to temephos. Molecular study using PCR-RFLP method to trace the G119S mutation in ACE-1 gene showed lack of the mutation responsible for organophosphate insecticide resistance in the temephos-selected strain of An. stephensi.Conclusion: This study showed that the altered enzymes but not targets site insensitivity of ACE-1 are responsible for temephos resistance in An. stephensi in south of Iran.

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

    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...

  12. Mechanisms of resistance to decitabine in the myelodysplastic syndrome.

    Taichun Qin

    Full Text Available The DNA methylation inhibitor 5-aza-2'-deoxycytidine (DAC is approved for the treatment of myelodysplastic syndromes (MDS, but resistance to DAC develops during treatment and mechanisms of resistance remain unknown. Therefore, we investigated mechanisms of primary and secondary resistance to DAC in MDS.We performed Quantitative Real-Time PCR to examine expression of genes related to DAC metabolism prior to therapy in 32 responders and non-responders with MDS as well as 14 patients who achieved a complete remission and subsequently relapsed while on therapy (secondary resistance. We then performed quantitative methylation analyses by bisulfite pyrosequencing of 10 genes as well as Methylated CpG Island Amplification Microarray (MCAM analysis of global methylation in secondary resistance.Most genes showed no differences by response, but the CDA/DCK ratio was 3 fold higher in non-responders than responders (P<.05, suggesting that this could be a mechanism of primary resistance. There were no significant differences at relapse in DAC metabolism genes, and no DCK mutations were detected. Global methylation measured by the LINE1 assay was lower at relapse than at diagnosis (P<.05. On average, the methylation of 10 genes was lower at relapse (16.1% compared to diagnosis (18.1% (P<.05. MCAM analysis showed decreased methylation of an average of 4.5% (range 0.6%-9.7% of the genes at relapse. By contrast, new cytogenetic changes were found in 20% of patients.Pharmacological mechanisms are involved in primary resistance to DAC, whereas hypomethylation does not prevent a relapse for patients with DAC treatment.

  13. Bedaquiline resistance: Its emergence, mechanism and prevention.

    Nguyen, Thi Van Anh; Anthony, Richard M; Bañuls, Anne-Laure; Vu, Dinh Hoa; Alffenaar, Jan-Willem C

    2017-01-01

    Bedaquiline, a new anti-tuberculosis drug, has already been used in more than 50 countries. The emergence of bedaquiline resistance is alarming, as it may result in the rapid loss of this new drug. This paper aims to review currently identified mechanisms of resistance, the emergence of bedaquiline

  14. Pharmaceutical Approaches to Target Antibiotic Resistance Mechanisms.

    Schillaci, Domenico; Spanò, Virginia; Parrino, Barbara; Carbone, Anna; Montalbano, Alessandra; Barraja, Paola; Diana, Patrizia; Cirrincione, Girolamo; Cascioferro, Stella

    2017-10-26

    There is urgent need for new therapeutic strategies to fight the global threat of antibiotic resistance. The focus of this Perspective is on chemical agents that target the most common mechanisms of antibiotic resistance such as enzymatic inactivation of antibiotics, changes in cell permeability, and induction/activation of efflux pumps. Here we assess the current landscape and challenges in the treatment of antibiotic resistance mechanisms at both bacterial cell and community levels. We also discuss the potential clinical application of chemical inhibitors of antibiotic resistance mechanisms as add-on treatments for serious drug-resistant infections. Enzymatic inhibitors, such as the derivatives of the β-lactamase inhibitor avibactam, are closer to the clinic than other molecules. For example, MK-7655, in combination with imipenem, is in clinical development for the treatment of infections caused by carbapenem-resistant Enterobacteriaceae and Pseudomonas aeruginosa, which are difficult to treat. In addition, other molecules targeting multidrug-resistance mechanisms, such as efflux pumps, are under development and hold promise for the treatment of multidrug resistant infections.

  15. Mechanisms of Resistance to Neurotoxins (Addendum)

    Schubert, David

    2003-01-01

    .... During all of these events, some groups of nerve cells are spared relative to others. It is therefore likely that biochemical mechanisms exist which lead to increased resistance to oxidative stress and other forms of cytotoxicity...

  16. Drug Targets and Mechanisms of Resistance in the Anaerobic Protozoa

    Upcroft, Peter; Upcroft, Jacqueline A.

    2001-01-01

    The anaerobic protozoa Giardia duodenalis, Trichomonas vaginalis, and Entamoeba histolytica infect up to a billion people each year. G. duodenalis and E. histolytica are primarily pathogens of the intestinal tract, although E. histolytica can form abscesses and invade other organs, where it can be fatal if left untreated. T. vaginalis infection is a sexually transmitted infection causing vaginitis and acute inflammatory disease of the genital mucosa. T. vaginalis has also been reported in the urinary tract, fallopian tubes, and pelvis and can cause pneumonia, bronchitis, and oral lesions. Respiratory infections can be acquired perinatally. T. vaginalis infections have been associated with preterm delivery, low birth weight, and increased mortality as well as predisposing to human immunodeficiency virus infection, AIDS, and cervical cancer. All three organisms lack mitochondria and are susceptible to the nitroimidazole metronidazole because of similar low-redox-potential anaerobic metabolic pathways. Resistance to metronidazole and other drugs has been observed clinically and in the laboratory. Laboratory studies have identified the enzyme that activates metronidazole, pyruvate:ferredoxin oxidoreductase, to its nitroso form and distinct mechanisms of decreasing drug susceptibility that are induced in each organism. Although the nitroimidazoles have been the drug family of choice for treating the anaerobic protozoa, G. duodenalis is less susceptible to other antiparasitic drugs, such as furazolidone, albendazole, and quinacrine. Resistance has been demonstrated for each agent, and the mechanism of resistance has been investigated. Metronidazole resistance in T. vaginalis is well documented, and the principal mechanisms have been defined. Bypass metabolism, such as alternative oxidoreductases, have been discovered in both organisms. Aerobic versus anaerobic resistance in T. vaginalis is discussed. Mechanisms of metronidazole resistance in E. histolytica have recently

  17. Obesity, insulin resistance and comorbidities – Mechanisms of association

    Castro, Ana Valeria B.; Kolka, Cathryn M.; Kim, Stella P.; Bergman, Richard N.

    2015-01-01

    Overall excess of fat, usually defined by the body mass index, is associated with metabolic (e.g. glucose intolerance, type 2 diabetes mellitus (T2DM), dyslipidemia) and non-metabolic disorders (e.g. neoplasias, polycystic ovary syndrome, non-alcoholic fat liver disease, glomerulopathy, bone fragility etc.). However, more than its total amount, the distribution of adipose tissue throughout the body is a better predictor of the risk to the development of those disorders. Fat accumulation in the abdominal area and in non-adipose tissue (ectopic fat), for example, is associated with increased risk to develop metabolic and non-metabolic derangements. On the other hand, observations suggest that individuals who present peripheral adiposity, characterized by large hip and thigh circumferences, have better glucose tolerance, reduced incidence of T2DM and of metabolic syndrome. Insulin resistance (IR) is one of the main culprits in the association between obesity, particularly visceral, and metabolic as well as non-metabolic diseases. In this review we will highlight the current pathophysiological and molecular mechanisms possibly involved in the link between increased VAT, ectopic fat, IR and comorbidities. We will also provide some insights in the identification of these abnormalities. PMID:25211442

  18. Potential mechanisms of resistance to microtubule inhibitors.

    Kavallaris, Maria; Annereau, Jean-Philippe; Barret, Jean-Marc

    2008-06-01

    Antimitotic drugs targeting the microtubules, such as the taxanes and vinca alkaloids, are widely used in the treatment of neoplastic diseases. Development of drug resistance over time, however, limits the efficacy of these agents and poses a clinical challenge to long-term improvement of patient outcomes. Understanding the mechanism(s) of drug resistance becomes paramount to allowing for alternative, if not improved, therapeutic options that might circumvent this challenge. Vinflunine, a novel microtubule inhibitor, has shown superior preclinical antitumor activity, and displays a different pattern of resistance, compared with other agents in the vinca alkaloid class.

  19. Mechanism of quinolone resistance in anaerobic bacteria.

    Oh, H; Edlund, C

    2003-06-01

    Several recently developed quinolones have excellent activity against a broad range of aerobic and anaerobic bacteria and are thus potential drugs for the treatment of serious anaerobic and mixed infections. Resistance to quinolones is increasing worldwide, but is still relatively infrequent among anaerobes. Two main mechanisms, alteration of target enzymes (gyrase and topoisomerase IV) caused by chromosomal mutations in encoding genes, or reduced intracellular accumulation due to increased efflux of the drug, are associated with quinolone resistance. These mechanisms have also been found in anaerobic species. High-level resistance to the newer broad-spectrum quinolones often requires stepwise mutations in target genes. The increasing emergence of resistance among anaerobes may be a consequence of previous widespread use of quinolones, which may have enriched first-step mutants in the intestinal tract. Quinolone resistance in the Bacteroides fragilis group strains is strongly correlated with amino acid substitutions at positions 82 and 86 in GyrA (equivalent to positions 83 and 87 of Escherichia coli). Several studies have indicated that B. fragilis group strains possess efflux pump systems that actively expel quinolones, leading to resistance. DNA gyrase seems also to be the primary target for quinolones in Clostridium difficile, since amino acid substitutions in GyrA and GyrB have been detected in resistant strains. To what extent other mechanisms, such as mutational events in other target genes or alterations in outer-membrane proteins, contribute to resistance among anaerobes needs to be further investigated.

  20. Mechanisms of Candida biofilm drug resistance

    Taff, Heather T; Mitchell, Kaitlin F; Edward, Jessica A; Andes, David R

    2013-01-01

    Candida commonly adheres to implanted medical devices, growing as a resilient biofilm capable of withstanding extraordinarily high antifungal concentrations. As currently available antifungals have minimal activity against biofilms, new drugs to treat these recalcitrant infections are urgently needed. Recent investigations have begun to shed light on the mechanisms behind the profound resistance associated with the biofilm mode of growth. This resistance appears to be multifactorial, involving both mechanisms similar to conventional, planktonic antifungal resistance, such as increased efflux pump activity, as well as mechanisms specific to the biofilm lifestyle. A unique biofilm property is the production of an extracellular matrix. Two components of this material, β-glucan and extracellular DNA, promote biofilm resistance to multiple antifungals. Biofilm formation also engages several stress response pathways that impair the activity of azole drugs. Resistance within a biofilm is often heterogeneous, with the development of a subpopulation of resistant persister cells. In this article we review the molecular mechanisms underlying Candida biofilm antifungal resistance and their relative contributions during various growth phases. PMID:24059922

  1. Mechanisms of insulin resistance in obesity

    Ye, Jianping

    2014-01-01

    Obesity increases the risk for type 2 diabetes through induction of insulin resistance. Treatment of type 2 diabetes has been limited by little translational knowledge of insulin resistance although there have been several well-documented hypotheses for insulin resistance. In those hypotheses, inflammation, mitochondrial dysfunction, hyperinsulinemia and lipotoxicity have been the major concepts and have received a lot of attention. Oxidative stress, endoplasmic reticulum (ER) stress, genetic background, aging, fatty liver, hypoxia and lipodystrophy are active subjects in the study of these concepts. However, none of those concepts or views has led to an effective therapy for type 2 diabetes. The reason is that there has been no consensus for a unifying mechanism of insulin resistance. In this review article, literature is critically analyzed and reinterpreted for a new energy-based concept of insulin resistance, in which insulin resistance is a result of energy surplus in cells. The energy surplus signal is mediated by ATP and sensed by adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Decreasing ATP level by suppression of production or stimulation of utilization is a promising approach in the treatment of insulin resistance. In support, many of existing insulin sensitizing medicines inhibit ATP production in mitochondria. The effective therapies such as weight loss, exercise, and caloric restriction all reduce ATP in insulin sensitive cells. This new concept provides a unifying cellular and molecular mechanism of insulin resistance in obesity, which may apply to insulin resistance in aging and lipodystrophy. PMID:23471659

  2. Insecticide resistance in vector Chagas disease: evolution, mechanisms and management.

    Mougabure-Cueto, Gastón; Picollo, María Inés

    2015-09-01

    Chagas disease is a chronic parasitic infection restricted to America. The disease is caused by the protozoa Trypanosoma cruzi, which is transmitted to human through the feces of infected triatomine insects. Because no treatment is available for the chronic forms of the disease, vector chemical control represents the best way to reduce the incidence of the disease. Chemical control has been based principally on spraying dwellings with insecticide formulations and led to the reduction of triatomine distribution and consequent interruption of disease transmission in several areas from endemic region. However, in the last decade it has been repeatedly reported the presence triatomnes, mainly Triatoma infestans, after spraying with pyrethroid insecticides, which was associated to evolution to insecticide resistance. In this paper the evolution of insecticide resistance in triatomines is reviewed. The insecticide resistance was detected in 1970s in Rhodnius prolixus and 1990s in R. prolixus and T. infestans, but not until the 2000s resistance to pyrthroids in T. infestans associated to control failures was described in Argentina and Bolivia. The main resistance mechanisms (i.e. enhanced metabolism, altered site of action and reduced penetration) were described in the T. infestans resistant to pyrethrods. Different resistant profiles were demonstrated suggesting independent origin of the different resistant foci of Argentina and Bolivia. The deltamethrin resistance in T. infestans was showed to be controlled by semi-dominant, autosomally inherited factors. Reproductive and developmental costs were also demonstrated for the resistant T. infestans. A discussion about resistance and tolerance concepts and the persistence of T. infestans in Gran Chaco region are presented. In addition, theoretical concepts related to toxicological, evolutionary and ecological aspects of insecticide resistance are discussed in order to understand the particular scenario of pyrethroid

  3. Mechanisms of bacterial resistance to antimicrobial agents.

    van Duijkeren, Engeline; Schink, Anne-Kathrin; Roberts, Marilyn C; Wang, Yang; Schwarz, Stefan

    During the past decades resistance to virtually all antimicrobial agents has been observed in bacteria of animal origin. This chapter describes in detail the mechanisms so far encountered for the various classes of antimicrobial agents. The main mechanisms include enzymatic inactivation by either

  4. Chronic myeloid leukemia patients sensitive and resistant to imatinib treatment show different metabolic responses.

    Jiye A

    Full Text Available The BCR-ABL tyrosine kinase inhibitor imatinib is highly effective for chronic myeloid leukemia (CML. However, some patients gradually develop resistance to imatinib, resulting in therapeutic failure. Metabonomic and genomic profiling of patients' responses to drug interventions can provide novel information about the in vivo metabolism of low-molecular-weight compounds and extend our insight into the mechanism of drug resistance. Based on a multi-platform of high-throughput metabonomics, SNP array analysis, karyotype and mutation, the metabolic phenotypes and genomic polymorphisms of CML patients and their diverse responses to imatinib were characterized. The untreated CML patients (UCML showed different metabolic patterns from those of healthy controls, and the discriminatory metabolites suggested the perturbed metabolism of the urea cycle, tricarboxylic acid cycle, lipid metabolism, and amino acid turnover in UCML. After imatinib treatment, patients sensitive to imatinib (SCML and patients resistant to imatinib (RCML had similar metabolic phenotypes to those of healthy controls and UCML, respectively. SCML showed a significant metabolic response to imatinib, with marked restoration of the perturbed metabolism. Most of the metabolites characterizing CML were adjusted to normal levels, including the intermediates of the urea cycle and tricarboxylic acid cycle (TCA. In contrast, neither cytogenetic nor metabonomic analysis indicated any positive response to imatinib in RCML. We report for the first time the associated genetic and metabonomic responses of CML patients to imatinib and show that the perturbed in vivo metabolism of UCML is independent of imatinib treatment in resistant patients. Thus, metabonomics can potentially characterize patients' sensitivity or resistance to drug intervention.

  5. Resistance to lambda-cyhalothrin in Spanish field populations of Ceratitis capitata and metabolic resistance mediated by P450 in a resistant strain.

    Arouri, Rabeh; Le Goff, Gaelle; Hemden, Hiethem; Navarro-Llopis, Vicente; M'saad, Mariem; Castañera, Pedro; Feyereisen, René; Hernández-Crespo, Pedro; Ortego, Félix

    2015-09-01

    The withdrawal of malathion in the European Union in 2009 resulted in a large increase in lambda-cyhalothrin applications for the control of the Mediterranean fruit fly, Ceratitis capitata, in Spanish citrus crops. Spanish field populations of C. capitata have developed resistance to lambda-cyhalothrin (6-14-fold), achieving LC50 values (129-287 ppm) higher than the recommended concentration for field treatments (125 ppm). These results contrast with the high susceptibility to lambda-cyhalothrin found in three Tunisian field populations. We have studied the mechanism of resistance in the laboratory-selected resistant strain W-1Kλ (205-fold resistance). Bioassays with synergists showed that resistance was almost completely suppressed by the P450 inhibitor PBO. The study of the expression of 53 P450 genes belonging to the CYP4, CYP6, CYP9 and CYP12 families in C. capitata revealed that CYP6A51 was overexpressed (13-18-fold) in the resistant strain. The W-1Kλ strain also showed high levels of cross-resistance to etofenprox (240-fold) and deltamethrin (150-fold). Field-evolved resistance to lambda-cyhalothrin has been found in C. capitata. Metabolic resistance mediated by P450 appears to be the main resistance mechanism in the resistant strain W-1Kλ. The levels of cross-resistance found may compromise the effectiveness of other pyrethroids for the control of this species. © 2014 Society of Chemical Industry. © 2014 Society of Chemical Industry.

  6. Mechanisms Involved in the Improvement of Lipotoxicity and Impaired Lipid Metabolism by Dietary α-Linolenic Acid Rich Salvia hispanica L (Salba) Seed in the Heart of Dyslipemic Insulin-Resistant Rats

    Creus, Agustina; Ferreira, María R.; Oliva, María E.; Lombardo, Yolanda B.

    2016-01-01

    This study explores the mechanisms underlying the altered lipid metabolism in the heart of dyslipemic insulin-resistant (IR) rats fed a sucrose-rich diet (SRD) and investigates if chia seeds (rich in α-linolenic acid 18:3, n-3 ALA) improve/reverse cardiac lipotoxicity. Wistar rats received an SRD-diet for three months. Half of the animals continued with the SRD up to month 6. The other half was fed an SRD in which the fat source, corn oil (CO), was replaced by chia seeds from month 3 to 6 (SRD+chia). A reference group consumed a control diet (CD) all the time. Triglyceride, long-chain acyl CoA (LC ACoA) and diacylglycerol (DAG) contents, pyruvate dehydrogenase complex (PDHc) and muscle-type carnitine palmitoyltransferase 1 (M-CPT1) activities and protein mass levels of M-CPT1, membrane fatty acid transporter (FAT/CD36), peroxisome proliferator activated receptor α (PPARα) and uncoupling protein 2 (UCP2) were analyzed. Results show that: (a) the hearts of SRD-fed rats display lipotoxicity suggesting impaired myocardial lipid utilization; (b) Compared with the SRD group, dietary chia normalizes blood pressure; reverses/improves heart lipotoxicity, glucose oxidation, the increased protein mass level of FAT/CD36, and the impaired insulin stimulated FAT/CD36 translocation to the plasma membrane. The enhanced M-CPT1 activity is markedly reduced without similar changes in protein mass. PPARα slightly decreases, while the UCP2 protein level remains unchanged in all groups. Normalization of dyslipidemia and IR by chia reduces plasma fatty acids (FAs) availability, suggesting that a different milieu prevents the robust translocation of FAT/CD36. This could reduce the influx of FAs, decreasing the elevated M-CPT1 activity and lipid storage and improving glucose oxidation in cardiac muscles of SRD-fed rats. PMID:26828527

  7. Efflux pumps as antimicrobial resistance mechanisms.

    Poole, Keith

    2007-01-01

    Antibiotic resistance continues to hamper antimicrobial chemotherapy of infectious disease, and while biocide resistance outside of the laboratory is as yet unrealized, in vitro and in vivo episodes of reduced biocide susceptibility are not uncommon. Efflux mechanisms, both drug-specific and multidrug, are important determinants of intrinsic and/or acquired resistance to these antimicrobials in important human pathogens. Multidrug efflux mechanisms are generally chromosome-encoded, with their expression typically resultant from mutations in regulatory genes, while drug-specific efflux mechanisms are encoded by mobile genetic elements whose acquisition is sufficient for resistance. While it has been suggested that drug-specific efflux systems originated from efflux determinants of self-protection in antibiotic-producing Actinomycetes, chromosomal multidrug efflux determinants, at least in Gram-negative bacteria, are appreciated as having an intended housekeeping function unrelated to drug export and resistance. Thus, it will be important to elucidate the intended natural function of these efflux mechanisms in order, for example, to anticipate environmental conditions or circumstances that might promote their expression and, so, compromise antimicrobial chemotherapy. Given the clinical significance of antimicrobial exporters, it is clear that efflux must be considered in formulating strategies for treatment of drug-resistant infections, both in the development of new agents, for example, less impacted by efflux or in targeting efflux directly with efflux inhibitors.

  8. The Emerging Role of Branched-Chain Amino Acids in Insulin Resistance and Metabolism

    Mee-Sup Yoon

    2016-07-01

    Full Text Available Insulin is required for maintenance of glucose homeostasis. Despite the importance of insulin sensitivity to metabolic health, the mechanisms that induce insulin resistance remain unclear. Branched-chain amino acids (BCAAs belong to the essential amino acids, which are both direct and indirect nutrient signals. Even though BCAAs have been reported to improve metabolic health, an increased BCAA plasma level is associated with a high risk of metabolic disorder and future insulin resistance, or type 2 diabetes mellitus (T2DM. The activation of mammalian target of rapamycin complex 1 (mTORC1 by BCAAs has been suggested to cause insulin resistance. In addition, defective BCAA oxidative metabolism might occur in obesity, leading to a further accumulation of BCAAs and toxic intermediates. This review provides the current understanding of the mechanism of BCAA-induced mTORC1 activation, as well as the effect of mTOR activation on metabolic health in terms of insulin sensitivity. Furthermore, the effects of impaired BCAA metabolism will be discussed in detail.

  9. Mechanisms of drug resistance in cancer cells

    Iqbal, M.P.

    2003-01-01

    Development of drug resist chemotherapy. For the past several years, investigators have been striving hard to unravel mechanisms of drug resistance in cancer cells. Using different experimental models of cancer, some of the major mechanisms of drug resistance identified in mammalian cells include: (a) Altered transport of the drug (decreased influx of the drug; increased efflux of the drug (role of P-glycoprotein; role of polyglutamation; role of multiple drug resistance associated protein)), (b) Increase in total amount of target enzyme/protein (gene amplification), (c) alteration in the target enzyme/protein (low affinity enzyme), (d) Elevation of cellular glutathione, (e) Inhibition of drug-induced apoptosis (mutation in p53 tumor suppressor gene; increased expression of bcl-xl gene). (author)

  10. RELATIONSHIP BETWEEN URIC ACID METABOLISM AND INSULIN RESISTANCE

    辻本, 伸宏; 金内, 雅夫; 尾崎, 博基; 藤田, 泰三; 中嶋, 民夫; 土肥, 和紘

    1998-01-01

    To investigate the relationship between uric acid (UA) metabolism and insulin resistance, serum creatinine concentration (Scr), serum UA concentration (SuA) and the urinary excretion of creatinine and UA were determined in 25 non-diabetic patients. Creatinine clearance (Ccr) and UA clearance/creatinine clearance ratio (CuA/Ccr) were also calculated. Insulin resistance was evaluated by the euglycemic glucose clamp tech- nique and expressed as the mean value of the glucose infusion rate (M-valu...

  11. Mechanisms of antibiotic resistance in Staphylococcus aureus.

    Pantosti, Annalisa; Sanchini, Andrea; Monaco, Monica

    2007-06-01

    Staphylococcus aureus can exemplify better than any other human pathogen the adaptive evolution of bacteria in the antibiotic era, as it has demonstrated a unique ability to quickly respond to each new antibiotic with the development of a resistance mechanism, starting with penicillin and methicillin, until the most recent, linezolid and daptomycin. Resistance mechanisms include enzymatic inactivation of the antibiotic (penicillinase and aminoglycoside-modification enzymes), alteration of the target with decreased affinity for the antibiotic (notable examples being penicillin-binding protein 2a of methicillin-resistant S. aureus and D-Ala-D-Lac of peptidoglycan precursors of vancomycin-resistant strains), trapping of the antibiotic (for vancomycin and possibly daptomycin) and efflux pumps (fluoroquinolones and tetracycline). Complex genetic arrays (staphylococcal chromosomal cassette mec elements or the vanA operon) have been acquired by S. aureus through horizontal gene transfer, while resistance to other antibiotics, including some of the most recent ones (e.g., fluoroquinolones, linezolid and daptomycin) have developed through spontaneous mutations and positive selection. Detection of the resistance mechanisms and their genetic basis is an important support to antibiotic susceptibility surveillance in S. aureus.

  12. Mechanisms of resistance to alkylating agents

    Damia, G.; D‘Incalci, M.

    1998-01-01

    Alkylating agents are the most widely used anticancer drugs whose main target is the DNA, although how exactly the DNA lesions cause cell death is still not clear. The emergence of resistance to this class of drugs as well as to other antitumor agents is one of the major causes of failure of cancer treatment. This paper reviews some of the best characterized mechanisms of resistance to alkylating agents. Pre- and post-target mechanisms are recognized, the former able to limit the formation of...

  13. Alcohol metabolism in hangover sensitive versus hangover resistant social drinkers

    Mackus, Marlou; van Schrojenstein Lantman, Marith; van de Loo, A.J.A.E.; Kraneveld, A.D.; Garssen, J.; Verster, J.C.

    2018-01-01

    Background Previous research demonstrated that urinary ethanol concentrations were significantly lower in hangover resistant individuals compared to drinkers who reported having a hangover. This finding suggests that the rate of ethanol metabolism is faster in drinkers who do not experience an

  14. Insulin resistance, metabolic syndrome, and lipids in African women

    2016-01-27

    Jan 27, 2016 ... high‑density lipoprotein (TG/HDL), total cholesterol (TC)/HDL, and atherogenic index of ... Key words: Insulin resistance, metabolic syndrome, triglycerides, women ... been reported that a TG/HDL ratio of >3.0 is predictive of.

  15. Some resistance mechanisms to ultraviolet radiation

    Alcantara D, D.

    2002-12-01

    The cyclical exposure of bacterial cells to the ultraviolet light (UV) it has as consequence an increment in the resistance to the lethal effects of this type of radiation, increment that happens as a result of a selection process of favorable genetic mutations induced by the same UV light. With object to study the reproducibility of the genetic changes and the associate mechanisms to the resistance to UV in the bacteria Escherichia coli, was irradiated cyclically with UV light five different derived cultures of a single clone, being obtained five stumps with different resistance grades. The genetic mapping Hfr revealed that so much the mutation events like of selection that took place during the adaptation to the UV irradiation, happened of random manner, that is to say, each one of the resistant stumps it is the result of the unspecified selection of mutations arisen at random in different genes related with the repair and duplication of the DNA. (Author)

  16. Berberine Moderates Glucose and Lipid Metabolism through Multipathway Mechanism

    Qian Zhang

    2011-01-01

    Full Text Available Berberine is known to improve glucose and lipid metabolism disorders, but the mechanism is still under investigation. In this paper, we explored the effects of berberine on the weight, glucose levels, lipid metabolism, and serum insulin of KKAy mice and investigated its possible glucose and lipid-regulating mechanism. We randomly divided KKAy mice into two groups: berberine group (treated with 250 mg/kg/d berberine and control group. Fasting blood glucose (FBG, weight, total cholesterol (TC, triglyceride (TG, high-density lipoprotein-cholesterol (HDL-c, low-density lipoprotein-cholesterol (LDL-c, and fasting serum insulin were measured in both groups. The oral glucose tolerance test (OGTT was performed. RT2 PCR array gene expression analysis was performed using skeletal muscle of KKAy mice. Our data demonstrated that berberine significantly decreased FBG, area under the curve (AUC, fasting serum insulin (FINS, homeostasis model assessment insulin resistance (HOMA-IR index, TC, and TG, compared with those of control group. RT2 profiler PCR array analysis showed that berberine upregulated the expression of glucose transporter 4 (GLUT4, mitogen-activated protein kinase 14 (MAPK14, MAPK8(c-jun N-terminal kinase, JNK, peroxisome proliferator-activated receptor α (PPARα, uncoupling protein 2 (UCP2, and hepatic nuclear factor 4α(HNF4α, whereas it downregulated the expression of PPARγ, CCAAT/enhancer-binding protein (CEBP, PPARγ coactivator 1α(PGC 1α, and resistin. These results suggest that berberine moderates glucose and lipid metabolism through a multipathway mechanism that includes AMP-activated protein kinase-(AMPK- p38 MAPK-GLUT4, JNK pathway, and PPARα pathway.

  17. Global Governance Mechanisms to Address Antimicrobial Resistance.

    Padiyara, Ponnu; Inoue, Hajime; Sprenger, Marc

    2018-01-01

    Since their discovery, antibiotics, and more broadly, antimicrobials, have been a cornerstone of modern medicine. But the overuse and misuse of these drugs have led to rising rates of antimicrobial resistance, which occurs when bacteria adapt in ways that render antibiotics ineffective. A world without effective antibiotics can have drastic impacts on population health, global development, and the global economy. As a global common good, antibiotic effectiveness is vulnerable to the tragedy of the commons, where a shared limited resource is overused by a community when each individual exploits the finite resource for their own benefit. A borderless threat like antimicrobial resistance requires global governance mechanisms to mitigate its emergence and spread, and it is the responsibility of all countries and relevant multilateral organizations. These mechanisms can be in the form of legally binding global governance mechanisms such as treaties and regulatory standards or nonbinding mechanisms such as political declarations, resolutions, or guidelines. In this article, we argue that while both are effective methods, the strong, swift, and coordinated action needed to address rising rates of antimicrobial resistance will be better served through legally binding governance mechanisms.

  18. Mechanisms of Intrinsic Tumor Resistance to Immunotherapy

    John Rieth

    2018-05-01

    Full Text Available An increased understanding of the interactions between the immune system and tumors has opened the door to immunotherapy for cancer patients. Despite some success with checkpoint inhibitors including ipilimumab, pembrolizumab, and nivolumab, most cancer patients remain unresponsive to such immunotherapy, likely due to intrinsic tumor resistance. The mechanisms most likely involve reducing the quantity and/or quality of antitumor lymphocytes, which ultimately are driven by any number of developments: tumor mutations and adaptations, reduced neoantigen generation or expression, indoleamine 2,3-dioxygenase (IDO overexpression, loss of phosphatase and tensin homologue (PTEN expression, and overexpression of the Wnt–β-catenin pathway. Current work in immunotherapy continues to identify various tumor resistance mechanisms; future work is needed to develop adjuvant treatments that target those mechanisms, in order to improve the efficacy of immunotherapy and to expand its scope.

  19. Voltage-gated sodium channel polymorphism and metabolic resistance in pyrethroid-resistant Aedes aegypti from Brazil.

    Martins, Ademir Jesus; Lins, Rachel Mazzei Moura de Andrade; Linss, Jutta Gerlinde Birgitt; Peixoto, Alexandre Afranio; Valle, Denise

    2009-07-01

    The nature of pyrethroid resistance in Aedes aegypti Brazilian populations was investigated. Quantification of enzymes related to metabolic resistance in two distinct populations, located in the Northeast and Southeast regions, revealed increases in Glutathione-S-transferase (GST) and Esterase levels. Additionally, polymorphism was found in the IIS6 region of Ae. aegypti voltage-gated sodium channel (AaNa(V)), the pyrethroid target site. Sequences were classified in two haplotype groups, A and B, according to the size of the intron in that region. Rockefeller, a susceptible control lineage, contains only B sequences. In field populations, some A sequences present a substitution in the 1011 site (Ile/Met). When resistant and susceptible individuals were compared, the frequency of both A (with the Met mutation) and B sequences were slightly increased in resistant specimens. The involvement of the AaNa(V) polymorphism in pyrethroid resistance and the metabolic mechanisms that lead to potential cross-resistance between organophosphate and pyrethroids are discussed.

  20. [Resistance risk, cross-resistance and biochemical resistance mechanism of Laodelphax striatellus to buprofezin].

    Mao, Xu-lian; Liu, Jin; Li, Xu-ke; Chi, Jia-jia; Liu, Yong-jie

    2016-01-01

    In order to investigate the resistance development law and biochemical resistance mechanism of Laodelphax striatellus to buprofezin, spraying rice seedlings was used to continuously screen resistant strains of L. striatellus and dipping rice seedlings was applied to determine the toxicity and cross-resistance of L. striatellus to insecticides. After 32-generation screening with buprofezin, L. striatellus developed 168.49 folds resistance and its reality heritability (h2) was 0.11. If the killing rate was 80%-90%, L. striatellus was expected to develop 10-fold resistance to buprofezin only after 5 to 6 generations breeding. Because the actual reality heritability of field populations was usually lower than that of the resistant strains, the production of field populations increasing with 10-fold resistance would need much longer time. The results of cross-resistance showed that resistant strain had high level cross-resistance with thiamethoxam and imidacloprid, low level cross-resistance with acetamiprid, and no cross-resistance with pymetrozine and chlorpyrifos. The activity of detoxification enzymes of different strains and the syergism of synergist were measured. The results showed that cytochrome P450 monooxygenase played a major role in the resistance of L. striatellus to buprofezin, the esterase played a minor role and the GSH-S-transferase had no effect. Therefore, L. striatellus would have high risk to develop resistance to buprofezin when used in the field and might be delayed by using pymetrozine and chlorpyrifos.

  1. Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance

    Højlund, Kurt

    2014-01-01

    . These metabolic disorders are all characterized by reduced plasma adiponectin and insulin resistance in peripheral tissues. Quantitatively skeletal muscle is the major site of insulin resistance. Both low plasma adiponectin and insulin resistance contribute to an increased risk of type 2 diabetes...... described a novel syndrome characterized by postprandial hyperinsulinemic hypoglycemia and insulin resistance. This syndrome is caused by a mutation in the tyrosine kinase domain of the insulin receptor gene (INSR). We have studied individuals with this mutation as a model of inherited insulin resistance....... Type 2 diabetes, obesity and PCOS are characterized by pronounced defects in the insulin-stimulated glucose uptake, in particular glycogen synthesis and to a lesser extent glucose oxidation, and the ability of insulin to suppress lipid oxidation. In inherited insulin resistance, however, only insulin...

  2. Insulin resistance and postreceptor changes of liver metabolism in fat-fed mice

    Hedeskov, Carl Jørgen; Capito, Kirsten; Hansen, Svend Erik

    1992-01-01

    Medicinsk biokemi, animal diabetes, insulin resistance, postreceptor defects, liver metabolism, high-fat diet......Medicinsk biokemi, animal diabetes, insulin resistance, postreceptor defects, liver metabolism, high-fat diet...

  3. Enhanced 2,4-D Metabolism in Two Resistant Papaver rhoeas Populations from Spain

    Joel Torra

    2017-09-01

    Full Text Available Corn poppy (Papaver rhoeas, the most problematic broadleaf weed in winter cereals in Southern Europe, has developed resistance to the widely-used herbicide, 2,4-D. The first reported resistance mechanism in this species to 2,4-D was reduced translocation from treated leaves to the rest of the plant. However, the presence of other non-target site resistance (NTSR mechanisms has not been investigated up to date. Therefore, the main objective of this research was to reveal if enhanced 2,4-D metabolism is also present in two Spanish resistant (R populations to synthetic auxins. With this aim, HPLC experiments at two 2,4-D rates (600 and 2,400 g ai ha−1 were conducted to identify and quantify the metabolites produced and evaluate possible differences in 2,4-D degradation between resistant (R and susceptible (S plants. Secondarily, to determine the role of cytochrome P450 in the resistance response, dose-response experiments were performed using malathion as its inhibitor. Three populations were used: S, only 2,4-D R (R-703 and multiple R to 2,4-D and ALS inhibitors (R-213. HPLC studies indicated the presence of two hydroxy metabolites in these R populations in shoots and roots, which were not detected in S plants, at both rates. Therefore, enhanced metabolism becomes a new NTSR mechanism in these two P. rhoeas populations from Spain. Results from the dose-response experiments also showed that pre-treatment of R plants with the cytochrome P450 (P450 inhibitor malathion reversed the phenotype to 2,4-D from resistant to susceptible in both R populations. Therefore, it could be hypothesized that a malathion inhibited P450 is responsible of the formation of the hydroxy metabolites detected in the metabolism studies. This and previous research indicate that two resistant mechanisms to 2,4-D could be present in populations R-703 and R-213: reduced translocation and enhanced metabolism. Future experiments are required to confirm these hypotheses

  4. Insulin-resistance and lipids metabolism in women at menopause

    Marina Dmitrуina Gresko

    2018-01-01

    Full Text Available The article describes lipid metabolism in women during premenopausal and considered their relationship with the level of insulin sensitivity and abdominal obesity. Examined 20 women aged 46-48 years, with fixed transition to pre-menopause on the bases of menstrual cycle dysfunction or amenorrhea during a year as well as a decrease of visualized follicular reserve according to the results of ultrasonic examination of the organs of the small pelvis, were involved into investigation. Body mass increase with abdominal obese formation and disorders of the lipid metabolism against a background of insulin resistance is observed in women during pre-menopause against a background of sexual hormones deficiency.

  5. Chemotherapy resistance mechanisms in advanced skin cancer

    Bhuvanesh Sukhlal Kalal

    2017-03-01

    Full Text Available Melanoma is a most dangerous and deadly type of skin cancer, and considered intrinsically resistant to both radiotherapy and chemotherapy. It has become a major public health concern as the incidence of melanoma has been rising steadily over recent decades with a 5-year survival remaining less than 5%. Detection of the disease in early stage may be curable, but late stage metastatic disease that has spread to other organs has an extremely poor prognosis with a median survival of less than 10 months. Since metastatic melanoma is unresponsive to therapy that is currently available, research is now focused on different treatment strategies such as combinations of surgery, chemotherapy and radiotherapy. The molecular basis of resistance to chemotherapy seen in melanoma is multifactorial; defective drug transport system, altered apoptotic pathway, deregulation of apoptosis and/or changes in enzymatic systems that mediate cellular metabolic machinery. Understanding of alterations in molecular processes involved in drug resistance may help in developing new therapeutic approaches to treatment of malignant melanoma.

  6. New extracellular resistance mechanism for cisplatin.

    Centerwall, Corey R; Kerwood, Deborah J; Goodisman, Jerry; Toms, Bonnie B; Dabrowiak, James C

    2008-01-01

    The HSQC NMR spectrum of 15N-cisplatin in cell growth media shows resonances corresponding to the monocarbonato complex, cis-[Pt(NH3)2(CO3)Cl](-), 4, and the dicarbonato complex, cis-[Pt(NH3)2(CO3)2](-2), 5, in addition to cisplatin itself, cis-[Pt(NH3)2Cl2], 1. The presence of Jurkat cells reduces the amount of detectable carbonato species by (2.8+/-0.7) fmol per cell and has little effect on species 1. Jurkat cells made resistant to cisplatin reduce the amount of detectable carbonato species by (7.9+/-5.6) fmol per cell and also reduce the amount of 1 by (3.4+/-0.9) fmol per cell. The amount of detectable carbonato species is also reduced by addition of the drug to medium that has previously been in contact with normal Jurkat cells (cells removed); the reduction is greater when drug is added to medium previously in contact with resistant Jurkat cells (cells removed). This shows that the platinum species are modified by a cell-produced substance that is released to the medium. Since the modified species have been shown not to enter or bind to cells, and since resistant cells modify more than non-resistant cells, the modification constitutes a new extracellular mechanism for cisplatin resistance which merits further attention.

  7. Insecticides resistance in the Culex quinquefasciatus populations from northern Thailand and possible resistance mechanisms.

    Yanola, Jintana; Chamnanya, Saowanee; Lumjuan, Nongkran; Somboon, Pradya

    2015-09-01

    The mosquito vector Culex quinquefasciatus is known to be resistant to insecticides worldwide, including Thailand. This study was the first investigation of the insecticide resistance mechanisms, involving metabolic detoxification and target site insensitivity in C. quinquefasciatus from Thailand. Adult females reared from field-caught larvae from six provinces of northern Thailand were determined for resistant status by exposing to 0.05% deltamethrin, 0.75% permethrin and 5% malathion papers using the standard WHO susceptibility test. The overall mortality rates were 45.8%, 11.4% and 80.2%, respectively. A fragment of voltage-gated sodium channel gene was amplified and sequenced to identify the knock down resistance (kdr) mutation. The ace-1 gene mutation was determined by using PCR-RFLP. The L1014F kdr mutation was observed in all populations, but the homozygous mutant F/F1014 genotype was found only in two of the six provinces where the kdr mutation was significantly correlated with deltamethrin resistance. However, none of mosquitoes had the G119S mutation in the ace-1 gene. A laboratory deltamethrin resistant strain, Cq_CM_R, has been established showing a highly resistant level after selection for a few generations. The mutant F1014 allele frequency was significantly increased after one generation of selection. A synergist assay was performed to assess the metabolic detoxifying enzymes. Addition of bis(4-nitrophenyl)-phosphate (BNPP) and diethyl maleate (DEM), inhibitors of esterases and glutathione S-transferases (GST), respectively, into the larval bioassay of the Cq_CM strain with deltamethrin showed no significant reduction. By contrast, addition of piperonyl butoxide (PBO), an inhibitor of cytochrome P450 monooxygenases, showed a 9-fold reduction of resistance. Resistance to pyrethroids in C. quinquefasciatus is widely distributed in northern Thailand. This study reports for the first time for the detection of the L1014F kdr mutation in wild populations

  8. Globular adiponectin ameliorates metabolic insulin resistance via AMPK-mediated restoration of microvascular insulin responses

    Zhao, Lina; Fu, Zhuo; Wu, Jing; Aylor, Kevin W; Barrett, Eugene J; Cao, Wenhong; Liu, Zhenqi

    2015-01-01

    Abstract Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance, and microvasculature plays a critical role in the regulation of insulin action in muscle. Here we tested whether adiponectin replenishment could improve metabolic insulin sensitivity in male rats fed a high-fat diet (HFD) via the modulation of microvascular insulin responses. Male Sprague–Dawley rats were fed either a HFD or low-fat diet (LFD) for 4 weeks. Small resistance artery myograph changes in tension, muscle microvascular recruitment and metabolic response to insulin were determined. Compared with rats fed a LFD, HFD feeding abolished the vasodilatory actions of globular adiponectin (gAd) and insulin on pre-constricted distal saphenous arteries. Pretreatment with gAd improved insulin responses in arterioles isolated from HFD rats, which was blocked by AMP-activated protein kinase (AMPK) inhibition. Similarly, HFD abolished microvascular responses to either gAd or insulin and decreased insulin-stimulated glucose disposal by ∼60%. However, supplementing gAd fully rescued insulin’s microvascular action and significantly improved the metabolic responses to insulin in HFD male rats and these actions were abolished by inhibition of either AMPK or nitric oxide production. We conclude that HFD induces vascular adiponectin and insulin resistance but gAd administration can restore vascular insulin responses and improve insulin’s metabolic action via an AMPK- and nitric oxide-dependent mechanism in male rats. Key points Adiponectin is an adipokine with anti-inflammatory and anti-diabetic properties. Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance in obesity and diabetes. Insulin resistance is present in muscle microvasculature and this may contribute to decreased insulin delivery to, and action in, muscle. In this study we examined whether adiponectin ameliorates metabolic insulin resistance by affecting muscle

  9. The depressed central carbon and energy metabolisms is associated to the acquisition of levofloxacin resistance in Vibrio alginolyticus.

    Cheng, Zhi-Xue; Yang, Man-Jun; Peng, Bo; Peng, Xuan-Xian; Lin, Xiang-Min; Li, Hui

    2018-06-15

    The overuse and misuse of antibiotics lead to bacterial antibiotic resistance, challenging human health and intensive cultivation. It is especially required to understand for the mechanism of antibiotic resistance to control antibiotic-resistant pathogens. The present study characterized the differential proteome of levofloxacin-resistant Vibrio alginolyticus with the most advanced iTRAQ quantitative proteomics technology. A total of 160 proteins of differential abundance were identified, where 70 were decreased and 90 were increased. Further analysis demonstrated that crucial metabolic pathways like TCA cycle were significantly down-regulated. qRT-PCR analysis demonstrated the decreased gene expression of glycolysis/gluconeogenesis, the TCA cycle, and fatty acid biosynthesis. Moreover, Na(+)-NQR complex gene expression, membrane potential and the adenylate energy charge ratio were decreased, indicating that the decreased central carbon metabolism is associated to the acquisition of levofloxacin resistance. Therefore, the reduced central carbon and energy metabolisms form a characteristic feature as fitness costs of V. alginolyticus in resistance to levofloxacin. The overuse and misuse of antibiotics lead to bacterial antibiotic resistance, challenging human health and intensive cultivation. Understanding for the antibiotic resistance mechanisms is especially required to control these antibiotic-resistant pathogens. The present study characterized the differential proteome of levofloxacin-resistant Vibrio alginolyticus using the most advanced iTRAQ quantitative proteomics technology. A total of 160 differential abundance of proteins were identified with 70 decreases and 90 increases by liquid chromatography matrix assisted laser desorption ionization mass spectrometry. Most interestingly, crucial metabolic pathways such as the TCA cycle sharply fluctuated. This is the first report that the reduced central carbon and energy metabolisms form a characteristic feature

  10. Metabolic Response to Four Weeks of Muscular Endurance Resistance Training

    John W. Farrell III

    2017-10-01

    Full Text Available Background: Previous investigations have shown that muscular endurance resistance training (MERT is conducive in improving the onset of blood lactate accumulation (OBLA. However, the metabolic response and time course for adaption is still unclear. Objective: The aims of the current study were to evaluate and track the metabolic response to an individual session of MERT as well as to assess performance adaptations of supplementing an aerobic exercise training program with four weeks of MERT. Methods: Seventeen aerobically active men were randomly assigned to either the experimental (EX or control group (CON, 9 EX and 8 CON. Baseline measures included a graded exercise test (GXT and 1-repetition maximum (1RM testing for leg press (LP, leg curl (LC, and leg extension (LE. CON continued their regular aerobic activity while the EX supplemented their regular aerobic exercise with 4 weeks of MERT. Results: No significant group differences were observed for all pre-training variables. Following four weeks of training no significant differences in cardiorespiratory or metabolic variables were observed for either group. However, significant improvements in LC and LE 1-RM were observed in EX compared to CON. Substantial accumulations in blood lactate were observed following each MERT session. Conclusion: Four weeks of MERT did not improve cardiorespiratory or metabolic variables, but did significantly improve LC and LE. MERT was also observed to induce a blood lactate response similar to that of HIIT. These findings suggest greater than four weeks is need to see metabolic adaptations conducive for improved aerobic performance using MERT.

  11. Mechanism of insulin resistance in normal pregnancy.

    Hodson, K; Man, C Dalla; Smith, F E; Thelwall, P E; Cobelli, C; Robson, S C; Taylor, R

    2013-08-01

    Normal pregnancy is associated with insulin resistance although the mechanism is not understood. Increased intramyocellular lipid is closely associated with the insulin resistance of type 2 diabetes and obesity, and the aim of this study was to determine whether this was so for the physiological insulin resistance of pregnancy. Eleven primiparous healthy pregnant women (age: 27-39 years, body mass index 24.0±3.1 kg/m2) and no personal or family history of diabetes underwent magnetic resonance studies to quantify intramyocellular lipid, plasma lipid fractions, and insulin sensitivity. The meal-related insulin sensitivity index was considerably lower in pregnancy (45.6±9.9 vs. 193.0±26.1; 10(-4) dl/kg/min per pmol/l, p=0.0002). Fasting plasma triglyceride levels were elevated 3-fold during pregnancy (2.3±0.2 vs. 0.8±0.1 mmol/l, pinsulin resistance is distinct from that underlying type 2 diabetes. © Georg Thieme Verlag KG Stuttgart · New York.

  12. Fat metabolism during exercise: mechanisms of regulation

    Monique da Silva Gevaerd

    2006-12-01

    Full Text Available Fats are important energetic fuel to exercise. However, the regulation of fat uptake during exercise is unclear. The main objective of this review was to focus on physiological control mechanisms of mobilization, transport and fat uptake during exercise. The articles of fat metabolism were searched in Pubmed and Lilacs indexes. Classical and current papers were preferred. Evidence suggests that transport of fatty acids (FA from extracellular to intracellular spaces could be the main factor to limit fatty acid uptake. Future studies on fat uptake during exercise can focus on this mechanism. In intense exercise, the lower blood fl ow in the adipose tissue and higher fatty acid reesterifi cation rate impairs fat uptake during exercise. Supplementation of the FA has been used, however, the ideal quantities and forms to prevent gastrointestinal discomfort were not yet determined. In the biological point of view, intramuscular reserve of FA could be more effi cient, because is not necessary to FA to cross the cell membrane. RESUMO Os lipídios são considerados importantes fontes energéticas para a realização de exercícios físicos. Entretanto, os mecanismos de regulação do consumo desse substrato durante o exercício não estão totalmente esclarecidos. O objetivo principal da presente revisão foi abordar mecanismos fisiológicos de controle da mobilização, transporte e utilização de gordura durante o exercício. Os trabalhos indexados no banco de dados Pubmed e Lilacs sobre metabolismo de gordura, foram analisados e os clássicos e recentes foram preferencialmente utilizados. A partir dos dados recentes da literatura, especula-se que o transporte de ácidos graxos do meio extracelular para o meio intracelular pode constituir um dos principais mecanismos limitantes no consumo desse substrato. Estudos sobre o consumo de lipídios durante o exercício devem ser focados sobre esse mecanismo. Em exercício intenso, o menor fl uxo de sangue

  13. Mechanisms linking brain insulin resistance to Alzheimer's disease

    Matioli, Maria Niures P.S.; Nitrini, Ricardo

    2015-01-01

    Several studies have indicated that Diabetes Mellitus (DM) can increase the risk of developing Alzheimer's disease (AD). This review briefly describes current concepts in mechanisms linking DM and insulin resistance/deficiency to AD. Insulin/insulin-like growth factor (IGF) resistance can contribute to neurodegeneration by several mechanisms which involve: energy and metabolism deficits, impairment of Glucose transporter-4 function, oxidative and endoplasmic reticulum stress, mitochondrial dysfunction, accumulation of AGEs, ROS and RNS with increased production of neuro-inflammation and activation of pro-apoptosis cascade. Impairment in insulin receptor function and increased expression and activation of insulin-degrading enzyme (IDE) have also been described. These processes compromise neuronal and glial function, with a reduction in neurotransmitter homeostasis. Insulin/IGF resistance causes the accumulation of AβPP-Aβ oligomeric fibrils or insoluble larger aggregated fibrils in the form of plaques that are neurotoxic. Additionally, there is production and accumulation of hyper-phosphorylated insoluble fibrillar tau which can exacerbate cytoskeletal collapse and synaptic disconnection. PMID:29213950

  14. Mechanisms linking brain insulin resistance to Alzheimer's disease

    Maria Niures P.S. Matioli

    Full Text Available Several studies have indicated that Diabetes Mellitus (DM can increase the risk of developing Alzheimer's disease (AD. This review briefly describes current concepts in mechanisms linking DM and insulin resistance/deficiency to AD. Insulin/insulin-like growth factor (IGF resistance can contribute to neurodegeneration by several mechanisms which involve: energy and metabolism deficits, impairment of Glucose transporter-4 function, oxidative and endoplasmic reticulum stress, mitochondrial dysfunction, accumulation of AGEs, ROS and RNS with increased production of neuro-inflammation and activation of pro-apoptosis cascade. Impairment in insulin receptor function and increased expression and activation of insulin-degrading enzyme (IDE have also been described. These processes compromise neuronal and glial function, with a reduction in neurotransmitter homeostasis. Insulin/IGF resistance causes the accumulation of AβPP-Aβ oligomeric fibrils or insoluble larger aggregated fibrils in the form of plaques that are neurotoxic. Additionally, there is production and accumulation of hyper-phosphorylated insoluble fibrillar tau which can exacerbate cytoskeletal collapse and synaptic disconnection.

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

    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.

  16. Insecticide resistance is mediated by multiple mechanisms in recently introduced Aedes aegypti from Madeira Island (Portugal).

    Seixas, Gonçalo; Grigoraki, Linda; Weetman, David; Vicente, José Luís; Silva, Ana Clara; Pinto, João; Vontas, John; Sousa, Carla Alexandra

    2017-07-01

    Aedes aegypti is a major mosquito vector of arboviruses, including dengue, chikungunya and Zika. In 2005, Ae. aegypti was identified for the first time in Madeira Island. Despite an initial insecticide-based vector control program, the species expanded throughout the Southern coast of the island, suggesting the presence of insecticide resistance. Here, we characterized the insecticide resistance status and the underlying mechanisms of two populations of Ae. aegypti from Madeira Island, Funchal and Paúl do Mar. WHO susceptibility bioassays indicated resistance to cyfluthrin, permethrin, fenitrothion and bendiocarb. Use of synergists significantly increased mortality rates, and biochemical assays indicated elevated activities of detoxification enzymes, suggesting the importance of metabolic resistance. Microarray-based transcriptome analysis detected significant upregulation in both populations of nine cytochrome P450 oxidase genes (including four known pyrethroid metabolizing enzymes), the organophosphate metabolizer CCEae3a, Glutathione-S-transferases, and multiple putative cuticle proteins. Genotyping of knockdown resistance loci linked to pyrethroid resistance revealed fixation of the 1534C mutation, and presence with moderate frequencies of the V1016I mutation in each population. Significant resistance to three major insecticide classes (pyrethroid, carbamate and organophosphate) is present in Ae. aegypti from Madeira Island, and appears to be mediated by multiple mechanisms. Implementation of appropriate resistance management strategies including rotation of insecticides with alternative modes of action, and methods other than chemical-based vector control are strongly advised to delay or reverse the spread of resistance and achieve efficient control.

  17. Gut microbiome and lipid metabolism : from associations to mechanisms

    Wang, Zheng; Koonen, Debby; Hofker, Marten; Fu, Jingyuan

    Purpose of review The gut microbiome has now been convincingly linked to human metabolic health but the underlying causality and mechanisms remain poorly understood. This review focuses on the recent progress in establishing the associations between gut microbiome species and lipid metabolism in

  18. Klinefelter syndrome, insulin resistance, metabolic syndrome, and diabetes: review of literature and clinical perspectives.

    Salzano, Andrea; D'Assante, Roberta; Heaney, Liam M; Monaco, Federica; Rengo, Giuseppe; Valente, Pietro; Pasquali, Daniela; Bossone, Eduardo; Gianfrilli, Daniele; Lenzi, Andrea; Cittadini, Antonio; Marra, Alberto M; Napoli, Raffaele

    2018-03-23

    Klinefelter syndrome (KS), the most frequent chromosomic abnormality in males, is associated with hypergonadotropic hypogonadism and an increased risk of cardiovascular diseases (CVD). The mechanisms involved in increasing risk of cardiovascular morbidity and mortality are not completely understood. This review summarises the current understandings of the complex relationship between KS, metabolic syndrome and cardiovascular risk in order to plan future studies and improve current strategies to reduce mortality in this high-risk population. We searched PubMed, Web of Science, and Scopus for manuscripts published prior to November 2017 using key words "Klinefelter syndrome" AND "insulin resistance" OR "metabolic syndrome" OR "diabetes mellitus" OR "cardiovascular disease" OR "testosterone". Manuscripts were collated, studied and carried forward for discussion where appropriate. Insulin resistance, metabolic syndrome, and type 2 diabetes are more frequently diagnosed in KS than in the general population; however, the contribution of hypogonadism to metabolic derangement is highly controversial. Whether this dangerous combination of risk factors fully explains the CVD burden of KS patients remains unclear. In addition, testosterone replacement therapy only exerts a marginal action on the CVD system. Since fat accumulation and distribution seem to play a relevant role in triggering metabolic abnormalities, an early diagnosis and a tailored intervention strategy with drugs aimed at targeting excessive visceral fat deposition appear necessary in patients with KS.

  19. Phorate can reverse P450 metabolism-based herbicide resistance in Lolium rigidum.

    Busi, Roberto; Gaines, Todd Adam; Powles, Stephen

    2017-02-01

    Organophosphate insecticides can inhibit specific cytochrome P450 enzymes involved in metabolic herbicide resistance mechanisms, leading to synergistic interactions between the insecticide and the herbicide. In this study we report synergistic versus antagonistic interactions between the organophosphate insecticide phorate and five different herbicides observed in a population of multiple herbicide-resistant Lolium rigidum. Phorate synergised with three different herbicide modes of action, enhancing the activity of the ALS inhibitor chlorsulfuron (60% LD 50 reduction), the VLCFAE inhibitor pyroxasulfone (45% LD 50 reduction) and the mitosis inhibitor trifluralin (70% LD 50 reduction). Conversely, phorate antagonised the two thiocarbamate herbicides prosulfocarb and triallate with a 12-fold LD 50 increase. We report the selective reversal of P450-mediated metabolic multiple resistance to chlorsulfuron and trifluralin in the grass weed L. rigidum by synergistic interaction with the insecticide phorate, and discuss the putative mechanistic basis. This research should encourage diversity in herbicide use patterns for weed control as part of a long-term integrated management effort to reduce the risk of selection of metabolism-based multiple herbicide resistance in L. rigidum. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

  20. Analysis of the metabolic resistance of Ambrosia artemisiifolia L. to the herbicides action

    Y.V. Lykholat

    2018-03-01

    Full Text Available Action and aftereffect of the herbicides with different modes of action on the common ragweed population were studied in the field and greenhouse experiments. Activation of glutathione S-transferase has been detected due to the action of herbicides Harness and Guardian-Tetra both in leaves of juvenile plants and in ragweed seeds, which indicates intensive detoxification of herbicides during weed ontogenesis. Electrophoretic analysis showed that four components in protein spectra of ragweed seeds were inherent in seeds collected from herbicides-treated plants only. Using the method of isoelectric focusing, three specific peroxidase isoforms associated with a certain mechanism of herbicidal action on the parent plants were found in leaves of the next generation plants. The results confirm the intensive adaptive changes in A. artemisiifolia population that could provide the metabolic resistance to different modes of the herbicide action. Keywords: Common ragweed, Metabolic resistance, Herbicide, Mode of action, Isoforms, Isoelectric

  1. Mechanisms of hexavalent chromium resistance and removal by microorganisms.

    Joutey, Nezha Tahri; Sayel, Hanane; Bahafid, Wifak; El Ghachtouli, Naïma

    2015-01-01

    Chromium has been and is extensively used worldwide in multiple industrial processes and is routinely discharged to the environment from such processes. Therefore, this heavy metal is a potential threat to the environment and to public health, primarily because it is non-biodegradable and environmentally persistent. Chromium exists in several oxidation states, the most stable of which are trivalent Cr(Ill) and hexavalent Cr(VI) species. Each species possesses its own individual chemical characteristics and produces its own biological effects. For example, Cr (Ill) is an essential oligoelement for humans, whereas Cr(VI) is carcinogenic and mutagenic. Several chemical methods are used to remove Cr(VI) from contaminated sites. Each of these methods has advantages and disadvantages. Currently, bioremediation is often the preferred method to deal with Cr contaminated sites, because it is eco-friendly, cost-effective and is a "natural" technology. Many yeast, bacterial and fungal species have been assessed for their suitability to reduce or remove Cr(VI) contamination. The mechanisms by which these microorganisms resist and reduce Cr(VI) are variable and are species dependent. There are several Cr-resistance mechanisms that are displayed by microorganisms. These include active efflux of Cr compounds, metabolic reduction of Cr(VI) to Cr (ill), and either intercellular or extracellular prec1p1tation. Microbial Cr (VI) removal typically involves three stages: binding of chromium to the cell surface, translocation of chromium into the cell, and reduction of Cr(VI) to Cr (ill). Cr(VI) reduction by microorganisms may proceed on the cell surface, outside the cell, or intracellularly, either directly via chromate reductase enzymes, or indirectly via metabolite reduction of Cr(VI). The uptake of chromium ions is a biphasic process. The primary step is known as biosorption, a metabolic energyindependent process. Thereafter, bioaccumulation occurs, but is much slower, and is

  2. Analysis and modeling of resistive switching mechanisms oriented to resistive random-access memory

    Huang Da; Wu Jun-Jie; Tang Yu-Hua

    2013-01-01

    With the progress of the semiconductor industry, the resistive random-access memory (RAM) has drawn increasing attention. The discovery of the memristor has brought much attention to this study. Research has focused on the resistive switching characteristics of different materials and the analysis of resistive switching mechanisms. We discuss the resistive switching mechanisms of different materials in this paper and analyze the differences of those mechanisms from the view point of circuitry to establish their respective circuit models. Finally, simulations are presented. We give the prospect of using different materials in resistive RAM on account of their resistive switching mechanisms, which are applied to explain their resistive switchings

  3. Skeletal muscle lipid metabolism in exercise and insulin resistance

    Kiens, Bente

    2006-01-01

    Lipids as fuel for energy provision originate from different sources: albumin-bound long-chain fatty acids (LCFA) in the blood plasma, circulating very-low-density lipoproteins-triacylglycerols (VLDL-TG), fatty acids from triacylglycerol located in the muscle cell (IMTG), and possibly fatty acids...... of insulin resistance in skeletal muscle, including possible molecular mechanisms involved, is discussed....

  4. Metabolic consequences of obesity and insulin resistance in polycystic ovary syndrome: diagnostic and methodological challenges.

    Jeanes, Yvonne M; Reeves, Sue

    2017-06-01

    Women with polycystic ovary syndrome (PCOS) have a considerable risk of metabolic dysfunction. This review aims to present contemporary knowledge on obesity, insulin resistance and PCOS with emphasis on the diagnostic and methodological challenges encountered in research and clinical practice. Variable diagnostic criteria for PCOS and associated phenotypes are frequently published. Targeted searches were conducted to identify all available data concerning the association of obesity and insulin resistance with PCOS up to September 2016. Articles were considered if they were peer reviewed, in English and included women with PCOS. Obesity is more prevalent in women with PCOS, but studies rarely reported accurate assessments of adiposity, nor split the study population by PCOS phenotypes. Many women with PCOS have insulin resistance, though there is considerable variation reported in part due to not distinguishing subgroups known to have an impact on insulin resistance as well as limited methodology to measure insulin resistance. Inflammatory markers are positively correlated with androgen levels, but detailed interactions need to be identified. Weight management is the primary therapy; specific advice to reduce the glycaemic load of the diet and reduce the intake of pro-inflammatory SFA and advanced glycation endproducts have provided promising results. It is important that women with PCOS are educated about their increased risk of metabolic complications in order to make timely and appropriate lifestyle modifications. Furthermore, well-designed robust studies are needed to evaluate the mechanisms behind the improvements observed with dietary interventions.

  5. [Adipocytokines and metabolic syndrome--molecular mechanism and clinical implication].

    Matsuda, Morihiro; Shimomura, Iichiro

    2004-06-01

    Recent progress in adipocyte-biology shows that adipocytes are not merely fat-storing cells but that they secrete a variety of hormones, cytekines, growth factors and other bioactive substabces, conceptualized as adipocytokines. These include plasminogen activator inhibitor 1(PAI-1), tumor necrosis factor(TNF-alpha), leptin and adiponectin. Dysregulated productions of these adipocytekines participate in the pathogenesis of obesity-associated metabolic syndrome such as insulin resistance, type 2 diabetes, hyperlipidemia, and vascular diseases. Increased productions of PAI-1 and TNF-alpha from accumulated fat contribute to the formation of thrombosis and insulin resistance in obesity, respectively. Lack of leptin causes metabolic syndrome. Adiponectin exerts insulin-sensitizing and anti-atherogenic effects, hence decrease of plasma adiponectin is causative for insulin resistance and atherosclerosis in obesity.

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

    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

  7. Branched-chain amino acids in metabolic signalling and insulin resistance

    Lynch, Christopher J.; Adams, Sean H.

    2015-01-01

    Branched-chain amino acids (BCAAs) are important nutrient signals that have direct and indirect effects. Frequently, BCAAs have been reported to mediate antiobesity effects, especially in rodent models. However, circulating levels of BCAAs tend to be increased in individuals with obesity and are associated with worse metabolic health and future insulin resistance or type 2 diabetes mellitus (T2DM). A hypothesized mechanism linking increased levels of BCAAs and T2DM involves leucine-mediated activation of the mammalian target of rapamycin complex 1 (mTORC1), which results in uncoupling of insulin signalling at an early stage. A BCAA dysmetabolism model proposes that the accumulation of mitotoxic metabolites (and not BCAAs per se) promotes β-cell mitochondrial dysfunction, stress signalling and apoptosis associated with T2DM. Alternatively, insulin resistance might promote aminoacidaemia by increasing the protein degradation that insulin normally suppresses, and/or by eliciting an impairment of efficient BCAA oxidative metabolism in some tissues. Whether and how impaired BCAA metabolism might occur in obesity is discussed in this Review. Research on the role of individual and model-dependent differences in BCAA metabolism is needed, as several genes (BCKDHA, PPM1K, IVD and KLF15) have been designated as candidate genes for obesity and/or T2DM in humans, and distinct phenotypes of tissue-specific branched chain ketoacid dehydrogenase complex activity have been detected in animal models of obesity and T2DM. PMID:25287287

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

    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.

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

    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

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

    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.

  11. Metabolic imidacloprid resistance in the brown planthopper, Nilaparvata lugens, relies on multiple P450 enzymes.

    Zhang, Yixi; Yang, Yuanxue; Sun, Huahua; Liu, Zewen

    2016-12-01

    Target insensitivity contributing to imidacloprid resistance in Nilaparvata lugens has been reported to occur either through point mutations or quantitative change in nicotinic acetylcholine receptors (nAChRs). However, the metabolic resistance, especially the enhanced detoxification by P450 enzymes, is the major mechanism in fields. From one field-originated N. lugens population, an imidacloprid resistant strain G25 and a susceptible counterpart S25 were obtained to analyze putative roles of P450s in imidacloprid resistance. Compared to S25, over-expression of twelve P450 genes was observed in G25, with ratios above 5.0-fold for CYP6AY1, CYP6ER1, CYP6CS1, CYP6CW1, CYP4CE1 and CYP425B1. RNAi against these genes in vivo and recombinant tests on the corresponding proteins in vitro revealed that four P450s, CYP6AY1, CYP6ER1, CYP4CE1 and CYP6CW1, played important roles in imidacloprid resistance. The importance of the four P450s was not equal at different stages of resistance development based on their over-expression levels, among which CYP6ER1 was important at all stages, and that the others might only contribute at certain stages. The results indicated that, to completely reflect roles of P450s in insecticide resistances, their over-expression in resistant individuals, expression changes at the stages of resistance development, and catalytic activities against insecticides should be considered. In this study, multiple P450s, CYP6AY1, CYP6ER1, CYP4CE1 and CYP6CW1, have proven to be important in imidacloprid resistance. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Intramuscular Lipid Metabolism in the Insulin Resistance of Smoking

    Bergman, Bryan C.; Perreault, Leigh; Hunerdosse, Devon M.; Koehler, Mary C.; Samek, Ali M.; Eckel, Robert H.

    2009-01-01

    OBJECTIVE Smoking decreases insulin action and increases the risk of type 2 diabetes in humans. Mechanisms responsible for smoking-induced insulin resistance are unclear. We hypothesized smokers would have increased intramuscular triglyceride (IMTG) and diacylglycerol (DAG) concentration and decreased fractional synthesis rate (FSR) compared with nonsmokers. RESEARCH DESIGN AND METHODS Nonsmokers (n = 18, aged 20 ± 0.5 years, BMI 22 ± 0.4 kg/m2, body fat 20 ± 2%, 0 cigarettes per day) and smo...

  13. Resistance mechanisms to plant viruses: an overview

    Goldbach, R.W.; Bucher, E.C.; Prins, A.H.

    2003-01-01

    To obtain virus-resistant host plants, a range of operational strategies can be followed nowadays. While for decades plant breeders have been able to introduce natural resistance genes in susceptible genotypes without knowing precisely what these resistance traits were, currently a growing number of

  14. Diabetes, insulin resistance, and metabolic syndrome in horses.

    Johnson, Philip J; Wiedmeyer, Charles E; LaCarrubba, Alison; Ganjam, V K; Messer, Nat T

    2012-05-01

    Analogous to the situation in human medicine, contemporary practices in horse management, which incorporate lengthy periods of physical inactivity coupled with provision of nutritional rations characterized by inappropriately high sugar and starch, have led to obesity being more commonly recognized by practitioners of equine veterinary practice. In many of these cases, obesity is associated with insulin resistance (IR) and glucose intolerance. An equine metabolic syndrome (MS) has been described that is similar to the human MS in that both IR and aspects of obesity represent cornerstones of its definition. Unlike its human counterpart, identification of the equine metabolic syndrome (EMS) portends greater risk for development of laminitis, a chronic, crippling affliction of the equine hoof. When severe, laminitis sometimes necessitates euthanasia. Unlike the human condition, the risk of developing type 2 diabetes mellitus and many other chronic conditions, for which the risk is recognized as increased in the face of MS, is less likely in horses. The equine veterinary literature has been replete with reports of scientific investigations regarding the epidemiology, pathophysiology, and treatment of EMS. © 2012 Diabetes Technology Society.

  15. Resistance Training for Diabetes Prevention and Therapy: Experimental Findings and Molecular Mechanisms

    Barbara Strasser

    2013-01-01

    Full Text Available Type 2 diabetes mellitus (T2D is characterized by insulin resistance, impaired glycogen synthesis, lipid accumulation, and impaired mitochondrial function. Exercise training has received increasing recognition as a cornerstone in the prevention and treatment of T2D. Emerging research suggests that resistance training (RT has the power to combat metabolic dysfunction in patients with T2D and seems to be an effective measure to improve overall metabolic health and reduce metabolic risk factors in diabetic patients. However, there is limited mechanistic insight into how these adaptations occur. This review provides an overview of the intervention data on the impact of RT on glucose metabolism. In addition, the molecular mechanisms that lead to adaptation in skeletal muscle in response to RT and that are associated with possible beneficial metabolic responses are discussed. Some of the beneficial adaptations exerted by RT include increased GLUT4 translocation in skeletal muscle, increased insulin sensitivity and hence restored metabolic flexibility. Increased energy expenditure and excess postexercise oxygen consumption in response to RT may be other beneficial effects. RT is increasingly establishing itself as an effective measure to improve overall metabolic health and reduce metabolic risk factors in diabetic patients.

  16. Multiple mechanisms increase levels of resistance in Rapistrum rugosum to ALS herbicides

    Zhara M Hatami

    2016-02-01

    Full Text Available Rapistrum rugosum (turnip weed is a common weed of wheat fields in Iran, which is most often controlled by tribenuron-methyl (TM, a sulfonylurea (SU belonging to the acetolactate synthase (ALS inhibiting herbicides group. Several cases of unexplained control failure of R. rugosum by TM have been seen, especially in Golestan province-Iran. Hence, there is lack of research in evaluation of the level of resistance of the R. rugosum populations to TM, using whole plant dose–response and enzyme assays, then investigating some potential resistance mechanisms Results revealed that the resistance factor (RF for resistant (R populations was 2.5 to 6.6 fold higher than susceptible (S plant. Neither foliar retention, nor 14C-TM absorption and translocation were the mechanisms responsible for resistance in turnip weed. Metabolism of TM was the second resistant mechanism in two populations (Ag-R5 and G-1, in which three metabolites were found. The concentration of TM for 50% inhibition of ALS enzyme activity in vitro showed a high level of resistance to the herbicide (resistance factors were from 28 to 38 and cross-resistance to sulfonyl-aminocarbonyl-triazolinone (SCT, pyrimidinyl-thiobenzoate (PTB and triazolopyrimidine (TP, with no cross-resistance to imidazolinone (IMI. Substitution Pro 197 to Ser 197 provided resistance to four of five ALS-inhibiting herbicides including SU, TP, PTB and SCT with no resistance to IMI. These results documented the first case of R. rugosum resistant population worldwide and demonstrated that both RST and NRST mechanisms are involved to the resistance level to TM.

  17. Insulin resistance as a physiological defense against metabolic stress

    Nolan, Christopher J; Ruderman, Neil B; Kahn, Steven E

    2015-01-01

    Stratifying the management of type 2 diabetes (T2D) has to take into account marked variability in patient phenotype due to heterogeneity in its pathophysiology, different stages of the disease process, and multiple other patient factors including comorbidities. The focus here is on the very...... with intensive insulin therapy, could therefore be harmful. Treatments that nutrient off-load to lower glucose are more likely to be beneficial. The concepts of "IR as an adaptive defense mechanism" and "insulin-induced metabolic stress" may provide explanation for some of the unexpected outcomes of recent major...... clinical trials in T2D. Potential molecular mechanisms underlying these concepts; their clinical implications for stratification of T2D management, particularly in overweight and obese patients with difficult glycemic control; and future research requirements are discussed....

  18. Mechanisms and circumvention of cellular resistance to cisplatin.

    Hospers, Geesiena Alberdina Petronella

    1989-01-01

    Cisplatin (CDDP) is an active cytostatic agent. A limitation to its effectiveness initially or appearing during cystatic treatment is the occurrence of resistance. This thesis describes mechanisms wich are responsible for acquired cellular CDDP resistance. To investigate cellular CDDP resistance, a

  19. Shigella Antimicrobial Drug Resistance Mechanisms, 2004-2014.

    Nüesch-Inderbinen, Magdalena; Heini, Nicole; Zurfluh, Katrin; Althaus, Denise; Hächler, Herbert; Stephan, Roger

    2016-06-01

    To determine antimicrobial drug resistance mechanisms of Shigella spp., we analyzed 344 isolates collected in Switzerland during 2004-2014. Overall, 78.5% of isolates were multidrug resistant; 10.5% were ciprofloxacin resistant; and 2% harbored mph(A), a plasmid-mediated gene that confers reduced susceptibility to azithromycin, a last-resort antimicrobial agent for shigellosis.

  20. Metabolic Compensation of Fitness Costs Is a General Outcome for Antibiotic-Resistant Pseudomonas aeruginosa Mutants Overexpressing Efflux Pumps.

    Olivares Pacheco, Jorge; Alvarez-Ortega, Carolina; Alcalde Rico, Manuel; Martínez, José Luis

    2017-07-25

    It is generally assumed that the acquisition of antibiotic resistance is associated with a fitness cost. We have shown that overexpression of the MexEF-OprN efflux pump does not decrease the fitness of a resistant Pseudomonas aeruginosa strain compared to its wild-type counterpart. This lack of fitness cost was associated with a metabolic rewiring that includes increased expression of the anaerobic nitrate respiratory chain when cells are growing under fully aerobic conditions. It was not clear whether this metabolic compensation was exclusive to strains overexpressing MexEF-OprN or if it extended to other resistant strains that overexpress similar systems. To answer this question, we studied a set of P. aeruginosa mutants that independently overexpress the MexAB-OprM, MexCD-OprJ, or MexXY efflux pumps. We observed increased expression of the anaerobic nitrate respiratory chain in all cases, with a concomitant increase in NO 3 consumption and NO production. These efflux pumps are proton/substrate antiporters, and their overexpression may lead to intracellular H + accumulation, which may in turn offset the pH homeostasis. Indeed, all studied mutants showed a decrease in intracellular pH under anaerobic conditions. The fastest way to eliminate the excess of protons is by increasing oxygen consumption, a feature also displayed by all analyzed mutants. Taken together, our results support metabolic rewiring as a general mechanism to avoid the fitness costs derived from overexpression of P. aeruginosa multidrug efflux pumps. The development of drugs that block this metabolic "reaccommodation" might help in reducing the persistence and spread of antibiotic resistance elements among bacterial populations. IMPORTANCE It is widely accepted that the acquisition of resistance confers a fitness cost in such a way that in the absence of antibiotics, resistant populations will be outcompeted by susceptible ones. Based on this assumption, antibiotic cycling regimes have been

  1. Metabolic resistance in Nilaparvata lugens to etofenprox, a non-ester pyrethroid insecticide.

    Sun, Huahua; Yang, Baojun; Zhang, Yixi; Liu, Zewen

    2017-03-01

    Etofenprox, a non-ester pyrethroid insecticide, will be registered to control rice pests such as the brown planthopper (BPH, Nilaparvata lugens Stål) in mainland China. Insecticide resistance is always a problem to the effective control of N. lugens by chemical insecticides. An etofenprox resistance selection of N. lugens was performed in order to understand the related mechanisms. Through successive selection by etofenprox for 16 generations in the laboratory, an etofenprox-resistant strain (G16) with the resistance ratio (RR) of 422.3-fold was obtained. The resistance was partly synergised (2.68-fold) with the metabolic inhibitor PBO, suggesting a role for P450 monooxygenases. In this study, 11 P450 genes were significantly up-regulated in G16, among which eight genes was above 2.0-fold higher than that in US16, a population with the same origin of G16 but without contacting any insecticide in the laboratory. The expression level of four genes (CYP6AY1, CYP6FU1 and CYP408A1 from Clade 3, and CYP425A1 from Clade 4) were above 4.0-fold when compared to US16. RNA interference (RNAi) was performed to evaluate the importance of the selected P450s in etofenprox resistance. When CYP6FU1, CYP425A1 or CYP6AY1 was interfered, the susceptibility was significantly recovered in both G16 and US16, while the knockdown of CYP408A1 or CYP353D1 did not cause significant changes in etofenprox susceptibility. We supposed that CYP6FU1 was the most important P450 member for etofenprox resistance because of the highest expression level and the most noticeable effects on resistance ratios following RNAi. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Selection for chlorpyrifos resistance in Liriomyza sativae Blanchard: Cross-resistance patterns, stability and biochemical mechanisms.

    Askari-Saryazdi, Ghasem; Hejazi, Mir Jalil; Ferguson, J Scott; Rashidi, Mohammad-Reza

    2015-10-01

    The vegetable leafminer (VLM), Liriomyza sativae (Diptera: Agromyzidae) is a serious pest of vegetable crops and ornamentals worldwide. In cropping systems with inappropriate management strategies, development of resistance to insecticides in leafminers is probable. Chlorpyrifos is a commonly used pesticide for controlling leafminers in Iran, but resistance to this insecticide in leafminers has not been characterized. In order to develop strategies to minimize resistance in the field and greenhouse, a laboratory selected chlorpyrifos resistant strain of L. sativae was used to characterize resistance and determine the rate of development and stability of resistance. Selecting for resistance in the laboratory after 23 generations yielded a chlorpyrifos resistant selected strain (CRSS) with a resistance ratio of 40.34, determined on the larval stage. CRSS exhibited no cross-resistance to other tested insecticides except for diazinon. Synergism and biochemical assays indicated that esterases (EST) had a key role in metabolic resistance to chlorpyrifos, but glutathione S-transferase (GST) and mixed function oxidase (MFO) were not mediators in this resistance. In CRSS acetylcholinesterase (AChE) was more active than the susceptible strain, Sharif (SH). AChE in CRSS was also less sensitive to inhibition by propoxur. The kinetics parameters (Km and Vmax) of AChE indicated that affinities and hydrolyzing efficiencies of this enzyme in CRSS were higher than SH. Susceptibility to chlorpyrifos in L. sativae was re-gained in the absence of insecticide pressure. Synergism, biochemical and cross-resistance assays revealed that overactivity of metabolic enzymes and reduction in target site sensitivity are probably joint factors in chlorpyrifos resistance. An effective insecticide resistance management program is necessary to prevent fast resistance development in crop systems. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Molecular Mechanisms of Estrogen and Antiestrogen Resistance

    Clarke, Robert

    2003-01-01

    .... " In this application, the studies are focused on antiestrogen resistance. With respect to the career development aspects, several original studies and reviews relevant to this application have been published, others have been submitted for publication...

  4. Molecular mechanisms of bortezomib resistant adenocarcinoma cells.

    Erika Suzuki

    Full Text Available Bortezomib (Velcade™ is a reversible proteasome inhibitor that is approved for the treatment of multiple myeloma (MM. Despite its demonstrated clinical success, some patients are deprived of treatment due to primary refractoriness or development of resistance during therapy. To investigate the role of the duration of proteasome inhibition in the anti-tumor response of bortezomib, we established clonal isolates of HT-29 adenocarcinoma cells adapted to continuous exposure of bortezomib. These cells were ~30-fold resistant to bortezomib. Two novel and distinct mutations in the β5 subunit, Cys63Phe, located distal to the binding site in a helix critical for drug binding, and Arg24Cys, found in the propeptide region were found in all resistant clones. The latter mutation is a natural variant found to be elevated in frequency in patients with MM. Proteasome activity and levels of both the constitutive and immunoproteasome were increased in resistant cells, which correlated to an increase in subunit gene expression. These changes correlated with a more rapid recovery of proteasome activity following brief exposure to bortezomib. Increased recovery rate was not due to increased proteasome turnover as similar findings were seen in cells co-treated with cycloheximide. When we exposed resistant cells to the irreversible proteasome inhibitor carfilzomib we noted a slower rate of recovery of proteasome activity as compared to bortezomib in both parental and resistant cells. Importantly, carfilzomib maintained its cytotoxic potential in the bortezomib resistant cell lines. Therefore, resistance to bortezomib, can be overcome with irreversible inhibitors, suggesting prolonged proteasome inhibition induces a more potent anti-tumor response.

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

    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...

  6. Mechanisms of Resistance to Endocrine Therapy in Breast Cancer: Focus on Signaling Pathways, miRNAs and Genetically Based Resistance

    García-Becerra, Rocío; Santos, Nancy; Díaz, Lorenza; Camacho, Javier

    2013-01-01

    Breast cancer is the most frequent malignancy diagnosed in women. Approximately 70% of breast tumors express the estrogen receptor (ER). Tamoxifen and aromatase inhibitors (AIs) are the most common and effective therapies for patients with ERα-positive breast cancer. Alone or combined with chemotherapy, tamoxifen significantly reduces disease progression and is associated with more favorable impact on survival in patients. Unfortunately, endocrine resistance occurs, either de novo or acquired during the course of the treatment. The mechanisms that contribute to hormonal resistance include loss or modification in the ERα expression, regulation of signal transduction pathways, altered expression of specific microRNAs, balance of co-regulatory proteins, and genetic polymorphisms involved in tamoxifen metabolic activity. Because of the clinical consequences of endocrine resistance, new treatment strategies are arising to make the cells sensitive to tamoxifen. Here, we will review the current knowledge on mechanisms of endocrine resistance in breast cancer cells. In addition, we will discuss novel therapeutic strategies to overcome such resistance. Undoubtedly, circumventing endocrine resistance should help to improve therapy for the benefit of breast cancer patients. PMID:23344024

  7. Integrating Mechanisms for Insulin Resistance: Common Threads and Missing Links

    Samuel, Varman T.; Shulman, Gerald I.

    2012-01-01

    Insulin resistance is a complex metabolic disorder that defies a single etiological pathway. Accumulation of ectopic lipid metabolites, activation of the unfolded protein response (UPR) pathway and innate immune pathways have all been implicated in the pathogenesis of insulin resistance. However, these pathways are also closely linked to changes in fatty acid uptake, lipogenesis, and energy expenditure that can impact ectopic lipid deposition. Ultimately, accumulation of specific lipid metabolites (diacylglycerols and/or ceramides) in liver and skeletal muscle, may be a common pathway leading to impaired insulin signaling and insulin resistance. PMID:22385956

  8. Molecular mechanisms of methicillin resistance in Staphylococcus aureus.

    Domínguez, M A; Liñares, J; Martín, R

    1997-09-01

    Methicillin-resistant Staphylococcus aureus (MRSA) strains are among the most common nosocomial pathogens. The most significant mechanism of resistance to methicillin in this-species is the acquisition of a genetic determinant (mecA gene). However, resistance seems to have a more complex molecular basis, since additional chromosomal material is involved in such resistance. Besides, overproduction of penicillinase and/or alterations in the PBPs can contribute to the formation of resistance phenotypes. Genetic and environmental factors leading to MRSA are reviewed.

  9. Mechanism of Resistance to Glyphosate in Lolium perenne from Argentina

    Marcos Yanniccari

    2017-10-01

    Full Text Available In Argentina, glyphosate resistance was reported in a Lolium perenne population after 12 years of successful herbicide use. The aim of the current paper was to put in evidence for the mechanism of glyphosate resistance of this weed. Susceptible leaves treated with different doses of glyphosate and incubated in vitro showed an accumulation of shikimic acid of around three to five times the basal level, while no changes were detected in leaves of glyphosate-resistant plants. The resistance mechanism prevents shikimate accumulation in leaves, even under such tissue-isolation conditions. The activity of the glyphosate target enzyme (EPSPS: 5-enolpyruvylshikimate-3-phosphate synthase was quantified at different herbicide concentrations. EPSPS from resistant plants showed no difference in glyphosate-sensitivity compared to EPSPS from susceptible plants, and, accordingly, no amino acid substitution causing mutations associated with resistance were found. While the glyphosate target enzymes were equally sensitive, the basal EPSPS activity in glyphosate resistant plants was approximately 3-fold higher than the EPSPS activity in susceptible plants. This increased EPSPS activity in glyphosate resistant plants was associated with a 15-fold higher expression of EPSPS compared with susceptible plants. Therefore, the over-expression of EPSPS appears to be the main mechanism responsible for resistance to glyphosate. This mechanism has a constitutive character and has important effects on plant fitness, as recently reported.

  10. Mechanisms of action of systemic antibiotics used in periodontal treatment and mechanisms of bacterial resistance to these drugs

    Geisla Mary Silva Soares

    2012-06-01

    Full Text Available Antibiotics are important adjuncts in the treatment of infectious diseases, including periodontitis. The most severe criticisms to the indiscriminate use of these drugs are their side effects and, especially, the development of bacterial resistance. The knowledge of the biological mechanisms involved with the antibiotic usage would help the medical and dental communities to overcome these two problems. Therefore, the aim of this manuscript was to review the mechanisms of action of the antibiotics most commonly used in the periodontal treatment (i.e. penicillin, tetracycline, macrolide and metronidazole and the main mechanisms of bacterial resistance to these drugs. Antimicrobial resistance can be classified into three groups: intrinsic, mutational and acquired. Penicillin, tetracycline and erythromycin are broad-spectrum drugs, effective against gram-positive and gram-negative microorganisms. Bacterial resistance to penicillin may occur due to diminished permeability of the bacterial cell to the antibiotic; alteration of the penicillin-binding proteins, or production of β-lactamases. However, a very small proportion of the subgingival microbiota is resistant to penicillins. Bacteria become resistant to tetracyclines or macrolides by limiting their access to the cell, by altering the ribosome in order to prevent effective binding of the drug, or by producing tetracycline/macrolide-inactivating enzymes. Periodontal pathogens may become resistant to these drugs. Finally, metronidazole can be considered a prodrug in the sense that it requires metabolic activation by strict anaerobe microorganisms. Acquired resistance to this drug has rarely been reported. Due to these low rates of resistance and to its high activity against the gram-negative anaerobic bacterial species, metronidazole is a promising drug for treating periodontal infections.

  11. Mechanisms of Evolution in High-Consequence Drug Resistance Plasmids

    Susu He

    2016-12-01

    Full Text Available The dissemination of resistance among bacteria has been facilitated by the fact that resistance genes are usually located on a diverse and evolving set of transmissible plasmids. However, the mechanisms generating diversity and enabling adaptation within highly successful resistance plasmids have remained obscure, despite their profound clinical significance. To understand these mechanisms, we have performed a detailed analysis of the mobilome (the entire mobile genetic element content of a set of previously sequenced carbapenemase-producing Enterobacteriaceae (CPE from the National Institutes of Health Clinical Center. This analysis revealed that plasmid reorganizations occurring in the natural context of colonization of human hosts were overwhelmingly driven by genetic rearrangements carried out by replicative transposons working in concert with the process of homologous recombination. A more complete understanding of the molecular mechanisms and evolutionary forces driving rearrangements in resistance plasmids may lead to fundamentally new strategies to address the problem of antibiotic resistance.

  12. Mechanism of Innate Resistance to Viral Encephalitis.

    1976-12-01

    development of immunity (20). Although serum antibody was not detected in recipients of immune SC unless they were challenged wih virus, it is reasonable to...inununo- suppression, cytotoxicity 21. ASSIRACr m(nm -oel ab w noomeao aid Momlw by block nmbu) Factors that influence the phenotypic expression of...both strains of mice withstood IP challenge with virus. In contrast, only resistant mice (C3H/RV) were able to withstand IC challenge . Similarly, C3H

  13. Fatty acid metabolism, energy expenditure and insulin resistance in muscle.

    Turner, Nigel; Cooney, Gregory J; Kraegen, Edward W; Bruce, Clinton R

    2014-02-01

    Fatty acids (FAs) are essential elements of all cells and have significant roles as energy substrates, components of cellular structure and signalling molecules. The storage of excess energy intake as fat in adipose tissue is an evolutionary advantage aimed at protecting against starvation, but in much of today's world, humans are faced with an unlimited availability of food, and the excessive accumulation of fat is now a major risk for human health, especially the development of type 2 diabetes (T2D). Since the first recognition of the association between fat accumulation, reduced insulin action and increased risk of T2D, several mechanisms have been proposed to link excess FA availability to reduced insulin action, with some of them being competing or contradictory. This review summarises the evidence for these mechanisms in the context of excess dietary FAs generating insulin resistance in muscle, the major tissue involved in insulin-stimulated disposal of blood glucose. It also outlines potential problems with models and measurements that may hinder as well as help improve our understanding of the links between FAs and insulin action.

  14. Physiological mechanism of resistance to anthracnose of different ...

    However, enzyme activity of resistant cultivars improved markedly after pathogen inoculation, while those of susceptible cultivars did not change. This study broadens the understanding of the mechanisms of disease resistance in Camellia. Keywords: Anthracnose, Camellia oleifera, phenylalanine ammonia lyase, ...

  15. Biomarkers and mechanisms of natural disease resistance in dairy cows

    Altena, van S.E.C.

    2016-01-01

    The aim of this thesis was to define and test biomarkers for disease resistance in dairy cows and to determine the underlying mechanism in natural disease resistance. The health status of the cows is an important issue in dairy farming. Due to the mandatory reduction in the use of antibiotics,

  16. Conduction Mechanism of Valence Change Resistive Switching Memory: A Survey

    Ee Wah Lim

    2015-09-01

    Full Text Available Resistive switching effect in transition metal oxide (TMO based material is often associated with the valence change mechanism (VCM. Typical modeling of valence change resistive switching memory consists of three closely related phenomena, i.e., conductive filament (CF geometry evolution, conduction mechanism and temperature dynamic evolution. It is widely agreed that the electrochemical reduction-oxidation (redox process and oxygen vacancies migration plays an essential role in the CF forming and rupture process. However, the conduction mechanism of resistive switching memory varies considerably depending on the material used in the dielectric layer and selection of electrodes. Among the popular observations are the Poole-Frenkel emission, Schottky emission, space-charge-limited conduction (SCLC, trap-assisted tunneling (TAT and hopping conduction. In this article, we will conduct a survey on several published valence change resistive switching memories with a particular interest in the I-V characteristic and the corresponding conduction mechanism.

  17. Nucleus geometry and mechanical properties of resistance spot ...

    Keywords. Automotive steels; resistance spot welding; mechanical properties; nucleus geometry. 1. .... High va- lues of hardness can be explained with martensitic forma- ... interface of DP450–DP600 steels may have stainless steel properties.

  18. Impaired Glucose Metabolism Despite Decreased Insulin Resistance After Renal Transplantation

    Manfred Hecking

    2012-06-01

    Full Text Available The pathophysiology underlying new-onset diabetes after transplantation (NODAT is unresolved. We obtained demographics and laboratory data from all 1064 renal transplant recipients followed at our outpatient clinic in 2009/2010, randomly assigned 307 patients without previously diagnosed diabetes to a routine 2-hour oral glucose tolerance test (OGTT, and compared the metabolic results to a large, unrelated cross-sectional cohort of non-transplanted subjects. Among renal transplant recipients, 11% had a history of NODAT, and 12% had type 1 and type 2 diabetes. 42% of all OGTTs were abnormal (9% diabetic, predominantly in older patients who received tacrolimus. Compared to non-transplanted subjects, basal glucose was lower and HbA1c higher in renal transplant patients. Compared to non-transplanted subjects, insulin secretion was inferior, and insulin sensitivity improved at ≥6 months, as well as 3 months post-transplantation:(The Figure shows linear spline interpolation; all p for overall difference between non-Tx and Tx patients <0.02, using likelihood ratio testing. Our results indicate that impaired insulin secretion is the predominant problem after renal transplantation, suggesting benefit for therapeutic regimens that preserve beta cell function after renal transplantation. The mechanism of increased insulin sensitivity might be pathophysiologically similar to pancreatogenic diabetes.fx1

  19. Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin resistant phenotypes

    Malin, Steven K; Haus, Jacob M; Solomon, Thomas

    2013-01-01

    Impaired fasting glucose (IFG) blunts the reversal of impaired glucose tolerance (IGT) after exercise training. Metabolic inflexibility has been implicated in the etiology of insulin resistance, however, the efficacy of exercise on peripheral and hepatic insulin sensitivity or substrate utilizati...

  20. Exposures to arsenite and methylarsonite produce insulin resistance and impair insulin-dependent glycogen metabolism in hepatocytes.

    Zhang, Chongben; Fennel, Emily M J; Douillet, Christelle; Stýblo, Miroslav

    2017-12-01

    Environmental exposure to inorganic arsenic (iAs) has been shown to disturb glucose homeostasis, leading to diabetes. Previous laboratory studies have suggested several mechanisms that may underlie the diabetogenic effects of iAs exposure, including (i) inhibition of insulin signaling (leading to insulin resistance) in glucose metabolizing peripheral tissues, (ii) inhibition of insulin secretion by pancreatic β cells, and (iii) dysregulation of the methylation or expression of genes involved in maintenance of glucose or insulin metabolism and function. Published studies have also shown that acute or chronic iAs exposures may result in depletion of hepatic glycogen stores. However, effects of iAs on pathways and mechanisms that regulate glycogen metabolism in the liver have never been studied. The present study examined glycogen metabolism in primary murine hepatocytes exposed in vitro to arsenite (iAs 3+ ) or its methylated metabolite, methylarsonite (MAs 3+ ). The results show that 4-h exposures to iAs 3+ and MAs 3+ at concentrations as low as 0.5 and 0.2 µM, respectively, decreased glycogen content in insulin-stimulated hepatocytes by inhibiting insulin-dependent activation of glycogen synthase (GS) and by inducing activity of glycogen phosphorylase (GP). Further investigation revealed that both iAs 3+ and MAs 3+ inhibit insulin-dependent phosphorylation of protein kinase B/Akt, one of the mechanisms involved in the regulation of GS and GP by insulin. Thus, inhibition of insulin signaling (i.e., insulin resistance) is likely responsible for the dysregulation of glycogen metabolism in hepatocytes exposed to iAs 3+ and MAs 3+ . This study provides novel information about the mechanisms by which iAs exposure impairs glucose homeostasis, pointing to hepatic metabolism of glycogen as one of the targets.

  1. Enhanced activity of carbohydrate- and lipid-metabolizing enzymes in insecticide-resistant populations of the maize weevil, Sitophilus zeamais.

    Araújo, R A; Guedes, R N C; Oliveira, M G A; Ferreira, G H

    2008-08-01

    Insecticide resistance is frequently associated with fitness disadvantages in the absence of insecticides. However, intense past selection with insecticides may allow the evolution of fitness modifier alleles that mitigate the cost of insecticide resistance and their consequent fitness disadvantages. Populations of Sitophilus zeamais with different levels of susceptibility to insecticides show differences in the accumulation and mobilization of energy reserves. These differences may allow S. zeamais to better withstand toxic compounds without reducing the beetles' reproductive fitness. Enzymatic assays with carbohydrate- and lipid-metabolizing enzymes were, therefore, carried out to test this hypothesis. Activity levels of trehalase, glycogen phosphorylase, lipase, glycosidase and amylase were determined in two insecticide-resistant populations showing (resistant cost) or not showing (resistant no-cost) associated fitness cost, and in an insecticide-susceptible population. Respirometry bioassays were also carried out with these weevil populations. The resistant no-cost population showed significantly higher body mass and respiration rate than the other two populations, which were similar. No significant differences in glycogen phosphorylase and glycosidase were observed among the populations. Among the enzymes studied, trehalase and lipase showed higher activity in the resistant cost population. The results obtained in the assays with amylase also indicate significant differences in activity among the populations, but with higher activity in the resistant no-cost population. The inverse activity trends of lipases and amylases in both resistant populations, one showing fitness disadvantage without insecticide exposure and the other not showing it, may underlay the mitigation of insecticide resistance physiological costs observed in the resistant no-cost population. The higher amylase activity observed in the resistant no-cost population may favor energy storage

  2. Elevated serum tartrate-resistant acid phosphatase isoform 5a levels in metabolic syndrome.

    Huang, Yi-Jhih; Huang, Tsai-Wang; Chao, Tsu-Yi; Sun, Yu-Shan; Chen, Shyi-Jou; Chu, Der-Ming; Chen, Wei-Liang; Wu, Li-Wei

    2017-09-29

    Tartrate-resistant phosphatase isoform 5a is expressed in tumor-associated macrophages and is a biomarker of chronic inflammation. Herein, we correlated serum tartrate-resistant phosphatase isoform 5a levels with metabolic syndrome status and made comparisons with traditional markers of inflammation, including c-reactive protein and interleukin-6. One hundred healthy volunteers were randomly selected, and cut-off points for metabolic syndrome related inflammatory biomarkers were determined using receiver operating characteristic curves. Linear and logistic regression models were subsequently used to correlate inflammatory markers with the risk of metabolic syndrome. Twenty-two participants met the criteria for metabolic syndrome, and serum tartrate-resistant phosphatase isoform 5a levels of >5.8 μg/L were associated with metabolic syndrome (c-statistics, 0.730; p = 0.001; 95% confidence interval, 0.618-0.842). In addition, 1 μg/L increases in tartrate-resistant phosphatase isoform 5a levels were indicative of a 1.860 fold increase in the risk of metabolic syndrome (p = 0.012). Elevated serum tartrate-resistant phosphatase isoform 5a levels are associated with the risk of metabolic syndrome, with a cut-off level of 5.8 μg/L.

  3. The role of energy & fatty acid metabolism in obesity and insulin resistance

    Heemskerk, Mattijs Maria

    2015-01-01

    In today’s world, more people die from complications of overweight than from underweight. But not all individuals are equally prone to develop metabolic complications, such as obesity and insulin resistance. This thesis focuses on the differences in the energy and fatty acid metabolism that play a

  4. Effect of aspartic acid and glutamate on metabolism and acid stress resistance of Acetobacter pasteurianus.

    Yin, Haisong; Zhang, Renkuan; Xia, Menglei; Bai, Xiaolei; Mou, Jun; Zheng, Yu; Wang, Min

    2017-06-15

    Acetic acid bacteria (AAB) are widely applied in food, bioengineering and medicine fields. However, the acid stress at low pH conditions limits acetic acid fermentation efficiency and high concentration of vinegar production with AAB. Therefore, how to enhance resistance ability of the AAB remains as the major challenge. Amino acids play an important role in cell growth and cell survival under severe environment. However, until now the effects of amino acids on acetic fermentation and acid stress resistance of AAB have not been fully studied. In the present work the effects of amino acids on metabolism and acid stress resistance of Acetobacter pasteurianus were investigated. Cell growth, culturable cell counts, acetic acid production, acetic acid production rate and specific production rate of acetic acid of A. pasteurianus revealed an increase of 1.04, 5.43, 1.45, 3.30 and 0.79-folds by adding aspartic acid (Asp), and cell growth, culturable cell counts, acetic acid production and acetic acid production rate revealed an increase of 0.51, 0.72, 0.60 and 0.94-folds by adding glutamate (Glu), respectively. For a fully understanding of the biological mechanism, proteomic technology was carried out. The results showed that the strengthening mechanism mainly came from the following four aspects: (1) Enhancing the generation of pentose phosphates and NADPH for the synthesis of nucleic acid, fatty acids and glutathione (GSH) throughout pentose phosphate pathway. And GSH could protect bacteria from low pH, halide, oxidative stress and osmotic stress by maintaining the viability of cells through intracellular redox equilibrium; (2) Reinforcing deamination of amino acids to increase intracellular ammonia concentration to maintain stability of intracellular pH; (3) Enhancing nucleic acid synthesis and reparation of impaired DNA caused by acid stress damage; (4) Promoting unsaturated fatty acids synthesis and lipid transport, which resulted in the improvement of cytomembrane

  5. Molecular Mechanisms of Chromium in Alleviating Insulin Resistance

    Hua, Yinan; Clark, Suzanne; Ren, Jun; Sreejayan, Nair

    2011-01-01

    Type 2 diabetes is often associated with obesity, dyslipidemia, and cardiovascular anomalies and is a major health problem approaching global epidemic proportions. Insulin resistance, a prediabetic condition, precedes the onset of frank type 2 diabetes and offers potential avenues for early intervention to treat the disease. Although lifestyle modifications and exercise can reduce the incidence of diabetes, compliance has proved to be difficult, warranting pharmacological interventions. However, most of the currently available drugs that improve insulin sensitivity have adverse effects. Therefore, attractive strategies to alleviate insulin resistance include dietary supplements. One such supplement is chromium, which has been shown reduce insulin resistance in some, but not all, studies. Furthermore, the molecular mechanisms of chromium in alleviating insulin resistance remain elusive. This review examines emerging reports on the effect of chromium, as well as molecular and cellular mechanisms by which chromium may provide beneficial effects in alleviating insulin resistance. PMID:22423897

  6. Riboflavin analogs as antiinfectives: occurrence, mode of action, metabolism and resistance.

    Pedrolli, Danielle Biscaro; Jankowitsch, Frank; Schwarz, Julia; Langer, Simone; Nakanishi, Shinobu; Frei, Eva; Mack, Matthias

    2013-01-01

    Antimetabolites are molecules, which are structurally similar to molecules needed to carry out primary metabolic reactions.The inhibitory activity of an antimetabolite depends on its successful competition with the natural substrate, ligand, modulator or cofactor of a given biomolecule. Antimetabolites are indispensable as molecular tools in order to understand biological processes. Beyond that,antimetabolites have a large variety of applications in the pharmaceutical and food industries. The identification of the structural riboflavin(vitamin B2) analog roseoflavin in Streptomyces davawensis demonstrates that anti-vitamins/cofactor analogs may serve as lead structures for the development of novel antibiotics. The latter is supported by the recent finding that roseoflavin had a profound inhibiting effect on the growth and infectivity of the human bacterial pathogen Listeria monocytogenes at very low concentrations. Roseoflavin is studied in our laboratory as a model compound. We investigate the biosynthesis, the possible large-scale production, the metabolization,the mechanism of action and the resistance mechanism of the producer organism in order to pave the way for the structured analysis of other vitamin analogs yet to be discovered. These compounds hopefully will help to replenish the arsenal of antimicrobials urgently needed to fight multiresistant bacterial pathogens.

  7. Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin-resistant phenotypes.

    Malin, Steven K; Haus, Jacob M; Solomon, Thomas P J; Blaszczak, Alecia; Kashyap, Sangeeta R; Kirwan, John P

    2013-11-15

    Impaired fasting glucose (IFG) blunts the reversal of impaired glucose tolerance (IGT) after exercise training. Metabolic inflexibility has been implicated in the etiology of insulin resistance; however, the efficacy of exercise on peripheral and hepatic insulin sensitivity or substrate utilization in adults with IFG, IGT, or IFG + IGT is unknown. Twenty-four older (66.7 ± 0.8 yr) obese (34.2 ± 0.9 kg/m(2)) adults were categorized as IFG (n = 8), IGT (n = 8), or IFG + IGT (n = 8) according to a 75-g oral glucose tolerance test (OGTT). Subjects underwent 12-wk of exercise (60 min/day for 5 days/wk at ∼85% HRmax) and were instructed to maintain a eucaloric diet. A euglycemic hyperinsulinemic clamp (40 mU·m(2)·min(-1)) with [6,6-(2)H]glucose was used to determine peripheral and hepatic insulin sensitivity. Nonoxidative glucose disposal and metabolic flexibility [insulin-stimulated respiratory quotient (RQ) minus fasting RQ] were also assessed. Glucose incremental area under the curve (iAUCOGTT) was calculated from the OGTT. Exercise increased clamp-derived peripheral and hepatic insulin sensitivity more in adults with IFG or IGT alone than with IFG + IGT (P work is required to assess the molecular mechanism(s) by which chronic hyperglycemia modifies insulin sensitivity following exercise training.

  8. Cross-resistance, inheritance and biochemical mechanisms of imidacloprid resistance in B-biotype Bemisia tabaci.

    Wang, Zhenyu; Yao, Mingde; Wu, Yidong

    2009-11-01

    The B-type Bemisia tabaci (Gennadius) has become established in many regions in China, and neonicotinoids are extensively used to control this pest. Imidacloprid resistance in a laboratory-selected strain of B-type B. tabaci was characterised in order to provide the basis for recommending resistance management tactics. The NJ-Imi strain of B-type B. tabaci was selected from the NJ strain with imidacloprid for 30 generations. The NJ-Imi strain exhibited 490-fold resistance to imidacloprid, high levels of cross-resistance to three other neonicotinoids, low levels of cross-resistance to monosultap, cartap and spinosad, but no cross-resistance to abamectin and cypermethrin. Imidacloprid resistance in the NJ-Imi strain was autosomal and semi-dominant. It is shown that enhanced detoxification mediated by cytochrome-P450-dependent monooxygenases contributes to imidacloprid resistance to some extent in the NJ-Imi strain. Results from synergist bioassays and cross-resistance patterns indicated that target-site insensitivity may be involved in imidacloprid resistance in the NJ-Imi strain of B. tabaci. Although oxidative detoxification mediated by P450 monooxygenases is involved in imidacloprid resistance in the NJ-Imi strain of B-type B. tabaci, target-site modification as an additional resistance mechanism cannot be ruled out. Considering the high risk of cross-resistance, neonicotinoids should be regarded as a single group when implementing an insecticide rotation scheme in B. tabaci control. (c) 2009 Society of Chemical Industry.

  9. Investigating the molecular mechanisms of organophosphate and pyrethroid resistance in the fall armyworm Spodoptera frugiperda.

    Renato A Carvalho

    Full Text Available The fall armyworm Spodoptera frugiperda is an economically important pest of small grain crops that occurs in all maize growing regions of the Americas. The intensive use of chemical pesticides for its control has led to the selection of resistant populations, however, to date, the molecular mechanisms underlying resistance have not been characterised. In this study the mechanisms involved in the resistance of two S. frugiperda strains collected in Brazil to chlorpyrifos (OP strain or lambda-cyhalothrin (PYR strain were investigated using molecular and genomic approaches. To examine the possible role of target-site insensitivity the genes encoding the organophosphate (acetylcholinesterase, AChE and pyrethroid (voltage-gated sodium channel, VGSC target-site proteins were PCR amplified. Sequencing of the S. frugiperda ace-1 gene identified several nucleotide changes in the OP strain when compared to a susceptible reference strain (SUS. These result in three amino acid substitutions, A201S, G227A and F290V, that have all been shown previously to confer organophosphate resistance in several other insect species. Sequencing of the gene encoding the VGSC in the PYR strain, identified mutations that result in three amino acid substitutions, T929I, L932F and L1014F, all of which have been shown previously to confer knockdown/super knockdown-type resistance in several arthropod species. To investigate the possible role of metabolic detoxification in the resistant phenotype of the OP and PYR stains all EST sequences available for S. frugiperda were used to design a gene-expression microarray. This was then used to compare gene expression in the resistant strains with the susceptible reference strain. Members of several gene families, previously implicated in metabolic resistance in other insects were found to be overexpressed in the resistant strains including glutathione S-transferases, cytochrome P450s and carboxylesterases. Taken together these results

  10. Investigating the molecular mechanisms of organophosphate and pyrethroid resistance in the fall armyworm Spodoptera frugiperda.

    Carvalho, Renato A; Omoto, Celso; Field, Linda M; Williamson, Martin S; Bass, Chris

    2013-01-01

    The fall armyworm Spodoptera frugiperda is an economically important pest of small grain crops that occurs in all maize growing regions of the Americas. The intensive use of chemical pesticides for its control has led to the selection of resistant populations, however, to date, the molecular mechanisms underlying resistance have not been characterised. In this study the mechanisms involved in the resistance of two S. frugiperda strains collected in Brazil to chlorpyrifos (OP strain) or lambda-cyhalothrin (PYR strain) were investigated using molecular and genomic approaches. To examine the possible role of target-site insensitivity the genes encoding the organophosphate (acetylcholinesterase, AChE) and pyrethroid (voltage-gated sodium channel, VGSC) target-site proteins were PCR amplified. Sequencing of the S. frugiperda ace-1 gene identified several nucleotide changes in the OP strain when compared to a susceptible reference strain (SUS). These result in three amino acid substitutions, A201S, G227A and F290V, that have all been shown previously to confer organophosphate resistance in several other insect species. Sequencing of the gene encoding the VGSC in the PYR strain, identified mutations that result in three amino acid substitutions, T929I, L932F and L1014F, all of which have been shown previously to confer knockdown/super knockdown-type resistance in several arthropod species. To investigate the possible role of metabolic detoxification in the resistant phenotype of the OP and PYR stains all EST sequences available for S. frugiperda were used to design a gene-expression microarray. This was then used to compare gene expression in the resistant strains with the susceptible reference strain. Members of several gene families, previously implicated in metabolic resistance in other insects were found to be overexpressed in the resistant strains including glutathione S-transferases, cytochrome P450s and carboxylesterases. Taken together these results provide

  11. Volume Resistivity and Mechanical Behavior of Epoxy Nanocomposite Materials

    M. F. Abdelkarim

    2015-04-01

    Full Text Available Electrical and mechanical properties of polymer composite materials are investigated through the determination of resistivity and hardness for composites samples. Epoxy composite samples have been prepared with different concentrations of certain inorganic fillers such as; Titanium dioxide (TiO2 and Silica (SiO2, of various size (micro, nano and hybrid to study the electrical and mechanical behavior. The volume resistivity reaches 3.23×1014 ohm.cm for the micro silica composite. Surface of composite material has been mechanically examined by hardness test. The results show that the resistivity of microcomposites and nanocmposites are increased with the decrease of filler concentration. But the resistivity of hybrid composites is increased with the increase of filler concentration. Maximum hardness value was obtained from hybrid silica composite with 0.1% filler concentration.

  12. Mechanisms of Evolution in High-Consequence Drug Resistance Plasmids.

    He, Susu; Chandler, Michael; Varani, Alessandro M; Hickman, Alison B; Dekker, John P; Dyda, Fred

    2016-12-06

    The dissemination of resistance among bacteria has been facilitated by the fact that resistance genes are usually located on a diverse and evolving set of transmissible plasmids. However, the mechanisms generating diversity and enabling adaptation within highly successful resistance plasmids have remained obscure, despite their profound clinical significance. To understand these mechanisms, we have performed a detailed analysis of the mobilome (the entire mobile genetic element content) of a set of previously sequenced carbapenemase-producing Enterobacteriaceae (CPE) from the National Institutes of Health Clinical Center. This analysis revealed that plasmid reorganizations occurring in the natural context of colonization of human hosts were overwhelmingly driven by genetic rearrangements carried out by replicative transposons working in concert with the process of homologous recombination. A more complete understanding of the molecular mechanisms and evolutionary forces driving rearrangements in resistance plasmids may lead to fundamentally new strategies to address the problem of antibiotic resistance. The spread of antibiotic resistance among Gram-negative bacteria is a serious public health threat, as it can critically limit the types of drugs that can be used to treat infected patients. In particular, carbapenem-resistant members of the Enterobacteriaceae family are responsible for a significant and growing burden of morbidity and mortality. Here, we report on the mechanisms underlying the evolution of several plasmids carried by previously sequenced clinical Enterobacteriaceae isolates from the National Institutes of Health Clinical Center (NIH CC). Our ability to track genetic rearrangements that occurred within resistance plasmids was dependent on accurate annotation of the mobile genetic elements within the plasmids, which was greatly aided by access to long-read DNA sequencing data and knowledge of their mechanisms. Mobile genetic elements such as

  13. Identification of Mechanical parameters for Resistance Welding Machines

    Wu, Pei; Zhang, Wenqi; Bay, Niels

    2003-01-01

    Mechanical dynamic responses of resistance welding machine have a significant influence on weld quality and electrode service life, it must be considered when the real welding production is carried out or the welding process is simulated. The mathematical models for characterizing the mechanical...

  14. Mass spectrometry-based metabolic profiling of gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cells.

    Fujimura, Yoshinori; Ikenaga, Naoki; Ohuchida, Kenoki; Setoyama, Daiki; Irie, Miho; Miura, Daisuke; Wariishi, Hiroyuki; Murata, Masaharu; Mizumoto, Kazuhiro; Hashizume, Makoto; Tanaka, Masao

    2014-03-01

    Gemcitabine resistance (GR) is one of the critical issues for therapy for pancreatic cancer, but the mechanism still remains unclear. Our aim was to increase the understanding of GR by metabolic profiling approach. To establish GR cells, 2 human pancreatic cancer cell lines, SUIT-2 and CAPAN-1, were exposed to increasing concentration of gemcitabine. Both parental and chemoresistant cells obtained by this treatment were subjected to metabolic profiling based on liquid chromatography-mass spectrometry. Multivariate statistical analyses, both principal component analysis and orthogonal partial least squares discriminant analysis, distinguished metabolic signature of responsiveness and resistance to gemcitabine in both SUIT-2 and CAPAN-1 cells. Among significantly different (P metabolic pathways such as amino acid, nucleotide, energy, cofactor, and vitamin pathways. Decreases in glutamine and proline levels as well as increases in aspartate, hydroxyproline, creatine, and creatinine levels were observed in chemoresistant cells from both cell lines. These results suggest that metabolic profiling can isolate distinct features of pancreatic cancer in the metabolome of gemcitabine-sensitive and GR cells. These findings may contribute to the biomarker discovery and an enhanced understanding of GR in pancreatic cancer.

  15. Mechanisms of triglyceride metabolism in patients with bile acid diarrhea

    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

  16. Mechanism of microsomal metabolism of benzene to phenol

    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.

  17. Mechanisms of triglyceride metabolism in patients with bile acid diarrhea.

    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.

  18. Mechanism of sulfonylurea herbicide resistance in the broadleaf weed, Kochia scoparia

    Saari, L.L.; Cotterman, J.C.; Primiani, M.M.

    1990-01-01

    Selection of kochia (Kochia scoparia) biotypes resistant to the sulfonylurea herbicide chlorsulfuron has occurred through the continued use of this herbicide in monoculture cereal-growing areas in the United States. The apparent sulfonylurea resistance observed in kochia was confirmed in greenhouse tests. Fresh and dry weight accumulation in the resistance kochia was 2- to >350-fold higher in the presence of four sulfonylurea herbicides as compared to the susceptible biotype. Acetolactate synthase (ALS) activity isolated from sulfonylurea-resistant kochia was less sensitive to inhibition by three classes of ALS-inhibiting herbicides, sulfonylureas, imidazolinones, and sulfonanilides. The decrease in ALS sensitivity to inhibition (as measured by the ratio of resistant I 50 to susceptible I 50 ) was 5- to 28-fold, 2- to 6-fold, and 20-fold for sulfonylurea herbicides, imidazolinone herbicides, and a sulfonanilide herbicide, respectively. No differences were observed in the ALS-specific activities or the rates of [ 14 C]chlorsulfuron uptake, translocation, and metabolism between susceptible and resistant kochia biotypes. The K m values for pyruvate using ALS from susceptible and resistant kochia were 2.13 and 1.74 mM, respectively. Based on these results, the mechanism of sulfonylurea resistance in this kochia biotype is due solely to a less sulfonylurea-sensitive ALS enzyme

  19. [Improving industrial microbial stress resistance by metabolic engineering: a review].

    Fu, Ruiyan; Li, Yin

    2010-09-01

    Metabolic engineering is a technologic platform for industrial strain improvement and aims not only at modifying microbial metabolic fluxes, but also improving the physiological performance of industrial microbes. Microbes will meet multiple stresses in industrial processes. Consequently, elicited gene responses might result in a decrease in overall cell fitness and the efficiency of biotransformation. Thus, it is crucial to develop robust and productive microbial strains that can be integrated into industrial-scale bioprocesses. In this review, we focus on the progress of these novel methods and strategies for engineering stress-tolerance phenotypes referring to rational metabolic engineering and inverse metabolic engineering in recent years. In addition, we also address problems existing in this area and future research needs of microbial physiological functionality engineering.

  20. Mechanisms of antimicrobial resistance among hospital-associated pathogens.

    Khan, Ayesha; Miller, William R; Arias, Cesar A

    2018-04-01

    The introduction of antibiotics revolutionized medicine in the 20th-century permitting the treatment of once incurable infections. Widespread use of antibiotics, however, has led to the development of resistant organisms, particularly in the healthcare setting. Today, the clinician is often faced with pathogens carrying a cadre of resistance determinants that severely limit therapeutic options. The genetic plasticity of microbes allows them to adapt to stressors via genetic mutations, acquisition or sharing of genetic material and modulation of genetic expression leading to resistance to virtually any antimicrobial used in clinical practice. Areas covered: This is a comprehensive review that outlines major mechanisms of resistance in the most common hospital-associated pathogens including bacteria and fungi. Expert commentary: Understanding the genetic and biochemical mechanisms of such antimicrobial adaptation is crucial to tackling the rapid spread of resistance, can expose unconventional therapeutic targets to combat multidrug resistant pathogens and lead to more accurate prediction of antimicrobial susceptibility using rapid molecular diagnostics. Clinicians making treatment decisions based on the molecular basis of resistance may design therapeutic strategies that include de-escalation of broad spectrum antimicrobial usage, more focused therapies or combination therapies. These strategies are likely to improve patient outcomes and decrease the risk of resistance in hospital settings.

  1. The metabolic and temporal basis of muscle hypertrophy in response to resistance exercise.

    Brook, Matthew S; Wilkinson, Daniel J; Smith, Kenneth; Atherton, Philip J

    2016-09-01

    Constituting ∼40% of body mass, skeletal muscle has essential locomotory and metabolic functions. As such, an insight into the control of muscle mass is of great importance for maintaining health and quality-of-life into older age, under conditions of cachectic disease and with rehabilitation. In healthy weight-bearing individuals, muscle mass is maintained by the equilibrium between muscle protein synthesis (MPS) and muscle protein breakdown; when this balance tips in favour of MPS hypertrophy occurs. Despite considerable research into pharmacological/nutraceutical interventions, resistance exercise training (RE-T) remains the most potent stimulator of MPS and hypertrophy (in the majority of individuals). However, the mechanism(s) and time course of hypertrophic responses to RE-T remain poorly understood. We would suggest that available data are very much in favour of the notion that the majority of hypertrophy occurs in the early phases of RE-T (though still controversial to some) and that, for the most part, continued gains are hard to come by. Whilst the mechanisms of muscle hypertrophy represent the culmination of mechanical, auto/paracrine and endocrine events, the measurement of MPS remains a cornerstone for understanding the control of hypertrophy - mainly because it is the underlying driving force behind skeletal muscle hypertrophy. Development of sophisticated isotopic techniques (i.e. deuterium oxide) that lend to longer term insight into the control of hypertrophy by sustained RE-T will be paramount in providing insights into the metabolic and temporal regulation of hypertrophy. Such technologies will have broad application in muscle mass intervention for both athletes and for mitigating disease/age-related cachexia and sarcopenia, alike.

  2. Study on a mechanical snubber with an adjustment mechanism for resisting force

    Ohmata, Kenichiro; Miyanaga, Hiroyuki.

    1991-01-01

    The mechanical snubber is an earthquakeproof device for a piping system under particular circumstances such as high temperature and radioactivity. It restrains the piping system by a strong resisting force during an earthquake. This strong force can cause elastic failure of grooves on a brake disk, where steel balls are placed. In this report, an improved mechanical snubber having an adjustment mechanism for resisting force is proposed in order to obtain a mechanical snubber which has almost the same restraint effect and less resisting force in comparison with a conventional mechanical snubber. The resisting force characteristics and the restraint effect of the improved mechanical snubber applied to a simple beam are discussed both numerically and experimentally. The digital simulations are carried out using the Continuous System Simulation Language (CSSL). (author)

  3. Amino Acid Metabolism and Transport Mechanisms as Potential Antifungal Targets

    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.

  4. Use of mutagenesis, genetic mapping and next generation transcriptomics to investigate insecticide resistance mechanisms.

    Predrag Kalajdzic

    Full Text Available Insecticide resistance is a worldwide problem with major impact on agriculture and human health. Understanding the underlying molecular mechanisms is crucial for the management of the phenomenon; however, this information often comes late with respect to the implementation of efficient counter-measures, particularly in the case of metabolism-based resistance mechanisms. We employed a genome-wide insertional mutagenesis screen to Drosophila melanogaster, using a Minos-based construct, and retrieved a line (MiT[w(-]3R2 resistant to the neonicotinoid insecticide Imidacloprid. Biochemical and bioassay data indicated that resistance was due to increased P450 detoxification. Deep sequencing transcriptomic analysis revealed substantial over- and under-representation of 357 transcripts in the resistant line, including statistically significant changes in mixed function oxidases, peptidases and cuticular proteins. Three P450 genes (Cyp4p2, Cyp6a2 and Cyp6g1 located on the 2R chromosome, are highly up-regulated in mutant flies compared to susceptible Drosophila. One of them (Cyp6g1 has been already described as a major factor for Imidacloprid resistance, which validated the approach. Elevated expression of the Cyp4p2 was not previously documented in Drosophila lines resistant to neonicotinoids. In silico analysis using the Drosophila reference genome failed to detect transcription binding factors or microRNAs associated with the over-expressed Cyp genes. The resistant line did not contain a Minos insertion in its chromosomes, suggesting a hit-and-run event, i.e. an insertion of the transposable element, followed by an excision which caused the mutation. Genetic mapping placed the resistance locus to the right arm of the second chromosome, within a ∼1 Mb region, where the highly up-regulated Cyp6g1 gene is located. The nature of the unknown mutation that causes resistance is discussed on the basis of these results.

  5. Multidrug-Resistant Candida: Epidemiology, Molecular Mechanisms, and Treatment.

    Arendrup, Maiken Cavling; Patterson, Thomas F

    2017-08-15

    Invasive Candida infections remain an important cause of morbidity and mortality, especially in hospitalized and immunocompromised or critically ill patients. A limited number of antifungal agents from only a few drug classes are available to treat patients with these serious infections. Resistance can be either intrinsic or acquired. Resistance mechanisms are not exchanged between Candida; thus, acquired resistance either emerges in response to an antifungal selection pressure in the individual patient or, more rarely, occur due to horizontal transmission of resistant strains between patients. Although multidrug resistance is uncommon, increasing reports of multidrug resistance to the azoles, echinocandins, and polyenes have occurred in several Candida species, most notably Candida glabrata and more recently Candida auris. Drivers are overall antifungal use, subtherapeutic drug levels at sites of infection/colonization, drug sequestration in the biofilm matrix, and, in the setting of outbreaks, suboptimal infection control. Moreover, recent research suggests that DNA mismatch repair gene mutations may facilitate acquisition of resistance mutations in C. glabrata specifically. Diagnosis of antifungal-resistant Candida infections is critical to the successful management of patients with these infections. Reduction of unnecessary use of antifungals via antifungal stewardship is critical to limit multidrug resistance emergence. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

  6. Diversity and evolution of drug resistance mechanisms in Mycobacterium tuberculosis

    Al-Saeedi M

    2017-10-01

    Full Text Available Mashael Al-Saeedi, Sahal Al-Hajoj Department of Infection and Immunity, Mycobacteriology Research Section, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia Abstract: Despite the efficacy of antibiotics to protect humankind against many deadly pathogens, such as Mycobacterium tuberculosis, nothing can prevent the emergence of drug-resistant strains. Several mechanisms facilitate drug resistance in M. tuberculosis including compensatory evolution, epistasis, clonal interference, cell wall integrity, efflux pumps, and target mimicry. In this study, we present recent findings relevant to these mechanisms, which can enable the discovery of new drug targets and subsequent development of novel drugs for treatment of drug-resistant M. tuberculosis. Keywords: Mycobacterium tuberculosis, antibiotic resistance, compensatory evolution, epistasis, efflux pumps, fitness cost

  7. [The mechanisms underlying the therapeutic effects of reflexotherapy and drinking mineral waters in the patients presenting with metabolic syndrome].

    Zhernov, V A; Frolkov, V K; Zubarkina, M M

    Both acupuncture and drinking mineral water can influence the metabolism of carbohydrates and lipids as well as their hormonal regulation, but the possibility of the application of these therapeutic factors for the correction of insulin resistance has not been studied in the patients presenting with metabolic syndrome. The objective of the present study was to evaluate the effects produced by the intake of drinking mineral water and acupuncture on the various parameters characterizing the patients suffering from metabolic syndrome in combination with altered insulin resistance. Ninety patients with this condition included in the study underwent the analysis of their the blood pressure, body mass index, blood glucose and lipid levels, insulin and cortisol secretion. We undertook the analysis of the effects of the single and repeated intakes of Essentuki No 17 mineral water included in the combined treatment of the patients with metabolic syndrome and revealed many common responses of the organism to its therapeutic action. Specifically, the stress-type reactions suggested the initiation of the adaptive processes in the system of hormonal regulation of carbohydrate and lipid metabolism. Simultaneously, the manifestations of insulin resistance became less pronounced indicating that both acupuncture and drinking mineral water suppressed the action of the main pathogenic mechanisms underlying the development of metabolic syndrome. Moreover, it was shown that acupuncture had a stronger hypotensive effect in the combination with the decrease of the overproduction of cortisol whereas the intake of the mineral water had a greater metabolic potential and contributed to the intensification of the basal secretion of glucocorticoids. Both reflexotherapy and drinking mineral water have a well apparent effect on the pathogenetic reactions of the metabolic syndrome and therefore can be used in addition to the standard therapy to activate the non-specific, phylogenetically

  8. Treatment Resistance Mechanisms of Malignant Glioma Tumor Stem Cells

    Schmalz, Philip G.R.; Shen, Michael J.; Park, John K.

    2011-01-01

    Malignant gliomas are highly lethal because of their resistance to conventional treatments. Recent evidence suggests that a minor subpopulation of cells with stem cell properties reside within these tumors. These tumor stem cells are more resistant to radiation and chemotherapies than their counterpart differentiated tumor cells and may underlie the persistence and recurrence of tumors following treatment. The various mechanisms by which tumor stem cells avoid or repair the damaging effects of cancer therapies are discussed

  9. HOMA1-IR and HOMA2-IR indexes in identifying insulin resistance and metabolic syndrome - Brazilian Metabolic Syndrome Study (BRAMS)

    Geloneze, B; Vasques, ACJ; Stabe, CFC; Pareja, JC; Rosado, LEFPD; de Queiroz, EC; Tambascia, MA

    2009-01-01

    Objective: To investigate cut-off values for HOMA1-IR and HOMA2-IR to identify insulin resistance (IR) and metabolic syndrome (MS), and to assess the association of the indexes with components of the MS. Methods: Nondiabetic subjects from the Brazilian Metabolic Syndrome Study were studied (n = 1,203, 18 to 78 years). The cut-off values for IR were determined from the 9011 percentile in the healthy group (n = 297) and, for MS, a ROC curve was generated for the total sample. Results: In the he...

  10. Metabolic activity, urease production, antibiotic resistance and virulence in dual species biofilms of Staphylococcus epidermidis and Staphylococcus aureus

    Vandecandelaere, Ilse; Van Nieuwerburgh, Filip; Deforce, Dieter

    2017-01-01

    In this paper, the metabolic activity in single and dual species biofilms of Staphylococcus epidermidis and Staphylococcus aureus isolates was investigated. Our results demonstrated that there was less metabolic activity in dual species biofilms compared to S. aureus biofilms. However, this was not observed if S. aureus and S. epidermidis were obtained from the same sample. The largest effect on metabolic activity was observed in biofilms of S. aureus Mu50 and S. epidermidis ET-024. A transcriptomic analysis of these dual species biofilms showed that urease genes and genes encoding proteins involved in metabolism were downregulated in comparison to monospecies biofilms. These results were subsequently confirmed by phenotypic assays. As metabolic activity is related to acid production, the pH in dual species biofilms was slightly higher compared to S. aureus Mu50 biofilms. Our results showed that S. epidermidis ET-024 in dual species biofilms inhibits metabolic activity of S. aureus Mu50, leading to less acid production. As a consequence, less urease activity is required to compensate for low pH. Importantly, this effect was biofilm-specific. Also S. aureus Mu50 genes encoding virulence-associated proteins (Spa, SplF and Dps) were upregulated in dual species biofilms compared to monospecies biofilms and using Caenorhabditis elegans infection assays, we demonstrated that more nematodes survived when co-infected with S. epidermidis ET-024 and S. aureus mutants lacking functional spa, splF or dps genes, compared to nematodes infected with S. epidermidis ET-024 and wild- type S. aureus. Finally, S. epidermidis ET-024 genes encoding resistance to oxacillin, erythromycin and tobramycin were upregulated in dual species biofilms and increased resistance was subsequently confirmed. Our data indicate that both species in dual species biofilms of S. epidermidis and S. aureus influence each other’s behavior, but additional studies are required necessary to elucidate the exact

  11. An Evolutionarily Conserved Mechanism for Intrinsic and Transferable Polymyxin Resistance.

    Xu, Yongchang; Wei, Wenhui; Lei, Sheng; Lin, Jingxia; Srinivas, Swaminath; Feng, Youjun

    2018-04-10

    Polymyxins, a family of cationic antimicrobial cyclic peptides, act as a last line of defense against severe infections by Gram-negative pathogens with carbapenem resistance. In addition to the intrinsic resistance to polymyxin E (colistin) conferred by Neisseria eptA , the plasmid-borne mobilized colistin resistance gene mcr-1 has been disseminated globally since the first discovery in Southern China, in late 2015. However, the molecular mechanisms for both intrinsic and transferable resistance to colistin remain largely unknown. Here, we aim to address this gap in the knowledge of these proteins. Structural and functional analyses of EptA and MCR-1 and -2 have defined a conserved 12-residue cavity that is required for the entry of the lipid substrate, phosphatidylethanolamine (PE). The in vitro and in vivo data together have allowed us to visualize the similarities in catalytic activity shared by EptA and MCR-1 and -2. The expression of either EptA or MCR-1 or -2 is shown to remodel the surface of enteric bacteria (e.g., Escherichia coli , Salmonella enterica , Klebsiella pneumoniae , etc.), rendering them resistant to colistin. The parallels in the PE substrate-binding cavities among EptA, MCR-1, and MCR-2 provide a comprehensive understanding of both intrinsic and transferable colistin resistance. Domain swapping between EptA and MCR-1 and -2 reveals that the two domains (transmembrane [TM] region and p hospho e thanol a mine [PEA] transferase) are not functionally exchangeable. Taken together, the results represent a common mechanism for intrinsic and transferable PEA resistance to polymyxin, a last-resort antibiotic against multidrug-resistant pathogens. IMPORTANCE EptA and MCR-1 and -2 remodel the outer membrane, rendering bacteria resistant to colistin, a final resort against carbapenem-resistant pathogens. Structural and functional analyses of EptA and MCR-1 and -2 reveal parallel PE lipid substrate-recognizing cavities, which explains intrinsic and

  12. Pathophysiological mechanisms of death resistance in colorectal carcinoma.

    Huang, Ching-Ying; Yu, Linda Chia-Hui

    2015-11-07

    Colon cancers develop adaptive mechanisms to survive under extreme conditions and display hallmarks of unlimited proliferation and resistance to cell death. The deregulation of cell death is a key factor that contributes to chemoresistance in tumors. In a physiological context, balance between cell proliferation and death, and protection against cell damage are fundamental processes for maintaining gut epithelial homeostasis. The mechanisms underlying anti-death cytoprotection and tumor resistance often bear common pathways, and although distinguishing them would be a challenge, it would also provide an opportunity to develop advanced anti-cancer therapeutics. This review will outline cell death pathways (i.e., apoptosis, necrosis, and necroptosis), and discuss cytoprotective strategies in normal intestinal epithelium and death resistance mechanisms of colon tumor. In colorectal cancers, the intracellular mechanisms of death resistance include the direct alteration of apoptotic and necroptotic machinery and the upstream events modulating death effectors such as tumor suppressor gene inactivation and pro-survival signaling pathways. The autocrine, paracrine and exogenous factors within a tumor microenvironment can also instigate resistance against apoptotic and necroptotic cell death in colon cancers through changes in receptor signaling or transporter uptake. The roles of cyclooxygenase-2/prostaglandin E2, growth factors, glucose, and bacterial lipopolysaccharides in colorectal cancer will be highlighted. Targeting anti-death pathways in the colon cancer tissue might be a promising approach outside of anti-proliferation and anti-angiogenesis strategies for developing novel drugs to treat refractory tumors.

  13. Metabolic syndrome criteria as predictors of insulin resistance, inflammation and mortality in chronic hemodialysis patients.

    Vogt, Barbara Perez; Souza, Priscilla L; Minicucci, Marcos Ferreira; Martin, Luis Cuadrado; Barretti, Pasqual; Caramori, Jacqueline Teixeira

    2014-10-01

    Abstract Background: Chronic kidney disease (CKD) and metabolic syndrome are characterized by overlapping disorders, including glucose intolerance, hypertension, dyslipidemia, and, in some cases, obesity. However, there are no specific criteria for the diagnosis of metabolic syndrome in CKD. Metabolic syndrome can also be associated with increased risk of mortality. Some traditional risk factors may protect dialysis patients from mortality, known as "reverse epidemiology." Metabolic syndrome might undergo reverse epidemiology. The objectives were to detect differences in frequency and metabolic characteristics associated with three sets of diagnostic criteria for metabolic syndrome, to evaluate the accuracy of insulin resistance (IR) and inflammation to identify patients with metabolic syndrome, and to investigate the effects of metabolic syndrome by three sets of diagnostic criteria on mortality in chronic hemodialysis patients. An observational study was conducted. Diagnostic criteria for metabolic syndrome proposed by National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), International Diabetes Federation (IDF), and Harmonizing the Metabolic Syndrome (HMetS) statement were applied to 98 hemodialysis patients. The prevalence of metabolic syndrome was 51%, 66.3%, and 75.3% according to NCEP ATP III, IDF, and HMetS criteria, respectively. Diagnosis of metabolic syndrome by HMetS was simultaneously capable of revealing both inflammation and IR, whereas NCEP ATP III and IDF criteria were only able to identify IR. Mortality risk increased in the presence of metabolic syndrome regardless of the criteria used. The prevalence of metabolic syndrome in hemodialysis varies according to the diagnostic criteria used. IR and inflammation predict metabolic syndrome only when diagnosed by HMetS criteria. HMetS was the diagnostic criteria that can predict the highest risk of mortality.

  14. Association of Serum Ferritin Levels with Metabolic Syndrome and Insulin Resistance.

    Padwal, Meghana K; Murshid, Mohsin; Nirmale, Prachee; Melinkeri, R R

    2015-09-01

    The impact of CVDs and Type II DM is increasing over the last decade. It has been estimated that by 2025 their incidence will double. Ferritin is one of the key proteins regulating iron homeostasis and is a widely available clinical biomarker of iron status. Some studies suggest that prevalence of atherosclerosis and insulin resistance increases significantly with increasing serum ferritin. Metabolic syndrome is known to be associated with increased risk of atherosclerosis as well as insulin resistance. The present study was designed to explore the association of serum ferritin levels with metabolic syndrome and insulin resistance. The present study was prospective, cross sectional. The study protocol was approved by IEC. The study group consisted of 90 participants (50 cases of metabolic syndrome and 40 age and sex matched controls). Diagnosis of metabolic syndrome was done as per NCEP ATP III criteria. Estimation of serum Ferritin and Insulin was done by Chemiluminescence Immunoassay (CLIA) while Glucose by Glucose Oxidase and Peroxidase (GOD-POD) method. Insulin Resistance was calculated by HOMA IR score. Data obtained was statistically analysed by using student t-test. We found statistically significant rise in the levels of serum ferritin (p=syndrome as compared with controls. High serum ferritin levels though within normal range are significantly associated with both metabolic syndrome and insulin resistance.

  15. Macrolide resistance mechanisms in Enterobacteriaceae: Focus on azithromycin.

    Gomes, Cláudia; Martínez-Puchol, Sandra; Palma, Noemí; Horna, Gertrudis; Ruiz-Roldán, Lidia; Pons, Maria J; Ruiz, Joaquim

    2017-02-01

    From its introduction in 1952 onwards, the clinical use of macrolides has been steadily increasing, both in human and veterinary medicine. Although initially designed to the treatment of Gram-positive microorganisms, this antimicrobial family has also been used to treat specific Gram-negative bacteria. Some of them, as azithromycin, are considered in the armamentarium against Enterobacteriaceae infections. However, the facility that this bacterial genus has to gain or develop mechanisms of antibiotic resistance may compromise the future usefulness of these antibiotics to fight against Enterobacteriaceae infections. The present review is focused on the mechanisms of macrolide resistance, currently described in Enterobacteriaceae.

  16. Insulin resistance, metabolic syndrome, and lipids in African women ...

    HDL, and atherogenic index of plasma; log (TG/HDL) were calculated and compared with IR. Metabolic syndrome was sought for using both the WHO and the harmonized joint criteria. Results: The mean age was 44.4 (13.1) years. Hypertension ...

  17. Drug discovery strategies in the field of tumor energy metabolism: Limitations by metabolic flexibility and metabolic resistance to chemotherapy.

    Amoedo, N D; Obre, E; Rossignol, R

    2017-08-01

    The search for new drugs capable of blocking the metabolic vulnerabilities of human tumors has now entered the clinical evaluation stage, but several projects already failed in phase I or phase II. In particular, very promising in vitro studies could not be translated in vivo at preclinical stage and beyond. This was the case for most glycolysis inhibitors that demonstrated systemic toxicity. A more recent example is the inhibition of glutamine catabolism in lung adenocarcinoma that failed in vivo despite a strong addiction of several cancer cell lines to glutamine in vitro. Such contradictory findings raised several questions concerning the optimization of drug discovery strategies in the field of cancer metabolism. For instance, the cell culture models in 2D or 3D might already show strong limitations to mimic the tumor micro- and macro-environment. The microenvironment of tumors is composed of cancer cells of variegated metabolic profiles, supporting local metabolic exchanges and symbiosis, but also of immune cells and stroma that further interact with and reshape cancer cell metabolism. The macroenvironment includes the different tissues of the organism, capable of exchanging signals and fueling the tumor 'a distance'. Moreover, most metabolic targets were identified from their increased expression in tumor transcriptomic studies, or from targeted analyses looking at the metabolic impact of particular oncogenes or tumor suppressors on selected metabolic pathways. Still, very few targets were identified from in vivo analyses of tumor metabolism in patients because such studies are difficult and adequate imaging methods are only currently being developed for that purpose. For instance, perfusion of patients with [ 13 C]-glucose allows deciphering the metabolomics of tumors and opens a new area in the search for effective targets. Metabolic imaging with positron emission tomography and other techniques that do not involve [ 13 C] can also be used to evaluate tumor

  18. Resistance Status and Resistance Mechanisms in a Strain of Aedes aegypti (Diptera: Culicidae) From Puerto Rico.

    Estep, Alden S; Sanscrainte, Neil D; Waits, Christy M; Louton, Jessica E; Becnel, James J

    2017-11-07

    Puerto Rico (PR) has a long history of vector-borne disease and insecticide-resistant Aedes aegypti (L.). Defining contributing mechanisms behind phenotypic resistance is critical for effective vector control intervention. However, previous studies from PR have each focused on only one mechanism of pyrethroid resistance. This study examines the contribution of P450-mediated enzymatic detoxification and sodium channel target site changes to the overall resistance phenotype of Ae. aegypti collected from San Juan, PR, in 2012. Screening of a panel of toxicants found broad resistance relative to the lab susceptible Orlando (ORL1952) strain. We identified significant resistance to representative Type I, Type II, and nonester pyrethroids, a sodium channel blocker, and a sodium channel blocking inhibitor, all of which interact with the sodium channel. Testing of fipronil, a chloride channel agonist, also showed low but significant levels of resistance. In contrast, the PR and ORL1952 strains were equally susceptible to chlorfenapyr, which has been suggested as an alternative public health insecticide. Molecular characterization of the strain indicated that two common sodium channel mutations were fixed in the population. Topical bioassay with piperonyl butoxide (PBO) indicated cytochrome P450-mediated detoxification accounts for approximately half of the resistance profile. Transcript expression screening of cytochrome P450s and glutathione-S-transferases identified the presence of overexpressed transcripts. This study of Puerto Rican Ae. aegypti with significant contributions from both genetic changes and enzymatic detoxification highlights the necessity of monitoring for resistance but also defining the multiple resistance mechanisms to inform effective mosquito control. Published by Oxford University Press on behalf of Entomological Society of America 2017. This work is written by US Government employees and is in the public domain in the US.

  19. Attenuation of insulin-evoked responses in brain networks controlling appetite and reward in insulin resistance: the cerebral basis for impaired control of food intake in metabolic syndrome?

    Anthony, Karen; Reed, Laurence J; Dunn, Joel T; Bingham, Emma; Hopkins, David; Marsden, Paul K; Amiel, Stephanie A

    2006-11-01

    The rising prevalence of obesity and type 2 diabetes is a global challenge. A possible mechanism linking insulin resistance and weight gain would be attenuation of insulin-evoked responses in brain areas relevant to eating in systemic insulin resistance. We measured brain glucose metabolism, using [(18)F]fluorodeoxyglucose positron emission tomography, in seven insulin-sensitive (homeostasis model assessment of insulin resistance [HOMA-IR] = 1.3) and seven insulin-resistant (HOMA-IR = 6.3) men, during suppression of endogenous insulin by somatostatin, with and without an insulin infusion that elevated insulin to 24.6 +/- 5.2 and 23.2 +/- 5.8 mU/l (P = 0.76), concentrations similar to fasting levels of the resistant subjects and approximately threefold above those of the insulin-sensitive subjects. Insulin-evoked change in global cerebral metabolic rate for glucose was reduced in insulin resistance (+7 vs. +17.4%, P = 0.033). Insulin was associated with increased metabolism in ventral striatum and prefrontal cortex and with decreased metabolism in right amygdala/hippocampus and cerebellar vermis (P reward. Diminishing the link be-tween control of food intake and energy balance may contribute to development of obesity in insulin resistance.

  20. Developmental plasticity and epigenetic mechanisms underpinning metabolic and cardiovascular diseases.

    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.

  1. Testing and Modeling of Mechanical Characteristics of Resistance Welding Machines

    Wu, Pei; Zhang, Wenqi; Bay, Niels

    2003-01-01

    for both upper and lower electrode systems. This has laid a foundation for modeling the welding process and selecting the welding parameters considering the machine factors. The method is straightforward and easy to be applied in industry since the whole procedure is based on tests with no requirements......The dynamic mechanical response of resistance welding machine is very important to the weld quality in resistance welding especially in projection welding when collapse or deformation of work piece occurs. It is mainly governed by the mechanical parameters of machine. In this paper, a mathematical...... model for characterizing the dynamic mechanical responses of machine and a special test set-up called breaking test set-up are developed. Based on the model and the test results, the mechanical parameters of machine are determined, including the equivalent mass, damping coefficient, and stiffness...

  2. Cross-resistance of bisultap resistant strain of Nilaparvata lugens and its biochemical mechanism.

    Ling, Shanfeng; Zhang, Runjie

    2011-02-01

    The resistant (R) strain of the planthopper Nilaparvata lugens (Stål) selected for bisultap resistance displayed 7.7-fold resistance to bisultap and also had cross-resistance to nereistoxin (monosultap, thiocyclam, and cartap), chlorpyrifos, dimethoate, and malathion but no cross-resistance to buprofezin, imidacloprid, and fipronil. To find out the biochemical mechanism of resistance to bisultap, biochemical assay was done. The results showed that cytochrome P450 monooxygenases (P450) activity in R strain was 2.71-fold that in susceptible strain (S strain), in which the changed activity for general esterase (EST) was 1.91 and for glutathione S-transferases only 1.32. Piperonyl butoxide (PBO) could significantly inhibit P450 activity (percentage of inhibition [PI]: 37.31%) in the R strain, with ESTs PI = 16.04% by triphenyl phosphate (TPP). The results also demonstrated that diethyl maleate had no synergism with bisultap. However, PBO displayed significant synergism in three different strains, and the synergism increased with resistance (S strain 1.42, Lab strain, 2.24 and R strain, 3.23). TPP also showed synergism for three strains, especially in R strain (synergistic ratio = 2.47). An in vitro biochemical study and in vivo synergistic study indicated that P450 might be play important role in the biochemical mechanism of bisultap resistance and that esterase might be the important factor of bisultap resistance. Acetylcholinesterase (AChE) insensitivity play important role in bisultap resistance. We suggest that buprofezin, imidacloprid, and fipronil could be used in resistance management programs for N. lugens via alternation and rotation with bisultap.

  3. Mechanism of high-temperature resistant water-base mud

    Luo, P

    1981-01-01

    Based on experiments, the causes and laws governing the changes in the performance of water-base mud under high temperature are analyzed, and the requisites and mechanism of treating agents resisting high temperature are discussed. Ways and means are sought for inhibiting, delaying and making use of the effect of high temperature on the performance of mud, while new ideas and systematic views have been expressed on the preparation of treating agents and set-up of a high temperature resistant water-base mud system. High temperature dispersion and high temperature surface inactivation of clay in the mud, as well as their effect and method of utilization are reviewed. Subjects also touched upon include degradation and cross-linking of the high-temperature resistant treating agents, their use and effect. Based on the above, the preparation of a water-base and system capable of resisting 180 to 250/sup 0/C is recommended.

  4. Mechanism of cisplatin resistance in human urothelial carcinoma cells.

    Yu, Hui-Min; Wang, Tsing-Cheng

    2012-05-01

    An isogenic pair of cisplatin-susceptible (NTUB1) and -resistant (NTUB1/P) human urothelial carcinoma cell lines was used to elucidate the mechanism of cisplatin resistance. The significantly lower intracellular platinum (IP) concentration, which resulted from the decreased cisplatin uptake, was found in NTUB1/P cells. The enhancement of IP concentration did not increase the susceptibility of NTUB1/P cells to cisplatin treatment. The reduction of IP concentration as well was unable to enhance the cisplatin-resistance in susceptible NTUB1 cells. This indicated that reduction of IP concentration was not the account for the development of cisplatin resistance here. Instead, the over expression of anti-apoptotic Bcl-2, anti-oxidative heme oxygenase-1 (HO-1) and cell cycle regulator p16INK4 seemed to be more important for the gaining of cisplatin in these human urothelial carcinoma cell. Copyright © 2012 Elsevier Ltd. All rights reserved.

  5. Environmental resistance and mechanical performance of basalt and glass fibers

    Wei Bin; Cao Hailin; Song Shenhua

    2010-01-01

    The treated basalt and glass fibers with sodium hydroxide and hydrochloric acid solutions for different times were analyzed, respectively. This paper summarized the mass loss ratio and the strength maintenance ratios of the fibers after treatment. The fibers' surface corrosion morphologies were characterized using scanning electron microscopy and their compositions were detected using energy dispersive X-ray spectroscopy. The acid resistance was much better than the alkali resistance for the basalt fibers. Nevertheless, for the glass fibers the situation is different: the acid resistance was almost the same as the alkali resistance. Among the two types of aqueous environments evaluated, the alkali solution is the most aggressive to the fibers' surface. The possible corrosion mechanisms are revealed.

  6. Molecular mechanisms of cisplatin resistance in cervical cancer

    Zhu H

    2016-06-01

    Full Text Available Haiyan Zhu, Hui Luo, Wenwen Zhang, Zhaojun Shen, Xiaoli Hu, Xueqiong Zhu Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China Abstract: Patients with advanced or recurrent cervical cancer have poor prognosis, and their 1-year survival is only 10%–20%. Chemotherapy is considered as the standard treatment for patients with advanced or recurrent cervical cancer, and cisplatin appears to treat the disease effectively. However, resistance to cisplatin may develop, thus substantially compromising the efficacy of cisplatin to treat advanced or recurrent cervical cancer. In this article, we systematically review the recent literature and summarize the recent advances in our understanding of the molecular mechanisms underlying cisplatin resistance in cervical cancer. Keywords: cisplatin, epithelial–mesenchymal transition, microRNA, molecular mechanism, resistance

  7. An Evolutionarily Conserved Mechanism for Intrinsic and Transferable Polymyxin Resistance

    Yongchang Xu

    2018-04-01

    Full Text Available Polymyxins, a family of cationic antimicrobial cyclic peptides, act as a last line of defense against severe infections by Gram-negative pathogens with carbapenem resistance. In addition to the intrinsic resistance to polymyxin E (colistin conferred by Neisseria eptA, the plasmid-borne mobilized colistin resistance gene mcr-1 has been disseminated globally since the first discovery in Southern China, in late 2015. However, the molecular mechanisms for both intrinsic and transferable resistance to colistin remain largely unknown. Here, we aim to address this gap in the knowledge of these proteins. Structural and functional analyses of EptA and MCR-1 and -2 have defined a conserved 12-residue cavity that is required for the entry of the lipid substrate, phosphatidylethanolamine (PE. The in vitro and in vivo data together have allowed us to visualize the similarities in catalytic activity shared by EptA and MCR-1 and -2. The expression of either EptA or MCR-1 or -2 is shown to remodel the surface of enteric bacteria (e.g., Escherichia coli, Salmonella enterica, Klebsiella pneumoniae, etc., rendering them resistant to colistin. The parallels in the PE substrate-binding cavities among EptA, MCR-1, and MCR-2 provide a comprehensive understanding of both intrinsic and transferable colistin resistance. Domain swapping between EptA and MCR-1 and -2 reveals that the two domains (transmembrane [TM] region and phosphoethanolamine [PEA] transferase are not functionally exchangeable. Taken together, the results represent a common mechanism for intrinsic and transferable PEA resistance to polymyxin, a last-resort antibiotic against multidrug-resistant pathogens.

  8. The operational mechanism of ferroelectric-driven organic resistive switches

    Kemerink, M.; Asadi, K.; Blom, P.W.M.; Leeuw, D.M. de

    2012-01-01

    The availability of a reliable memory element is crucial for the fabrication of 'plastic' logic circuits. We use numerical simulations to show that the switching mechanism of ferroelectric-driven organic resistive switches is the stray field of the polarized ferroelectric phase. The stray field

  9. The operational mechanism of ferroelectric-driven organic resistive switches

    Kemerink, M.; Asadi, K. (Kamal); Blom, P.W.M.; Leeuw, de D.M.

    2012-01-01

    The availability of a reliable memory element is crucial for the fabrication of ‘plastic’ logic circuits. We use numerical simulations to show that the switching mechanism of ferroelectric-driven organic resistive switches is the stray field of the polarized ferroelectric phase. The stray field

  10. The operational mechanism of ferroelectric-driven organic resistive switches

    Kemerink, Martijn; Asadi, Kamal; Blom, Paul W. M.; de Leeuw, Dago M.

    The availability of a reliable memory element is crucial for the fabrication of 'plastic' logic circuits. We use numerical simulations to show that the switching mechanism of ferroelectric-driven organic resistive switches is the stray field of the polarized ferroelectric phase. The stray field

  11. Neuroendocrinology of insulin resistance : metabolic and endocrine aspects of adiposity

    van Dijk, G; de Vries, K; Benthem, L; Nyakas, C; Buwalda, B; Scheurink, AJW

    2003-01-01

    Abdominal obesity is a major risk factor to attract the insulin resistance syndrome. It is proposed that abdominal obesity exposes the liver to elevated levels of free fatty acids, which activate a neuroendocrine reflex, leading to increased circulating levels of glucocorticoids. Besides directly

  12. Lifestyle-induced metabolic inflexibility and accelerated ageing syndrome: insulin resistance, friend or foe?

    Bell Jimmy D

    2009-04-01

    Full Text Available Abstract The metabolic syndrome may have its origins in thriftiness, insulin resistance and one of the most ancient of all signalling systems, redox. Thriftiness results from an evolutionarily-driven propensity to minimise energy expenditure. This has to be balanced with the need to resist the oxidative stress from cellular signalling and pathogen resistance, giving rise to something we call 'redox-thriftiness'. This is based on the notion that mitochondria may be able to both amplify membrane-derived redox growth signals as well as negatively regulate them, resulting in an increased ATP/ROS ratio. We suggest that 'redox-thriftiness' leads to insulin resistance, which has the effect of both protecting the individual cell from excessive growth/inflammatory stress, while ensuring energy is channelled to the brain, the immune system, and for storage. We also suggest that fine tuning of redox-thriftiness is achieved by hormetic (mild stress signals that stimulate mitochondrial biogenesis and resistance to oxidative stress, which improves metabolic flexibility. However, in a non-hormetic environment with excessive calories, the protective nature of this system may lead to escalating insulin resistance and rising oxidative stress due to metabolic inflexibility and mitochondrial overload. Thus, the mitochondrially-associated resistance to oxidative stress (and metabolic flexibility may determine insulin resistance. Genetically and environmentally determined mitochondrial function may define a 'tipping point' where protective insulin resistance tips over to inflammatory insulin resistance. Many hormetic factors may induce mild mitochondrial stress and biogenesis, including exercise, fasting, temperature extremes, unsaturated fats, polyphenols, alcohol, and even metformin and statins. Without hormesis, a proposed redox-thriftiness tipping point might lead to a feed forward insulin resistance cycle in the presence of excess calories. We therefore suggest

  13. Network analysis of S. aureus response to ramoplanin reveals modules for virulence factors and resistance mechanisms and characteristic novel genes.

    Subramanian, Devika; Natarajan, Jeyakumar

    2015-12-10

    Staphylococcus aureus is a major human pathogen and ramoplanin is an antimicrobial attributed for effective treatment. The goal of this study was to examine the transcriptomic profiles of ramoplanin sensitive and resistant S. aureus to identify putative modules responsible for virulence and resistance-mechanisms and its characteristic novel genes. The dysregulated genes were used to reconstruct protein functional association networks for virulence-factors and resistance-mechanisms individually. Strong link between metabolic-pathways and development of virulence/resistance is suggested. We identified 15 putative modules of virulence factors. Six hypothetical genes were annotated with novel virulence activity among which SACOL0281 was discovered to be an essential virulence factor EsaD. The roles of MazEF toxin-antitoxin system, SACOL0202/SACOL0201 two-component system and that of amino-sugar and nucleotide-sugar metabolism in virulence are also suggested. In addition, 14 putative modules of resistance mechanisms including modules of ribosomal protein-coding genes and metabolic pathways such as biotin-synthesis, TCA-cycle, riboflavin-biosynthesis, peptidoglycan-biosynthesis etc. are also indicated. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Intestinal Microbiota Contributes to Energy Balance, Metabolic Inflammation, and Insulin Resistance in Obesity

    Joseph F. Cavallari

    2017-09-01

    Full Text Available Obesity is associated with increased risk of developing metabolic diseases such as type 2 diabetes. The origins of obesity are multi-factorial, but ultimately rooted in increased host energy accumulation or retention. The gut microbiota has been implicated in control of host energy balance and nutrient extraction from dietary sources. The microbiota also impacts host immune status and dysbiosis-related inflammation can augment insulin resistance, independently of obesity. Advances in microbial metagenomic analyses and directly manipulating bacterial-host models of obesity have contributed to our understanding of the relationship between gut bacteria and metabolic disease. Foodborne, or drug-mediated perturbations to the gut microbiota can increase metabolic inflammation, insulin resistance, and dysglycemia. There is now some evidence that specific bacterial species can influence obesity and related metabolic defects such as insulin sensitivity. Components of bacteria are sufficient to impact obesity-related changes in metabolism. In fact, different microbial components derived from the bacterial cell wall can increase or decrease insulin resistance. Improving our understanding of the how components of the microbiota alter host metabolism is positioned to aid in the development of dietary interventions, avoiding triggers of dysbiosis, and generating novel therapeutic strategies to combat increasing rates of obesity and diabetes.

  15. Brain Insulin Resistance at the Crossroads of Metabolic and Cognitive Disorders in Humans.

    Kullmann, Stephanie; Heni, Martin; Hallschmid, Manfred; Fritsche, Andreas; Preissl, Hubert; Häring, Hans-Ulrich

    2016-10-01

    Ever since the brain was identified as an insulin-sensitive organ, evidence has rapidly accumulated that insulin action in the brain produces multiple behavioral and metabolic effects, influencing eating behavior, peripheral metabolism, and cognition. Disturbances in brain insulin action can be observed in obesity and type 2 diabetes (T2D), as well as in aging and dementia. Decreases in insulin sensitivity of central nervous pathways, i.e., brain insulin resistance, may therefore constitute a joint pathological feature of metabolic and cognitive dysfunctions. Modern neuroimaging methods have provided new means of probing brain insulin action, revealing the influence of insulin on both global and regional brain function. In this review, we highlight recent findings on brain insulin action in humans and its impact on metabolism and cognition. Furthermore, we elaborate on the most prominent factors associated with brain insulin resistance, i.e., obesity, T2D, genes, maternal metabolism, normal aging, inflammation, and dementia, and on their roles regarding causes and consequences of brain insulin resistance. We also describe the beneficial effects of enhanced brain insulin signaling on human eating behavior and cognition and discuss potential applications in the treatment of metabolic and cognitive disorders. Copyright © 2016 the American Physiological Society.

  16. Drug metabolizing enzyme systems and their relationship to toxic mechanisms

    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

  17. Sixteen weeks of resistance training can decrease the risk of metabolic syndrome in healthy postmenopausal women

    Conceição MS

    2013-09-01

    Full Text Available Miguel Soares Conceição,1 Valéria Bonganha,1 Felipe Cassaro Vechin,2 Ricardo Paes de Barros Berton,1 Manoel Emílio Lixandrão,1 Felipe Romano Damas Nogueira,1 Giovana Vergínia de Souza,1 Mara Patricia Traina Chacon-Mikahil,1 Cleiton Augusto Libardi2 1Exercise Physiology Laboratory, School of Physical Education, State University of Campinas, Campinas, 2Laboratory of Neuromuscular Adaptation to Strength Training, School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil Background: The postmenopausal phase has been considered an aggravating factor for developing metabolic syndrome. Notwithstanding, no studies have as yet investigated the effects of resistance training on metabolic syndrome in postmenopausal women. Thus, the purpose of this study was to verify whether resistance training could reduce the risk of metabolic syndrome in postmenopausal women. Methods: Twenty postmenopausal women were randomly assigned to a resistance training protocol (n = 10, 53.40 ± 3.95 years, 64.58 ± 9.22 kg or a control group (n = 10, 53.0 ± 5.7 years, 64.03 ± 5.03 kg. In the resistance training protocol, ten exercises were performed, with 3 × 8–10 maximal repetitions three times per week, and the load was increased every week. Two-way analysis of variance was used to evaluate specific metabolic syndrome Z-score, high density lipoprotein cholesterol, fasting blood glucose, triglycerides, waist circumference, blood pressure, strength, and body composition. The level of statistical significance was set at P < 0.05. Results: The main results demonstrated a significant decrease of metabolic syndrome Z-score when the postmenopausal women performed resistance training (P = 0.0162. Moreover, we observed decreases in fasting blood glucose for the resistance training group (P = 0.001, and also significant improvements in lean body mass (P = 0.042, 2.46%, reduction of body fat percentage (P = 0.001, −6.75% and noticeable increases in

  18. Characterisation of Dynamic Mechanical Properties of Resistance Welding Machines

    Wu, Pei; Zhang, Wenqi; Bay, Niels

    2005-01-01

    characterizing the dynamic mechanical characteristics of resistance welding machines is suggested, and a test set-up is designed determining the basic, independent machine parameters required in the model. The model is verified by performing a series of mechanical tests as well as real projection welds.......The dynamic mechanical properties of a resistance welding machine have significant influence on weld quality, which must be considered when simulating the welding process numerically. However, due to the complexity of the machine structure and the mutual coupling of components of the machine system......, it is very difficult to measure or calculate the basic, independent machine parameters required in a mathematical model of the machine dynamics, and no test method has so far been presented in literature, which can be applied directly in an industrial environment. In this paper, a mathematical model...

  19. Mechanisms of antifungal drug resistance in Candida dubliniensis.

    Coleman, David C

    2010-06-01

    Candida dubliniensis was first described in 1995 and is the most closely related species to the predominant human fungal pathogen Candida albicans. C. dubliniensis is significantly less prevalent and less pathogenic than C. albicans and is primarily associated with infections in HIV-infected individuals and other immunocompromised cohorts. The population structure of C. dubliniensis consists of three well-defined major clades and is significantly less diverse than C. albicans. The majority of C. dubliniensis isolates are susceptible to antifungal drugs commonly used to treat Candida infections. To date only two major patterns of antifungal drug resistance have been identified and the molecular mechanisms of these are very similar to the resistance mechanisms that have been described previously in C. albicans. However, significant differences are evident in the predominant antifungal drug mechanisms employed by C. dubliniensis, differences that reflect its more clonal nature, its lower prevalence and characteristics of its genome, the complete sequence of which has only recently been determined.

  20. Analysis and modeling of resistive switching mechanism oriented to fault tolerance of resistive memory based on memristor

    Huang Da; Wu Jun-Jie; Tang Yu-Hua

    2014-01-01

    With the progress of the semiconductor industry, resistive memories, especially the memristor, have drawn increasing attention. The resistive memory based on memrsitor has not been commercialized mainly because of data error. Currently, there are more studies focused on fault tolerance of resistive memory. This paper studies the resistive switching mechanism which may have time-varying characteristics. Resistive switching mechanism is analyzed and its respective circuit model is established based on the memristor Spice model

  1. Galantamine alleviates inflammation and insulin resistance in patients with metabolic syndrome in a randomized trial.

    Consolim-Colombo, Fernanda M; Sangaleti, Carine T; Costa, Fernando O; Morais, Tercio L; Lopes, Heno F; Motta, Josiane M; Irigoyen, Maria C; Bortoloto, Luiz A; Rochitte, Carlos Eduardo; Harris, Yael Tobi; Satapathy, Sanjaya K; Olofsson, Peder S; Akerman, Meredith; Chavan, Sangeeta S; MacKay, Meggan; Barnaby, Douglas P; Lesser, Martin L; Roth, Jesse; Tracey, Kevin J; Pavlov, Valentin A

    2017-07-20

    Metabolic syndrome (MetS) is an obesity-driven condition of pandemic proportions that increases the risk of type 2 diabetes and cardiovascular disease. Pathophysiological mechanisms are poorly understood, though inflammation has been implicated in MetS pathogenesis. The aim of this study was to assess the effects of galantamine, a centrally acting acetylcholinesterase inhibitor with antiinflammatory properties, on markers of inflammation implicated in insulin resistance and cardiovascular risk, and other metabolic and cardiovascular indices in subjects with MetS. In this randomized, double-blind, placebo-controlled trial, subjects with MetS (30 per group) received oral galantamine 8 mg daily for 4 weeks, followed by 16 mg daily for 8 weeks or placebo. The primary outcome was inflammation assessed through plasma levels of cytokines and adipokines associated with MetS. Secondary endpoints included body weight, fat tissue depots, plasma glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), cholesterol (total, HDL, LDL), triglycerides, BP, heart rate, and heart rate variability (HRV). Galantamine resulted in lower plasma levels of proinflammatory molecules TNF (-2.57 pg/ml [95% CI -4.96 to -0.19]; P = 0.035) and leptin (-12.02 ng/ml [95% CI -17.71 to -6.33]; P < 0.0001), and higher levels of the antiinflammatory molecules adiponectin (2.71 μg/ml [95% CI 1.93 to 3.49]; P < 0.0001) and IL-10 (1.32 pg/ml, [95% CI 0.29 to 2.38]; P = 0.002) as compared with placebo. Galantamine also significantly lowered plasma insulin and HOMA-IR values, and altered HRV. Low-dose galantamine alleviates inflammation and insulin resistance in MetS subjects. These findings support further study of galantamine in MetS therapy. ClinicalTrials.gov, number NCT02283242. Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil, and the NIH.

  2. The effect of insulin resistance on amygdale glucose metabolism alterations in experimental Alzheimer’s disease

    Ya. V. Gorina

    2017-01-01

    Full Text Available Purpose. Glucose metabolism is tightly regulated in the brain. Aberrant glucose metabolism is an important feature of neurodegenerative diseases, as inAlzheimer’s disease. The transport of glucose to the cell membrane is realized through the activity of insulin-regulated aminopeptidase (IRAP which controls transfer of glucose transporter to the plasma membrane. IRAP is considered as one of the key markers of insulin resistance in Alzheimer’s disease. However, the question of the mechanism of the action of the IRAP remains open. The aim of the study was to study the effect of IRAP expression on cells of the neuronal and glial lineage, glucose transporter (GLUT4 expression in the brain amygdala on emotional memory in animals with experimental Alzheimer’s disease.Materials and methods. The study was performed with two experimental models of Alzheimer’s disease in mice. The experimental group was mice of the CD1 line, males aged 4 months (Alzheimer’s disease model with the intra-hippocampal administration of beta-amyloid 1-42 (1 µl bilaterally in the CA1 area. The control group was mice of the CD1 line, males aged 4 months (sham-operated animals with the intrahippocampal administration of Phosphate buffered salin (1 µl bilaterally in the CA1. The genetic model of Alzheimer’s disease is the B6SLJ-Tg line mice (APPSwFlLon, PSEN1*M146L*L286V 6799Vas, males aged 4 months. The control group consisted of C57BL/6xSJL mice, males aged 4 months. Evaluation of emotional memory was carried out using “Fear conditioning” protocol. Expression of molecule-markers of insulin-resistance in the amygdala was studied by immunohistochemistry followed by confocal microscopy.Results. Aberrant associative learning and emotional memory was revealed in animals with an experimental model of Alzheimer’s disease. A decrease (p ≤ 0,05 of IRAP expression on cells of neuronal and glial nature, associated with GLUT4 down-regulation was detected in amygdala of

  3. Dissemination and Mechanism for the MCR-1 Colistin Resistance.

    Rongsui Gao

    2016-11-01

    Full Text Available Polymyxins are the last line of defense against lethal infections caused by multidrug resistant Gram-negative pathogens. Very recently, the use of polymyxins has been greatly challenged by the emergence of the plasmid-borne mobile colistin resistance gene (mcr-1. However, the mechanistic aspects of the MCR-1 colistin resistance are still poorly understood. Here we report the comparative genomics of two new mcr-1-harbouring plasmids isolated from the human gut microbiota, highlighting the diversity in plasmid transfer of the mcr-1 gene. Further genetic dissection delineated that both the trans-membrane region and a substrate-binding motif are required for the MCR-1-mediated colistin resistance. The soluble form of the membrane protein MCR-1 was successfully prepared and verified. Phylogenetic analyses revealed that MCR-1 is highly homologous to its counterpart PEA lipid A transferase in Paenibacili, a known producer of polymyxins. The fact that the plasmid-borne MCR-1 is placed in a subclade neighboring the chromosome-encoded colistin-resistant Neisseria LptA (EptA potentially implies parallel evolutionary paths for the two genes. In conclusion, our finding provids a first glimpse of mechanism for the MCR-1-mediated colistin resistance.

  4. Molecular mechanisms of cisplatin resistance in cervical cancer.

    Zhu, Haiyan; Luo, Hui; Zhang, Wenwen; Shen, Zhaojun; Hu, Xiaoli; Zhu, Xueqiong

    2016-01-01

    Patients with advanced or recurrent cervical cancer have poor prognosis, and their 1-year survival is only 10%-20%. Chemotherapy is considered as the standard treatment for patients with advanced or recurrent cervical cancer, and cisplatin appears to treat the disease effectively. However, resistance to cisplatin may develop, thus substantially compromising the efficacy of cisplatin to treat advanced or recurrent cervical cancer. In this article, we systematically review the recent literature and summarize the recent advances in our understanding of the molecular mechanisms underlying cisplatin resistance in cervical cancer.

  5. Oxidative stress and metabolic syndrome: Effects of a natural antioxidants enriched diet on insulin resistance.

    Mancini, Antonio; Martorana, Giuseppe Ettore; Magini, Marinella; Festa, Roberto; Raimondo, Sebastiano; Silvestrini, Andrea; Nicolotti, Nicola; Mordente, Alvaro; Mele, Maria Cristina; Miggiano, Giacinto Abele Donato; Meucci, Elisabetta

    2015-04-01

    Oxidative stress (OS) could play a role in metabolic syndrome-related manifestations contributing to insulin resistance (IR). The aim of the present study was to gain insight the relationships between OS, IR and other hormones involved in caloric balance, explaining the effects of a natural antioxidant-enriched diet in patients affected by metabolic syndrome. We investigated the effects of dietary antioxidants on IR, studying 53 obese (20 males and 33 females, 18-66 years old, BMI 36.3 ± 5.5 kg/m 2 ), with IR evaluated by Homeostasis Model Assessment (HOMA)-index, comparing 4 treatments: hypocaloric diet alone (group A) or plus metformin 1000 mg/daily (group B), natural antioxidants-enriched hypocaloric diet alone (group C) or plus metformin (group D). A personalized program, with calculated antioxidant intake of 800-1000 mg/daily, from fruit and vegetables, was administered to group C and D. The glycemic and insulinemic response to oral glucose load, and concentrations of total-, LDL- and HDL-cholesterol, triglycerides, uric acid, C reactive protein, fT3, fT4, TSH, insulin-like growth factor 1 were evaluated before and after 3-months. Plasma Total antioxidant capacity was determined by H 2 O 2 -metmyoglobin system, which interacting with the chromogen ABTS generates a radical with latency time (LAG) proportional to antioxidant content. Despite a similar BMI decrease, we found a significant decrease of HOMA and insulin peak only in group B and D. Insulin response (AUC) showed the greatest decrease in group D (25.60  ±  8.96%) and was significantly lower in group D vs B. No differences were observed in glucose response, lipid metabolism and TAC (expressed as LAG values). TSH values were significantly suppressed in group D vs B. These data suggest that dietary antioxidants ameliorate insulin-sensitivity in obese subjects with IR by enhancing the effect of insulin-sensitizing drugs albeit with molecular mechanisms which remain yet to be elucidated

  6. Reduced expression of nuclear-encoded genes involved in mitochondrial oxidative metabolism in skeletal muscle of insulin-resistant women with polycystic ovary syndrome

    Skov, Vibe; Glintborg, Dorte; Knudsen, Steen

    2007-01-01

    Insulin resistance in skeletal muscle is a major risk factor for the development of type 2 diabetes in women with polycystic ovary syndrome (PCOS). In patients with type 2 diabetes, insulin resistance in skeletal muscle is associated with abnormalities in insulin signaling, fatty acid metabolism......, and mitochondrial oxidative phosphorylation (OXPHOS). In PCOS patients, the molecular mechanisms of insulin resistance are, however, less well characterized. To identify biological pathways of importance for the pathogenesis of insulin resistance in PCOS, we compared gene expression in skeletal muscle...... of metabolically characterized PCOS patients (n = 16) and healthy control subjects (n = 13) using two different approaches for global pathway analysis: gene set enrichment analysis (GSEA 1.0) and gene map annotator and pathway profiler (GenMAPP 2.0). We demonstrate that impaired insulin-stimulated total, oxidative...

  7. Insulin resistance for glucose metabolism in disused soleus muscle of mice

    Seider, M. J.; Nicholson, W. F.; Booth, F. W.

    1981-01-01

    Results of this study on mice provide the first direct evidence of insulin resistance for glucose metabolism in skeletal muscle that has undergone a previous period of reduced muscle usage. This lack of responsiveness to insulin developed in one day and in the presence of hypoinsulinemia. Future studies will utilize the model of hindlimb immobilization to determine the causes of these changes.

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

    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.

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

    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.

  10. [Molecular characterization of resistance mechanisms: methicillin resistance Staphylococcus aureus, extended spectrum β-lactamases and carbapenemases].

    Oteo, Jesús; Belén Aracil, María

    2015-07-01

    Multi-drug resistance in bacterial pathogens increases morbidity and mortality in infected patients and it is a threat to public health concern by their high capacity to spread. For both reasons, the rapid detection of multi-drug resistant bacteria is critical. Standard microbiological procedures require 48-72 h to provide the antimicrobial susceptibility results, thus there is emerging interest in the development of rapid detection techniques. In recent years, the use of selective and differential culture-based methods has widely spread. However, the capacity for detecting antibiotic resistance genes and their low turnaround times has made molecular methods a reference for diagnosis of multidrug resistance. This review focusses on the molecular methods for detecting some mechanisms of antibiotic resistance with a high clinical and epidemiological impact: a) Enzymatic resistance to broad spectrum β-lactam antibiotics in Enterobacteriaceae, mainly extended spectrum β-lactamases (ESBL) and carbapenemases; and b) methicillin resistance in Staphylococcus aureus. Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

  11. Targeting Metabolic Symbiosis to Overcome Resistance to Anti-angiogenic Therapy

    Laura Pisarsky

    2016-05-01

    Full Text Available Despite the approval of several anti-angiogenic therapies, clinical results remain unsatisfactory, and transient benefits are followed by rapid tumor recurrence. Here, we demonstrate potent anti-angiogenic efficacy of the multi-kinase inhibitors nintedanib and sunitinib in a mouse model of breast cancer. However, after an initial regression, tumors resume growth in the absence of active tumor angiogenesis. Gene expression profiling of tumor cells reveals metabolic reprogramming toward anaerobic glycolysis. Indeed, combinatorial treatment with a glycolysis inhibitor (3PO efficiently inhibits tumor growth. Moreover, tumors establish metabolic symbiosis, illustrated by the differential expression of MCT1 and MCT4, monocarboxylate transporters active in lactate exchange in glycolytic tumors. Accordingly, genetic ablation of MCT4 expression overcomes adaptive resistance against anti-angiogenic therapy. Hence, targeting metabolic symbiosis may be an attractive avenue to avoid resistance development to anti-angiogenic therapy in patients.

  12. Metabolic mechanisms behind the type 2 diabetes susceptible phenotype in low birth weight individuals

    Ribel-Madsen, Amalie

    Background and aims: Low birth weight (LBW) individuals have an increased risk of developing insulin resistance and type 2 diabetes compared with normal birth weight (NBW) individuals. Accordingly, young, healthy, LBW men of the study population examined in the present plasma metabolome studies...... show impaired hepatic insulin sensitivity and, in contrast to NBW men, develop impaired peripheral insulin sensitivity in response to a 5-day high-fat overfeeding. However, the metabolic mechanisms behind the type 2 diabetes susceptible phenotype in LBW individuals are not clear. Our primary aim...... available for lipogenesis, including the synthesis of lipotoxic lipids such as ceramides and diacylglycerols that impair insulin signalling. In the second study, we demonstrated that LBW men had higher plasma alanine, proline, methionine, citrulline, and total amino acid levels after the HFHC diet compared...

  13. Molecular characterization of insulin resistance and glycolytic metabolism in the rat uterus

    Zhang, Yuehui; Sun, Xue; Sun, Xiaoyan; Meng, Fanci; Hu, Min; Li, Xin; Li, Wei; Wu, Xiao-Ke; Brännström, Mats; Shao, Ruijin; Billig, Håkan

    2016-01-01

    Peripheral insulin resistance and hyperandrogenism are the primary features of polycystic ovary syndrome (PCOS). However, how insulin resistance and hyperandrogenism affect uterine function and contribute to the pathogenesis of PCOS are open questions. We treated rats with insulin alone or in combination with human chorionic gonadotropin (hCG) and showed that peripheral insulin resistance and hyperandrogenism alter uterine morphology, cell phenotype, and cell function, especially in glandular epithelial cells. These defects are associated with an aberration in the PI3K/Akt signaling pathway that is used as an indicator for the onset of insulin resistance in classical metabolic tissues. Concomitantly, increased GSK3β (Ser-9) phosphorylation and decreased ERK1/2 phosphorylation in rats treated with insulin and hCG were also observed. We also profiled the expression of glucose transporter (Glut) isoform genes in the uterus under conditions of insulin resistance and/or hyperandrogenism. Finally, we determined the expression pattern of glycolytic enzymes and intermediates during insulin resistance and hyperandrogenism in the uterus. These findings suggest that the PI3K/Akt and MAPK/ERK signaling pathways play a role in the onset of uterine insulin resistance, and they also suggest that changes in specific Glut isoform expression and alterations to glycolytic metabolism contribute to the endometrial dysfunction observed in PCOS patients. PMID:27461373

  14. The Effect of a Resistance Training Course on Some Cardiovascular Risk Factors in Females with Metabolic Syndrome

    M Salesi

    2016-07-01

    Full Text Available Introduction: Metabolic syndrome is considered as a risk factor for many chronic diseases such as type 2 diabetes and cardiovascular diseases. The syndrome is caused by such factors as poor nutrition, sedentary lifestyle, and genetic predisposition, while higher muscle strength levels are associated with a lower metabolic syndrome. Therefore, the present study aimed to evaluate the response of some cardiovascular risk factors in females with metabolic syndrome after 10 weeks of resistance training (RT. Methods: In this study, 26 postmenopausal sedentary women without any diseases participated, who were selected via voluntary purposive sampling and randomly divided into two experimental and control groups. The subjects participated in anthropometric tests, including height, waist and hip ratios, weight, subcutaneous fat and blood sampling. The experimental group performed the RT for 3sessions in 10weeks with 40 to 50 percent of maximum repetition. Results: The study results suggested that after 10 weeks of RT in the experimental group, weight (p<0.001, total cholesterol (p<0.03 and triglyceride (p<0.001 indices were significantly decreased in comparison with those of the control group. BMI, waist ratio, fat percentage, systolic blood pressure and HDL significantly changed between pre and post-test of the experimental group, though these changes were not reported to be significant between the experimental and control groups. Conclusion: The findings of the present study revealed that a regular resistance training program could improve the cardiovascular risk factor in females with metabolic syndrome. However, the effective mechanisms in improving metabolic syndrome symptoms subsequent to exercise are not clearly recognized yet.

  15. Metabolic Syndrome Is Associated with Atrial Electrical and Mechanical Dysfunction

    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

  16. Early metabolic effects and mechanism of ammonium transport in yeast

    Pena, A.; Pardo, J.P.; Ramirez, J.

    1987-01-01

    Studies were performed to define the effects and mechanism of NH+4 transport in yeast. The following results were obtained. Glucose was a better facilitator than ethanol-H 2 O 2 for ammonium transport; low concentrations of uncouplers or respiratory inhibitors could inhibit the transport with ethanol as the substrate. With glucose, respiratory inhibitors showed only small inhibitory effects, and only high concentrations of azide or trifluoromethoxy carbonylcyanide phenylhydrazone could inhibit ammonium transport. Ammonium in the free state could be concentrated approximately 200-fold by the cells. Also, the addition of ammonium produced stimulation of both respiration and fermentation; an increased rate of H+ extrusion and an alkalinization of the interior of the cell; a decrease of the membrane potential, as monitored by fluorescent cyanine; an immediate decrease of the levels of ATP and an increase of ADP, which may account for the stimulation of both fermentation and respiration; and an increase of the levels of inorganic phosphate. Ammonium was found to inhibit 86Rb+ transport much less than K+. Also, while K+ produced a competitive type of inhibition, that produced by NH4+ was of the noncompetitive type. From the distribution ratio of ammonium and the pH gradient, an electrochemical potential gradient of around -180 mV was calculated. The results indicate that ammonium is transported in yeast by a mechanism similar to that of monovalent alkaline cations, driven by a membrane potential. The immediate metabolic effects of this cation seem to be due to an increased [H+]ATPase, to which its transport is coupled. However, the carriers seem to be different. The transport system studied in this work was that of low affinity

  17. Use and Misuse of Antimicrobial Drugs in Poultry and Livestock: Mechanisms of Antimicrobial Resistance

    Toni Poole* and Cynthia Sheffield

    2013-07-01

    Full Text Available Food safety begins on the farm with management practices that contribute to an abundant, safe, and affordable food supply. To attain this goal antimicrobials have been used in all stages of food animal production in the United States and elsewhere around the world at one time or another. Among food–production animals antimicrobials are used for growth promotion, disease prophylaxis or disease treatment, and are generally administered to the entire flock or herd. Over many decades bacteria have become resistant to multiple antimicrobial classes in a cumulative manner. Bacteria exhibit a number of well characterized mechanisms of resistance to antimicrobials that include: 1 modification of the antimicrobial; 2 alteration of the drug target; 3 decreased access of drug to target; and 4 implementation of an alternative metabolic pathway not affected by the drug. The mechanisms of resistance are complex and depend on the type of bacterium involved (e.g. Gram–positive or Gram–negative and the class of drug. Some bacterial species have accumulated resistance to nearly all antimicrobial classes due to a combination of intrinsic and acquired processes. This has and will continue to lead to clinical failures of antimicrobial treatment in both human and animal medicine.

  18. Mechanical And Microstructural Evaluation Of A Wear Resistant Steel

    Santos, F.L.F. dos; Vieira, A.G.; Correa, E.C.S.; Pinheiro, I.P.

    2010-01-01

    In the present work, the analysis of the mechanical properties and the microstructural features of a high strength low alloy steel, containing chromium, molybdenum and boron, subjected to different heat treatments, was conducted. After austenitizing at 910 deg C for 10 minutes, three operations were carried out: oil quenching, oil quenching followed by tempering at 200 deg C for 120 minutes and austempering at 400 deg C for 5 minutes followed by water cooling. The analysis was performed through tensile and hardness tests, optical microscopy and X-ray diffraction. The bainitic structure led to high strength and toughness, both essential mechanical properties for wear resistant steels. The occurrence of allotriomorphic ferrite and retained austenite in the samples also increased the wear resistance. This phenomenon is related to the fact that both structures are able to be deformed and, in the case of the retained austenite, the transformation induced plasticity TRIP effect may take place as the material is used. (author)

  19. Mechanisms of resistance to HER family targeting antibodies

    Kruser, Tim J. [Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI (United States); Wheeler, Deric L., E-mail: dlwheeler@wisc.edu [Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI (United States)

    2010-04-15

    The epidermal growth factor (EGF) family of receptor tyrosine kinases consists of four members: EGFR (HER1/ErbB1), HER2/neu (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). Receptor activation via ligand binding leads to downstream signaling that influence cell proliferation, angiogenesis, invasion and metastasis. Aberrant expression or activity of EGFR and HER2 have been strongly linked to the etiology of several human epithelial cancers including but not limited to head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and breast cancer. With this, intense efforts have been made to inhibit the activity of the EGFR and HER2 by designing antibodies against the ligand binding domains (cetuximab, panitumumab and trastuzumab) or small molecules against the tyrosine kinase domains (erlotinib, gefitinib, and lapatinib). Both approaches have shown considerable clinical promise. However, increasing evidence suggests that the majority of patients do not respond to these therapies, and those who show initial response ultimately become refractory to treatment. While mechanisms of resistance to tyrosine kinase inhibitors have been extensively studied, resistance to monoclonal antibodies is less well understood, both in the laboratory and in the clinical setting. In this review, we discuss resistance to antibody-based therapies against the EGFR and HER2, similarities between these resistance profiles, and strategies to overcome resistance to HER family targeting monoclonal antibody therapy.

  20. The sites and mechanisms of postoperative insulin resistance

    Nygren, Jonas

    1997-01-01

    The Sites and Mechanisms of Postoperative InsulinResistance by Jonas Nygren, M.D. Departments of Surgery and Endocrinology and Diabetes, Karolinska Hospital and Institute, SE-171 76, Stockholm, Sweden In Sweden with nine million inhabitants, 450,000 operations(outpatients excluded) are performed every year resulting in2,250,000 treatment days in hospital. Surgical operations are part ofthe treatment for 44% of all patients admitted to hospital careoccupying 24% of all ...

  1. Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat.

    Smith, S J; Cases, S; Jensen, D R; Chen, H C; Sande, E; Tow, B; Sanan, D A; Raber, J; Eckel, R H; Farese, R V

    2000-05-01

    Triglycerides (or triacylglycerols) represent the major form of stored energy in eukaryotes. Triglyceride synthesis has been assumed to occur primarily through acyl CoA:diacylglycerol transferase (Dgat), a microsomal enzyme that catalyses the final and only committed step in the glycerol phosphate pathway. Therefore, Dgat has been considered necessary for adipose tissue formation and essential for survival. Here we show that Dgat-deficient (Dgat-/-) mice are viable and can still synthesize triglycerides. Moreover, these mice are lean and resistant to diet-induced obesity. The obesity resistance involves increased energy expenditure and increased activity. Dgat deficiency also alters triglyceride metabolism in other tissues, including the mammary gland, where lactation is defective in Dgat-/- females. Our findings indicate that multiple mechanisms exist for triglyceride synthesis and suggest that the selective inhibition of Dgat-mediated triglyceride synthesis may be useful for treating obesity.

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

    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.

  3. Ciprofloxacin-resistant Escherichia coli in Central Greece: mechanisms of resistance and molecular identification

    Mavroidi Angeliki

    2012-12-01

    Full Text Available Abstract Background Fluoroquinolone resistant E. coli isolates, that are also resistant to other classes of antibiotics, is a significant challenge to antibiotic treatment and infection control policies. In Central Greece a significant increase of ciprofloxacin-resistant Escherichia coli has occurred during 2011, indicating the need for further analysis. Methods A total of 106 ciprofloxacin-resistant out of 505 E. coli isolates consecutively collected during an eight months period in a tertiary Greek hospital of Central Greece were studied. Antimicrobial susceptibility patterns and mechanisms of resistance to quinolones were assessed, whereas selected isolates were further characterized by multilocus sequence typing and β-lactamase content. Results Sequence analysis of the quinolone-resistance determining region of the gyrA and parC genes has revealed that 63% of the ciprofloxacin-resistant E. coli harbored a distinct amino acid substitution pattern (GyrA:S83L + D87N; ParC:S80I + E84V, while 34% and 3% carried the patterns GyrA:S83L + D87N; ParC:S80I and GyrA:S83L + D87N; ParC:S80I + E84G respectively. The aac (6’-1b-cr plasmid-mediated quinolone resistance determinant was also detected; none of the isolates was found to carry the qnrA, qnrB and qnrS. Genotyping of a subset of 35 selected ciprofloxacin-resistant E. coli by multilocus sequence typing has revealed the presence of nine sequence types; ST131 and ST410 were the most prevalent and were exclusively correlated with hospital and health care associated infections, while strains belonging to STs 393, 361 and 162 were associated with community acquired infections. The GyrA:S83L + D87N; ParC:S80I + E84V substitution pattern was found exclusively among ST131 ciprofloxacin-resistant E. coli. Extended-spectrum β-lactamase-positive ST131 ciprofloxacin-resistant isolates produced CTX-M-type enzymes; eight the CTX-M-15 and one the CTX-M-3 variant. CTX-M-1 like and KPC-2 enzymes were detected

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

    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.

  5. Central and Peripheral Mechanisms of Antipsychotic Medication Induced Metabolic Dysregulation

    2016-10-01

    effects characterized by substantial weight gain, glucose intolerance, insulin resistance , hypertension and dyslipidemia as well as increased risks for...sufficiently powered to resolve potential effects of D2R absence on APDs’ effects on glucose tolerance, insulin resistance , glucose stimulated insulin ...Zachary Freyberg, to optimize the dietary conditions responsible for inducing the development of insulin resistance . Initial studies with standard 60

  6. Insulin resistance and its association with the components of the metabolic syndrome among obese children and adolescents

    Mass-Díaz Eliezer; Madrigal-Azcárate Adrián; Medina-Bravo Patricia; Klünder-Klünder Miguel; Juárez-López Carlos; Flores-Huerta Samuel

    2010-01-01

    Abstract Background Insulin resistance is the primary metabolic disorder associated with obesity; yet little is known about its role as a determinant of the metabolic syndrome in obese children. The aim of this study is to assess the association between the degree of insulin resistance and the different components of the metabolic syndrome among obese children and adolescents. Methods An analytical, cross-sectional and population-based study was performed in forty-four public primary schools ...

  7. Resistant mechanisms and molecular epidemiology of imipenem-resistant Acinetobacter baumannii.

    Xiao, Shu-Zhen; Chu, Hai-Qing; Han, Li-Zhong; Zhang, Zhe-Min; Li, Bing; Zhao, Lan; Xu, Liyun

    2016-09-01

    The aim of the study was to investigate the resistant mechanisms and homology of imipenem-resistant Acinetobacter baumannii (A. baumannii). A total of 46 non-duplicate imipenem‑resistant A. baumannii clinical isolates were collected from three tertiary hospitals between July, 2011 and June, 2012. The minimal inhibitory concentrations (MICs) of antimicrobial agents were determined using the agar dilution method. Phenylalanine‑arginine β-naphthylamide was used to detect the presence of the efflux pump-mediated resistant mechanism. Polymerase chain reaction was employed to amplify genes associated with drug resistance, including β‑lactamase genes, efflux pump genes and outer membrane protein gene CarO. A few amplicons were randomly selected and sequenced. Multilocus sequence analysis (MLST) was employed in typing A. baumanni. A. baumannii was resistant to imipenem, simultaneously showing resistance to several other antimicrobials. In addtition, 13 A. baumannii were found to mediate drug resistance through operation of the efflux pump. Of the various drug resistance genes tested, blaOXA‑51 was present in 46 isolates, blaOXA‑23 gene was present in 44 isolates and blaNDM gene was found in only one strain. Other drug resistant‑associated genes, including blaKPC, blaIMP, blaOXA-24, blaOXA‑58, blaSHV, blaGIM and blaVIM were not detected. Mutation of adeS and outer membrane protein gene CarO were found in a few of the imipenem‑resistant isolates. The MLST analysis revealed that all 46 clinical isolates were clustered into 11 genotypes and the most frequent genotype was ST208. In conclusion, β‑lactamase genes, genes involved in efflux pump and mutation of outer membrane protein encoding gene may be important in mediating imipenem resistance in A. baumannii. Of the 11 different genotypes, ST11 was shared by the majority of A. baumannii, which may be due to horizontal transfer of patients from hospitals.

  8. Evidence of Insulin Resistance and Other Metabolic Alterations in Boys with Duchenne or Becker Muscular Dystrophy

    Maricela Rodríguez-Cruz

    2015-01-01

    Full Text Available Aim. Our aim was (1 to determine the frequency of insulin resistance (IR in patients with Duchenne/Becker muscular dystrophy (DMD/BMD, (2 to identify deleted exons of DMD gene associated with obesity and IR, and (3 to explore some likely molecular mechanisms leading to IR. Materials and Methods. In 66 patients with DMD/BMD without corticosteroids treatment, IR, obesity, and body fat mass were evaluated. Molecules involved in glucose metabolism were analyzed in muscle biopsies. Results show that 18.3%, 22.7%, and 68% were underweight, overweight, or obese, and with high adiposity, respectively; 48.5% and 36.4% presented hyperinsulinemia and IR, respectively. Underweight patients (27.3% exhibited hyperinsulinemia and IR. Carriers of deletions in exons 45 (OR = 9.32; 95% CI = 1.16–74.69 and 50 (OR = 8.73; 95% CI = 1.17–65.10 from DMD gene presented higher risk for IR than noncarriers. We observed a greater staining of cytoplasmic aggregates for GLUT4 in muscle biopsies than healthy muscle tissue. Conclusion. Obesity, hyperinsulinemia, and IR were observed in DMD/BMD patients and are independent of corticosteroids treatment. Carriers of deletion in exons 45 or 50 from DMD gene are at risk for developing IR. It is suggested that alteration in GLUT4 in muscle fibers from DMD patients could be involved in IR.

  9. Embryo mechanics: balancing force production with elastic resistance during morphogenesis.

    Davidson, Lance A

    2011-01-01

    Morphogenesis requires the spatial and temporal control of embryo mechanics, including force production and mechanical resistance to those forces, to coordinate tissue deformation and large-scale movements. Thus, biomechanical processes play a key role in directly shaping the embryo. Additional roles for embryo mechanics during development may include the patterning of positional information and to provide feedback to ensure the success of morphogenetic movements in shaping the larval body and organs. To understand the multiple roles of mechanics during development requires familiarity with engineering principles of the mechanics of structures, the viscoelastic properties of biomaterials, and the integration of force and stress within embryonic structures as morphogenesis progresses. In this chapter, we review the basic engineering principles of biomechanics as they relate to morphogenesis, introduce methods for quantifying embryo mechanics and the limitations of these methods, and outline a formalism for investigating the role of embryo mechanics in birth defects. We encourage the nascent field of embryo mechanics to adopt standard engineering terms and test methods so that studies of diverse organisms can be compared and universal biomechanical principles can be revealed. Copyright © 2011 Elsevier Inc. All rights reserved.

  10. Protein metabolism in marine animals: the underlying mechanism of growth.

    Fraser, Keiron P P; Rogers, Alex D

    2007-01-01

    Growth is a fundamental process within all marine organisms. In soft tissues, growth is primarily achieved by the synthesis and retention of proteins as protein growth. The protein pool (all the protein within the organism) is highly dynamic, with proteins constantly entering the pool via protein synthesis or being removed from the pool via protein degradation. Any net change in the size of the protein pool, positive or negative, is termed protein growth. The three inter-related processes of protein synthesis, degradation and growth are together termed protein metabolism. Measurement of protein metabolism is vital in helping us understand how biotic and abiotic factors affect growth and growth efficiency in marine animals. Recently, the developing fields of transcriptomics and proteomics have started to offer us a means of greatly increasing our knowledge of the underlying molecular control of protein metabolism. Transcriptomics may also allow us to detect subtle changes in gene expression associated with protein synthesis and degradation, which cannot be detected using classical methods. A large literature exists on protein metabolism in animals; however, this chapter concentrates on what we know of marine ectotherms; data from non-marine ectotherms and endotherms are only discussed when the data are of particular relevance. We first consider the techniques available to measure protein metabolism, their problems and what validation is required. Protein metabolism in marine organisms is highly sensitive to a wide variety of factors, including temperature, pollution, seasonality, nutrition, developmental stage, genetics, sexual maturation and moulting. We examine how these abiotic and biotic factors affect protein metabolism at the level of whole-animal (adult and larval), tissue and cellular protein metabolism. Available gene expression data, which help us understand the underlying control of protein metabolism, are also discussed. As protein metabolism appears to

  11. Neratinib resistance and cross-resistance to other HER2-targeted drugs due to increased activity of metabolism enzyme cytochrome P4503A4

    Breslin, Susan; Lowry, Michelle C; O'Driscoll, Lorraine

    2017-01-01

    Background: Neratinib is in Phase 3 clinical trials but, unfortunately, the development of resistance is inevitable. Here, we investigated the effects of acquired neratinib resistance on cellular phenotype and the potential mechanism of this resistance. Methods: Neratinib-resistant variants of HER2-positive breast cancer cells were developed and their cross-resistance investigated using cytotoxicity assays. Similarly, sensitivity of trastuzumab-resistant and lapatinib-resistant cells to nerat...

  12. Insulin resistance and its association with the components of the metabolic syndrome among obese children and adolescents.

    Juárez-López, Carlos; Klünder-Klünder, Miguel; Medina-Bravo, Patricia; Madrigal-Azcárate, Adrián; Mass-Díaz, Eliezer; Flores-Huerta, Samuel

    2010-06-07

    Insulin resistance is the primary metabolic disorder associated with obesity; yet little is known about its role as a determinant of the metabolic syndrome in obese children. The aim of this study is to assess the association between the degree of insulin resistance and the different components of the metabolic syndrome among obese children and adolescents. An analytical, cross-sectional and population-based study was performed in forty-four public primary schools in Campeche City, Mexico. A total of 466 obese children and adolescents between 11-13 years of age were recruited. Fasting glucose and insulin concentrations, high density lipoprotein cholesterol, triglycerides, waist circumference, systolic and diastolic blood pressures were measured; insulin resistance and metabolic syndrome were also evaluated. Out of the total population studied, 69% presented low values of high density lipoprotein cholesterol, 49% suffered from abdominal obesity, 29% had hypertriglyceridemia, 8% presented high systolic and 13% high diastolic blood pressure, 4% showed impaired fasting glucose, 51% presented insulin resistance and 20% metabolic syndrome. In spite of being obese, 13% of the investigated population did not present any metabolic disorder. For each one of the components of the metabolic syndrome, when insulin resistance increased so did odds ratios as cardiometabolic risk factors. Regardless of age and gender an increased degree of insulin resistance is associated with a higher prevalence of disorders in each of the components of the metabolic syndrome and with a heightened risk of suffering metabolic syndrome among obese children and adolescents.

  13. Antimicrobial Resistance of Hypervirulent Klebsiella pneumoniae: Epidemiology, Hypervirulence-Associated Determinants, and Resistance Mechanisms

    Chang-Ro Lee

    2017-11-01

    Full Text Available Klebsiella pneumoniae is one of the most clinically relevant species in immunocompromised individuals responsible for community-acquired and nosocomial infections, including pneumonias, urinary tract infections, bacteremias, and liver abscesses. Since the mid-1980s, hypervirulent K. pneumoniae, generally associated with the hypermucoviscosity phenotype, has emerged as a clinically significant pathogen responsible for serious disseminated infections, such as pyogenic liver abscesses, osteomyelitis, and endophthalmitis, in a generally younger and healthier population. Hypervirulent K. pneumoniae infections were primarily found in East Asia and now are increasingly being reported worldwide. Although most hypervirulent K. pneumoniae isolates are antibiotic-susceptible, some isolates with combined virulence and resistance, such as the carbapenem-resistant hypervirulent K. pneumoniae isolates, are increasingly being detected. The combination of multidrug resistance and enhanced virulence has the potential to cause the next clinical crisis. To better understand the basic biology of hypervirulent K. pneumoniae, this review will provide a summarization and discussion focused on epidemiology, hypervirulence-associated factors, and antibiotic resistance mechanisms of such hypervirulent strains. Epidemiological analysis of recent clinical isolates in China warns the global dissemination of hypervirulent K. pneumoniae strains with extensive antibiotic resistance in the near future. Therefore, an immediate response to recognize the global dissemination of this hypervirulent strain with resistance determinants is an urgent priority.

  14. Investigating the mechanisms of glyphosate resistance in goosegrass (Eleusine indica (L.) Gaertn.) by RNA sequencing technology.

    Chen, Jingchao; Huang, Hongjuan; Wei, Shouhui; Huang, Zhaofeng; Wang, Xu; Zhang, Chaoxian

    2017-01-01

    Glyphosate is an important non-selective herbicide that is in common use worldwide. However, evolved glyphosate-resistant (GR) weeds significantly affect crop yields. Unfortunately, the mechanisms underlying resistance in GR weeds, such as goosegrass (Eleusine indica (L.) Gaertn.), an annual weed found worldwide, have not been fully elucidated. In this study, transcriptome analysis was conducted to further assess the potential mechanisms of glyphosate resistance in goosegrass. The RNA sequencing libraries generated 24 597 462 clean reads. De novo assembly analysis produced 48 852 UniGenes with an average length of 847 bp. All UniGenes were annotated using seven databases. Sixteen candidate differentially expressed genes selected by digital gene expression analysis were validated by quantitative real-time PCR (qRT-PCR). Among these UniGenes, the EPSPS and PFK genes were constitutively up-regulated in resistant (R) individuals and showed a higher copy number than that in susceptible (S) individuals. The expressions of four UniGenes relevant to photosynthesis were inhibited by glyphosate in S individuals, and this toxic response was confirmed by gas exchange analysis. Two UniGenes annotated as glutathione transferase (GST) were constitutively up-regulated in R individuals, and were induced by glyphosate both in R and S. In addition, the GST activities in R individuals were higher than in S. Our research confirmed that two UniGenes (PFK, EPSPS) were strongly associated with target resistance, and two GST-annotated UniGenes may play a role in metabolic glyphosate resistance in goosegrass. © 2016 The Authors The Plant Journal © 2016 John Wiley & Sons Ltd.

  15. Metabolic changes during development of Walker-256 carcinosarcoma resistance to doxorubicin.

    Todor, I N; Lukyanova, N Yu; Shvets, Yu V; Lozovska, Yu V; Chekhun, V F

    2015-03-01

    To study indices of energy metabolism, content of K(+) and Mg(++) both in peripheral blood and in Walker-256 carcinosarcoma during development of resistance to doxorubicin. Resistance of Walker-256 carcinosarcoma to doxorubicin has been developed through 12 subsequent transplantations of tumor after the chemotherapy. Parental strain was inhibited by drug by 65%, while transitional resistant substrains - by 30% and 2%, respectively. Determination of biochemical indices in blood serum and homogenates of tumor tissue, level of potassium, magnesium, lactate, glucose, activities of lactate dehydrogenase and glucose-6-phosphate dehydrogenase was performed with the help of biochemical and immune-enzyme analyzer GBG ChemWell 2990 (USA) using standard kits. Polarography was used to determine indices of mitochondrial oxidative phosphorylation. Study of mitochondrial membrane potential was carried out on flow cytometer Beckman Coulter Epics XL using dye JC-1. It has been determined that development of drug resistance causes the decrease of K(+), Mg(++), glucose content in blood serum and increase of these indices in tumor tissue. At the same time, gradual tumor's loss of sensitivity is characterized by decrease of glycolysis activity in it and activation of mitochondrial oxidative phosphorylation and pentose phosphate pathway of glucose degradation, which causes more intensive formation of NADPH. Development of drug resistance of tumor causes certain metabolic changes in organism and tumor. Further study of such changes will make possible to determine tumor and extratumor markers of resistance.

  16. The Ablation of Mitochondrial Protein Phosphatase Pgam5 Confers Resistance Against Metabolic Stress.

    Sekine, Shiori; Yao, Akari; Hattori, Kazuki; Sugawara, Sho; Naguro, Isao; Koike, Masato; Uchiyama, Yasuo; Takeda, Kohsuke; Ichijo, Hidenori

    2016-03-01

    Phosphoglycerate mutase family member 5 (PGAM5) is a mitochondrial protein phosphatase that has been reported to be involved in various stress responses from mitochondrial quality control to cell death. However, its roles in vivo are largely unknown. Here, we show that Pgam5-deficient mice are resistant to several metabolic insults. Under cold stress combined with fasting, Pgam5-deficient mice better maintained body temperature than wild-type mice and showed an extended survival rate. Serum triglycerides and lipid content in brown adipose tissue (BAT), a center of adaptive thermogenesis, were severely reduced in Pgam5-deficient mice. Moreover, although Pgam5 deficiency failed to maintain proper mitochondrial integrity in BAT, it reciprocally resulted in the dramatic induction of fibroblast growth factor 21 (FGF21) that activates various functions of BAT including thermogenesis. Thus, the enhancement of lipid metabolism and FGF21 may contribute to the cold resistance of Pgam5-deficient mice under fasting condition. Finally, we also found that Pgam5-deficient mice are resistant to high-fat-diet-induced obesity. Our study uncovered that PGAM5 is involved in the whole-body metabolism in response to stresses that impose metabolic challenges on mitochondria.

  17. The Ablation of Mitochondrial Protein Phosphatase Pgam5 Confers Resistance Against Metabolic Stress

    Shiori Sekine

    2016-03-01

    Full Text Available Phosphoglycerate mutase family member 5 (PGAM5 is a mitochondrial protein phosphatase that has been reported to be involved in various stress responses from mitochondrial quality control to cell death. However, its roles in vivo are largely unknown. Here, we show that Pgam5-deficient mice are resistant to several metabolic insults. Under cold stress combined with fasting, Pgam5-deficient mice better maintained body temperature than wild-type mice and showed an extended survival rate. Serum triglycerides and lipid content in brown adipose tissue (BAT, a center of adaptive thermogenesis, were severely reduced in Pgam5-deficient mice. Moreover, although Pgam5 deficiency failed to maintain proper mitochondrial integrity in BAT, it reciprocally resulted in the dramatic induction of fibroblast growth factor 21 (FGF21 that activates various functions of BAT including thermogenesis. Thus, the enhancement of lipid metabolism and FGF21 may contribute to the cold resistance of Pgam5-deficient mice under fasting condition. Finally, we also found that Pgam5-deficient mice are resistant to high-fat-diet-induced obesity. Our study uncovered that PGAM5 is involved in the whole-body metabolism in response to stresses that impose metabolic challenges on mitochondria.

  18. Differential metabolic rearrangements after cold storage are correlated with chilling injury resistance of peach fruits

    Claudia A Bustamante

    2016-09-01

    Full Text Available Reconfiguration of the metabolome is a key component involved in the acclimation to cold in plants; however, few studies have been devoted to the analysis of the overall metabolite changes after cold storage of fruits prior to consumption. Here, metabolite profiling of six peach varieties with differential susceptibility to develop mealiness, a chilling-injury (CI symptom, was performed. According to metabolic content at harvest; after cold treatment; and after ripening, either following cold treatment or not; peach fruits clustered in distinct groups, depending on harvest-time, cold treatment, and ripening state. Both common and distinct metabolic responses among the six varieties were found; common changes including dramatic galactinol and raffinose rise; GABA, Asp and Phe increase; and 2-oxo-glutarate and succinate decrease. Raffinose content after long cold treatment quantitatively correlated to the degree of mealiness resistance of the different peach varieties; and thus, raffinose emerges as a candidate biomarker of this CI disorder. Xylose increase after cold treatment was found only in the susceptible genotypes, indicating a particular cell wall reconfiguration of these varieties while being cold-stored. Overall, results indicate that peach fruit differential metabolic rearrangements due to cold treatment, rather than differential metabolic priming before cold, are better related with CI resistance. The plasticity of peach fruit metabolism renders it possible to induce a diverse metabolite array after cold, which is successful, in some genotypes, to avoid CI

  19. Mechanisms of Hepatitis C Viral Resistance to Direct Acting Antivirals.

    Ahmed, Asma; Felmlee, Daniel J

    2015-12-18

    There has been a remarkable transformation in the treatment of chronic hepatitis C in recent years with the development of direct acting antiviral agents targeting virus encoded proteins important for viral replication including NS3/4A, NS5A and NS5B. These agents have shown high sustained viral response (SVR) rates of more than 90% in phase 2 and phase 3 clinical trials; however, this is slightly lower in real-life cohorts. Hepatitis C virus resistant variants are seen in most patients who do not achieve SVR due to selection and outgrowth of resistant hepatitis C virus variants within a given host. These resistance associated mutations depend on the class of direct-acting antiviral drugs used and also vary between hepatitis C virus genotypes and subtypes. The understanding of these mutations has a clear clinical implication in terms of choice and combination of drugs used. In this review, we describe mechanism of action of currently available drugs and summarize clinically relevant resistance data.

  20. Mechanisms of Hepatitis C Viral Resistance to Direct Acting Antivirals

    Asma Ahmed

    2015-12-01

    Full Text Available There has been a remarkable transformation in the treatment of chronic hepatitis C in recent years with the development of direct acting antiviral agents targeting virus encoded proteins important for viral replication including NS3/4A, NS5A and NS5B. These agents have shown high sustained viral response (SVR rates of more than 90% in phase 2 and phase 3 clinical trials; however, this is slightly lower in real-life cohorts. Hepatitis C virus resistant variants are seen in most patients who do not achieve SVR due to selection and outgrowth of resistant hepatitis C virus variants within a given host. These resistance associated mutations depend on the class of direct-acting antiviral drugs used and also vary between hepatitis C virus genotypes and subtypes. The understanding of these mutations has a clear clinical implication in terms of choice and combination of drugs used. In this review, we describe mechanism of action of currently available drugs and summarize clinically relevant resistance data.

  1. On the mechanism of chloroquine resistance in Plasmodium falciparum.

    Chinappi, Mauro; Via, Allegra; Marcatili, Paolo; Tramontano, Anna

    2010-01-01

    Resistance to chloroquine of malaria strains is known to be associated with a parasite protein named PfCRT, the mutated form of which is able to reduce chloroquine accumulation in the digestive vacuole of the pathogen. Whether the protein mediates extrusion of the drug acting as a channel or as a carrier and which is the protonation state of its chloroquine substrate is the subject of a scientific debate. We present here an analytical approach that explores which combination of hypotheses on the mechanism of transport and the protonation state of chloroquine are consistent with available equilibrium experimental data. We show that the available experimental data are not, by themselves, sufficient to conclude whether the protein acts as a channel or as a transporter, which explains the origin of their different interpretation by different authors. Interestingly, though, each of the two models is only consistent with a subset of hypotheses on the protonation state of the transported molecule. The combination of these results with a sequence and structure analysis of PfCRT, which strongly suggests that the molecule is a carrier, indicates that the transported species is either or both the mono and di-protonated forms of chloroquine. We believe that our results, besides shedding light on the mechanism of chloroquine resistance in P. falciparum, have implications for the development of novel therapies against resistant malaria strains and demonstrate the usefulness of an approach combining systems biology strategies with structural bioinformatics and experimental data.

  2. On the mechanism of chloroquine resistance in Plasmodium falciparum.

    Chinappi, Mauro

    2010-11-19

    Resistance to chloroquine of malaria strains is known to be associated with a parasite protein named PfCRT, the mutated form of which is able to reduce chloroquine accumulation in the digestive vacuole of the pathogen. Whether the protein mediates extrusion of the drug acting as a channel or as a carrier and which is the protonation state of its chloroquine substrate is the subject of a scientific debate. We present here an analytical approach that explores which combination of hypotheses on the mechanism of transport and the protonation state of chloroquine are consistent with available equilibrium experimental data. We show that the available experimental data are not, by themselves, sufficient to conclude whether the protein acts as a channel or as a transporter, which explains the origin of their different interpretation by different authors. Interestingly, though, each of the two models is only consistent with a subset of hypotheses on the protonation state of the transported molecule. The combination of these results with a sequence and structure analysis of PfCRT, which strongly suggests that the molecule is a carrier, indicates that the transported species is either or both the mono and di-protonated forms of chloroquine. We believe that our results, besides shedding light on the mechanism of chloroquine resistance in P. falciparum, have implications for the development of novel therapies against resistant malaria strains and demonstrate the usefulness of an approach combining systems biology strategies with structural bioinformatics and experimental data.

  3. On the Mechanism of Chloroquine Resistance in Plasmodium falciparum

    Marcatili, Paolo; Tramontano, Anna

    2010-01-01

    Resistance to chloroquine of malaria strains is known to be associated with a parasite protein named PfCRT, the mutated form of which is able to reduce chloroquine accumulation in the digestive vacuole of the pathogen. Whether the protein mediates extrusion of the drug acting as a channel or as a carrier and which is the protonation state of its chloroquine substrate is the subject of a scientific debate. We present here an analytical approach that explores which combination of hypotheses on the mechanism of transport and the protonation state of chloroquine are consistent with available equilibrium experimental data. We show that the available experimental data are not, by themselves, sufficient to conclude whether the protein acts as a channel or as a transporter, which explains the origin of their different interpretation by different authors. Interestingly, though, each of the two models is only consistent with a subset of hypotheses on the protonation state of the transported molecule. The combination of these results with a sequence and structure analysis of PfCRT, which strongly suggests that the molecule is a carrier, indicates that the transported species is either or both the mono and di-protonated forms of chloroquine. We believe that our results, besides shedding light on the mechanism of chloroquine resistance in P. falciparum, have implications for the development of novel therapies against resistant malaria strains and demonstrate the usefulness of an approach combining systems biology strategies with structural bioinformatics and experimental data. PMID:21124966

  4. Mechanisms Underlying the Antidepressant Response and Treatment Resistance

    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.

  5. Reprogramming of Seed Metabolism Facilitates Pre-harvest Sprouting Resistance of Wheat

    Liu, Caixiang; Ding, Feng; Hao, Fuhua; Yu, Men; Lei, Hehua; Wu, Xiangyu; Zhao, Zhengxi; Guo, Hongxiang; Yin, Jun; Wang, Yulan; Tang, Huiru

    2016-02-01

    Pre-harvest sprouting (PHS) is a worldwide problem for wheat production and transgene antisense-thioredoxin-s (anti-trx-s) facilitates outstanding resistance. To understand the molecular details of PHS resistance, we analyzed the metabonomes of the transgenic and wild-type (control) wheat seeds at various stages using NMR and GC-FID/MS. 60 metabolites were dominant in these seeds including sugars, organic acids, amino acids, choline metabolites and fatty acids. At day-20 post-anthesis, only malate level in transgenic wheat differed significantly from that in controls whereas at day-30 post-anthesis, levels of amino acids and sucrose were significantly different between these two groups. For mature seeds, most metabolites in glycolysis, TCA cycle, choline metabolism, biosynthesis of proteins, nucleotides and fatty acids had significantly lower levels in transgenic seeds than in controls. After 30-days post-harvest ripening, most metabolites in transgenic seeds had higher levels than in controls including amino acids, sugars, organic acids, fatty acids, choline metabolites and NAD+. These indicated that anti-trx-s lowered overall metabolic activities of mature seeds eliminating pre-harvest sprouting potential. Post-harvest ripening reactivated the metabolic activities of transgenic seeds to restore their germination vigor. These findings provided essential molecular phenomic information for PHS resistance of anti-trx-s and a credible strategy for future developing PHS resistant crops.

  6. Beneficial effect of pistachio consumption on glucose metabolism, insulin resistance, inflammation, and related metabolic risk markers: a randomized clinical trial.

    Hernández-Alonso, Pablo; Salas-Salvadó, Jordi; Baldrich-Mora, Mònica; Juanola-Falgarona, Martí; Bulló, Mònica

    2014-11-01

    To examine whether a pistachio-rich diet reduces the prediabetes stage and improves its metabolic risk profile. Prediabetic subjects were recruited to participate in this Spanish randomized clinical trial between 20 September 2011 and 4 February 2013. In a crossover manner, 54 subjects consumed two diets, each for 4 months: a pistachio-supplemented diet (PD) and a control diet (CD). A 2-week washout period separated study periods. Diets were isocaloric and matched for protein, fiber, and saturated fatty acids. A total of 55% of the CD calories came from carbohydrates and 30% from fat, whereas for the PD, these percentages were 50 and 35%, respectively (including 57 g/day of pistachios). Fasting glucose, insulin, and HOMA of insulin resistance decreased significantly after the PD compared with the CD. Other cardiometabolic risk markers such as fibrinogen, oxidized LDL, and platelet factor 4 significantly decreased under the PD compared with the CD (P pistachio intervention (P pistachio consumption is emerging as a useful nutritional strategy for the prediabetic state. Data suggest that pistachios have a glucose- and insulin-lowering effect, promote a healthier metabolic profile, and reverse certain metabolic deleterious consequences of prediabetes. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  7. Associations of vitamin D with insulin resistance, obesity, type 2 diabetes, and metabolic syndrome.

    Wimalawansa, Sunil J

    2018-01-01

    The aim of this study is to determine the relationships of vitamin D with diabetes, insulin resistance obesity, and metabolic syndrome. Intra cellular vitamin D receptors and the 1-α hydroxylase enzyme are distributed ubiquitously in all tissues suggesting a multitude of functions of vitamin D. It plays an indirect but an important role in carbohydrate and lipid metabolism as reflected by its association with type 2 diabetes (T2D), metabolic syndrome, insulin secretion, insulin resistance, polycystic ovarian syndrome, and obesity. Peer-reviewed papers, related to the topic were extracted using key words, from PubMed, Medline, and other research databases. Correlations of vitamin D with diabetes, insulin resistance and metabolic syndrome were examined for this evidence-based review. In addition to the well-studied musculoskeletal effects, vitamin D decreases the insulin resistance, severity of T2D, prediabetes, metabolic syndrome, inflammation, and autoimmunity. Vitamin D exerts autocrine and paracrine effects such as direct intra-cellular effects via its receptors and the local production of 1,25(OH) 2 D 3 , especially in muscle and pancreatic β-cells. It also regulates calcium homeostasis and calcium flux through cell membranes, and activation of a cascade of key enzymes and cofactors associated with metabolic pathways. Cross-sectional, observational, and ecological studies reported inverse correlations between vitamin D status with hyperglycemia and glycemic control in patients with T2D, decrease the rate of conversion of prediabetes to diabetes, and obesity. However, no firm conclusions can be drawn from current studies, because (A) studies were underpowered; (B) few were designed for glycemic outcomes, (C) the minimum (or median) serum 25(OH) D levels achieved are not measured or reported; (D) most did not report the use of diabetes medications; (E) some trials used too little (F) others used too large, unphysiological and infrequent doses of vitamin D; and

  8. Insulin resistance and protein energy metabolism in patients with advanced chronic kidney disease.

    Siew, Edward D; Ikizler, Talat Alp

    2010-01-01

    Insulin resistance (IR), the reciprocal of insulin sensitivity is a known complication of advanced chronic kidney disease (CKD) and is associated with a number of metabolic derangements. The complex metabolic abnormalities observed in CKD such as vitamin D deficiency, obesity, metabolic acidosis, inflammation, and accumulation of "uremic toxins" are believed to contribute to the etiology of IR and acquired defects in the insulin-receptor signaling pathway in this patient population. Only a few investigations have explored the validity of commonly used assessment methods in comparison to gold standard hyperinsulinemic hyperglycemic clamp technique in CKD patients. An important consequence of insulin resistance is its role in the pathogenesis of protein energy wasting, a state of metabolic derangement characterized by loss of somatic and visceral protein stores not entirely accounted for by inadequate nutrient intake. In the general population, insulin resistance has been associated with accelerated protein catabolism. Among end-stage renal disease (ESRD) patients, enhanced muscle protein breakdown has been observed in patients with Type II diabetes compared to ESRD patients without diabetes. In the absence of diabetes mellitus (DM) or severe obesity, insulin resistance is detectable in dialysis patients and strongly associated with increased muscle protein breakdown, primarily mediated by the ubiquitin-proteasome pathway. Recent epidemiological data indicate a survival advantage and better nutritional status in insulin-free Type II DM patients treated with insulin sensitizer thiazolidinediones. Given the high prevalence of protein energy wasting in ESRD and its unequivocal association with adverse clinical outcomes, insulin resistance may represent an important modifiable target for intervention in the ESRD population.

  9. Infection control implications of heterogeneous resistance mechanisms in carbapenem-resistant Enterobacteriaceae (CRE).

    Goodman, K E; Simner, P J; Tamma, P D; Milstone, A M

    2016-01-01

    The Centers for Disease Control and Prevention (CDC) defines carbapenem-resistant Enterobacteriaceae (CRE) based upon a phenotypic demonstration of carbapenem resistance. However, considerable heterogeneity exists within this definitional umbrella. CRE may mechanistically differ by whether they do or do not produce carbapenemases. Moreover, patients can acquire CRE through multiple pathways: endogenously through antibiotic selective pressure on intestinal microbiota, exogenously through horizontal transmission or through a combination of these factors. Some evidence suggests that non-carbapenemase-producing CRE may be more frequently acquired by antibiotic exposure and carbapenemase-producing CRE via horizontal transmission, but definitive data are lacking. This review examines types of CRE resistance mechanisms, antibiotic exposure and horizontal transmission pathways of CRE acquisition, and the implications of these heterogeneities to the development of evidence-based CRE healthcare epidemiology policies. In our Expert Commentary & Five-Year View, we outline specific nosocomial CRE knowledge gaps and potential methodological approaches for their resolution.

  10. Insulin resistance, the metabolic syndrome, diabetes, and cardiovascular disease risk in women with PCOS.

    Teede, H J; Hutchison, S; Zoungas, S; Meyer, C

    2006-08-01

    Polycystic ovary syndrome is the most common endocrinopathy of reproductive aged women affecting 6-10% of the population. Traditionally considered a reproductive disorder manifesting as chronic anovulation, infertility, and hyperandrogenism, management has primarily focused on short-term reproductive outcomes. Recently, however, significant metabolic aspects in conjunction with longer-term health sequealae of PCOS have been recognized. The metabolic features are primarily related to underlying insulin resistance (IR), which is now understood to play an important role in both the pathogenesis and long-term sequelae of PCOS.

  11. Induction of drug-metabolizing enzymes: mechanisms and consequences

    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.

  12. Use of antimicrobials in veterinary medicine and mechanisms of resistance.

    Schwarz, S; Chaslus-Dancla, E

    2001-01-01

    This review deals with the application of antimicrobial agents in veterinary medicine and food animal production and the possible consequences arising from the widespread and multipurpose use of antimicrobials. The various mechanisms that bacteria have developed to escape the inhibitory effects of the antimicrobials most frequently used in the veterinary field are reported in detail. Resistance of bacteria to tetracyclines, macrolide-lincosamide-streptogramin antibiotics, beta-lactam antibiotics, aminoglycosides, sulfonamides, trimethoprim, fluoroquinolones and chloramphenicol/florfenicol is described with regard to enzymatic inactivation, decreased intracellular drug accumulation and modification/protection/replacement of the target sites. In addition, basic information is given about mobile genetic elements which carry the respective resistance genes, such as plasmids, transposons, and gene cassettes/integrons, and their ways of spreading via conjugation, mobilisation, transduction, and transformation.

  13. Mycoplasma bovis: Mechanisms of Resistance and Trends in Antimicrobial Susceptibility.

    Lysnyansky, Inna; Ayling, Roger D

    2016-01-01

    Mycoplasma bovis is a cell-wall-less bacterium and belongs to the class Mollicutes. It is the most important etiological agent of bovine mycoplasmoses in North America and Europe, causing respiratory disease, mastitis, otitis media, arthritis, and reproductive disease. Clinical disease associated with M. bovis is often chronic, debilitating, and poorly responsive to antimicrobial therapy, resulting in significant economic loss, the full extent of which is difficult to estimate. Until M. bovis vaccines are universally available, sanitary control measures and antimicrobial treatment are the only approaches that can be used in attempts to control M. bovis infections. However, in vitro studies show that many of the current M. bovis isolates circulating in Europe have high minimum inhibitory concentrations (MIC) for many of the commercially available antimicrobials. In this review we summarize the current MIC trends indicating the development of antimicrobial resistance in M. bovis as well as the known molecular mechanisms by which resistance is acquired.

  14. Mycoplasma bovis: mechanisms of resistance and trends in antimicrobial susceptibility

    Inna eLysnyansky

    2016-04-01

    Full Text Available Mycoplasma bovis is a cell-wall-less bacterium and belongs to the class Mollicutes. It is the most important etiological agent of bovine mycoplasmoses in North America and Europe, causing respiratory disease, mastitis, otitis media, arthritis, and reproductive disease. Clinical disease associated with M. bovis is often chronic, debilitating, and poorly responsive to antimicrobial therapy, resulting in significant economic loss, the full extent of which is difficult to estimate. Until M. bovis vaccines are universally available, sanitary control measures and antimicrobial treatment are the only approaches that can be used in attempts to control M. bovis infections. However, in vitro studies show that many of the current M. bovis isolates circulating in Europe have high minimum inhibitory concentrations (MIC for many of the commercially available antimicrobials. In this review we summarize the current MIC trends indicating the development of antimicrobial resistance in M. bovis as well as the known molecular mechanisms by which resistance is acquired.

  15. Induced Pluripotent Stem Cell-Derived Endothelial Cells in Insulin Resistance and Metabolic Syndrome.

    Carcamo-Orive, Ivan; Huang, Ngan F; Quertermous, Thomas; Knowles, Joshua W

    2017-11-01

    Insulin resistance leads to a number of metabolic and cellular abnormalities including endothelial dysfunction that increase the risk of vascular disease. Although it has been particularly challenging to study the genetic determinants that predispose to abnormal function of the endothelium in insulin-resistant states, the possibility of deriving endothelial cells from induced pluripotent stem cells generated from individuals with detailed clinical phenotyping, including accurate measurements of insulin resistance accompanied by multilevel omic data (eg, genetic and genomic characterization), has opened new avenues to study this relationship. Unfortunately, several technical barriers have hampered these efforts. In the present review, we summarize the current status of induced pluripotent stem cell-derived endothelial cells for modeling endothelial dysfunction associated with insulin resistance and discuss the challenges to overcoming these limitations. © 2017 American Heart Association, Inc.

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

    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.

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

    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.

  18. Beneficial mechanisms of aerobic exercise on hepatic lipid metabolism in non-alcoholic fatty liver disease.

    Guo, Rui; Liong, Emily C; So, Kwok Fai; Fung, Man-Lung; Tipoe, George L

    2015-04-01

    Non-alcoholic fatty liver disease (NAFLD) refers to any fatty liver disease that is not due to excessive use of alcohol. NAFLD probably results from abnormal hepatic lipid metabolism and insulin resistance. Aerobic exercise is shown to improve NAFLD. This review aimed to evaluate the molecular mechanisms involved in the beneficial effects of aerobic exercise on NAFLD. We searched articles in English on the role of aerobic exercise in NAFLD therapy in PubMed. The mechanisms of chronic aerobic exercise in regulating the outcome of NAFLD include: (i) reducing intrahepatic fat content by down-regulating sterol regulatory element-binding protein-1c and up-regulating peroxisome proliferator-activated receptor gamma expression levels; (ii) decreasing hepatic oxidative stress through modulating the reactive oxygen species, and enhancing antioxidant enzymes such as catalase and glutathione peroxidase; (iii) ameliorating hepatic inflammation via the inhibition of pro-inflammatory mediators such as tumor necrosis factor-alpha and interleukin-1 beta; (iv) attenuating mitochondrial dependent apoptosis by reducing cytochrome C released from the mitochondria to the cytosol; and (v) inducing hepato-protective autophagy. Aerobic exercise, via different mechanisms, significantly decreases the fat content of the liver and improves the outcomes of patients with NAFLD.

  19. Nanoparticle mechanics: deformation detection via nanopore resistive pulse sensing

    Darvish, Armin; Goyal, Gaurav; Aneja, Rachna; Sundaram, Ramalingam V. K.; Lee, Kidan; Ahn, Chi Won; Kim, Ki-Bum; Vlahovska, Petia M.; Kim, Min Jun

    2016-07-01

    Solid-state nanopores have been widely used in the past for single-particle analysis of nanoparticles, liposomes, exosomes and viruses. The shape of soft particles, particularly liposomes with a bilayer membrane, can greatly differ inside the nanopore compared to bulk solution as the electric field inside the nanopores can cause liposome electrodeformation. Such deformations can compromise size measurement and characterization of particles, but are often neglected in nanopore resistive pulse sensing. In this paper, we investigated the deformation of various liposomes inside nanopores. We observed a significant difference in resistive pulse characteristics between soft liposomes and rigid polystyrene nanoparticles especially at higher applied voltages. We used theoretical simulations to demonstrate that the difference can be explained by shape deformation of liposomes as they translocate through the nanopores. Comparing our results with the findings from electrodeformation experiments, we demonstrated that the rigidity of liposomes can be qualitatively compared using resistive pulse characteristics. This application of nanopores can provide new opportunities to study the mechanics at the nanoscale, to investigate properties of great value in fundamental biophysics and cellular mechanobiology, such as virus deformability and fusogenicity, and in applied sciences for designing novel drug/gene delivery systems.Solid-state nanopores have been widely used in the past for single-particle analysis of nanoparticles, liposomes, exosomes and viruses. The shape of soft particles, particularly liposomes with a bilayer membrane, can greatly differ inside the nanopore compared to bulk solution as the electric field inside the nanopores can cause liposome electrodeformation. Such deformations can compromise size measurement and characterization of particles, but are often neglected in nanopore resistive pulse sensing. In this paper, we investigated the deformation of various

  20. Characteristics and contributions of hyperandrogenism to insulin resistance and other metabolic profiles in polycystic ovary syndrome.

    Huang, Rong; Zheng, Jun; Li, Shengxian; Tao, Tao; Ma, Jing; Liu, Wei

    2015-05-01

    To investigate the different characteristics in Chinese Han women with polycystic ovary syndrome, and to analyze the significance of hyperandrogenism in insulin resistance and other metabolic profiles. A cross-sectional study. Medical university hospital. A total of 229 women with polycystic ovary syndrome aged 18-45 years. Women with polycystic ovary syndrome, diagnosed by Rotterdam criteria, were divided into four groups according to the quartile intervals of free androgen index levels. Comparisons between groups were performed using one-way analysis of variance. Stepwise logistic regression analysis was performed to investigate the association between homeostasis model assessment-insulin resistance and independent variables. Within the four phenotypes, women with phenotype 1 (hyperandrogenism, oligo/anovulation, and polycystic ovaries) exhibited higher total testosterone, free androgen index, androstenedione, low-density lipoprotein, and lower quantitative insulin sensitivity check index (p polycystic ovaries) showed lower total cholesterol, low-density lipoprotein, and homeostasis model assessment-insulin resistance, but higher high-density lipoprotein (p < 0.05). The levels of triglycerides, total cholesterol, low-density lipoprotein, and homeostasis model assessment-insulin resistance significantly increased, but high-density lipoprotein and quantitative insulin sensitivity check index decreased with the elevation of free androgen index intervals. After adjustment for lipid profiles, free androgen index was significantly associated with homeostasis model assessment-insulin resistance in both lean and overweight/obese women (odds ratio 1.302, p = 0.039 in lean vs. odds ratio 1.132, p = 0.036 in overweight/obese). Phenotypes 1 and 4 represent groups with the most and least severe metabolic profiles, respectively. Hyperandrogenism, particularly with elevated free androgen index, is likely a key contributing factor for insulin resistance and for the aggravation

  1. Cisplatin resistance: a cellular self-defense mechanism resulting from multiple epigenetic and genetic changes.

    Shen, Ding-Wu; Pouliot, Lynn M; Hall, Matthew D; Gottesman, Michael M

    2012-07-01

    Cisplatin is one of the most effective broad-spectrum anticancer drugs. Its effectiveness seems to be due to the unique properties of cisplatin, which enters cells via multiple pathways and forms multiple different DNA-platinum adducts while initiating a cellular self-defense system by activating or silencing a variety of different genes, resulting in dramatic epigenetic and/or genetic alternations. As a result, the development of cisplatin resistance in human cancer cells in vivo and in vitro by necessity stems from bewilderingly complex genetic and epigenetic changes in gene expression and alterations in protein localization. Extensive published evidence has demonstrated that pleiotropic alterations are frequently detected during development of resistance to this toxic metal compound. Changes occur in almost every mechanism supporting cell survival, including cell growth-promoting pathways, apoptosis, developmental pathways, DNA damage repair, and endocytosis. In general, dozens of genes are affected in cisplatin-resistant cells, including pathways involved in copper metabolism as well as transcription pathways that alter the cytoskeleton, change cell surface presentation of proteins, and regulate epithelial-to-mesenchymal transition. Decreased accumulation is one of the most common features resulting in cisplatin resistance. This seems to be a consequence of numerous epigenetic and genetic changes leading to the loss of cell-surface binding sites and/or transporters for cisplatin, and decreased fluid phase endocytosis.

  2. Corrosion resistance of zirconium: general mechanisms, behaviour in nitric acid

    Pinard Legry, G.

    1990-01-01

    Corrosion resistance of zirconium results from the strong affinity of this metal for oxygen; as a result a thin protective oxide film is spontaneously formed in air or aqueous media, its thickness and properties depending on the physicochemical conditions at the interface. This film passivates the underlying metal but obviously if the passive film is partially or completely removed, localised or generalised corrosion phenomena will occur. In nitric acid, this depassivation may be chemical (fluorides) or mechanical (straining, creep, fretting). In these cases it is useful to determine the physicochemical conditions (concentration, temperature, potential, stress) which will have to be observed to use safely zirconium and its alloys in nitric acid solutions [fr

  3. Effect of mechanical properties on erosion resistance of ductile materials

    Levin, Boris Feliksovih

    Solid particle erosion (SPE) resistance of ductile Fe, Ni, and Co-based alloys as well as commercially pure Ni and Cu was studied. A model for SPE behavior of ductile materials is presented. The model incorporates the mechanical properties of the materials at the deformation conditions associated with SPE process, as well as the evolution of these properties during the erosion induced deformation. An erosion parameter was formulated based on consideration of the energy loss during erosion, and incorporates the material's hardness and toughness at high strain rates. The erosion model predicts that materials combining high hardness and toughness can exhibit good erosion resistance. To measure mechanical properties of materials, high strain rate compression tests using Hopkinson bar technique were conducted at strain rates similar to those during erosion. From these tests, failure strength and strain during erosion were estimated and used to calculate toughness of the materials. The proposed erosion parameter shows good correlation with experimentally measured erosion rates for all tested materials. To analyze subsurface deformation during erosion, microhardness and nanoindentation tests were performed on the cross-sections of the eroded materials and the size of the plastically deformed zone and the increase in materials hardness due to erosion were determined. A nanoindentation method was developed to estimate the restitution coefficient within plastically deformed regions of the eroded samples which provides a measure of the rebounding ability of a material during particle impact. An increase in hardness near the eroded surface led to an increase in restitution coefficient. Also, the stress rates imposed below the eroded surface were comparable to those measured during high strain-rate compression tests (10sp3-10sp4 ssp{-1}). A new parameter, "area under the microhardness curve" was developed that represents the ability of a material to absorb impact energy. By

  4. Understanding pea resistance mechanisms in response to Fusarium oxysporum through proteomic analysis.

    Castillejo, María Ángeles; Bani, Moustafa; Rubiales, Diego

    2015-07-01

    Fusarium oxysporum f. sp. pisi (Fop) is an important and destructive pathogen affecting pea crop (Pisum sativum) throughout the world. Control of this disease is achieved mainly by integration of different disease management procedures. However, the constant evolution of the pathogen drives the necessity to broaden the molecular basis of resistance to Fop. Our proteomic study was performed on pea with the aim of identifying proteins involved in different resistance mechanisms operating during F. oxysporum infection. For such purpose, we used a two-dimensional electrophoresis (2-DE) coupled to mass spectrometry (MALDI-TOF/TOF) analysis to study the root proteome of three pea genotypes showing different resistance response to Fop race 2. Multivariate statistical analysis identified 132 differential protein spots under the experimental conditions (genotypes/treatments). All of these protein spots were subjected to mass spectrometry analysis to deduce their possible functions. A total of 53 proteins were identified using a combination of peptide mass fingerprinting (PMF) and MSMS fragmentation. The following main functional categories were assigned to the identified proteins: carbohydrate and energy metabolism, nucleotides and aminoacid metabolism, signal transduction and cellular process, folding and degradation, redox and homeostasis, defense, biosynthetic process and transcription/translation. Results obtained in this work suggest that the most susceptible genotypes have increased levels of enzymes involved in the production of reducing power which could then be used as cofactor for enzymes of the redox reactions. This is in concordance with the fact that a ROS burst occurred in the same genotypes, as well as an increase of PR proteins. Conversely, in the resistant genotype proteins responsible to induce changes in the membrane and cell wall composition related to reinforcement were identified. Results are discussed in terms of the differential response to Fop

  5. Mechanism of Bacillus subtilis spore inactivation by and resistance to supercritical CO2 plus peracetic acid.

    Setlow, B; Korza, G; Blatt, K M S; Fey, J P; Setlow, P

    2016-01-01

    Determine how supercritical CO2 (scCO2 ) plus peracetic acid (PAA) inactivates Bacillus subtilis spores, factors important in spore resistance to scCO2 -PAA, and if spores inactivated by scCO2 -PAA are truly dead. Spores of wild-type B. subtilis and isogenic mutants lacking spore protective proteins were treated with scCO2 -PAA in liquid or dry at 35°C. Wild-type wet spores (aqueous suspension) were more susceptible than dry spores. Treated spores were examined for viability (and were truly dead), dipicolinic acid (DPA), mutations, permeability to nucleic acid stains, germination under different conditions, energy metabolism and outgrowth. ScCO2 -PAA-inactivated spores retained DPA, and survivors had no notable DNA damage. However, DPA was released from inactivated spores at a normally innocuous temperature (85°C), and colony formation from treated spores was salt sensitive. The inactivated spores germinated but did not outgrow, and these germinated spores had altered plasma membrane permeability and defective energy metabolism. Wet or dry coat-defective spores had increased scCO2 -PAA sensitivity, and dry spores but not wet spores lacking DNA protective proteins were more scCO2 -PAA sensitive. These findings suggest that scCO2 -PAA inactivates spores by damaging spores' inner membrane. The spore coat provided scCO2 -PAA resistance for both wet and dry spores. DNA protective proteins provided scCO2 -PAA resistance only for dry spores. These results provide information on mechanisms of spore inactivation of and resistance to scCO2 -PAA, an agent with increasing use in sterilization applications. © 2015 The Society for Applied Microbiology.

  6. Synthesis, antitubercular activity and mechanism of resistance of highly effective thiacetazone analogues.

    Geoffrey D Coxon

    Full Text Available Defining the pharmacological target(s of currently used drugs and developing new analogues with greater potency are both important aspects of the search for agents that are effective against drug-sensitive and drug-resistant Mycobacterium tuberculosis. Thiacetazone (TAC is an anti-tubercular drug that was formerly used in conjunction with isoniazid, but removed from the antitubercular chemotherapeutic arsenal due to toxic side effects. However, several recent studies have linked the mechanisms of action of TAC to mycolic acid metabolism and TAC-derived analogues have shown increased potency against M. tuberculosis. To obtain new insights into the molecular mechanisms of TAC resistance, we isolated and analyzed 10 mutants of M. tuberculosis that were highly resistant to TAC. One strain was found to be mutated in the methyltransferase MmaA4 at Gly101, consistent with its lack of oxygenated mycolic acids. All remaining strains harbored missense mutations in either HadA (at Cys61 or HadC (at Val85, Lys157 or Thr123, which are components of the β-hydroxyacyl-ACP dehydratase complex that participates in the mycolic acid elongation step. Separately, a library of 31 new TAC analogues was synthesized and evaluated against M. tuberculosis. Two of these compounds, 15 and 16, exhibited minimal inhibitory concentrations 10-fold lower than the parental molecule, and inhibited mycolic acid biosynthesis in a dose-dependent manner. Moreover, overexpression of HadAB HadBC or HadABC in M. tuberculosis led to high level resistance to these compounds, demonstrating that their mode of action is similar to that of TAC. In summary, this study uncovered new mutations associated with TAC resistance and also demonstrated that simple structural optimization of the TAC scaffold was possible and may lead to a new generation of TAC-derived drug candidates for the potential treatment of tuberculosis as mycolic acid inhibitors.

  7. BAD-dependent regulation of fuel metabolism and K(ATP) channel activity confers resistance to epileptic seizures.

    Giménez-Cassina, Alfredo; Martínez-François, Juan Ramón; Fisher, Jill K; Szlyk, Benjamin; Polak, Klaudia; Wiwczar, Jessica; Tanner, Geoffrey R; Lutas, Andrew; Yellen, Gary; Danial, Nika N

    2012-05-24

    Neuronal excitation can be substantially modulated by alterations in metabolism, as evident from the anticonvulsant effect of diets that reduce glucose utilization and promote ketone body metabolism. We provide genetic evidence that BAD, a protein with dual functions in apoptosis and glucose metabolism, imparts reciprocal effects on metabolism of glucose and ketone bodies in brain cells. These effects involve phosphoregulation of BAD and are independent of its apoptotic function. BAD modifications that reduce glucose metabolism produce a marked increase in the activity of metabolically sensitive K(ATP) channels in neurons, as well as resistance to behavioral and electrographic seizures in vivo. Seizure resistance is reversed by genetic ablation of the K(ATP) channel, implicating the BAD-K(ATP) axis in metabolic control of neuronal excitation and seizure responses. Copyright © 2012 Elsevier Inc. All rights reserved.

  8. Sulfur amino acid metabolism in doxorubicin-resistant breast cancer cells

    Ryu, Chang Seon; Kwak, Hui Chan; Lee, Kye Sook; Kang, Keon Wook; Oh, Soo Jin; Lee, Ki Ho; Kim, Hwan Mook; Ma, Jin Yeul; Kim, Sang Kyum

    2011-01-01

    Although methionine dependency is a phenotypic characteristic of tumor cells, it remains to be determined whether changes in sulfur amino acid metabolism occur in cancer cells resistant to chemotherapeutic medications. We compared expression/activity of sulfur amino acid metabolizing enzymes and cellular levels of sulfur amino acids and their metabolites between normal MCF-7 cells and doxorubicin-resistant MCF-7 (MCF-7/Adr) cells. The S-adenosylmethionine/S-adenosylhomocysteine ratio, an index of transmethylation potential, in MCF-7/Adr cells decreased to ∼ 10% relative to that in MCF-7 cells, which may have resulted from down-regulation of S-adenosylhomocysteine hydrolase. Expression of homocysteine-clearing enzymes, such as cystathionine beta-synthase, methionine synthase/methylene tetrahydrofolate reductase, and betaine homocysteine methyltransferase, was up-regulated in MCF-7/Adr cells, suggesting that acquiring doxorubicin resistance attenuated methionine-dependence and activated transsulfuration from methionine to cysteine. Homocysteine was similar, which is associated with a balance between the increased expressions of homocysteine-clearing enzymes and decreased extracellular homocysteine. Despite an elevation in cysteine, cellular GSH decreased in MCF-7/Adr cells, which was attributed to over-efflux of GSH into the medium and down-regulation of the GSH synthesis enzyme. Consequently, MCF-7/Adr cells were more sensitive to the oxidative stress induced by bleomycin and menadione than MCF-7 cells. In conclusion, our results suggest that regulating sulfur amino acid metabolism may be a possible therapeutic target for chemoresistant cancer cells. These results warrant further investigations to determine the role of sulfur amino acid metabolism in acquiring anticancer drug resistance in cancer cells using chemical and biological regulators involved in sulfur amino acid metabolism. - Research highlights: → MCF-7/Adr cells showed decreases in cellular GSH

  9. Evidence of multiple insecticide resistance mechanisms in Anopheles gambiae populations in Bangui, Central African Republic.

    Olé Sangba, Marina Lidwine; Sidick, Aboubakar; Govoetchan, Renaud; Dide-Agossou, Christian; Ossè, Razaki A; Akogbeto, Martin; Ndiath, Mamadou Ousmane

    2017-01-13

    and metabolic mechanisms. The co-existence of these resistance mechanisms in A. gambiae may be a serious obstacle for the future success of malaria control programmes in this region.

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

    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

  11. Impact of the Triglyceride/High-Density Lipoprotein Cholesterol Ratio and the Hypertriglyceremic-Waist Phenotype to Predict the Metabolic Syndrome and Insulin Resistance.

    von Bibra, Helene; Saha, Sarama; Hapfelmeier, Alexander; Müller, Gabriele; Schwarz, Peter E H

    2017-07-01

    Insulin resistance is the underlying mechanism for the metabolic syndrome and associated dyslipidaemia that theoretically implies a practical tool for identifying individuals at risk for cardiovascular disease and type-2-diabetes. Another screening tool is the hypertriglyceremic-waist phenotype (HTW). There is important impact of the ethnic background but a lack of studied European populations for the association of the triglyceride/high-density lipoprotein cholesterol (HDL-C) ratio and insulin resistance. This observational, retrospective study evaluated lipid ratios and the HTW for predicting the metabolic syndrome/insulin resistance in 1932 non-diabetic individuals from Germany in the fasting state and during a glucose tolerance test. The relations of triglyceride/HDL-C, total-cholesterol/HDL-C, and low-density lipoprotein cholesterol/HDL-C with 5 surrogate estimates of insulin resistance/sensitivity and metabolic syndrome were analysed by linear regression analysis and receiver operating characteristics (ROC) in participants with normal (n=1 333) or impaired fasting glucose (n=599), also for the impact of gender. Within the lipid ratios, triglyceride/HDL-C had the strongest associations with insulin resistance/sensitivity markers. In the prediction of metabolic syndrome, diagnostic accuracy was good for triglyceride/HDL-C (area under the ROC curve 0.817) with optimal cut-off points (in mg/dl units) of 2.8 for men (80% sensitivity, 71% specificity) and 1.9 for women (80% sensitivity, 75% specificity) and fair for HTW and HOMA-IR (area under the curve 0.773 and 0.761). These data suggest the triglyceride/HDL-C ratio as a physiologically relevant and practical index for predicting the concomitant presence of metabolic syndrome, insulin resistance and dyslipidaemia for therapeutic and preventive care in apparently healthy European populations. © Georg Thieme Verlag KG Stuttgart · New York.

  12. Dietary leucine--an environmental modifier of insulin resistance acting on multiple levels of metabolism.

    Yazmin Macotela

    Full Text Available Environmental factors, such as the macronutrient composition of the diet, can have a profound impact on risk of diabetes and metabolic syndrome. In the present study we demonstrate how a single, simple dietary factor--leucine--can modify insulin resistance by acting on multiple tissues and at multiple levels of metabolism. Mice were placed on a normal or high fat diet (HFD. Dietary leucine was doubled by addition to the drinking water. mRNA, protein and complete metabolomic profiles were assessed in the major insulin sensitive tissues and serum, and correlated with changes in glucose homeostasis and insulin signaling. After 8 weeks on HFD, mice developed obesity, fatty liver, inflammatory changes in adipose tissue and insulin resistance at the level of IRS-1 phosphorylation, as well as alterations in metabolomic profile of amino acid metabolites, TCA cycle intermediates, glucose and cholesterol metabolites, and fatty acids in liver, muscle, fat and serum. Doubling dietary leucine reversed many of the metabolite abnormalities and caused a marked improvement in glucose tolerance and insulin signaling without altering food intake or weight gain. Increased dietary leucine was also associated with a decrease in hepatic steatosis and a decrease in inflammation in adipose tissue. These changes occurred despite an increase in insulin-stimulated phosphorylation of p70S6 kinase indicating enhanced activation of mTOR, a phenomenon normally associated with insulin resistance. These data indicate that modest changes in a single environmental/nutrient factor can modify multiple metabolic and signaling pathways and modify HFD induced metabolic syndrome by acting at a systemic level on multiple tissues. These data also suggest that increasing dietary leucine may provide an adjunct in the management of obesity-related insulin resistance.

  13. Metabolic syndrome, insulin resistance and other cardiovascular risk factors in university students.

    Barbosa, José Bonifácio; dos Santos, Alcione Miranda; Barbosa, Marcelo Mesquita; Barbosa, Márcio Mesquita; de Carvalho, Carolina Abreu; Fonseca, Poliana Cristina de Almeida; Fonseca, Jessica Magalhães; Barbosa, Maria do Carmo Lacerda; Bogea, Eduarda Gomes; da Silva, Antônio Augusto Moura

    2016-04-01

    A cross-sectional population-based study using questionnaire and anthropometric data was conducted on 968 university students of São Luís, Brazil, from which 590 showed up for blood collection. In the statistical analysis the Student t-test, Mann-Whitney and chi-square tests were used. The prevalence of metabolic syndrome by the Joint Interim Statement (JIS) criteria was 20.5%, almost three times more prevalent in men (32.2%) than in women (13.5%) (P University students of private institutions had higher prevalences of sedentary lifestyle, obesity, abdominal obesity, elevated triglycerides and metabolic syndrome than students from public institutions. High prevalences of metabolic syndrome, insulin resistance and other cardiovascular risk factors were found in this young population. This suggests that the burden of these diseases in the future will be increased.

  14. Acquired resistance to EGFR inhibitors: mechanisms and prevention strategies

    Viloria-Petit, Alicia M.; Kerbel, Robert S.

    2004-01-01

    Potent and specific, or relatively specific, inhibitors of epidermal growth factor receptor (EGFR) signaling, including monoclonal antibodies and small molecular weight compounds, have been successfully developed. Both types of agent have been found to have significant antitumor activity, especially when used in combination with radio- hormone- and chemotherapy in preclinical studies. Because of the potentiation of the conventional drug activity in these combination settings, inhibitors of EGFR signaling have often been referred to as sensitizers for chemotherapy or radiation, as well as drug resistance reversal agents. Phase II clinical trials in head-and-neck as well as lung cancer suggested this concept of chemosensitization might translate into the clinic, but this remains to be definitively proven in randomized, double-blind Phase III trials. Given the extensive preclinical literature on EGFR blocking drugs and the advanced clinical development of such agents, it is surprising that the possibility of development of acquired resistance to the EGFR inhibitors themselves, a common clinical problem with virtually all other currently used anticancer drugs, remains a largely unexplored subject of investigation. Here we summarize some of the possible mechanisms that can result in acquired resistance to EGFR-targeting drugs. Alternative combination therapies to circumvent and delay this problem are suggested

  15. Polymyxin susceptibility testing, interpretative breakpoints and resistance mechanisms: An update.

    Bakthavatchalam, Yamuna Devi; Pragasam, Agila Kumari; Biswas, Indranil; Veeraraghavan, Balaji

    2018-03-01

    Emerging multidrug-resistant (MDR) nosocomial pathogens are a great threat. Polymyxins, an old class of cationic polypeptide antibiotic, are considered as last-resort drugs in treating infections caused by MDR Gram-negative bacteria. Increased use of polymyxins in treating critically ill patients necessitates routine polymyxin susceptibility testing. However, susceptibility testing both of colistin and polymyxin B (PMB) is challenging. In this review, currently available susceptibility testing methods are briefly discussed. The multicomponent composition of colistin and PMB significantly influences susceptibility testing. In addition, poor diffusion in the agar medium, adsorption to microtitre plates and the synergistic effect of the surfactant polysorbate 80 with polymyxins have a great impact on the performance of susceptibility testing methods This review also describes recently identified chromosomal resistance mechanisms, including modification of lipopolysaccharide (LPS) with 4-amino-4-deoxy-l-arabinose (L-Ara4-N) and phosphoethanolamine (pEtN) resulting in alteration of the negative charge, as well as the plasmid-mediated colistin resistance determinants mcr-1, mcr-1.2, mcr-2 and mcr-3. Copyright © 2017 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.

  16. Aberrant lipogenesis is a metabolic marker for azole-resistant candida albicans (Conference Presentation)

    Karanja, Caroline; Hong, Weili; Younis, Waleed; Cheng, Ji-Xin; Seleem, Mohamed

    2017-02-01

    Candida is the single most important cause of fungal bloodstream infections worldwide causing significant mortality as high as 50%. This high mortality rate is, in part, due to the inability to rapidly diagnose and simultaneously initiate an effective antifungal therapy early in the disease process. Current culture-based diagnostics are often slow, requiring several days to complete, and are only 50% sensitive in diagnosing candidemia (Candida bloodstream infection). For every 12 hours of delay in starting correct antifungal therapy, the risk of death for a given patient with candidemia increases by 200%. To address this unmet need, we explored the potential of employing stimulated Raman Scattering (SRS) imaging to diagnose candidemia and probe metabolic differences between resistant and susceptible strain at a single cell level. Metabolism is integral to pathogenicity; microorganism have very short life cycles, and therefore only a few hours are needed to observe a full metabolic cycle. SRS imaging at C-H vibration frequency at 2850 cm-1 revealed a substantial difference in lipogenesis between the susceptible and resistant C. albicans. Treating the C. albicans with fluconazole, an antimicrobial drug that targets ergosterol biosynthesis only affected the lipogenesis in the susceptible strain. Our results show that single-cell metabolic imaging under a SRS microscope can be used for diagnose candidemia and early detection of antimicrobial susceptibility.

  17. Effect of tributyltin (TBT) in the metabolic activity of TBT-resistant and sensitive estuarine bacteria.

    Cruz, Andreia; Oliveira, Vanessa; Baptista, Inês; Almeida, Adelaide; Cunha, Angela; Suzuki, Satoru; Mendo, Sónia

    2012-01-01

    The effect of tributyltin (TBT) on growth and metabolic activity of three estuarine bacteria with different TBT resistance profiles was investigated in an organic-rich culture medium (TSB) and in phosphate buffered saline (PBS) buffer. Exposure to TBT was assessed by determining its effect on growth (OD(600 nm) measurement), bacterial productivity (leucine incorporation), viability (CFU counts), aggregation and cell size (from Live/Dead analysis), ATP and NADH concentrations. TBT exposure resulted in decrease of bacterial density, cell size, and metabolic activity. In addition, cell aggregates were observed in the TBT-treated cultures. TBT strongly affected bacterial cell metabolism and seemed to exert an effect on its equilibrium, interfering with cell activity. Also, TBT toxicity was lower when cells were grown in TSB than in PBS, suggesting that a nutrient-rich growth medium can protect cells from TBT toxicity. This study contributes to our understanding of the TBT-resistant cell behavior reflected in its physiology and metabolic activity. This information is of utmost importance for further studies of TBT bioremediation. Copyright © 2010 Wiley Periodicals, Inc.

  18. Peculiarities of antioxidant system and iron metabolism in organism during development of tumor resistance to cisplatin.

    Chekhun, V F; Lozovska, Y V; Burlaka, A P; Lukyanova, N Y; Todor, I N; Naleskina, L A

    2014-09-01

    To study in vivo the peculiarities of changes of iron metabolism and antioxidant system in dynamics of growth of Guerin carcinoma with different sensitivity to cisplatin. In order to evaluate the content of metallothionein-1 (MT-1) in tumor homogenates and blood serum of rats with cisplatin-sensitive and cisplatin-resistant Guerin carcinoma the immunoenzyme method was used. The evaluation of ceruloplasmin activity, content of "free iron" complexes, superoxide and NO-generating acti-vity of NADPH-oxidase and iNOS activity in neutrophils, blood serum and tumor homogenates was measured by EPR-spectro-scopy. Maximal accumulation of MT-1 in blood serum and tumor, more pronounced in resistant strain, at the border of latent and exponential phase of growth has been shown that is the evidence of protective role of this protein in the respect to the generation of free radical compounds. It has been determined that in animals with cisplatin-resistant strain of Guerin carcinoma, increase of "free iron" complexes is more apparent both on the level of tumor and organism on the background on increase of CP/TR ratio that is the consequence of organism antioxidant protection system disorder. Mentioned changes in metabolism of iron with its accumulation in tumor and further reprogramming of mitochondria metabolism and activity of NADPH-oxidase for non-transformed cells are favorable conditions for the formation of oxidative phenotype of tumor.

  19. Mechanisms of metabolic dysfunction in cancer-associated cachexia

    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

  20. Antifungal Resistance, Metabolic Routes as Drug Targets, and New Antifungal Agents: An Overview about Endemic Dimorphic Fungi

    Juliana Alves Parente-Rocha

    2017-01-01

    Full Text Available Diseases caused by fungi can occur in healthy people, but immunocompromised patients are the major risk group for invasive fungal infections. Cases of fungal resistance and the difficulty of treatment make fungal infections a public health problem. This review explores mechanisms used by fungi to promote fungal resistance, such as the mutation or overexpression of drug targets, efflux and degradation systems, and pleiotropic drug responses. Alternative novel drug targets have been investigated; these include metabolic routes used by fungi during infection, such as trehalose and amino acid metabolism and mitochondrial proteins. An overview of new antifungal agents, including nanostructured antifungals, as well as of repositioning approaches is discussed. Studies focusing on the development of vaccines against antifungal diseases have increased in recent years, as these strategies can be applied in combination with antifungal therapy to prevent posttreatment sequelae. Studies focused on the development of a pan-fungal vaccine and antifungal drugs can improve the treatment of immunocompromised patients and reduce treatment costs.

  1. Walnut consumption increases satiation but has no effect on insulin resistance or the metabolic profile over a 4-day period.

    Brennan, Aoife M; Sweeney, Laura L; Liu, Xiaowen; Mantzoros, Christos S

    2010-06-01

    Obesity and diabetes have been associated with increased consumption of highly processed foods, and reduced consumption of whole grains and nuts. It has been proposed, mainly on the basis of observational studies, that nuts may provide superior satiation, may lead to reduced calorie consumption, and may decrease the risk of type 2 diabetes; but evidence from randomized, interventional studies is lacking. A total of 20 men and women with the metabolic syndrome participated in a randomized, double-blind, crossover study of walnut consumption. Subjects had two 4-day admissions to the clinical research center where they were fed an isocaloric diet. In addition, they consumed shakes for breakfast containing either walnuts or placebo (shakes were standardized for calories, carbohydrate, and fat content). Appetite, insulin resistance, and metabolic parameters were measured. We found an increased level of satiety (overall P value = 0.0079) and sense of fullness (P = 0.05) in prelunch questionnaires following the walnut breakfast as compared to the placebo breakfast, with the walnut effect achieving significance on day 3 and 4 (P = 0.02 and P = 0.03). We did not find any change in resting energy expenditure, hormones known to mediate satiety, or insulin resistance when comparing the walnut vs. placebo diet. Walnut consumption over 4 days increased satiety by day 3. Long-term studies are needed to confirm the physiologic role of walnuts, the duration of time needed for these effects to occur, and to elucidate the underlying mechanisms.

  2. Non-Coding RNAs in Castration-Resistant Prostate Cancer: Regulation of Androgen Receptor Signaling and Cancer Metabolism.

    Shih, Jing-Wen; Wang, Ling-Yu; Hung, Chiu-Lien; Kung, Hsing-Jien; Hsieh, Chia-Ling

    2015-12-04

    Hormone-refractory prostate cancer frequently relapses from therapy and inevitably progresses to a bone-metastatic status with no cure. Understanding of the molecular mechanisms conferring resistance to androgen deprivation therapy has the potential to lead to the discovery of novel therapeutic targets for type of prostate cancer with poor prognosis. Progression to castration-resistant prostate cancer (CRPC) is characterized by aberrant androgen receptor (AR) expression and persistent AR signaling activity. Alterations in metabolic activity regulated by oncogenic pathways, such as c-Myc, were found to promote prostate cancer growth during the development of CRPC. Non-coding RNAs represent a diverse family of regulatory transcripts that drive tumorigenesis of prostate cancer and various other cancers by their hyperactivity or diminished function. A number of studies have examined differentially expressed non-coding RNAs in each stage of prostate cancer. Herein, we highlight the emerging impacts of microRNAs and long non-coding RNAs linked to reactivation of the AR signaling axis and reprogramming of the cellular metabolism in prostate cancer. The translational implications of non-coding RNA research for developing new biomarkers and therapeutic strategies for CRPC are also discussed.

  3. Global Phenotypic Characterization of Effects of Fluoroquinolone Resistance Selection on the Metabolic Activities and Drug Susceptibilities of Clostridium perfringens Strains

    Miseon Park

    2014-01-01

    Full Text Available Fluoroquinolone resistance affects toxin production of Clostridium perfringens strains differently. To investigate the effect of fluoroquinolone resistance selection on global changes in metabolic activities and drug susceptibilities, four C. perfringens strains and their norfloxacin-, ciprofloxacin-, and gatifloxacin-resistant mutants were compared in nearly 2000 assays, using phenotype microarray plates. Variations among mutant strains resulting from resistance selection were observed in all aspects of metabolism. Carbon utilization, pH range, osmotic tolerance, and chemical sensitivity of resistant strains were affected differently in the resistant mutants depending on both the bacterial genotype and the fluoroquinolone to which the bacterium was resistant. The susceptibilities to gentamicin and erythromycin of all resistant mutants except one increased, but some resistant strains were less susceptible to amoxicillin, cefoxitin, ceftriaxone, chloramphenicol, and metronidazole than their wild types. Sensitivity to ethidium bromide decreased in some resistant mutants and increased in others. Microarray analysis of two gatifloxacin-resistant mutants showed changes in metabolic activities that were correlated with altered expression of various genes. Both the chemical structures of fluoroquinolones and the genomic makeup of the wild types influenced the changes found in resistant mutants, which may explain some inconsistent reports of the effects of therapeutic use of fluoroquinolones on clinical isolates of bacteria.

  4. Insulin Resistance, Metabolic Syndrome, and Polycystic Ovary Syndrome in Obese Youth.

    Platt, Adrienne M

    2015-07-01

    School nurses are well aware of the childhood obesity epidemic in the United States, as one in three youth are overweight or obese. Co-morbidities found in overweight or obese adults were not commonly found in youth three decades ago but are now increasingly "normal" as the obesity epidemic continues to evolve. This article is the second of six related articles discussing the co-morbidities of childhood obesity and discusses the complex association between obesity and insulin resistance, metabolic syndrome, and polycystic ovary syndrome. Insulin resistance increases up to 50% during puberty, which may help to explain why youth are more likely to develop co-morbidities as teens. Treatment of these disorders is focused on changing lifestyle habits, as a child cannot change his or her pubertal progression, ethnicity, or family history. School nurses and other personnel can assist youth with insulin resistance, metabolic syndrome, and polycystic ovary syndrome by supporting their efforts to make changes, reinforcing that insulin resistance is not necessarily type 2 diabetes even if the child is taking medication, and intervening with negative peer pressure. © 2015 The Author(s).

  5. Cell Wall Remodeling by a Synthetic Analog Reveals Metabolic Adaptation in Vancomycin Resistant Enterococci.

    Pidgeon, Sean E; Pires, Marcos M

    2017-07-21

    Drug-resistant bacterial infections threaten to overburden our healthcare system and disrupt modern medicine. A large class of potent antibiotics, including vancomycin, operate by interfering with bacterial cell wall biosynthesis. Vancomycin-resistant enterococci (VRE) evade the blockage of cell wall biosynthesis by altering cell wall precursors, rendering them drug insensitive. Herein, we reveal the phenotypic plasticity and cell wall remodeling of VRE in response to vancomycin in live bacterial cells via a metabolic probe. A synthetic cell wall analog was designed and constructed to monitor cell wall structural alterations. Our results demonstrate that the biosynthetic pathway for vancomycin-resistant precursors can be hijacked by synthetic analogs to track the kinetics of phenotype induction. In addition, we leveraged this probe to interrogate the response of VRE cells to vancomycin analogs and a series of cell wall-targeted antibiotics. Finally, we describe a proof-of-principle strategy to visually inspect drug resistance induction. Based on our findings, we anticipate that our metabolic probe will play an important role in further elucidating the interplay among the enzymes involved in the VRE biosynthetic rewiring.

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

    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…

  7. HOMA1-IR and HOMA2-IR indexes in identifying insulin resistance and metabolic syndrome: Brazilian Metabolic Syndrome Study (BRAMS).

    Geloneze, Bruno; Vasques, Ana Carolina Junqueira; Stabe, Christiane França Camargo; Pareja, José Carlos; Rosado, Lina Enriqueta Frandsen Paez de Lima; Queiroz, Elaine Cristina de; Tambascia, Marcos Antonio

    2009-03-01

    To investigate cut-off values for HOMA1-IR and HOMA2-IR to identify insulin resistance (IR) and metabolic syndrome (MS), and to assess the association of the indexes with components of the MS. Nondiabetic subjects from the Brazilian Metabolic Syndrome Study were studied (n = 1,203, 18 to 78 years). The cut-off values for IR were determined from the 90th percentile in the healthy group (n = 297) and, for MS, a ROC curve was generated for the total sample. In the healthy group, HOMA-IR indexes were associated with central obesity, triglycerides and total cholesterol (p 2.7 and HOMA2-IR > 1.8; and, for MS were: HOMA1-IR > 2.3 (sensitivity: 76.8%; specificity: 66.7%) and HOMA2-IR > 1.4 (sensitivity: 79.2%; specificity: 61.2%). The cut-off values identified for HOMA1-IR and HOMA2-IR indexes have a clinical and epidemiological application for identifying IR and MS in Westernized admixtured multi-ethnic populations.

  8. Metabolic responses to high protein diet in Korean elite bodybuilders with high-intensity resistance exercise

    Choue Ryowon

    2011-07-01

    Full Text Available Abstract Background High protein diet has been known to cause metabolic acidosis, which is manifested by increased urinary excretion of nitrogen and calcium. Bodybuilders habitually consumed excessive dietary protein over the amounts recommended for them to promote muscle mass accretion. This study investigated the metabolic response to high protein consumption in the elite bodybuilders. Methods Eight elite Korean bodybuilders within the age from 18 to 25, mean age 21.5 ± 2.6. For data collection, anthropometry, blood and urinary analysis, and dietary assessment were conducted. Results They consumed large amounts of protein (4.3 ± 1.2 g/kg BW/day and calories (5,621.7 ± 1,354.7 kcal/day, as well as more than the recommended amounts of vitamins and minerals, including potassium and calcium. Serum creatinine (1.3 ± 0.1 mg/dl and potassium (5.9 ± 0.8 mmol/L, and urinary urea nitrogen (24.7 ± 9.5 mg/dl and creatinine (2.3 ± 0.7 mg/dl were observed to be higher than the normal reference ranges. Urinary calcium (0.3 ± 0.1 mg/dl, and phosphorus (1.3 ± 0.4 mg/dl were on the border of upper limit of the reference range and the urine pH was in normal range. Conclusions Increased urinary excretion of urea nitrogen and creatinine might be due to the high rates of protein metabolism that follow high protein intake and muscle turnover. The obvious evidence of metabolic acidosis in response to high protein diet in the subjects with high potassium intake and intensive resistance exercise were not shown in this study results. However, this study implied that resistance exercise with adequate mineral supplementation, such as potassium and calcium, could reduce or offset the negative effects of protein-generated metabolic changes. This study provides preliminary information of metabolic response to high protein intake in bodybuilders who engaged in high-intensity resistance exercise. Further studies will be needed to determine the effects of the intensity

  9. Insulin-resistant glucose metabolism in patients with microvascular angina--syndrome X

    Vestergaard, H; Skøtt, P; Steffensen, R

    1995-01-01

    Studies in patients with microvascular angina (MA) or the cardiologic syndrome X have shown a hyperinsulinemic response to an oral glucose challenge, suggesting insulin resistance and a role for increased serum insulin in coronary microvascular dysfunction. The aim of the present study was to exa......Studies in patients with microvascular angina (MA) or the cardiologic syndrome X have shown a hyperinsulinemic response to an oral glucose challenge, suggesting insulin resistance and a role for increased serum insulin in coronary microvascular dysfunction. The aim of the present study...... was to examine whether patients with MA are insulin-resistant. Nine patients with MA and seven control subjects were studied. All were sedentary and glucose-tolerant. Coronary arteriography was normal in all participants, and exercise-induced coronary ischemia was demonstrated in all MA patients. A euglycemic...... metabolism (8.4 +/- 0.9 v 12.5 +/- 1.3 mg.kg FFM-1.min-1, P

  10. Hepatic Proteomic Analysis Revealed Altered Metabolic Pathways in Insulin Resistant Akt1+/-/Akt2-/-Mice

    Pedersen, Brian A; Wang, Weiwen; Taylor, Jared F; Khattab, Omar S; Chen, Yu-Han; Edwards, Robert A; Yazdi, Puya G; Wang, Ping H

    2015-01-01

    Objective The aim of this study was to identify liver proteome changes in a mouse model of severe insulin resistance and markedly decreased leptin levels. Methods Two-dimensional differential gel electrophoresis was utilized to identify liver proteome changes in AKT1+/-/AKT2-/- mice. Proteins with altered levels were identified with tandem mass spectrometry. Ingenuity Pathway analysis was performed for the interpretation of the biological significance of the observed proteomic changes. Results 11 proteins were identified from 2 biological replicates to be differentially expressed by a ratio of at least 1.3 between age-matched insulin resistant (Akt1+/-/Akt2-/-) and wild type mice. Albumin and mitochondrial ornithine aminotransferase were detected from multiple spots, which suggest post-translational modifications. Enzymes of the urea cycle were common members of top regulated pathways. Conclusion Our results help to unveil the regulation of the liver proteome underlying altered metabolism in an animal model of severe insulin resistance. PMID:26455965

  11. Global metabolic analyses identify key differences in metabolite levels between polymyxin-susceptible and polymyxin-resistant Acinetobacter baumannii.

    Maifiah, Mohd Hafidz Mahamad; Cheah, Soon-Ee; Johnson, Matthew D; Han, Mei-Ling; Boyce, John D; Thamlikitkul, Visanu; Forrest, Alan; Kaye, Keith S; Hertzog, Paul; Purcell, Anthony W; Song, Jiangning; Velkov, Tony; Creek, Darren J; Li, Jian

    2016-02-29

    Multidrug-resistant Acinetobacter baumannii presents a global medical crisis and polymyxins are used as the last-line therapy. This study aimed to identify metabolic differences between polymyxin-susceptible and polymyxin-resistant A. baumannii using untargeted metabolomics. The metabolome of each A. baumannii strain was measured using liquid chromatography-mass spectrometry. Multivariate and univariate statistics and pathway analyses were employed to elucidate metabolic differences between the polymyxin-susceptible and -resistant A. baumannii strains. Significant differences were identified between the metabolic profiles of the polymyxin-susceptible and -resistant A. baumannii strains. The lipopolysaccharide (LPS) deficient, polymyxin-resistant 19606R showed perturbation in specific amino acid and carbohydrate metabolites, particularly pentose phosphate pathway (PPP) and tricarboxylic acid (TCA) cycle intermediates. Levels of nucleotides were lower in the LPS-deficient 19606R. Furthermore, 19606R exhibited a shift in its glycerophospholipid profile towards increased abundance of short-chain lipids compared to the parent polymyxin-susceptible ATCC 19606. In contrast, in a pair of clinical isolates 03-149.1 (polymyxin-susceptible) and 03-149.2 (polymyxin-resistant, due to modification of lipid A), minor metabolic differences were identified. Notably, peptidoglycan biosynthesis metabolites were significantly depleted in both of the aforementioned polymyxin-resistant strains. This is the first comparative untargeted metabolomics study to show substantial differences in the metabolic profiles of the polymyxin-susceptible and -resistant A. baumannii.

  12. Basic mechanisms of iron metabolism regulation and their clinical significance

    L. M. Meshсheryakova

    2014-01-01

    Full Text Available This article is а composition of literature and experimental data of iron metabolism. There were studied the level of DMT-1, ferroportin, hepcidin at different stages of anemia and hemochromatosis. It is clear that the level of DMT-1 regulates by the hepcidin. Increaseing of the hepcidin concentration and decreasing DMT-1 level in patients with hemochromatosis explained good results of treatment.

  13. Basic mechanisms of iron metabolism regulation and their clinical significance

    L. M. Meshсheryakova

    2015-01-01

    Full Text Available This article is а composition of literature and experimental data of iron metabolism. There were studied the level of DMT-1, ferroportin, hepcidin at different stages of anemia and hemochromatosis. It is clear that the level of DMT-1 regulates by the hepcidin. Increaseing of the hepcidin concentration and decreasing DMT-1 level in patients with hemochromatosis explained good results of treatment.

  14. Low Prevalence of Carbapenem-Resistant Bacteria in River Water: Resistance Is Mostly Related to Intrinsic Mechanisms.

    Tacão, Marta; Correia, António; Henriques, Isabel S

    2015-10-01

    Carbapenems are last-resort antibiotics to handle serious infections caused by multiresistant bacteria. The incidence of resistance to these antibiotics has been increasing and new resistance mechanisms have emerged. The dissemination of carbapenem resistance in the environment has been overlooked. The main goal of this research was to assess the prevalence and diversity of carbapenem-resistant bacteria in riverine ecosystems. The presence of frequently reported carbapenemase-encoding genes was inspected. The proportion of imipenem-resistant bacteria was on average 2.24 CFU/ml. Imipenem-resistant strains (n=110) were identified as Pseudomonas spp., Stenotrophomonas maltophilia, Aeromonas spp., Chromobacterium haemolyticum, Shewanella xiamenensis, and members of Enterobacteriaceae. Carbapenem-resistant bacteria were highly resistant to other beta-lactams such as quinolones, aminoglycosides, chloramphenicol, tetracyclines, and sulfamethoxazole/trimethoprim. Carbapenem resistance was mostly associated with intrinsically resistant bacteria. As intrinsic resistance mechanisms, we have identified the blaCphA gene in 77.3% of Aeromonas spp., blaL1 in all S. maltophilia, and blaOXA-48-like in all S. xiamenensis. As acquired resistance mechanisms, we have detected the blaVIM-2 gene in six Pseudomonas spp. (5.45%). Integrons with gene cassettes encoding resistance to aminoglycosides (aacA and aacC genes), trimethoprim (dfrB1b), and carbapenems (blaVIM-2) were found in Pseudomonas spp. Results suggest that carbapenem resistance dissemination in riverine ecosystems is still at an early stage. Nevertheless, monitoring these aquatic compartments for the presence of resistance genes and its host organisms is essential to outline strategies to minimize resistance dissemination.

  15. 2-deoxy-D-glucose-induced metabolic stress enhances resistance to Listeria monocytogenes infection in mice

    Miller, E. S.; Bates, R. A.; Koebel, D. A.; Fuchs, B. B.; Sonnenfeld, G.

    1998-01-01

    Exposure to different forms of psychological and physiological stress can elicit a host stress response, which alters normal parameters of neuroendocrine homeostasis. The present study evaluated the influence of the metabolic stressor 2-deoxy-D-glucose (2-DG; a glucose analog, which when administered to rodents, induces acute periods of metabolic stress) on the capacity of mice to resist infection with the facultative intracellular bacterial pathogen Listeria monocytogenes. Female BDF1 mice were injected with 2-DG (500 mg/kg b. wt.) once every 48 h prior to, concurrent with, or after the onset of a sublethal dose of virulent L. monocytogenes. Kinetics of bacterial growth in mice were not altered if 2-DG was applied concurrently or after the start of the infection. In contrast, mice exposed to 2-DG prior to infection demonstrated an enhanced resistance to the listeria challenge. The enhanced bacterial clearance in vivo could not be explained by 2-DG exerting a toxic effect on the listeria, based on the results of two experiments. First, 2-DG did not inhibit listeria replication in trypticase soy broth. Second, replication of L. monocytogenes was not inhibited in bone marrow-derived macrophage cultures exposed to 2-DG. Production of neopterin and lysozyme, indicators of macrophage activation, were enhanced following exposure to 2-DG, which correlated with the increased resistance to L. monocytogenes. These results support the contention that the host response to 2-DG-induced metabolic stress can influence the capacity of the immune system to resist infection by certain classes of microbial pathogens.

  16. Metabolic syndrome and Chronic Obstructive Pulmonary Disease (COPD): The interplay among smoking, insulin resistance and vitamin D.

    Piazzolla, Giuseppina; Castrovilli, Anna; Liotino, Vito; Vulpi, Maria Rosaria; Fanelli, Margherita; Mazzocca, Antonio; Candigliota, Mafalda; Berardi, Elsa; Resta, Onofrio; Sabbà, Carlo; Tortorella, Cosimo

    2017-01-01

    A close relationship between Metabolic Syndrome (MetS) and Chronic Obstructive Pulmonary Disease (COPD) has been described, but the exact nature of this link remains unclear. Current epidemiological data refer exclusively to the MetS prevalence among patients with COPD and data about the prevalence of COPD in MetS patients are still unavailable. To analyse and compare risk factors, clinical and metabolic characteristics, as well as the main respiratory function parameters, among patients affected by MetS, COPD or both diseases. We recruited 59 outpatients with MetS and 76 outpatients with COPD. After medical history collection, physical examination, blood sampling for routine analysis, spirometric evaluation, they were subdivided into MetS (n = 46), MetS+COPD (n = 60), COPD (n = 29). A MetS diagnosis was assigned to 62% of COPD patients recruited in the COPD Outpatients Clinic of the Pneumology Department, while the COPD prevalence in MetS patients enrolled in the Internal Medicine Metabolic Disorders Outpatients Clinic was 22%. More than 60% of subjects enrolled in each Department were unaware that they suffered from an additional disease. MetS+COPD patients exhibited significantly higher C-peptide levels. We also found a positive relation between C-peptide and pack-years in all subjects and a negative correlation between C-peptide and vitamin D only in current smokers. Finally, a negative association emerged between smoking and vitamin D. We have estimated, for the first time, the COPD prevalence in MetS and suggest a potential role of smoking in inducing insulin resistance. Moreover, a direct effect of smoking on vitamin D levels is proposed as a novel mechanism, which may account for both insulin resistance and COPD development.

  17. Weight-adjusted lean body mass and calf circumference are protective against obesity-associated insulin resistance and metabolic abnormalities

    Toshinari Takamura

    2017-07-01

    Interpretation: Weight-adjusted lean body mass and skeletal muscle area are protective against weight-associated insulin resistance and metabolic abnormalities. The calf circumference reflects lean body mass and may be useful as a protective marker against obesity-associated metabolic abnormalities.

  18. Life cycle synchronization is a viral drug resistance mechanism.

    Iulia A Neagu

    2018-02-01

    Full Text Available Viral infections are one of the major causes of death worldwide, with HIV infection alone resulting in over 1.2 million casualties per year. Antiviral drugs are now being administered for a variety of viral infections, including HIV, hepatitis B and C, and influenza. These therapies target a specific phase of the virus's life cycle, yet their ultimate success depends on a variety of factors, such as adherence to a prescribed regimen and the emergence of viral drug resistance. The epidemiology and evolution of drug resistance have been extensively characterized, and it is generally assumed that drug resistance arises from mutations that alter the virus's susceptibility to the direct action of the drug. In this paper, we consider the possibility that a virus population can evolve towards synchronizing its life cycle with the pattern of drug therapy. The periodicity of the drug treatment could then allow for a virus strain whose life cycle length is a multiple of the dosing interval to replicate only when the concentration of the drug is lowest. This process, referred to as "drug tolerance by synchronization", could allow the virus population to maximize its overall fitness without having to alter drug binding or complete its life cycle in the drug's presence. We use mathematical models and stochastic simulations to show that life cycle synchronization can indeed be a mechanism of viral drug tolerance. We show that this effect is more likely to occur when the variability in both viral life cycle and drug dose timing are low. More generally, we find that in the presence of periodic drug levels, time-averaged calculations of viral fitness do not accurately predict drug levels needed to eradicate infection, even if there is no synchronization. We derive an analytical expression for viral fitness that is sufficient to explain the drug-pattern-dependent survival of strains with any life cycle length. We discuss the implications of these findings for

  19. Wear resistance and fracture mechanics of WC-Co composites

    Kaytbay, Saleh; El-Hadek, Medhat

    2014-01-01

    Manufacturing of WC-Co composites using the electroless precipitation method at different sintering temperatures of 1 100, 1 250, 1 350 and 1 500 C was successfully achieved. The chemical composition of the investigated materials was 90 wt.% WC with 10 wt.% Co, and 80 wt.% WC with 20 wt.% Co. The specific density, densification, and Vickers microhardness measurements were found to increase with increased sintering temperature for both the WC-Co compositions. The composites of tungsten carbide with 10 wt.% Co had a higher specific density and Vickers microhardness measurements than those for the composites of tungsten carbide with 20 wt.% Co. Composites with WC-10 wt.% Co had better wear resistance. The stress-strain and transverse rupture strength increased monotonically with the increase in sintering temperatures, agreeing with the material hardness and wear resistance behavior. Fractographical scanning electron microscopy analysis of the fracture surface demonstrated a rough characteristic conical shape failure in the direction of the maximum shear stress. A proposed mechanism for the formation of the conical fracture surface under compression testing is presented. (orig.)

  20. Glass-ceramics frits for high mechanical resistance glazes

    Gajek, M.; Lis, J.; Partyka, J.; Wojczyk, M.

    2004-01-01

    The obtaining and application of glass-ceramics frits for glazes were discussed by many authors. This glazes are characterized by raised mechanical parameters and chemical resistance. Factors, that determines crystallization process are initial composition, heat treatment and nucleation agents. The kind of crystalline phases, crystal habit and the content of residual glass phase play the decisive role in the strengthening of the glaze. In this paper are shown results of investigation over controlled crystallization in the ternary systems; Li 2 O-Al 2 O 3 -SiO 2 , CaO-Al 2 O 3 -SiO 2 , ZnO-Al 2 O 3 -SiO 2 , MgO-Al 2 O 3 -SiO 2 , with or without nucleation agents. (author)

  1. Emerging Perspectives on Essential Amino Acid Metabolism in Obesity and the Insulin-Resistant State12

    Adams, Sean H.

    2011-01-01

    Dysregulation of insulin action is most often considered in the context of impaired glucose homeostasis, with the defining feature of diabetes mellitus being elevated blood glucose concentration. Complications arising from the hyperglycemia accompanying frank diabetes are well known and epidemiological studies point to higher risk toward development of metabolic disease in persons with impaired glucose tolerance. Although the central role of proper blood sugar control in maintaining metabolic health is well established, recent developments have begun to shed light on associations between compromised insulin action [obesity, prediabetes, and type 2 diabetes mellitus (T2DM)] and altered intermediary metabolism of fats and amino acids. For amino acids, changes in blood concentrations of select essential amino acids and their derivatives, in particular BCAA, sulfur amino acids, tyrosine, and phenylalanine, are apparent with obesity and insulin resistance, often before the onset of clinically diagnosed T2DM. This review provides an overview of these changes and places recent observations from metabolomics research into the context of historical reports in the areas of biochemistry and nutritional biology. Based on this synthesis, a model is proposed that links the FFA-rich environment of obesity/insulin resistance and T2DM with diminution of BCAA catabolic enzyme activity, changes in methionine oxidation and cysteine/cystine generation, and tissue redox balance (NADH/NAD+). PMID:22332087

  2. Metabolic syndrome, insulin resistance and other cardiovascular risk factors in university students

    José Bonifácio Barbosa

    2016-04-01

    Full Text Available Abstract A cross-sectional population-based study using questionnaire and anthropometric data was conducted on 968 university students of São Luís, Brazil, from which 590 showed up for blood collection. In the statistical analysis the Student t-test, Mann-Whitney and chi-square tests were used. The prevalence of metabolic syndrome by the Joint Interim Statement (JIS criteria was 20.5%, almost three times more prevalent in men (32.2% than in women (13.5% (P < 0.001. The prevalence of insulin resistance was 7.3% and the prevalence of low HDL-cholesterol was high (61.2%, both with no statistically significant differences by sex. Men showed a higher percentage of smoking, overweight, high blood pressure, high blood glucose and increased fasting hypertriglyceridemia. Women were more sedentary. University students of private institutions had higher prevalences of sedentary lifestyle, obesity, abdominal obesity, elevated triglycerides and metabolic syndrome than students from public institutions. High prevalences of metabolic syndrome, insulin resistance and other cardiovascular risk factors were found in this young population. This suggests that the burden of these diseases in the future will be increased.

  3. GLP-1 Elicits an Intrinsic Gut-Liver Metabolic Signal to Ameliorate Diet-Induced VLDL Overproduction and Insulin Resistance.

    Khound, Rituraj; Taher, Jennifer; Baker, Christopher; Adeli, Khosrow; Su, Qiaozhu

    2017-12-01

    Perturbations in hepatic lipid and very-low-density lipoprotein (VLDL) metabolism are involved in the pathogenesis of obesity and hepatic insulin resistance. The objective of this study is to delineate the mechanism of subdiaphragmatic vagotomy in preventing obesity, hyperlipidemia, and insulin resistance. By subjecting the complete subdiaphragmatic vagotomized mice to various nutritional conditions and investigating hepatic de novo lipogenesis pathway, we found that complete disruption of subdiaphragmatic vagal signaling resulted in a significant decrease of circulating VLDL-triglyceride compared with the mice obtained sham procedure. Vagotomy further prevented overproduction of VLDL-triglyceride induced by an acute fat load and a high-fat diet-induced obesity, hyperlipidemia, hepatic steatosis, and glucose intolerance. Mechanistic studies revealed that plasma glucagon-like peptide-1 was significantly raised in the vagotomized mice, which was associated with significant reductions in mRNA and protein expression of SREBP-1c (sterol regulatory element-binding protein 1c), SCD-1 (stearoyl-CoA desaturase-1), and FASN (fatty acid synthase), as well as enhanced hepatic insulin sensitivity. In vitro, treating mouse primary hepatocytes with a glucagon-like peptide-1 receptor agonist, exendin-4, for 48 hours inhibited free fatty acid, palmitic acid treatment induced de novo lipid synthesis, and VLDL secretion from hepatocytes. Elevation of glucagon-like peptide-1 in vagotomized mice may prevent VLDL overproduction and insulin resistance induced by high-fat diet. These novel findings, for the first time, delineate an intrinsic gut-liver regulatory circuit that is mediated by glucagon-like peptide-1 in regulating hepatic energy metabolism. © 2017 American Heart Association, Inc.

  4. Increased anaerobic metabolism is a distinctive signature in a colorectal cancer cellular model of resistance to antiepidermal growth factor receptor antibody.

    Monteleone, Francesca; Rosa, Roberta; Vitale, Monica; D'Ambrosio, Chiara; Succoio, Mariangela; Formisano, Luigi; Nappi, Lucia; Romano, Maria Fiammetta; Scaloni, Andrea; Tortora, Giampaolo; Bianco, Roberto; Zambrano, Nicola

    2013-03-01

    Cetuximab is a chimeric antibody approved for the treatment of metastatic colorectal cancer that selectively targets epidermal growth factor receptor (EGFR) signaling. Treatment efficacy with this drug is often impaired by acquired resistance and poor information has been accumulated on the mechanisms underlying such a phenomenon. By taking advantage of a syngenic cellular system of sensitivity and acquired resistance to anti-EGFR therapy in the colorectal carcinoma GEO cell line, we profiled protein expression differences between Cetuximab-sensitive and -resistant cells. Combined 2D DIGE and MS analyses revealed a main proteomic signature resulting from selective deregulation of various metabolic enzymes, including glucose-6-phosphate dehydrogenase, transketolase, lactate dehydrogenase B, and pyruvate dehydrogenase E1, which was also confirmed by Western blotting experiments. Lactate dehydrogenase B downregulation has been already related to an increased anaerobic utilization of glucose by tumor cells; accordingly, we verified that Cetuximab-resistant cells have a significantly higher production of lactate. Resistant cells also showed decreased nicotinamide adenine dinucleotide phosphate (NADPH) levels. Observed protein deregulations were not related to functional alterations of the hypoxia-inducible factor 1-associated pathways. Our data demonstrate that increased anaerobic metabolism is a prominent feature observed in the GEO syngenic model of acquired resistance to anti-EGFR therapy in colorectal cancer. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Insulin resistance and its association with the components of the metabolic syndrome among obese children and adolescents

    Mass-Díaz Eliezer

    2010-06-01

    Full Text Available Abstract Background Insulin resistance is the primary metabolic disorder associated with obesity; yet little is known about its role as a determinant of the metabolic syndrome in obese children. The aim of this study is to assess the association between the degree of insulin resistance and the different components of the metabolic syndrome among obese children and adolescents. Methods An analytical, cross-sectional and population-based study was performed in forty-four public primary schools in Campeche City, Mexico. A total of 466 obese children and adolescents between 11-13 years of age were recruited. Fasting glucose and insulin concentrations, high density lipoprotein cholesterol, triglycerides, waist circumference, systolic and diastolic blood pressures were measured; insulin resistance and metabolic syndrome were also evaluated. Results Out of the total population studied, 69% presented low values of high density lipoprotein cholesterol, 49% suffered from abdominal obesity, 29% had hypertriglyceridemia, 8% presented high systolic and 13% high diastolic blood pressure, 4% showed impaired fasting glucose, 51% presented insulin resistance and 20% metabolic syndrome. In spite of being obese, 13% of the investigated population did not present any metabolic disorder. For each one of the components of the metabolic syndrome, when insulin resistance increased so did odds ratios as cardiometabolic risk factors. Conclusions Regardless of age and gender an increased degree of insulin resistance is associated with a higher prevalence of disorders in each of the components of the metabolic syndrome and with a heightened risk of suffering metabolic syndrome among obese children and adolescents.

  6. The Effect of Resistance Training on Cardio-Metabolic Factors in Males with Type 2 Diabetes

    Ghalavand

    2014-10-01

    Full Text Available Background Diabetes is one of the most important metabolic diseases in the world and exercise is a common advice to manage diabetes and reduce its complications. Objectives The aim of this study was to investigate the effect of resistance training on blood glucose, blood pressure and resting heart rate in males with type 2 diabetes. Materials and Methods In this semi-experimental study, 20 males with type 2 diabetes with mean age of 46 ± 3.4 years old who met the inclusion criteria were selected. The participants were randomly assigned into resistance training (n = 10 and control (n = 10 groups. Resistance exercise training program was performed for eight weeks, three sessions per week. Cardiovascular and biochemical parameters were measured before and after the intervention. To analyze the measured parameters changes t-test was used at P ≤ 0.05 significance level. Results After eight weeks, a significant decrease in fasting blood sugar (P = 0.002, glycosylated hemoglobin (P = 0.025 and systolic blood pressure (P = 0.022 was observed in the resistance group. In addition, there was a significant difference in blood sugar (P = 0.003 and glycosylated hemoglobin (P = 0.031 between the two groups. Conclusions Findings of this study confirmed the positive influence of resistance training to control blood glucose and blood pressure in males with type 2 diabetes.

  7. New insights into the mechanisms of acetic acid resistance in Acetobacter pasteurianus using iTRAQ-dependent quantitative proteomic analysis.

    Xia, Kai; Zang, Ning; Zhang, Junmei; Zhang, Hong; Li, Yudong; Liu, Ye; Feng, Wei; Liang, Xinle

    2016-12-05

    Acetobacter pasteurianus is the main starter in rice vinegar manufacturing due to its remarkable abilities to resist and produce acetic acid. Although several mechanisms of acetic acid resistance have been proposed and only a few effector proteins have been identified, a comprehensive depiction of the biological processes involved in acetic acid resistance is needed. In this study, iTRAQ-based quantitative proteomic analysis was adopted to investigate the whole proteome of different acidic titers (3.6, 7.1 and 9.3%, w/v) of Acetobacter pasteurianus Ab3 during the vinegar fermentation process. Consequently, 1386 proteins, including 318 differentially expressed proteins (p150 proteins were differentially expressed. Specifically, proteins involved in amino acid metabolic processes and fatty acid biosynthesis were differentially expressed, which may contribute to the acetic acid resistance of Acetobacter. Transcription factors, two component systems and toxin-antitoxin systems were implicated in the modulatory network at multiple levels. In addition, the identification of proteins involved in redox homeostasis, protein metabolism, and the cell envelope suggested that the whole cellular system is mobilized in response to acid stress. These findings provide a differential proteomic profile of acetic acid resistance in Acetobacter pasteurianus and have potential application to highly acidic rice vinegar manufacturing. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Hepatitis C virus nonstructural protein 5A favors upregulation of gluconeogenic and lipogenic gene expression leading towards insulin resistance: a metabolic syndrome.

    Parvaiz, Fahed; Manzoor, Sobia; Iqbal, Jawed; McRae, Steven; Javed, Farrakh; Ahmed, Qazi Laeeque; Waris, Gulam

    2014-05-01

    Chronic hepatitis C is a lethal blood-borne infection often associated with a number of pathologies such as insulin resistance and other metabolic abnormalities. Insulin is a key hormone that regulates the expression of metabolic pathways and favors homeostasis. In this study, we demonstrated the molecular mechanism of hepatitis C virus (HCV) nonstructural protein 5A (NS5A)-induced metabolic dysregulation. We showed that transient expression of HCV NS5A in human hepatoma cells increased lipid droplet formation through enhanced lipogenesis. We also showed increased transcriptional expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α and diacylglycerol acyltransferase-1 (DGAT-1) in NS5A-expressing cells. On the other hand, there was significantly reduced transcriptional expression of microsomal triglyceride transfer protein (MTP) and peroxisome proliferator-activated receptor γ (PPARγ) in cells expressing HCV NS5A. Furthermore, increased gluconeogenic gene expression was observed in HCV-NS5A-expressing cells. In addition, it was also shown that HCV-NS5A-expressing hepatoma cells show serine phosphorylation of IRS-1, thereby hampering metabolic activity and contributing to insulin resistance. Therefore, this study reveals that HCV NS5A is involved in enhanced gluconeogenic and lipogenic gene expression, which triggers metabolic abnormality and impairs insulin signaling pathway.

  9. Metabolic actions of FGF21: molecular mechanisms and therapeutic implications

    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.

  10. Plasma metabolomics reveals membrane lipids, aspartate/asparagine and nucleotide metabolism pathway differences associated with chloroquine resistance in Plasmodium vivax malaria

    Salinas, Jorge L.; Monteiro, Wuelton M.; Val, Fernando; Cordy, Regina J.; Liu, Ken; Melo, Gisely C.; Siqueira, Andre M.; Magalhaes, Belisa; Galinski, Mary R.; Lacerda, Marcus V. G.; Jones, Dean P.

    2017-01-01

    Background Chloroquine (CQ) is the main anti-schizontocidal drug used in the treatment of uncomplicated malaria caused by Plasmodium vivax. Chloroquine resistant P. vivax (PvCR) malaria in the Western Pacific region, Asia and in the Americas indicates a need for biomarkers of resistance to improve therapy and enhance understanding of the mechanisms associated with PvCR. In this study, we compared plasma metabolic profiles of P. vivax malaria patients with PvCR and chloroquine sensitive parasites before treatment to identify potential molecular markers of chloroquine resistance. Methods An untargeted high-resolution metabolomics analysis was performed on plasma samples collected in a malaria clinic in Manaus, Brazil. Male and female patients with Plasmodium vivax were included (n = 46); samples were collected before CQ treatment and followed for 28 days to determine PvCR, defined as the recurrence of parasitemia with detectable plasma concentrations of CQ ≥100 ng/dL. Differentially expressed metabolic features between CQ-Resistant (CQ-R) and CQ-Sensitive (CQ-S) patients were identified using partial least squares discriminant analysis and linear regression after adjusting for covariates and multiple testing correction. Pathway enrichment analysis was performed using Mummichog. Results Linear regression and PLS-DA methods yielded 69 discriminatory features between CQ-R and CQ-S groups, with 10-fold cross-validation classification accuracy of 89.6% using a SVM classifier. Pathway enrichment analysis showed significant enrichment (p<0.05) of glycerophospholipid metabolism, glycosphingolipid metabolism, aspartate and asparagine metabolism, purine and pyrimidine metabolism, and xenobiotics metabolism. Glycerophosphocholines levels were significantly lower in the CQ-R group as compared to CQ-S patients and also to independent control samples. Conclusions The results show differences in lipid, amino acids, and nucleotide metabolism pathways in the plasma of CQ-R versus

  11. Effects of two programs of metabolic resistance training on strength and hypertrophy

    Carolina Brandt Meister

    Full Text Available Abstract Introduction: The effects of low intensity resistance training combined with vascular occlusion have been investigated by several studies. Similar results on strength and hypertrophy have been observed when such method was compared to high intensity protocols. However, due to the specific apparatus needed to apply vascular occlusion (ex.: Kaatsu on some exercises, alternative forms of metabolic training might be used. In the present study, an isometric contraction was performed within each concentric-eccentric transition phase, for every repetition, to elicit metabolic stress. Objective: The aim of the present study was to analyze the effects of two resistance training protocols with metabolic characteristics on strength (1MR, circumference (CIRC and muscle thickness (measured with ultrasonography [MT]. Subjective perception of discomfort was also recorded with an analogical-visual pain scale (AVP. Methods: Twelve young, healthy men were trained with two different methods during 10 weeks. The right limb was trained with an isometric contraction within each concentric-eccentric transition phases for every repetition (ISO whereas the left limb was trained with a pneumatic cuff to apply vascular occlusion (OC on the knee extensor muscles. Both methods were trained at 20% 1MR. Results: It was observed increases on medial tight CIRC, proximal MT, medial MT, distal MT and 1MR, with no difference between both methods. The perception of discomfort was greater for ISO at the end of the third set and lower than reported by OC, at the beginning and end of the training program. Conclusions: Both protocols produced similar gains on strength and hypertrophy. The advantages of training with low loads are important to elderly or rehabilitation training programs. Other studies that compare this method with conventional resistance training are warranted.

  12. Epicardial adipose tissue is associated with visceral fat, metabolic syndrome, and insulin resistance in menopausal women.

    Fernández Muñoz, María J; Basurto Acevedo, Lourdes; Córdova Pérez, Nydia; Vázquez Martínez, Ana Laura; Tepach Gutiérrez, Nayive; Vega García, Sara; Rocha Cruz, Alberto; Díaz Martínez, Alma; Saucedo García, Renata; Zárate Treviño, Arturo; González Escudero, Eduardo Alberto; Degollado Córdova, José Antonio

    2014-06-01

    Epicardial adipose tissue has been associated with several obesity-related parameters and with insulin resistance. Echocardiographic assessment of this tissue is an easy and reliable marker of cardiometabolic risk. However, there are insufficient studies on the relationship between epicardial fat and insulin resistance during the postmenopausal period, when cardiovascular risk increases in women. The objective of this study was to examine the association between epicardial adipose tissue and visceral adipose tissue, waist circumference, body mass index, and insulin resistance in postmenopausal women. A cross sectional study was conducted in 34 postmenopausal women with and without metabolic syndrome. All participants underwent a transthoracic echocardiogram and body composition analysis. A positive correlation was observed between epicardial fat and visceral adipose tissue, body mass index, and waist circumference. The values of these correlations of epicardial fat thickness overlying the aorta-right ventricle were r = 0.505 (P < .003), r = 0.545 (P < .001), and r = 0.515 (P < .003), respectively. Epicardial adipose tissue was higher in postmenopausal women with metabolic syndrome than in those without this syndrome (mean [standard deviation], 544.2 [122.9] vs 363.6 [162.3] mm(2); P = .03). Epicardial fat thickness measured by echocardiography was associated with visceral adipose tissue and other obesity parameters. Epicardial adipose tissue was higher in postmenopausal women with metabolic syndrome. Therefore, echocardiographic assessment of epicardial fat may be a simple and reliable marker of cardiovascular risk in postmenopausal women. Copyright © 2013 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.

  13. [Current options of insulin resistence correction in patients with metabolic syndrome].

    Demidova, T Iu; Ametov, A S; Titova, O I

    2006-01-01

    To study thiasolidindion drug pioglitazone for efficacy in metabolic syndrome (MS). Twenty patients with MS were examined at baseline and after 12 week therapy with pioglitazone. The examination included estimation of fasting and postprandial glycemia, insulin resistance index, HOMA-IR index, HbAlc, lipid profile, microalbuminuria (MAU), blood pressure, endothelium-related vasodilation. Pioglitazone therapy for 12 weeks significantly reduced HbAlc, fasting and postprandial glycemia, insulinemia, HOMA-IR, improved blood lipid spectrum, reduced visceral obesity. Positive effects were also achieved on blood pressure, MAU and endothelium-related vasodilation.

  14. [Prevalence of target organ damage and metabolic abnormalities in resistant hypertension].

    Armario, Pedro; Oliveras, Anna; Hernández Del Rey, Raquel; Ruilope, Luis Miguel; De La Sierra, Alejandro

    2011-10-15

    Patients with resistant hypertension (RH) are relatively frequently visited in specialized units of hypertension. The aim of this study was to assess the prevalence of target organ damage, central obesity and metabolic syndrome in a cohort of patients with RH consecutively included in the Register of Resistant Hypertension of the Spanish Society of Hypertension (SHE-LELHA). Cross-sectional, multicenter epidemiologic study in usual clinical practice conditions. Patients with clinical diagnosis of resistant hypertension, that is, office systolic and diastolic blood pressure ≥ 140 mm Hg and/or ≥ 90 mm Hg, respectively, despite a prescribed therapeutic schedule with an appropriate combination of three or more full-dose antihypertensive drugs, including a diuretic, were consecutively recruited from specialized hypertension units spread through Spain. Demographic and anthropometric characteristics as well as cardiovascular risk factors and associated conditions were recorded, and all the subjects underwent 24-h ambulatory blood pressure monitoring. Left ventricular hypertrophy was considered as a left ventricular mass index ≥ 125 g/m(2) in males and ≥ 110 g/m(2) in females. Left atrial enlargement was defined as an indexed left atrium diameter ≥ 26 mm/m(2). Microalbuminuria was defined as a urinary albumin/creatinine ratio ≥ 22 mg/g in males and ≥ 31 mg/g in females. 513 patients were included, aged 64±11 years old, 47% women. Central obesity was present in 65.7% (CI 95% 61.6-69.9), 38.6% (CI 95% 34.4-42.8) had diabetes and 63.7% (CI 95% 59.4-67.9) had metabolic syndrome. The prevalence of left ventricular hypertrophy and left atrial enlargement, determined by echocardiography was 57.1% (CI 95% 50.8-63.5) and 10.0% (CI 95% 6.3-13.7) respectively. Microalbuminuria was found in 46.6% (CI 95% 41.4-51.8) of the subjects. Patients with metabolic syndrome were significantly older (65.4±11 and 62.5±12 years; P=.0052), presented a higher prevalence of diabetes

  15. Modulation of cell metabolic pathways and oxidative stress signaling contribute to acquired melphalan resistance in multiple myeloma cells

    Zub, Kamila Anna; Sousa, Mirta Mittelstedt Leal de; Sarno, Antonio

    2015-01-01

    of the AKR1C family involved in prostaglandin synthesis contribute to the resistant phenotype. Finally, selected metabolic and oxidative stress response enzymes were targeted by inhibitors, several of which displayed a selective cytotoxicity against the melphalan-resistant cells and should be further...... and pathways not previously associated with melphalan resistance in multiple myeloma cells, including a metabolic switch conforming to the Warburg effect (aerobic glycolysis), and an elevated oxidative stress response mediated by VEGF/IL8-signaling. In addition, up-regulated aldo-keto reductase levels...

  16. Metabolic effects of resistance or high-intensity interval training among glycemic control-nonresponsive children with insulin resistance.

    Álvarez, C; Ramírez-Campillo, R; Ramírez-Vélez, R; Martínez, C; Castro-Sepúlveda, M; Alonso-Martínez, A; Izquierdo, M

    2018-01-01

    Little evidence exists on which variables of body composition or muscular strength mediates more glucose control improvements taking into account inter-individual metabolic variability to different modes of exercise training. We examined 'mediators' to the effects of 6-weeks of resistance training (RT) or high-intensity interval training (HIT) on glucose control parameters in physically inactive schoolchildren with insulin resistance (IR). Second, we also determined both training-induce changes and the prevalence of responders (R) and non-responders (NR) to decrease the IR level. Fifty-six physically inactive children diagnosed with IR followed a RT or supervised HIT program for 6 weeks. Participants were classified based on ΔHOMA-IR into glycemic control R (decrease in homeostasis model assessment-IR (HOMA-IR) training-induced changes to glucose control parameters; and third the report of R and NR to improve body composition, cardiovascular, metabolic and performance variables. Mediation analysis revealed that improvements (decreases) in abdominal fat by the waist circumference can explain more the effects (decreases) of HOMA-IR in physically inactive schoolchildren under RT or HIT regimes. The same analysis showed that increased one-maximum repetition leg-extension was correlated with the change in HOMA-IR (β=-0.058; P=0.049). Furthermore, a change in the waist circumference fully mediated the dose-response relationship between changes in the leg-extension strength and HOMA-IR (β'=-0.004; P=0.178). RT or HIT were associated with significant improvements in body composition, muscular strength, blood pressure and cardiometabolic parameters irrespective of improvement in glycemic control response. Both glucose control RT-R and HIT-R (respectively), had significant improvements in mean HOMA-IR, mean muscular strength leg-extension and mean measures of adiposity. The improvements in the lower body strength and the decreases in waist circumference can explain more

  17. Effect of exoskeletal joint constraint and passive resistance on metabolic energy expenditure: Implications for walking in paraplegia.

    Sarah R Chang

    Full Text Available An important consideration in the design of a practical system to restore walking in individuals with spinal cord injury is to minimize metabolic energy demand on the user. In this study, the effects of exoskeletal constraints on metabolic energy expenditure were evaluated in able-bodied volunteers to gain insight into the demands of walking with a hybrid neuroprosthesis after paralysis. The exoskeleton had a hydraulic mechanism to reciprocally couple hip flexion and extension, unlocked hydraulic stance controlled knee mechanisms, and ankles fixed at neutral by ankle-foot orthoses. These mechanisms added passive resistance to the hip (15 Nm and knee (6 Nm joints while the exoskeleton constrained joint motion to the sagittal plane. The average oxygen consumption when walking with the exoskeleton was 22.5 ± 3.4 ml O2/min/kg as compared to 11.7 ± 2.0 ml O2/min/kg when walking without the exoskeleton at a comparable speed. The heart rate and physiological cost index with the exoskeleton were at least 30% and 4.3 times higher, respectively, than walking without it. The maximum average speed achieved with the exoskeleton was 1.2 ± 0.2 m/s, at a cadence of 104 ± 11 steps/min, and step length of 70 ± 7 cm. Average peak hip joint angles (25 ± 7° were within normal range, while average peak knee joint angles (40 ± 8° were less than normal. Both hip and knee angular velocities were reduced with the exoskeleton as compared to normal. While the walking speed achieved with the exoskeleton could be sufficient for community ambulation, metabolic energy expenditure was significantly increased and unsustainable for such activities. This suggests that passive resistance, constraining leg motion to the sagittal plane, reciprocally coupling the hip joints, and weight of exoskeleton place considerable limitations on the utility of the device and need to be minimized in future designs of practical hybrid neuroprostheses for walking after paraplegia.

  18. Mechanisms of group A Streptococcus resistance to reactive oxygen species.

    Henningham, Anna; Döhrmann, Simon; Nizet, Victor; Cole, Jason N

    2015-07-01

    Streptococcus pyogenes, also known as group A Streptococcus (GAS), is an exclusively human Gram-positive bacterial pathogen ranked among the 'top 10' causes of infection-related deaths worldwide. GAS commonly causes benign and self-limiting epithelial infections (pharyngitis and impetigo), and less frequent severe invasive diseases (bacteremia, toxic shock syndrome and necrotizing fasciitis). Annually, GAS causes 700 million infections, including 1.8 million invasive infections with a mortality rate of 25%. In order to establish an infection, GAS must counteract the oxidative stress conditions generated by the release of reactive oxygen species (ROS) at the infection site by host immune cells such as neutrophils and monocytes. ROS are the highly reactive and toxic byproducts of oxygen metabolism, including hydrogen peroxide (H2O2), superoxide anion (O2•(-)), hydroxyl radicals (OH•) and singlet oxygen (O2*), which can damage bacterial nucleic acids, proteins and cell membranes. This review summarizes the enzymatic and regulatory mechanisms utilized by GAS to thwart ROS and survive under conditions of oxidative stress. © FEMS 2015.

  19. Dietary leucine--an environmental modifier of insulin resistance acting on multiple levels of metabolism

    Macotela, Yazmin; Emanuelli, Brice; Bång, Anneli M

    2011-01-01

    homeostasis and insulin signaling. After 8 weeks on HFD, mice developed obesity, fatty liver, inflammatory changes in adipose tissue and insulin resistance at the level of IRS-1 phosphorylation, as well as alterations in metabolomic profile of amino acid metabolites, TCA cycle intermediates, glucose...... and cholesterol metabolites, and fatty acids in liver, muscle, fat and serum. Doubling dietary leucine reversed many of the metabolite abnormalities and caused a marked improvement in glucose tolerance and insulin signaling without altering food intake or weight gain. Increased dietary leucine was also associated......Environmental factors, such as the macronutrient composition of the diet, can have a profound impact on risk of diabetes and metabolic syndrome. In the present study we demonstrate how a single, simple dietary factor--leucine--can modify insulin resistance by acting on multiple tissues...

  20. Weight-adjusted lean body mass and calf circumference are protective against obesity-associated insulin resistance and metabolic abnormalities.

    Takamura, Toshinari; Kita, Yuki; Nakagen, Masatoshi; Sakurai, Masaru; Isobe, Yuki; Takeshita, Yumie; Kawai, Kohzo; Urabe, Takeshi; Kaneko, Shuichi

    2017-07-01

    To test the hypothesis that preserved muscle mass is protective against obesity-associated insulin resistance and metabolic abnormalities, we analyzed the relationship of lean body mass and computed tomography-assessed sectional areas of specific skeletal muscles with insulin resistance and metabolic abnormalities in a healthy cohort. A total of 195 subjects without diabetes who had completed a medical examination were included in this study. Various anthropometric indices such as circumferences of the arm, waist, hip, thigh, and calf were measured. Body composition (fat and lean body mass) was determined by bioelectrical impedance analysis. Sectional areas of specific skeletal muscles (iliopsoas, erector spinae, gluteus, femoris, and rectus abdominis muscles) were measured using computed tomography. Fat and lean body mass were significantly correlated with metabolic abnormalities and insulin resistance indices. When adjusted by weight, relationships of fat and lean body mass with metabolic parameters were mirror images of each other. The weight-adjusted lean body mass negatively correlated with systolic and diastolic blood pressures; fasting plasma glucose, HbA1c, alanine aminotransferase, and triglyceride, and insulin levels; and hepatic insulin resistance indices, and positively correlated with HDL-cholesterol levels and muscle insulin sensitivity indices. Compared with weight-adjusted lean body mass, weight-adjusted sectional areas of specific skeletal muscles showed similar, but not as strong, correlations with metabolic parameters. Among anthropometric measures, the calf circumference best reflected lean body mass, and weight-adjusted calf circumference negatively correlated with metabolic abnormalities and insulin resistance indices. Weight-adjusted lean body mass and skeletal muscle area are protective against weight-associated insulin resistance and metabolic abnormalities. The calf circumference reflects lean body mass and may be useful as a protective

  1. genome-wide association and metabolic pathway analysis of corn earworm resistance in maize

    Marilyn L. Warburton; Erika D. Womack; Juliet D. Tang; Adam Thrash; J. Spencer Smith; Wenwei Xu; Seth C. Murray; W. Paul Williams

    2018-01-01

    Maize (Zea mays mays L.) is a staple crop of economic, industrial, and food security importance. Damage to the growing ears by corn earworm [Helicoverpa zea (Boddie)] is a major economic burden and increases secondary fungal infections and mycotoxin levels. To identify biochemical pathways associated with native resistance mechanisms, a genome-wide...

  2. No cross-resistance between imidacloprid and pymetrozine in the brown planthopper: status and mechanisms.

    Yang, Yuanxue; Huang, Lixin; Wang, Yunchao; Zhang, Yixi; Fang, Siqi; Liu, Zewen

    2016-06-01

    Cross-resistance between insecticides, especially from different groups, can be extremely unpredictable, and it has been a serious concern in pest control. Pymetrozine has been widely used to control Nilaparvata lugens with the suspension of imidacloprid for the resistance, and N. lugens has showed obvious pymetrozine resistance in recent years. To investigate the possible cross-resistance between imidacloprid and pymetrozine is very important to avoid the adverse effects on resistance development and pest control. Bioassays of two field populations in five consecutive years showed that imidacloprid resistance decreased greatly, while pymetrozine resistance increased significantly. The synergist piperonyl butoxide (PBO) could synergize both imidacloprid and pymetrozine in all field populations, which indicated the importance of P450s in the resistance to two insecticides. Imidacloprid resistance was reported to be associated with two P450s, CYP6AY1 and CYP6ER1, which could metabolize imidacloprid efficiently. However, the recombinant proteins of these two P450s did not show any enzymatic activity to metabolize pymetrozine. The pymetrozine susceptibility did not change when CYP6AY1 and CYP6ER1 mRNA levels were reduced by RNA interference (RNAi), although which could obviously decrease imidacloprid resistance. In vivo and in vitro studies provided evidences to demonstrate that there was no cross-resistance between imidacloprid and pymetrozine in N. lugens, which was different from the findings in Bemisia tabaci. Copyright © 2015. Published by Elsevier Inc.

  3. Understanding the molecular mechanism(s) of hepatitis C virus (HCV) induced interferon resistance.

    Qashqari, Hanadi; Al-Mars, Amany; Chaudhary, Adeel; Abuzenadah, Adel; Damanhouri, Ghazi; Alqahtani, Mohammed; Mahmoud, Maged; El Sayed Zaki, Maysaa; Fatima, Kaneez; Qadri, Ishtiaq

    2013-10-01

    Hepatitis C virus (HCV) is one of the foremost causes of chronic liver disease affecting over 300 million globally. HCV contains a positive-stranded RNA of ~9600 nt and is surrounded by the 5' and 3'untranslated regions (UTR). The only successful treatment regimen includes interferon (IFN) and ribavirin. Like many other viruses, HCV has also evolved various mechanisms to circumvent the IFN response by blocking (1) downstream signaling actions via STAT1, STAT2, IRF9 and JAK-STAT pathways and (2) repertoire of IFN Stimulatory Genes (ISGs). Several studies have identified complex host demographic and genetic factors as well as viral genetic heterogeneity associated with outcomes of IFN therapy. The genetic predispositions of over 2000 ISGS may render the patients to become resistant, thus identification of such parameters within a subset of population are necessary for management corollary. The ability of various HCV genotypes to diminish IFN antiviral responses plays critical role in the establishment of chronic infection at the acute stage of infection, thus highlighting importance of the resistance in HCV treated groups. The recently defined role of viral protein such as C, E2, NS3/NS4 and NS5A proteins in inducing the IFN resistance are discussed in this article. How the viral and host genetic composition and epistatic connectivity among polymorphic genomic sites synchronizes the evolutionary IFN resistance trend remains under investigation. However, these signals may have the potential to be employed for accurate prediction of therapeutic outcomes. In this review article, we accentuate the significance of host and viral components in IFN resistance with the aim to determine the successful outcome in patients. Copyright © 2013 Elsevier B.V. All rights reserved.

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

    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.,

  5. Poor Sleep Quality is Associated with Insulin Resistance in Postmenopausal Women With and Without Metabolic Syndrome.

    Kline, Christopher E; Hall, Martica H; Buysse, Daniel J; Earnest, Conrad P; Church, Timothy S

    2018-05-01

    Poor sleep quality has previously been shown to be related to insulin resistance in apparently healthy adults. However, it is unclear whether an association between sleep quality and insulin resistance exists among adults with metabolic syndrome (MetS). Participants included 347 overweight/obese postmenopausal women without type 2 diabetes (age: 57.5 ± 6.5 years; body mass index [BMI]: 31.7 ± 3.7 kg/m 2 ; 54% with MetS). Sleep quality was assessed with the six-item Medical Outcomes Study Sleep Scale; values were categorized into quartiles. Insulin resistance was calculated from fasting glucose and insulin with the homeostasis model assessment of insulin resistance (HOMA2-IR) method. Analysis of covariance models were used to examine the association between sleep quality and HOMA2-IR after accounting for MetS and covariates (e.g., BMI, cardiorespiratory fitness, and energy intake). Women with the worst sleep quality had significantly higher HOMA2-IR values than women in all other quartiles (P ≤ 0.05 for each), and women with MetS had significantly higher HOMA2-IR values than women without MetS (P quality and HOMA2-IR did not differ between those with or without MetS (P = 0.26). Women with MetS in the worst quartile of sleep quality had higher HOMA2-IR values than all other women (P 30 min to fall asleep, frequent restless sleep, and frequent daytime drowsiness were each related to higher HOMA2-IR values (each P quality is an important correlate of insulin resistance in postmenopausal women with and without MetS. Intervention studies are needed to determine whether improving sleep improves insulin resistance in populations at elevated cardiometabolic risk.

  6. Clinical epidemiology and resistance mechanisms of carbapenem-resistant Acinetobacter baumannii, French Guiana, 2008-2014.

    Mahamat, Aba; Bertrand, Xavier; Moreau, Brigitte; Hommel, Didier; Couppie, Pierre; Simonnet, Christine; Kallel, Hatem; Demar, Magalie; Djossou, Felix; Nacher, Mathieu

    2016-07-01

    This study investigated the clinical epidemiology and resistance mechanisms of Acinetobacter baumannii and characterised the clonal diversity of carbapenem-resistant A. baumannii (CRAB) during an ICU-associated outbreak at Cayenne Hospital, French Guiana. All non-duplicate A. baumannii isolates from 2008 to 2014 were tested for antibiotic susceptibility by disk diffusion. Multilocus sequence typing, pulsed-field gel electrophoresis (PFGE) and characterisation of carbapenemase-encoding genes were performed on CRAB. Of the 441 A. baumannii isolates, most were from males (54.0%) and were detected mainly from the ICU (30.8%) and medicine wards (21.8%). In the ICU, strains were mainly isolated from the respiratory tract (44.1%) and bloodstream (14.0%), whereas in medicine wards they mainly were from wound/drainage (36.5%) and bloodstream (25.0%). A. baumannii showed the greatest susceptibility to piperacillin/tazobactam (92.7%), imipenem (92.5%), colistin (95.6%) and amikacin (97.2%), being lower in the ICU and medicine wards compared with other wards. An outbreak of OXA-23-producing CRAB occurred in the 13-bed ICU in 2010. CRAB strains were more co-resistant to other antimicrobials compared with non-CRAB. Molecular genetics analysis revealed five sequence types [ST78, ST107 and ST642 and two new STs (ST830 and ST831)]. Analysis of PFGE profiles indicated cross-transmissions of CRAB within the ICU, between the ICU and one medicine ward during transfer of patients, and within that medicine ward. This study provides the first clinical and molecular data of A. baumannii from French Guiana and the Amazon basin. The ICU was the highest risk unit of this nosocomial outbreak of OXA-23-producing CRAB, which could subsequently disseminate within the hospital. Copyright © 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

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

    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 ...

  8. Molecular aspects of glucose homeostasis in skeletal muscle--A focus on the molecular mechanisms of insulin resistance.

    Carnagarin, Revathy; Dharmarajan, Arun M; Dass, Crispin R

    2015-12-05

    Among all the varied actions of insulin, regulation of glucose homeostasis is the most critical and intensively studied. With the availability of glucose from nutrient metabolism, insulin action in muscle results in increased glucose disposal via uptake from the circulation and storage of excess, thereby maintaining euglycemia. This major action of insulin is executed by redistribution of the glucose transporter protein, GLUT4 from intracellular storage sites to the plasma membrane and storage of glucose in the form of glycogen which also involves modulation of actin dynamics that govern trafficking of all the signal proteins of insulin signal transduction. The cellular mechanisms responsible for these trafficking events and the defects associated with insulin resistance are largely enigmatic, and this review provides a consolidated overview of the various molecular mechanisms involved in insulin-dependent glucose homeostasis in skeletal muscle, as insulin resistance at this major peripheral site impacts whole body glucose homeostasis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  9. Resistance of heat resisting steels and alloys to thermal and mechanical low-cycle fatigue

    Tulyakov, G.A.

    1980-01-01

    Carried out is a comparative evalUation of resistance of different materials to thermocyclic deformation and fracture on the base of the experimental data on thermal and mechanical low-cycle fatigUe. Considered are peculiarities of thermal fatigue resistance depending on strength and ductility of the material. It is shown, that in the range of the cycle small numbers before the fracture preference is given to the high-ductility cyclically strengthening austenitic steels of 18Cr-10Ni type with slight relation of yield strength to the σsub(0.2)/σsub(B) tensile strength Highly alloyed strength chromium-nickel steels, as well as cyclically destrengthening perlitic and ferritic steels with stronger σsub(0.2)/σsub(B) relation as compared with simple austenitic steels turn to be more long-lived in the range of the cycle great numbers berore fracture. Perlitic steels are stated to have the lowest parameter values of the K crack growth intensity under the similar limiting conditions of the experiment, while steels and alloys with austenite structure-higher values of the K parameter

  10. The association between the metabolic syndrome and alanine amino transferase is mediated by insulin resistance via related metabolic intermediates (the Cohort on diabetes and atherosclerosis Maastricht (CODAM) study)

    Jacobs, M.; Greevenbroek, van M.M.J.; Kallen, van der C.J.H.; Ferreira, I.; Feskens, E.J.M.; Jansen, E.H.J.M.; Schalkwijk, C.G.; Stehouwer, C.D.A.

    2011-01-01

    The metabolic syndrome is associated with nonalcoholic fatty liver disease (NAFLD) as well as with insulin resistance, inflammatory adipokines, endothelial dysfunction, and higher plasma levels of nonesterified fatty acids (NEFA), all of which may also affect the development of NAFLD. Therefore, we

  11. Influence of multidrug resistance and drug transport proteins on chemotherapy drug metabolism.

    Joyce, Helena; McCann, Andrew; Clynes, Martin; Larkin, Annemarie

    2015-05-01

    Chemotherapy involving the use of anticancer drugs remains an important strategy in the overall management of patients with metastatic cancer. Acquisition of multidrug resistance remains a major impediment to successful chemotherapy. Drug transporters in cell membranes and intracellular drug metabolizing enzymes contribute to the resistance phenotype and determine the pharmacokinetics of anticancer drugs in the body. ATP-binding cassette (ABC) transporters mediate the transport of endogenous metabolites and xenobiotics including cytotoxic drugs out of cells. Solute carrier (SLC) transporters mediate the influx of cytotoxic drugs into cells. This review focuses on the substrate interaction of these transporters, on their biology and what role they play together with drug metabolizing enzymes in eliminating therapeutic drugs from cells. The majority of anticancer drugs are substrates for the ABC transporter and SLC transporter families. Together, these proteins have the ability to control the influx and the efflux of structurally unrelated chemotherapeutic drugs, thereby modulating the intracellular drug concentration. These interactions have important clinical implications for chemotherapy because ultimately they determine therapeutic efficacy, disease progression/relapse and the success or failure of patient treatment.

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

    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.

  13. Neck circumference as a new anthropometric indicator for prediction of insulin resistance and components of metabolic syndrome in adolescents: Brazilian Metabolic Syndrome Study

    Cleliani de Cassia da Silva

    2014-06-01

    Full Text Available OBJECTIVE: To evaluate the correlation between neck circumference and insulin resistance and components of metabolic syndrome in adolescents with different adiposity levels and pubertal stages, as well as to determine the usefulness of neck circumference to predict insulin resistance in adolescents.METHODS:Cross-sectional study with 388 adolescents of both genders from ten to 19 years old. The adolescents underwent anthropometric and body composition assessment, including neck and waist circumferences, and biochemical evaluation. The pubertal stage was obtained by self-assessment, and the blood pressure, by auscultation. Insulin resistance was evaluated by the Homeostasis Model Assessment-Insulin Resistance. The correlation between two variables was evaluated by partial correlation coefficient adjusted for the percentage of body fat and pubertal stage. The performance of neck circumference to identify insulin resistance was tested by Receiver Operating Characteristic Curve.RESULTS: After the adjustment for percentage body fat and pubertal stage, neck circumference correlated with waist circumference, blood pressure, triglycerides and markers of insulin resistance in both genders.CONCLUSIONS: The results showed that the neck circumference is a useful tool for the detection of insulin resistance and changes in the indicators of metabolic syndrome in adolescents. The easiness of application and low cost of this measure may allow its use in Public Health services.

  14. Mechanism of action of gemfibrozil on lipoprotein metabolism.

    Saku, K; Gartside, P S; Hynd, B A; Kashyap, M L

    1985-01-01

    Gemfibrozil is a potent lipid regulating drug whose major effects are to increase plasma high density lipoproteins (HDL) and to decrease plasma triglycerides (TG) in a wide variety of primary and secondary dyslipoproteinemias. Its mechanism of action is not clear. Six patients with primary familial endogenous hypertriglyceridemia with fasting chylomicronemia (type V lipoprotein phenotype) with concurrent subnormal HDL cholesterol levels (HDL deficiency) were treated initially by diet and once...

  15. Adipose tissue gene expression analysis reveals changes in inflammatory, mitochondrial respiratory and lipid metabolic pathways in obese insulin-resistant subjects

    Soronen Jarkko

    2012-04-01

    Full Text Available Abstract Background To get insight into molecular mechanisms underlying insulin resistance, we compared acute in vivo effects of insulin on adipose tissue transcriptional profiles between obese insulin-resistant and lean insulin-sensitive women. Methods Subcutaneous adipose tissue biopsies were obtained before and after 3 and 6 hours of intravenously maintained euglycemic hyperinsulinemia from 9 insulin-resistant and 11 insulin-sensitive females. Gene expression was measured using Affymetrix HG U133 Plus 2 microarrays and qRT-PCR. Microarray data and pathway analyses were performed with Chipster v1.4.2 and by using in-house developed nonparametric pathway analysis software. Results The most prominent difference in gene expression of the insulin-resistant group during hyperinsulinemia was reduced transcription of nuclear genes involved in mitochondrial respiration (mitochondrial respiratory chain, GO:0001934. Inflammatory pathways with complement components (inflammatory response, GO:0006954 and cytokines (chemotaxis, GO:0042330 were strongly up-regulated in insulin-resistant as compared to insulin-sensitive subjects both before and during hyperinsulinemia. Furthermore, differences were observed in genes contributing to fatty acid, cholesterol and triglyceride metabolism (FATP2, ELOVL6, PNPLA3, SREBF1 and in genes involved in regulating lipolysis (ANGPTL4 between the insulin-resistant and -sensitive subjects especially during hyperinsulinemia. Conclusions The major finding of this study was lower expression of mitochondrial respiratory pathway and defective induction of lipid metabolism pathways by insulin in insulin-resistant subjects. Moreover, the study reveals several novel genes whose aberrant regulation is associated with the obese insulin-resistant phenotype.

  16. Investigating of four main carbapenem-resistance mechanisms in high-level carbapenem resistant Pseudomonas aeruginosa isolated from burn patients

    Soodabeh Rostami

    2018-02-01

    Conclusion: Emerging antimicrobial resistance in burn wound bacterial pathogens is a serious therapeutic challenge for clinicians. In the present study, most of the isolates were MDR. This finding indicated an alarming spread of resistant isolates and suggested that infection control strategies should be considered. Resistance to carbapenems is influenced by several factors, not all of which were evaluated in our study; however, the results showed that production of MBLs and overexpression of the mexB gene were the most frequent mechanisms in carbapenem-resistant isolates.

  17. Genomic Footprints of Selective Sweeps from Metabolic Resistance to Pyrethroids in African Malaria Vectors Are Driven by Scale up of Insecticide-Based Vector Control.

    Barnes, Kayla G; Weedall, Gareth D; Ndula, Miranda; Irving, Helen; Mzihalowa, Themba; Hemingway, Janet; Wondji, Charles S

    2017-02-01

    Insecticide resistance in mosquito populations threatens recent successes in malaria prevention. Elucidating patterns of genetic structure in malaria vectors to predict the speed and direction of the spread of resistance is essential to get ahead of the 'resistance curve' and to avert a public health catastrophe. Here, applying a combination of microsatellite analysis, whole genome sequencing and targeted sequencing of a resistance locus, we elucidated the continent-wide population structure of a major African malaria vector, Anopheles funestus. We identified a major selective sweep in a genomic region controlling cytochrome P450-based metabolic resistance conferring high resistance to pyrethroids. This selective sweep occurred since 2002, likely as a direct consequence of scaled up vector control as revealed by whole genome and fine-scale sequencing of pre- and post-intervention populations. Fine-scaled analysis of the pyrethroid resistance locus revealed that a resistance-associated allele of the cytochrome P450 monooxygenase CYP6P9a has swept through southern Africa to near fixation, in contrast to high polymorphism levels before interventions, conferring high levels of pyrethroid resistance linked to control failure. Population structure analysis revealed a barrier to gene flow between southern Africa and other areas, which may prevent or slow the spread of the southern mechanism of pyrethroid resistance to other regions. By identifying a genetic signature of pyrethroid-based interventions, we have demonstrated the intense selective pressure that control interventions exert on mosquito populations. If this level of selection and spread of resistance continues unabated, our ability to control malaria with current interventions will be compromised.

  18. Genomic Footprints of Selective Sweeps from Metabolic Resistance to Pyrethroids in African Malaria Vectors Are Driven by Scale up of Insecticide-Based Vector Control.

    Kayla G Barnes

    2017-02-01

    Full Text Available Insecticide resistance in mosquito populations threatens recent successes in malaria prevention. Elucidating patterns of genetic structure in malaria vectors to predict the speed and direction of the spread of resistance is essential to get ahead of the 'resistance curve' and to avert a public health catastrophe. Here, applying a combination of microsatellite analysis, whole genome sequencing and targeted sequencing of a resistance locus, we elucidated the continent-wide population structure of a major African malaria vector, Anopheles funestus. We identified a major selective sweep in a genomic region controlling cytochrome P450-based metabolic resistance conferring high resistance to pyrethroids. This selective sweep occurred since 2002, likely as a direct consequence of scaled up vector control as revealed by whole genome and fine-scale sequencing of pre- and post-intervention populations. Fine-scaled analysis of the pyrethroid resistance locus revealed that a resistance-associated allele of the cytochrome P450 monooxygenase CYP6P9a has swept through southern Africa to near fixation, in contrast to high polymorphism levels before interventions, conferring high levels of pyrethroid resistance linked to control failure. Population structure analysis revealed a barrier to gene flow between southern Africa and other areas, which may prevent or slow the spread of the southern mechanism of pyrethroid resistance to other regions. By identifying a genetic signature of pyrethroid-based interventions, we have demonstrated the intense selective pressure that control interventions exert on mosquito populations. If this level of selection and spread of resistance continues unabated, our ability to control malaria with current interventions will be compromised.

  19. L-Asparaginase of Leishmania donovani: Metabolic target and its role in Amphotericin B resistance

    Jasdeep Singh

    2017-12-01

    Full Text Available Emergence of Amphotericin B (AmB resistant Leishmania donovani has posed major therapeutic challenge against the parasite. Consequently, combination therapy aimed at multiple molecular targets, based on proteome wise network analysis has been recommended. In this regard we had earlier identified and proposed L-asparaginase of Leishmania donovani (LdAI as a crucial metabolic target. Here we report that both LdAI overexpressing axenic amastigote and promastigote forms of L. donovani survives better when challenged with AmB as compared to wild type strain. Conversely, qRT-PCR analysis showed an upregulation of LdAI in both forms upon AmB treatment. Our data demonstrates the importance of LdAI in imparting immediate protective response to the parasite upon AmB treatment. In the absence of structural and functional information, we modeled LdAI and validated its solution structure through small angle X-ray scattering (SAXS analysis. We identified its specific inhibitors through ligand and structure-based approach and characterized their effects on enzymatic properties (Km, Vmax, Kcat of LdAI. We show that in presence of two of the inhibitors L1 and L2, the survival of L. donovani is compromised whereas overexpression of LdAI in these cells restores viability. Taken together, our results conclusively prove that LdAI is a crucial metabolic enzyme conferring early counter measure against AmB treatment by Leishmania. Keywords: Leishmania donovani, L-asparaginase, Amphotericin B resistance, Metabolic target

  20. Low fish oil intake improves insulin sensitivity, lipid profile and muscle metabolism on insulin resistant MSG-obese rats.

    Yamazaki, Ricardo K; Brito, Gleisson A P; Coelho, Isabela; Pequitto, Danielle C T; Yamaguchi, Adriana A; Borghetti, Gina; Schiessel, Dalton Luiz; Kryczyk, Marcelo; Machado, Juliano; Rocha, Ricelli E R; Aikawa, Julia; Iagher, Fabiola; Naliwaiko, Katya; Tanhoffer, Ricardo A; Nunes, Everson A; Fernandes, Luiz Claudio

    2011-04-28

    Obesity is commonly associated with diabetes, cardiovascular diseases and cancer. The purpose of this study was to determinate the effect of a lower dose of fish oil supplementation on insulin sensitivity, lipid profile, and muscle metabolism in obese rats. Monosodium glutamate (MSG) (4 mg/g body weight) was injected in neonatal Wistar male rats. Three-month-old rats were divided in normal-weight control group (C), coconut fat-treated normal weight group (CO), fish oil-treated normal weight group (FO), obese control group (Ob), coconut fat-treated obese group (ObCO) and fish oil-treated obese group (ObFO). Obese insulin-resistant rats were supplemented with fish oil or coconut fat (1 g/kg/day) for 4 weeks. Insulin sensitivity, fasting blood biochemicals parameters, and skeletal muscle glucose metabolism were analyzed. Obese animals (Ob) presented higher Index Lee and 2.5 fold epididymal and retroperitoneal adipose tissue than C. Insulin sensitivity test (Kitt) showed that fish oil supplementation was able to maintain insulin sensitivity of obese rats (ObFO) similar to C. There were no changes in glucose and HDL-cholesterol levels amongst groups. Yet, ObFO revealed lower levels of total cholesterol (TC; 30%) and triacylglycerol (TG; 33%) compared to Ob. Finally, since exposed to insulin, ObFO skeletal muscle revealed an increase of 10% in lactate production, 38% in glycogen synthesis and 39% in oxidation of glucose compared to Ob. Low dose of fish oil supplementation (1 g/kg/day) was able to reduce TC and TG levels, in addition to improved systemic and muscle insulin sensitivity. These results lend credence to the benefits of n-3 fatty acids upon the deleterious effects of insulin resistance mechanisms.

  1. Low fish oil intake improves insulin sensitivity, lipid profile and muscle metabolism on insulin resistant MSG-obese rats

    Iagher Fabiola

    2011-04-01

    Full Text Available Abstract Background Obesity is commonly associated with diabetes, cardiovascular diseases and cancer. The purpose of this study was to determinate the effect of a lower dose of fish oil supplementation on insulin sensitivity, lipid profile, and muscle metabolism in obese rats. Methods Monosodium glutamate (MSG (4 mg/g body weight was injected in neonatal Wistar male rats. Three-month-old rats were divided in normal-weight control group (C, coconut fat-treated normal weight group (CO, fish oil-treated normal weight group (FO, obese control group (Ob, coconut fat-treated obese group (ObCO and fish oil-treated obese group (ObFO. Obese insulin-resistant rats were supplemented with fish oil or coconut fat (1 g/kg/day for 4 weeks. Insulin sensitivity, fasting blood biochemicals parameters, and skeletal muscle glucose metabolism were analyzed. Results Obese animals (Ob presented higher Index Lee and 2.5 fold epididymal and retroperitoneal adipose tissue than C. Insulin sensitivity test (Kitt showed that fish oil supplementation was able to maintain insulin sensitivity of obese rats (ObFO similar to C. There were no changes in glucose and HDL-cholesterol levels amongst groups. Yet, ObFO revealed lower levels of total cholesterol (TC; 30% and triacylglycerol (TG; 33% compared to Ob. Finally, since exposed to insulin, ObFO skeletal muscle revealed an increase of 10% in lactate production, 38% in glycogen synthesis and 39% in oxidation of glucose compared to Ob. Conclusions Low dose of fish oil supplementation (1 g/kg/day was able to reduce TC and TG levels, in addition to improved systemic and muscle insulin sensitivity. These results lend credence to the benefits of n-3 fatty acids upon the deleterious effects of insulin resistance mechanisms.

  2. Resistance to antivirals in human cytomegalovirus: mechanisms and clinical significance.

    Pérez, J L

    1997-09-01

    Long term therapies needed for managing human cytomegalovirus (HCMV) infections in immunosupressed patients provided the background for the emergence of the resistance to antivirals active against HCMV. In addition, laboratory selected mutants have also been readily achieved. Both clinical and laboratory resistant strains share the same determinants of resistance. Ganciclovir resistance may be due to a few mutations in the HCMV UL97 gene and/or viral DNA pol gene, the former being responsible for about 70% of clinical resistant isolates. Among them, V464, V594, S595 and F595 are the most frequent mutations. Because of their less extensive clinical use, much less is known about resistance to foscarnet and cidofovir (formerly, HPMPC) but in both cases, it has been associated to mutations in the DNA pol. Ganciclovir resistant strains showing DNA pol mutations are cross-resistant to cidofovir and their corresponding IC50 are normally higher than those from strains harboring only mutations at the UL97 gene. To date, foscarnet resistance seems to be independent of both ganciclovir and cidofovir resistance.

  3. Dissecting diabetes/metabolic disease mechanisms using pluripotent stem cells and genome editing tools

    Adrian Kee Keong Teo

    2015-09-01

    Major conclusions: hPSCs and the advancing genome editing tools appear to be a timely and potent combination for probing molecular mechanism(s underlying diseases such as diabetes and metabolic syndromes. The knowledge gained from these hiPSC-based disease modeling studies can potentially be translated into the clinics by guiding clinicians on the appropriate type of medication to use for each condition based on the mechanism of action of the disease.

  4. Mechanisms of changes in glucose metabolism and bodyweight after bariatric surgery

    Madsbad, Sten; Dirksen, Carsten; Holst, Jens Juul

    2014-01-01

    gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) induce changes in appetite through regulation of gut hormones, resulting in decreased hunger and increased satiation. Thus, VSG and RYBG more frequently result in remission of type 2 diabetes than does LAGB. With all three of these procedures, remission...... regulatory pathways that control appetite and glucose metabolism after bariatric surgery. Recent research suggests that changes in bile acid concentrations in the blood and altered intestinal microbiota might contribute to metabolic changes after surgery, but the mechanisms are unclear. In this Series paper......, we explore the possible mechanisms underlying the effects on glucose metabolism and bodyweight of LAGB, VSG, and RYGB surgery. Elucidation of these mechanisms is providing knowledge about bodyweight regulation and the pathophysiology of type 2 diabetes, and could help to identify new drug targets...

  5. Therapeutic fasting in patients with metabolic syndrome and impaired insulin resistance.

    Stange, Rainer; Pflugbeil, Christine; Michalsen, Andreas; Uehleke, Bernhard

    2013-01-01

    In this study, we evaluated whether a short- to mid-term fasting therapy (7-18 days) might improve insulin resistance according to the homeostasis model assessment for insulin resistance (HOMA-IR), measured during mid-term (80 days) follow-up observation in patients with metabolic syndrome. In this open label observational study in inpatients, criteria of metabolic syndrome were defined. Before medically controlled Buchinger fasting, a wash-out period for hypoglycemic agents was conducted. Further evaluation was carried out on day 80. 25 patients (13 males, 12 females, mean age 61.3 years) were included in this study (mean fasting duration 11.5 days). Out of 16 inpatients with type 2 diabetes, 4 had been treated with metformin, 3 with insulin, and 1 with glimepiride before the intervention. After therapy, body mass index (BMI), fasting insulin, fasting glucose, and HOMA-IR were all significantly reduced. Compared to baseline, HOMA-IR decreased by 33% in all patients, by 38% in patients with type 2 diabetes, and by 23% in patients without diabetes. At day 80, BMI further improved, while other parameters showed complete (insulin) or partial (glucose, HOMA-IR) rebound. At this time, HOMA-IR values showed an only insignificant improvement in 15% of all patients, in 20% of patients with type 2 diabetes, and in 6% of patients without diabetes. There was no correlation between change in BMI and change in HOMA-IR (r(2) = 0.008, baseline minus day 80). No serious side effects were observed. Fasting as a safe and acceptable procedure may cause short- and mid-term improvement of increased insulin resistance (HOMA-IR). Patients with type 2 diabetes benefit more than those without diabetes. A possible clinical significance of this effect should be explored in larger and controlled clinical trials. © 2014 S. Karger GmbH, Freiburg.

  6. Obstructive sleep apnoea is independently associated with the metabolic syndrome but not insulin resistance state

    Sithole J

    2006-11-01

    Full Text Available Abstract Obstructive sleep apnoea (OSA is a cardio-metabolic disorder. Whether metabolic syndrome (MS, insulin resistance (IR and albuminuria are independently associated with OSA is unclear, but defining the interactions between OSA and various cardiovascular (CV risk factors independent of obesity facilitates the development of therapeutic strategies to mitigate their increased CV risks. We prospectively recruited 38 subjects with OSA and 41 controls. Anthropometric measurements, glucose, lipids, insulin and blood pressure (BP were measured after an overnight fast. IR state was defined as homeostasis model assessment (HOMA value >3.99 and MS diagnosed according to the International Diabetes Federation (IDF criteria. Subjects with OSA were more obese, more insulin resistant, more hyperglycaemic, had higher Epworth score (measure of day time somnolence and systolic blood pressure levels. The prevalence of MS was higher in OSA compared with non-OSA subjects (74% vs 24%, p 103 cm would predict MS in patients with OSA at 75–78% sensitivity and 61–64% specificity. The agreement between MS and IR state in this cohort is poor. Thus, OSA is associated with MS independent of obesity predominantly due to increased triglyceride, glucose and Epworth score values but not IR or microalbuminuria status. This observation suggests an alternative pathogenic factor mediating the increased cardiovascular risk in patients with OSA and MS, other than that due to IR. The independent link between Epworth score and MS in patients with OSA implicates the role of daytime sleepiness and chronic hypoxia as a potential mediator. Given the discordant between MS and IR state, measurement of waist is useful for predicting mainly MS but not insulin resistance status in patients with OSA. Appropriate pharmacological intervention targeting these independent factors is important in reducing the increased CV risks among patients with OSA.

  7. Determination of metabolic resistance mechanisms in pyrethroid-resistant and fipronil-tolerant brown dog ticks

    Rhipicephalus sanguineus (Latreille) (Ixodida: Ixodidae) is a three-host dog tick found worldwide that is able to complete its’ entire lifecycle indoors. Options for the management of R. sanguineus are limited and its’ control relies largely on only a few acaricidal active ingredients. Previous stud...

  8. Induction of resistance to gray mold with benzothiadiazole modifies amino acid profile and increases proanthocyanidins in grape: primary versus secondary metabolism.

    Iriti, Marcello; Rossoni, Mara; Borgo, Michele; Ferrara, Luigia; Faoro, Franco

    2005-11-16

    Field treatments of grapevine (cv. Merlot) with the plant activator benzothiadiazole (BTH, 0.3 mM) induced resistance against gray mold caused by Botrytis cinerea. Both incidence and severity of the disease were reduced. The resistance was associated with an increase of total polyphenols in berry skins, in particular, the proanthocyanidin fraction, that increased up to 36%. The amino acid profile of leaves was also modified by treatments, particularly lysine, that augmented 4-fold. Other amino acids involved in resistance mechanisms to either biotic or abiotic stress increased as well. These results indicate that BTH treatments can be used to control gray mold, thereby limiting an excessive use of fungicides, and could be exploited to increase the content of micronutrients of high nutritional value, arising from both primary and secondary metabolisms.

  9. Innovative dairy cow management to improve resistance to metabolic and infectious diseases during the transition period.

    Lacasse, P; Vanacker, N; Ollier, S; Ster, C

    2018-02-01

    The incidence of metabolic and infectious diseases varies greatly during the lactation cycle. Most new cases of clinical mastitis appear at the beginning of lactation, and the incidence increases with the level of milk production. In addition to mastitis, many other infectious diseases become clinically apparent during the first 2weeks of lactation. During this time, cows are in a negative energy balance and must mobilize body reserves to balance the deficit between food energy intake and energy required for milk production. The relationships between energy deficit and metabolic diseases, such as ketosis and hepatic lipidosis, are well known. Furthermore, cows in energy deficit have a weakened immune system and are therefore more susceptible to infections. There is now good evidence that the increase in circulating non-esterified fatty acids impairs immune cell functions. Therefore, management approaches that reduce the negative energy balance and the increase in non-esterified fatty acids at the beginning of lactation are likely to improve resistance to infection. Improving the nutrient supply through periparturient nutritional management has been the subject of considerable research. However, another way to reduce the imbalance between nutrient supply and demand is to temporarily decrease the latter. In this review, we examine how management strategies such as conjugated linoleic acid feeding, prepartum milking, or limiting postpartum milk production could be used to reduce metabolic perturbations and immunosuppression during the transition period. At this stage, it appears that reducing the amount of milk harvested postpartum by means of partial milking in the first days after calving is the most promising approach to reduce metabolic stress and immunosuppression without compromising the productivity of high-yielding dairy cows. Copyright © 2017. Published by Elsevier Ltd.

  10. Genetic resistance in experimental autoimmune encephalomyelitis. I. Analysis of the mechanism of LeR resistance using radiation chimeras

    Pelfrey, C.M.; Waxman, F.J.; Whitacre, C.C.

    1989-01-01

    Experimental autoimmune encephalomyelitis (EAE) is a cell-mediated autoimmune disease of the central nervous system that has been extensively studied in the rat. The Lewis rat is highly susceptible to the induction of EAE, while the Lewis resistant (LeR) rat is known to be resistant. In this paper, we demonstrate that the LeR rat, which was derived from the Lewis strain by inbreeding of fully resistant animals, is histocompatible with the Lewis strain. Radiation chimeras, a tool for distinguishing between immunologic and nonimmunologic resistance mechanisms, were utilized to analyze the cellular mechanisms involved in genetic resistance to EAE. By transplanting bone marrow cells from LeR rats into irradiated Lewis recipients, Lewis rats were rendered resistant to EAE induction. Likewise, transplanting Lewis bone marrow cells into irradiated LeR recipients rendered LeR rats susceptible. Mixed lymphoid cell chimeras using bone marrow, spleen, and thymus cells in Lewis recipient rats revealed individual lymphoid cell types and cell interactions that significantly affected the incidence and severity of EAE. Our results suggest that LeR resistance is mediated by hematopoietic/immune cells, and that cells located in the spleen appear to play a critical role in the resistance/susceptibility to EAE induction. Depletion of splenic adherent cells did not change the patterns of EAE resistance. In vivo cell mixing studies suggested the presence of a suppressor cell population in the LeR spleen preparations which exerted an inhibitory effect on Lewis autoimmune responses. Thus, the mechanism of LeR resistance appears to be different from that in other EAE-resistant animals

  11. Metabolism

    ... Are More Common in People With Type 1 Diabetes Metabolic Syndrome Your Child's Weight Healthy Eating Endocrine System Blood Test: Basic Metabolic Panel (BMP) Activity: Endocrine System Growth Disorders Diabetes Center Thyroid Disorders Your Endocrine System Movie: Endocrine ...

  12. Long-lived hypopituitary Ames dwarf mice are resistant to the detrimental effects of high-fat diet on metabolic function and energy expenditure.

    Hill, Cristal M; Fang, Yimin; Miquet, Johanna G; Sun, Liou Y; Masternak, Michal M; Bartke, Andrzej

    2016-06-01

    Growth hormone (GH) signaling stimulates the production of IGF-1; however, increased GH signaling may induce insulin resistance and can reduce life expectancy in both mice and humans. Interestingly, disruption of GH signaling by reducing plasma GH levels significantly improves health span and extends lifespan in mice, as observed in Ames dwarf mice. In addition, these mice have increased adiposity, yet are more insulin sensitive compared to control mice. Metabolic stressors such as high-fat diet (HFD) promote obesity and may alter longevity through the GH signaling pathway. Therefore, our objective was to investigate the effects of a HFD (metabolic stressor) on genetic mechanisms that regulate metabolism during aging. We show that Ames dwarf mice fed HFD for 12 weeks had an increase in subcutaneous and visceral adiposity as a result of diet-induced obesity, yet are more insulin sensitive and have higher levels of adiponectin compared to control mice fed HFD. Furthermore, energy expenditure was higher in Ames dwarf mice fed HFD than in control mice fed HFD. Additionally, we show that transplant of epididymal white adipose tissue (eWAT) from Ames dwarf mice fed HFD into control mice fed HFD improves their insulin sensitivity. We conclude that Ames dwarf mice are resistant to the detrimental metabolic effects of HFD and that visceral adipose tissue of Ames dwarf mice improves insulin sensitivity in control mice fed HFD. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

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

    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

  14. Different Erythromycin Resistance Mechanisms in Group C and Group G Streptococci

    Kataja, Janne; Seppälä, Helena; Skurnik, Mikael; Sarkkinen, Hannu; Huovinen, Pentti

    1998-01-01

    Different mechanisms of erythromycin resistance predominate in group C and G streptococcus (GCS and GGS, respectively) isolates collected from 1992 to 1995 in Finland. Of the 21 erythromycin-resistant GCS and 32 erythromycin-resistant GGS isolates, 95% had the mefA or mefE drug efflux gene and 94% had the ermTR methylase gene, respectively.

  15. Central nervous insulin resistance: a promising target in the treatment of metabolic and cognitive disorders?

    Hallschmid, M; Schultes, B

    2009-11-01

    Research on functions and signalling pathways of insulin has traditionally focused on peripheral tissues such as muscle, fat and liver, while the brain was commonly believed to be insensitive to the effects of this hormone secreted by pancreatic beta cells. However, since the discovery some 30 years ago that insulin receptors are ubiquitously found in the central nervous system, an ever-growing research effort has conclusively shown that circulating insulin accesses the brain, which itself does not synthesise insulin, and exerts pivotal functions in central nervous networks. As an adiposity signal reflecting the amount of body fat, insulin provides direct negative feedback to hypothalamic nuclei that control whole-body energy and glucose homeostasis. Moreover, insulin affects distinct cognitive processes, e.g. by triggering the formation of psychological memory contents. Accordingly, metabolic and cognitive disorders such as obesity, type 2 diabetes mellitus and Alzheimer's disease are associated with resistance of central nervous structures to the effects of insulin, which may derive from genetic polymorphisms as well as from long-term exposure to excess amounts of circulating insulin due to peripheral insulin resistance. Thus, overcoming central nervous insulin resistance, e.g. by pharmacological interventions, appears to be an attractive strategy in the treatment and prevention of these disorders. Enhancement of central nervous insulin signalling by administration of intranasal insulin, insulin analogues and insulin sensitisers in basic research approaches has yielded encouraging results that bode well for the successful translation of these effects into future clinical practice.

  16. Biochemical mechanisms of imidacloprid resistance in Nilaparvata lugens: over-expression of cytochrome P450 CYP6AY1.

    Ding, Zhiping; Wen, Yucong; Yang, Baojun; Zhang, Yixi; Liu, Shuhua; Liu, Zewen; Han, Zhaojun

    2013-11-01

    Imidacloprid is a key insecticide extensively used for control of Nilaparvata lugens, and its resistance had been reported both in the laboratory selected strains and field populations. A target site mutation Y151S in two nicotinic acetylcholine receptor subunits and enhanced oxidative detoxification have been identified in the laboratory resistant strain, contributing importantly to imidacloprid resistance in N. lugens. To date, however, imidacloprid resistance in field population is primarily attributable to enhanced oxidative detoxification by over-expressed P450 monooxygenases. A resistant strain (Res), originally collected from a field population and continuously selected in laboratory with imidacloprid for more than 40 generations, had 180.8-fold resistance to imidacloprid, compared to a susceptible strain (Sus). Expression of different putative P450 genes at mRNA levels was detected and compared between Res and Sus strains, and six genes were found expressed significantly higher in Res strain than in Sus strain. CYP6AY1 was found to be the most different expressed P450 gene and its mRNA level in Res strain was 17.9 times of that in Sus strain. By expressing in E. coli cells, CYP6AY1 was found to metabolize imidacloprid efficiently with initial velocity calculated of 0.851 ± 0.073 pmol/min/pmol P450. When CYP6AY1 mRNA levels in Res strain was reduced by RNA interference, imidacloprid susceptibility was recovered. In four field populations with different resistance levels, high levels of CYP6AY1 transcript were also found. In vitro and in vivo studies provided evidences that the over-expression of CYP6AY1 was one of the key factors contributing to imidacloprid resistance in the laboratory selected strain Res, which might also be the important mechanism for imidacloprid resistance in field populations, when the target site mutation was not prevalent at present. Copyright © 2013 Elsevier Ltd. All rights reserved.

  17. Transcriptome of American oysters, Crassostrea virginica, in response to bacterial challenge: insights into potential mechanisms of disease resistance.

    McDowell, Ian C; Nikapitiya, Chamilani; Aguiar, Derek; Lane, Christopher E; Istrail, Sorin; Gomez-Chiarri, Marta

    2014-01-01

    The American oyster Crassostrea virginica, an ecologically and economically important estuarine organism, can suffer high mortalities in areas in the Northeast United States due to Roseovarius Oyster Disease (ROD), caused by the gram-negative bacterial pathogen Roseovarius crassostreae. The goals of this research were to provide insights into: 1) the responses of American oysters to R. crassostreae, and 2) potential mechanisms of resistance or susceptibility to ROD. The responses of oysters to bacterial challenge were characterized by exposing oysters from ROD-resistant and susceptible families to R. crassostreae, followed by high-throughput sequencing of cDNA samples from various timepoints after disease challenge. Sequence data was assembled into a reference transcriptome and analyzed through differential gene expression and functional enrichment to uncover genes and processes potentially involved in responses to ROD in the American oyster. While susceptible oysters experienced constant levels of mortality when challenged with R. crassostreae, resistant oysters showed levels of mortality similar to non-challenged oysters. Oysters exposed to R. crassostreae showed differential expression of transcripts involved in immune recognition, signaling, protease inhibition, detoxification, and apoptosis. Transcripts involved in metabolism were enriched in susceptible oysters, suggesting that bacterial infection places a large metabolic demand on these oysters. Transcripts differentially expressed in resistant oysters in response to infection included the immune modulators IL-17 and arginase, as well as several genes involved in extracellular matrix remodeling. The identification of potential genes and processes responsible for defense against R. crassostreae in the American oyster provides insights into potential mechanisms of disease resistance.

  18. Buprofezin susceptibility survey, resistance selection and preliminary determination of the resistance mechanism in Nilaparvata lugens (Homoptera: Delphacidae).

    Wang, Yanhua; Gao, Congfen; Xu, Zhiping; Zhu, Yu Cheng; Zhang, Jiushuang; Li, Wenhong; Dai, Dejiang; Lin, Youwei; Zhou, Weijun; Shen, Jinliang

    2008-10-01

    Buprofezin has been used for many years to control Nilaparvata lugens (Stål). Assessment of susceptibility change in the insect is essential for maintaining control efficiency and resistance management. Eleven-year surveys showed that most field populations were susceptible before 2004. However, substantially higher levels of resistance (up to 28-fold) were found in most of the rice fields in China after 2004. A field population was collected and periodically selected for buprofezin resistance in the laboratory. After 65 generations (56 were selected), the colony successfully obtained 3599-fold resistance to buprofezin. Synergism tests showed that O,O-diethyl-O-phenyl phosphorothioate (SV1), piperonyl butoxide (PBO) and diethyl maleate (DEM) increased buprofezin toxicity in the resistant strain by only 1.5-1.6 fold, suggesting that esterases, P450-monooxygenases and glutathione S-transferases had no substantial effect on buprofezin resistance development. The results from this study indicate that N. lugens has the potential to develop high resistance to buprofezin. A resistance management program with rotation of buprofezin and other pesticides may efficiently delay or slow down resistance development in the insect. Further investigation is also necessary to understand the resistance mechanisms in N. lugens.

  19. Creatine Loading, Resistance Exercise Performance, and Muscle Mechanics.

    Stevenson, Scott W.; Dudley, Gary A.

    2001-01-01

    Examined whether creatine (CR) monohydrate loading would alter resistance exercise performance, isometric strength, or in vivo contractile properties of the quadriceps femoris muscle compared with placebo loading in resistance-trained athletes. Overall, CR loading did not provide an ergogenic benefit for the unilateral dynamic knee extension…

  20. Genetic resistance to marrow transplantation as a leukemia defense mechanism

    Gallagher, M.T.; Lotzova, E.; Trentin, J.J.

    1976-01-01

    The normal role of genetic resistance to bone marrow transplantation was investigated. It is demonstrated, using three different systems e.g. colony studies in the spleen, spleen weight studies and mortality studies, that irradiated or unirradiated mice which show genetic resistance are able to recognize and reject intravenously transplanted parental lymphoma cells, while they accept normal parental bone marrow cells. Either the lymphoma cells have a new antigen which is recognized and reacted to by the cells responsible for genetic resistance and, or, bone marrow cells have a low level of Hh antigen which is increased greatly by the lymphoma transformation process, thereby resulting in the rejection of the lymphoma cells by the cells responsible for genetic resistance. Lymphoma resistance as well as genetic resistance can be overridden by increasing the number of cells injected. Genetic resistance seems to be restricted to the spleen and bone marrow. There is evidence that the normal biological role for genetic resistance may be lymphoma-leukemia surveillance

  1. Global insights into acetic acid resistance mechanisms and genetic stability of Acetobacter pasteurianus strains by comparative genomics

    Wang, Bin; Shao, Yanchun; Chen, Tao; Chen, Wanping; Chen, Fusheng

    2015-12-01

    Acetobacter pasteurianus (Ap) CICC 20001 and CGMCC 1.41 are two acetic acid bacteria strains that, because of their strong abilities to produce and tolerate high concentrations of acetic acid, have been widely used to brew vinegar in China. To globally understand the fermentation characteristics, acid-tolerant mechanisms and genetic stabilities, their genomes were sequenced. Genomic comparisons with 9 other sequenced Ap strains revealed that their chromosomes were evolutionarily conserved, whereas the plasmids were unique compared with other Ap strains. Analysis of the acid-tolerant metabolic pathway at the genomic level indicated that the metabolism of some amino acids and the known mechanisms of acetic acid tolerance, might collaboratively contribute to acetic acid resistance in Ap strains. The balance of instability factors and stability factors in the genomes of Ap CICC 20001 and CGMCC 1.41 strains might be the basis for their genetic stability, consistent with their stable industrial performances. These observations provide important insights into the acid resistance mechanism and the genetic stability of Ap strains and lay a foundation for future genetic manipulation and engineering of these two strains.

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

    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.

  3. Resistance of green lacewing, Chrysoperla carnea Stephens to nitenpyram: Cross-resistance patterns, mechanism, stability, and realized heritability.

    Mansoor, Muhammad Mudassir; Raza, Abu Bakar Muhammad; Abbas, Naeem; Aqueel, Muhammad Anjum; Afzal, Muhammad

    2017-01-01

    The green lacewing, Chrysoperla carnea Stephens (Neuroptera: Chrysopidae) is a major generalist predator employed in integrated pest management (IPM) plans for pest control on many crops. Nitenpyram, a neonicotinoid insecticide has widely been used against the sucking pests of cotton in Pakistan. Therefore, a field green lacewing strain was exposed to nitenpyram for five generations to investigate resistance evolution, cross-resistance pattern, stability, realized heritability, and mechanisms of resistance. Before starting the selection with nitenpyram, a field collected strain showed 22.08-, 23.09-, 484.69- and 602.90-fold resistance to nitenpyram, buprofezin, spinosad and acetamiprid, respectively compared with the Susceptible strain. After continuous selection for five generations (G1-G5) with nitenpyram in the laboratory, the Field strain (Niten-SEL) developed a resistance ratio of 423.95 at G6. The Niten-SEL strain at G6 showed no cross-resistance to buprofezin and acetamiprid and negative cross-resistance to spinosad compared with the Field strain (G1). For resistance stability, the Niten-SEL strain was left unexposed to any insecticide for four generations (G6-G9) and bioassay results at G10 showed that resistance to nitenpyram, buprofezin and spinosad was stable, while resistance to acetamiprid was unstable. The realized heritability values were 0.97, 0.16, 0.03, and -0.16 to nitenpyram, buprofezin, acetamiprid and spinosad, respectively, after five generations of selection. Moreover, the enzyme inhibitors (PBO or DEF) significantly decreased the nitenpyram resistance in the resistant strain, suggesting that resistance was due to microsomal oxidases and esterases. These results are very helpful for integration of green lacewings in IPM programs. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Neratinib resistance and cross-resistance to other HER2-targeted drugs due to increased activity of metabolism enzyme cytochrome P4503A4.

    Breslin, Susan; Lowry, Michelle C; O'Driscoll, Lorraine

    2017-02-28

    Neratinib is in Phase 3 clinical trials but, unfortunately, the development of resistance is inevitable. Here, we investigated the effects of acquired neratinib resistance on cellular phenotype and the potential mechanism of this resistance. Neratinib-resistant variants of HER2-positive breast cancer cells were developed and their cross-resistance investigated using cytotoxicity assays. Similarly, sensitivity of trastuzumab-resistant and lapatinib-resistant cells to neratinib was assessed. Cellular phenotype changes were evaluated using migration, invasion and anoikis assays. Immunoblotting for HER family members and drug efflux pumps, as well as enzyme activity assays were performed. Neratinib resistance conferred cross-resistance to trastuzumab, lapatinib and afatinib. Furthermore, the efficacy of neratinib was reduced in trastuzumab- and lapatinib-resistant cells. Neratinib-resistant cells were more aggressive than their drug-sensitive counterparts, with increased CYP3A4 activity identified as a novel mechanism of neratinib resistance. The potential of increased CYP3A4 activity as a biomarker and/or target to add value to neratinib warrants investigation.

  5. Hibiscus sabdariffa calyx palliates insulin resistance, hyperglycemia, dyslipidemia and oxidative rout in fructose-induced metabolic syndrome rats.

    Ajiboye, Taofeek O; Raji, Hikmat O; Adeleye, Abdulwasiu O; Adigun, Nurudeen S; Giwa, Oluwayemisi B; Ojewuyi, Oluwayemisi B; Oladiji, Adenike T

    2016-03-30

    The effect of Hibiscus sabdariffa calyx extract was evaluated in high-fructose-induced metabolic syndrome rats. Insulin resistance, hyperglycemia, dyslipidemia and oxidative rout were induced in rats using high-fructose diet. High-fructose diet-fed rats were administered 100 and 200 mg kg(-1) body weight of H. sabdariffa extract for 3 weeks, starting from week 7 of high-fructose diet treatment. High-fructose diet significantly (P Hibiscus extract. Overall, aqueous extract of H. sabdariffa palliates insulin resistance, hyperglycemia, dyslipidemia and oxidative rout in high-fructose-induced metabolic syndrome rats. © 2015 Society of Chemical Industry.

  6. Interaction of IFNL3 with insulin resistance, steatosis and lipid metabolism in chronic hepatitis C virus infection.

    Eslam, Mohammed; Booth, David R; George, Jacob; Ahlenstiel, Golo

    2013-11-07

    Metabolic changes are inextricably linked to chronic hepatitis C (CHC). Recently polymorphisms in the IFNL3 (IL28B) region have been shown to be strongly associated with spontaneous and treatment induced recovery from hepatitis C virus (HCV) infection. Further, circumstantial evidence suggests a link between IFNL3 single nucleotide polymorphisms and lipid metabolism, steatosis and insulin resistance in CHC. The emerging picture suggests that the responder genotypes of IFNL3 polymorphisms are associated with a higher serum lipid profile, and less frequent steatosis and insulin resistance. This review analyzes the current data regarding this interaction and its meaning for HCV pathogenesis and disease progression.

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

    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.

  8. Elucidating the mechanisms of resistance to tyrosine kinase inhibitors in lung cancer patients

    Asim Joshi

    2017-10-01

    Results: The whole exome data was analyzed using an in-house developed pipeline. Of all the known resistance mutations, we identified EGFR T790M mutation in five out of fifteen patients. Other than T790M we expect to identify novel resistance causing mutations from the analysis of ten patients with unknown resistance mechanisms. Functional validation of these resistance specific alterations would be performed in vitro using drug sensitive lung cancer cell lines.

  9. Heat-resistant mechanism of transgenic rape by 45Ca isotope tracer

    Xu Falun; Yang Yuanyou; Liu Ning; Liao Jiali; Yang Jijun; Tang Jun; Liu Zhibin; Yang Yi

    2012-01-01

    The Ca 2+ uptake differences of the rape with heat-resistant gene and the general rape were investigated by 45 Ca isotope tracer. The results showed that the rape with heat-resistant gene can strengthen the regulation of calcium absorption. The calcium regulation ability of the heat-resistant genes may be able to play in the rape aspect of the mechanism of resistance. (authors)

  10. Mechanisms of resistance to quinolones and epidemiological significance of Salmonella spp.

    Velhner, Maja

    2016-01-01

    Bacteria develop resistance to antimicrobial agents by a number of different mechanisms. The resistance to (fluoro)quinolones in Salmonella is of particular importance especially if therapy in humans is required. For decades there has been a significant interest in studying the biology of Salmonella because these bacteria are among the leading causes of foodborne illnesses around the globe. To this date, two main mechanisms of quinolone resistance have been established: alteration in the targ...

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

    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

  12. Decreased antimony uptake and overexpression of genes of thiol metabolism are associated with drug resistance in a canine isolate of Leishmania infantum

    Verónica Gómez Pérez

    2016-08-01

    Full Text Available Visceral leishmaniasis (VL caused by the protozoan parasite Leishmania infantum, is one of the most important zoonotic diseases affecting dogs and humans in the Mediterranean area. The presence of infected dogs as the main reservoir host of L. infantum is regarded as the most significant risk for potential human infection. We have studied the susceptibility profile to antimony and other anti-leishmania drugs (amphotericin B, miltefosine, paromomycin in Leishmania infantum isolates extracted from a dog before and after two therapeutic interventions with meglumine antimoniate (subcutaneous Glucantime®, 100 mg/kg/day for 28 days. After the therapeutic intervention, these parasites were significantly less susceptible to antimony than pretreatment isolate, presenting a resistance index of 6-fold to SbIII for promastigotes and >3-fold to SbIII and 3-fold to SbV for intracellular amastigotes. The susceptibility profile of this resistant L. infantum line is related to a decreased antimony uptake due to lower aquaglyceroporin-1 expression levels. Additionally, other mechanisms including an increase in thiols and overexpression of enzymes involved in thiol metabolism, such as ornithine decarboxylase, trypanothione reductase, mitochondrial tryparedoxin and mitochondrial tryparedoxin peroxidase, could contribute to the resistance as antimony detoxification mechanisms. A major contribution of this study in a canine L. infantum isolate is to find an antimony-resistant mechanism similar to that previously described in other human clinical isolates.

  13. Nutrition, insulin resistance and dysfunctional adipose tissue determine the different components of metabolic syndrome

    Paniagua, Juan Antonio

    2016-01-01

    Obesity is an excessive accumulation of body fat that may be harmful to health. Today, obesity is a major public health problem, affecting in greater or lesser proportion all demographic groups. Obesity is estimated by body mass index (BMI) in a clinical setting, but BMI reports neither body composition nor the location of excess body fat. Deaths from cardiovascular diseases, cancer and diabetes accounted for approximately 65% of all deaths, and adiposity and mainly abdominal adiposity are associated with all these disorders. Adipose tissue could expand to inflexibility levels. Then, adiposity is associated with a state of low-grade chronic inflammation, with increased tumor necrosis factor-α and interleukin-6 release, which interfere with adipose cell differentiation, and the action pattern of adiponectin and leptin until the adipose tissue begins to be dysfunctional. In this state the subject presents insulin resistance and hyperinsulinemia, probably the first step of a dysfunctional metabolic system. Subsequent to central obesity, insulin resistance, hyperglycemia, hypertriglyceridemia, hypoalphalipoproteinemia, hypertension and fatty liver are grouped in the so-called metabolic syndrome (MetS). In subjects with MetS an energy balance is critical to maintain a healthy body weight, mainly limiting the intake of high energy density foods (fat). However, high-carbohydrate rich (CHO) diets increase postprandial peaks of insulin and glucose. Triglyceride-rich lipoproteins are also increased, which interferes with reverse cholesterol transport lowering high-density lipoprotein cholesterol. In addition, CHO-rich diets could move fat from peripheral to central deposits and reduce adiponectin activity in peripheral adipose tissue. All these are improved with monounsaturated fatty acid-rich diets. Lastly, increased portions of ω-3 and ω-6 fatty acids also decrease triglyceride levels, and complement the healthy diet that is recommended in patients with MetS. PMID

  14. Kefir reduces insulin resistance and inflammatory cytokine expression in an animal model of metabolic syndrome.

    Rosa, Damiana D; Grześkowiak, Łukasz M; Ferreira, Célia L L F; Fonseca, Ana Carolina M; Reis, Sandra A; Dias, Mariana M; Siqueira, Nathane P; Silva, Leticia L; Neves, Clóvis A; Oliveira, Leandro L; Machado, Alessandra B F; Peluzio, Maria do Carmo G

    2016-08-10

    There is growing evidence that kefir can be a promising tool in decreasing the risk of many diseases, including metabolic syndrome (MetS). The aim of the present study was to evaluate the effect of kefir supplementation in the diet of Spontaneously Hypertensive Rats (SHR) in which MetS was induced with monosodium glutamate (MSG), and to determine its effect on metabolic parameters, inflammatory and oxidation marker expression and glycemic index control. Thirty animals were used in this experiment. For the induction of MetS, twenty two-day-old male SHR received five consecutive intradermal injections of MSG. For the Negative Control, ten newborn male SHR received intradermal injections of saline solution (0.9% saline solution). After weaning, animals received standard diet and water ad libitum until reaching 3 months old, for the development of MetS. They were then divided into three groups (n = 10): negative control (NC, 1 mL saline solution per day), positive control (PC, 1 mL saline solution per day) and the Kefir group (1 mL kefir per day). Feeding was carried out by gavage for 10 weeks and the animals received standard food and water ad libitum. Obesity, insulin resistance, pro- and anti-inflammatory markers, and the histology of pancreatic and adipose tissues were among the main variables evaluated. Compared to the PC group, kefir supplementation reduced plasma triglycerides, liver lipids, liver triglycerides, insulin resistance, fasting glucose, fasting insulin, thoracic circumference, abdominal circumference, products of lipid oxidation, pro-inflammatory cytokine expression (IL-1β) and increased anti-inflammatory cytokine expression (IL-10). The present findings indicate that kefir has the potential to benefit the management of MetS.

  15. Nutrition, insulin resistance and dysfunctional adipose tissue determine the different components of metabolic syndrome

    Juan; Antonio; Paniagua[1,2

    2016-01-01

    Obesity is an excessive accumulation of body fat that may be harmful to health. Today, obesity is a major public health problem, affecting in greater or lesser proportion all demographic groups. Obesity is estimated by body mass index (BMI) in a clinical setting, but BMI reports neither body composition nor the location of excess body fat.Deaths from cardiovascular diseases, cancer and diabetes accounted for approximately 65% of all deaths, and adiposity and mainly abdominal adiposity are associated with all these disorders. Adipose tissue could expand to inflexibility levels. Then, adiposity is associated with a state of low-grade chronic inflammation, with increased tumor necrosis factor-α and interleukin-6 release, which interfere with adipose cell differentiation, and the action pattern of adiponectin and leptin until the adipose tissue begins to be dysfunctional. In this state the subject presents insulin resistance and hyperinsulinemia, probably the first step of a dysfunctional metabolic system. Subsequent to central obesity, insulin resistance, hyperglycemia,hypertriglyceridemia, hypoalphalipoproteinemia, hypertension and fatty liver are grouped in the so-called metabolic syndrome (MetS). In subjects with MetS an energy balance is critical to maintain a healthy body weight, mainly limiting the intake of high energy density foods (fat). However, high-carbohydrate rich (CHO) diets increase postprandial peaks of insulin and glucose.Triglyceride-rich lipoproteins are also increased, which interferes with reverse cholesterol transport lowering highdensity lipoprotein cholesterol. In addition, CHO-rich diets could move fat from peripheral to central deposits and reduce adiponectin activity in peripheral adipose tissue. All these are improved with monounsaturated fatty acid-rich diets. Lastly, increased portions of ω-3 and ω-6 fatty acids also decrease triglyceride levels, and complement the healthy diet that is recommended in patients with MetS.

  16. Metabolic profiling for detection of Staphylococcus aureus infection and antibiotic resistance.

    Henrik Antti

    Full Text Available Due to slow diagnostics, physicians must optimize antibiotic therapies based on clinical evaluation of patients without specific information on causative bacteria. We have investigated metabolomic analysis of blood for the detection of acute bacterial infection and early differentiation between ineffective and effective antibiotic treatment. A vital and timely therapeutic difficulty was thereby addressed: the ability to rapidly detect treatment failures because of antibiotic-resistant bacteria. Methicillin-resistant Staphylococcus aureus (MRSA and methicillin-sensitive S. aureus (MSSA were used in vitro and for infecting mice, while natural MSSA infection was studied in humans. Samples of bacterial growth media, the blood of infected mice and of humans were analyzed with combined Gas Chromatography/Mass Spectrometry. Multivariate data analysis was used to reveal the metabolic profiles of infection and the responses to different antibiotic treatments. In vitro experiments resulted in the detection of 256 putative metabolites and mice infection experiments resulted in the detection of 474 putative metabolites. Importantly, ineffective and effective antibiotic treatments were differentiated already two hours after treatment start in both experimental systems. That is, the ineffective treatment of MRSA using cloxacillin and untreated controls produced one metabolic profile while all effective treatment combinations using cloxacillin or vancomycin for MSSA or MRSA produced another profile. For further evaluation of the concept, blood samples of humans admitted to intensive care with severe sepsis were analyzed. One hundred thirty-three putative metabolites differentiated severe MSSA sepsis (n = 6 from severe Escherichia coli sepsis (n = 10 and identified treatment responses over time. Combined analysis of human, in vitro, and mice samples identified 25 metabolites indicative of effective treatment of S. aureus sepsis. Taken together, this

  17. Defeating Leishmania resistance to miltefosine (hexadecylphosphocholine) by peptide-mediated drug smuggling: a proof of mechanism for trypanosomatid chemotherapy.

    Luque-Ortega, Juan Román; de la Torre, Beatriz G; Hornillos, Valentín; Bart, Jean-Mathieu; Rueda, Cristina; Navarro, Miguel; Amat-Guerri, Francisco; Acuña, A Ulises; Andreu, David; Rivas, Luis

    2012-08-10

    Miltefosine (hexadecylphosphocholine, HePC), the first orally active drug successful against leishmaniasis, is especially active on the visceral form of the disease. Resistance mechanisms are almost exclusively associated to dysfunction in HePC uptake systems. In order to evade the requirements of its cognate receptor/translocator, HePC-resistant Leishmania donovani parasites (R40 strain) were challenged with constructs consisting of an ω-thiol-functionalized HePC analogue conjugated to the cell-penetrating peptide (CPP) Tat(48-60), either through a disulfide or a thioether bond. The conjugates enter and kill both promastigote and intracellular amastigote forms of the R40 strain. Intracellular release of HePC by reduction of the disulfide-based conjugate was confirmed by means of double tagging at both the CPP (Quasar 670) and HePC (BODIPY) moieties. Scission of the conjugate, however, is not mandatory, as the metabolically more stable thioether conjugate retained substantial activity. The disulfide conjugate is highly active on the bloodstream form of Trypanosoma b. brucei, naturally resistant to HePC. Our results provide proof-of-mechanism for the use of CPP conjugates to avert drug resistance by faulty drug accumulation in parasites, as well as the possibility to extend chemotherapy into other parasites intrinsically devoid of membrane translocation systems. Copyright © 2012 Elsevier B.V. All rights reserved.

  18. Unravelling the resistance mechanism of lettuce against Nasonovia ribisnigri

    Broeke, ten, C.J.M.

    2013-01-01

    Aphids are serious pests of crop plant species, and host plant resistance is often the most effective and environmentally friendly control strategy to control these pests. One of these aphid pests is the black currant - lettuce aphid, Nasonovia ribisnigri (Mosely), an economically important pest of cultivated lettuce, Lactuca sativa L. Host plant resistance has been used since 1982 to control this aphid species and is mediated by the Nr-gene, originating from wild lettuce Lactuca virosa L. H...

  19. Will acarbose improve the metabolic abnormalities of insulin-resistant type 2 diabetes mellitus?

    Scott, R; Lintott, C J; Zimmet, P; Campbell, L; Bowen, K; Welborn, T

    1999-03-01

    Individuals with type 2 diabetes mellitus (n = 105; age 36-71 years) on diet therapy alone, and with quite good glycaemic control (mean HbA1c approximately 7.0%) were randomized to receive acarbose (100 mg three times daily) or placebo for 16 weeks, and changes in clinical and metabolic parameters indicative of Syndrome X were monitored. Fasting levels of glucose, glycosylated haemoglobin (HbA1c), true insulin, proinsulin, fibrinogen and lipids were measured four times weekly, and glucose, insulin, proinsulin and triglyceride responses to a standardized 1.6 MJ breakfast were determined at 0, 1 and 2 h post meal. Analysis was on an intention-to-treat basis. Fasting levels of glucose (P fasting glucose and triglyceride levels, lowers HbA1c and limits the glycaemic and insulin response to food in individuals with type 2 diabetes mellitus with Syndrome X. Pharmacological agents that improve the metabolic environment and reduce insulin resistance have the potential to limit the progression of atherogenesis associated with type 2 diabetes mellitus.

  20. Effects of turtle oil on insulin sensitivity and glucose metabolism in insulin resistant cell model

    Bai Jing; Tian Yaping; Guo Duo

    2007-01-01

    To evaluate the effects of turtle oil on insulin sensitivity and glucose metabolism in an insulin-resistant (IR) cell model which was established by the way of high concentration of insulin induction with HepG 2 cell in vitro culture. The IR cells were treated by turtle oil, the glucose consumption and 3 H-D-glucose incorporation rate in IR cells were detected by the way of glucose oxidase and 3 H-D-glucose incorporation assay respectively. The state of cell proliferation was tested by MTT method. The results showed that the incorporation rate of 3 H-D-glucose in IR cells was significantly lower than that in the control cells(P 3 H-D-glucose incorporation rate in either IR cells or control cells was increased with the increase of insulin concentration. Moreover, the 3 H-D-glucose incorporation rate of IR cells increased slower than that of control cells. The MTT assay showed that turtle oil can promote the proliferation of IR cell and control cell. The glucose uptake and glucose consumption in IR cell which treated with turtle oil was significantly increase than that in the control cells (P<0.05). Turtle oil can improve the insulin sensitivity and glucose metabolism in the IR cell model. (authors)

  1. Influence of functional nutrients on insulin resistance in horses with equine metabolic syndrome

    Krzysztof Marycz, Eberhard Moll and Jakub Grzesiak

    2014-04-01

    Full Text Available The obesity is a rising health problem both in veterinary and human medicine. In equine medicine excessive body weight is frequently related to insulin resistance and laminitis as is defined as equine metabolic syndrome (EMS. The dietetic management is considered as the crucial part of treatment strategy in the course of EMS. The main feeding recommendation is to administer the low energy diet in order to restore insulin efficiency and to lower body weight. In this study 14 horses of different breed, both sexes and different ages with diagnosed equine metabolic syndrome were fed, concurrently, with oats (3g/kg bw, hay (15g/kg bw and experimental dietary supplement containing selected herbs, aminoacids, butyric acid derivative, biotin and selected dietetic plant like artichoke. The influence of above dietary protocol on body weight, insulin level, and adipose tissue morphometry was investigated in horses from group A. Horses from group B fed only with oats (3g/kg bw and hay (15g/kg bw served as a control. Results of the experiment indicated that tested supplement could improve insulin efficiency and reduce body mass in experimental horses group.

  2. Home-based exercise may not decrease the insulin resistance in individuals with metabolic syndrome.

    Chen, Chiao-Nan; Chuang, Lee-Ming; Korivi, Mallikarjuna; Wu, Ying-Tai

    2015-01-01

    This study investigated the differences in exercise self-efficacy, compliance, and effectiveness of home-based exercise in individuals with and without metabolic syndrome (MetS). One hundred and ten individuals at risk for diabetes participated in this study. Subjects were categorized into individuals with MetS and individuals without MetS. Metabolic risk factors and exercise self-efficacy were evaluated for all subjects before and after 3 months of home-based exercise. Univariate analysis of variance was used to compare the effectiveness of a home-based exercise program between individuals with and without MetS. The home-based exercise program improved body mass index and lipid profile in individuals at risk for diabetes, regardless of MetS status at baseline. Individuals without MetS had higher exercise self-efficacy at baseline and performed greater exercise volume compared with individuals with MetS during the intervention. The increased exercise volume in individuals without MetS may contribute to their better control of insulin resistance than individuals with MetS. Furthermore, baseline exercise self-efficacy was correlated with exercise volume executed by subjects at home. We conclude that home-based exercise programs are beneficial for individuals at risk for diabetes. However, more intensive and/or supervised exercise intervention may be needed for those with MetS.

  3. Aerobic interval training reduces vascular resistances during submaximal exercise in obese metabolic syndrome individuals.

    Mora-Rodriguez, Ricardo; Fernandez-Elias, V E; Morales-Palomo, F; Pallares, J G; Ramirez-Jimenez, M; Ortega, J F

    2017-10-01

    The aim of this study was to determine the effects of high-intensity aerobic interval training (AIT) on exercise hemodynamics in metabolic syndrome (MetS) volunteers. Thirty-eight, MetS participants were randomly assigned to a training (TRAIN) or to a non-training control (CONT) group. TRAIN consisted of stationary interval cycling alternating bouts at 70-90% of maximal heart rate during 45 min day -1 for 6 months. CONT maintained baseline physical activity and no changes in cardiovascular function or MetS factors were detected. In contrast, TRAIN increased cardiorespiratory fitness (14% in VO 2PEAK ; 95% CI 9-18%) and improved metabolic syndrome (-42% in Z score; 95% CI 83-1%). After TRAIN, the workload that elicited a VO 2 of 1500 ml min -1 increased 15% (95% CI 5-25%; P exercise heart rate (109 ± 15-106 ± 13 beats min -1 ; P exercise in MetS patients. Specifically, it reduces diastolic blood pressure, systemic vascular resistances, and the double product. The reduction in double product, suggests decreased myocardial oxygen demands which could prevent the occurrence of adverse cardiovascular events during exercise in this population. CLINICALTRIALS. NCT03019796.

  4. Drug Resistance Mechanisms of Mycoplasma pneumoniae to Macrolide Antibiotics

    Xijie Liu

    2014-01-01

    Full Text Available Throat swabs from children with suspected Mycoplasma pneumoniae (M. pneumoniae infection were cultured for the presence of M. pneumoniae and its species specificity using the 16S rRNA gene. Seventy-six M. pneumoniae strains isolated from 580 swabs showed that 70 were erythromycin resistant with minimum inhibitory concentrations (MIC around 32–512 mg/L. Fifty M. pneumoniae strains (46 resistant, 4 sensitive were tested for sensitivity to tetracycline, ciprofloxacin, and gentamicin. Tetracycline and ciprofloxacin had some effect, and gentamicin had an effect on the majority of M. pneumoniae strains. Domains II and V of the 23S rRNA gene and the ribosomal protein L4 and L22 genes, both of which are considered to be associated with macrolide resistance, were sequenced and the sequences were compared with the corresponding sequences in M129 registered with NCBI and the FH strain. The 70 resistant strains all showed a 2063 or 2064 site mutation in domain V of the 23S rRNA but no mutations in domain II. Site mutations of L4 or L22 can be observed in either resistant or sensitive strains, although it is not known whether this is associated with drug resistance.

  5. Common variants in SOCS7 gene predict obesity, disturbances in lipid metabolism and insulin resistance.

    Tellechea, M L; Steinhardt, A Penas; Rodriguez, G; Taverna, M J; Poskus, E; Frechtel, G

    2013-05-01

    Specific Suppressor of Cytokine Signaling (SOCS) members, such as SOCS7, may play a role in the development of insulin resistance (IR) owing to their ability to inhibit insulin signaling pathways. The objective was to explore the association between common variants and related haplotypes in SOCS7 gene and metabolic traits related to obesity, lipid metabolism and IR. 780 unrelated men were included in a cross-sectional study. We selected three tagged SNPs that capture 100% of SNPs with minor allele frequency ≥ 0.10. Analyses were done separately for each SNP and followed up by haplotype analysis. rs8074124C was associated with both obesity (p = 0.005) and abdominal obesity (p = 0.002) and allele C carriers showed, in comparison with TT carriers, lower BMI (p = 0.001) and waist circumference (p = 0.001). rs8074124CC- carriers showed lower fasting insulin (p = 0.017) and HOMA-IR (p = 0.018) than allele T carriers. rs12051836C was associated with hypertriglyceridemia (p = 0.009) and hypertriglyceridemic waist (p = 0.006). rs12051836CC- carriers showed lower fasting insulin (p = 0.043) and HOMA-IR (p = 0.042). Haplotype-based association analysis (rs8074124 and rs12051836 in that order) showed associations with lipid and obesity -related phenotypes, consistent with single locus analysis. Haplotype analysis also revealed association between haplotype CT and both decreased HDL-C (p = 0.026) and HDL-C (p = 0.014) as a continuous variable. We found, for the first time, significant associations between SOCS7 common variants and related haplotypes and obesity, IR and lipid metabolism disorders. Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.

  6. Insecticide resistance, associated mechanisms and fitness aspects in two Brazilian Stegomyia aegypti (= Aedes aegypti) populations.

    Viana-Medeiros, P F; Bellinato, D F; Martins, A J; Valle, D

    2017-12-01

    In Brazil, insecticide resistance in Stegomyia aegypti (= Aedes aegypti) (Diptera: Culicidae) populations to pyrethroids and to the organophosphate (OP) temephos is disseminated. Currently, insect growth regulators (IGRs) and the OP malathion are employed against larvae and adults, respectively. Bioassays with mosquitoes from two northeast municipalities, Crato and Aracaju, revealed, in both populations, susceptibility to IGRs and malathion (RR 95  ≤ 2.0), confirming the effectiveness of these compounds. By contrast, temephos and deltamethrin (pyrethroid) resistance levels were high (RR 95  > 10), which is consistent with the use of intense chemical control. In Crato, RR 95 values were > 50 for both compounds. Knock-down-resistant (kdr) mutants in the voltage-gated sodium channel, the pyrethroid target site, were found in 43 and 32%, respectively, of Aracaju and Crato mosquitoes. Biochemical assays revealed higher metabolic resistance activity (esterases, mixed function oxidases and glutathione-S-transferases) at Aracaju. With respect to fitness aspects, mating effectiveness was equivalently impaired in both populations, but Aracaju mosquitoes showed more damaging effects in terms of longer larval development, decreased bloodmeal acceptance, reduced engorgement and lower numbers of eggs laid per female. Compared with mosquitoes in Crato, Aracaju mosquitoes exhibited lower OP and pyrethroid RR 95 , increased activity of detoxifying enzymes and greater effect on fitness. The potential relationship between insecticide resistance mechanisms and mosquito viability is discussed. © 2017 The Authors. Medical and Veterinary Entomology published by John Wiley & Sons Ltd on behalf of The Royal Entomological Society.

  7. Lipid metabolism disturbances contribute to insulin resistance and decrease insulin sensitivity by malathion exposure in Wistar rat.

    Lasram, Mohamed Montassar; Bouzid, Kahena; Douib, Ines Bini; Annabi, Alya; El Elj, Naziha; El Fazaa, Saloua; Abdelmoula, Jaouida; Gharbi, Najoua

    2015-04-01

    Several studies showed that organophosphorus pesticides disturb glucose homeostasis and can increase incidence of metabolic disorders and diabetes via insulin resistance. The current study investigates the influence of malathion on glucose metabolism regulation, in vivo, during subchronic exposure. Malathion was administered orally (200 mg/kg), once a day for 28 consecutive days. Plasma glucose, insulin and Glycated hemoglobin levels were significantly increased while hepatic glycogen content was decreased in intoxicated animals compared with the control group. Furthermore, there was a significant disturbance of lipid content in subchronic treated and post-treated rats deprived of malathion for one month. In addition, we used the homeostasis model assessment (HOMA) to assess insulin resistance (HOMA-IR) and pancreatic β-cell function (HOMA-β). Our results show that malathion increases insulin resistance biomarkers and decreases insulin sensitivity indices. Statistical analysis demonstrates that there was a positive and strong significant correlation between insulin level and insulin resistance indices, HOMA-IR, HOMA-β. Similarly, a negative and significant correlation was also found between insulin level and insulin sensitivity indices. For the first time, we demonstrate that malathion induces insulin resistance in vivo using homeostasis model assessment and these changes were detectable one month after the end of exposure. To explain insulin resistance induced by malathion we focus on lipid metabolism disturbances and their interaction with many proteins involved in insulin signaling pathways.

  8. Genetic Mechanisms of Antibiotic Resistance and the Role of Antibiotic Adjuvants.

    Pontes, Daniela Santos; de Araujo, Rodrigo Santos Aquino; Dantas, Natalina; Scotti, Luciana; Scotti, Marcus Tullius; de Moura, Ricardo Olimpio; Mendonca-Junior, Francisco Jaime Bezerra

    2018-01-01

    The ever increasing number of multidrug-resistant microorganism pathogens has become a great and global public health threat. Antibiotic mechanisms of action and the opposing mechanisms of resistance are intimately associated, but comprehension of the biochemical and molecular functions of such drugs is not a simple exercise. Both the environment, and genetic settings contribute to alterations in phenotypic resistance (natural bacterial evolution), and make it difficult to control the emergence and impacts of antibiotic resistance. Under such circumstances, comprehension of how bacteria develop and/or acquire antibiotic resistance genes (ARG) has a critical role in developing propositions to fight against these superbugs, and to search for new drugs. In this review, we present and discuss both general information and examples of common genetic and molecular mechanisms related to antibiotic resistance, as well as how the expression and interactions of ARGs are important to drug resistance. At the same time, we focus on the recent achievements in the search for antibiotic adjuvants, which help combat antibiotic resistance through deactivation of bacterial mechanisms of action such as β-lactamases. Recent advances involving the use of anti-resistance drugs such as: efflux pump inhibitors; anti-virulence drugs; drugs against quorum sensing; and against type II/III secretion systems are revealed. Such antibiotic adjuvants (as explored herein) collaborate against the problems of antibiotic resistance, and may restore or prolong the therapeutic activity of known antibiotics. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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

    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.

  10. Adipose tissue NAD+ biology in obesity and insulin resistance: From mechanism to therapy.

    Yamaguchi, Shintaro; Yoshino, Jun

    2017-05-01

    Nicotinamide adenine dinucleotide (NAD + ) biosynthetic pathway, mediated by nicotinamide phosphoribosyltransferase (NAMPT), a key NAD + biosynthetic enzyme, plays a pivotal role in controlling many biological processes, such as metabolism, circadian rhythm, inflammation, and aging. Over the past decade, NAMPT-mediated NAD + biosynthesis, together with its key downstream mediator, namely the NAD + -dependent protein deacetylase SIRT1, has been demonstrated to regulate glucose and lipid metabolism in a tissue-dependent manner. These discoveries have provided novel mechanistic and therapeutic insights into obesity and its metabolic complications, such as insulin resistance, an important risk factor for developing type 2 diabetes and cardiovascular disease. This review will focus on the importance of adipose tissue NAMPT-mediated NAD + biosynthesis and SIRT1 in the pathophysiology of obesity and insulin resistance. We will also critically explore translational and clinical aspects of adipose tissue NAD + biology. © 2017 WILEY Periodicals, Inc.

  11. Organ-Specific Differential NMR-Based Metabonomic Analysis of Soybean [Glycine max (L. Merr.] Fruit Reveals the Metabolic Shifts and Potential Protection Mechanisms Involved in Field Mold Infection

    Wen-yu Yang

    2017-04-01

    Full Text Available Prolonged, continuous rainfall is the main climatic characteristic of autumn in Southwest China, and it has been found to cause mildew outbreaks in pre-harvest soybean fields. Low temperature and humidity (LTH stress during soybean maturation in the field promotes pre-harvest mildew, resulting in damage to different organs of soybean fruits to different extents, but relatively little information on the resistance mechanisms in these fruits is available. Therefore, to understand the metabolic responses of soybean fruits to field mold (FM, the metabonomic variations induced by LTH were characterized using proton nuclear magnetic resonance spectroscopy (1H-NMR, and the primary metabolites from the pod, seed coat and cotyledon of pre-harvest soybean were quantified. Analysis of FM-damaged soybean germplasms with different degrees of resistance to FM showed that extracts were dominated by 66 primary metabolites, including amino acids, organic acids and sugars. Each tissue had a characteristic metabolic profile, indicating that the metabolism of proline in the cotyledon, lysine in the seed coat, and sulfur in the pod play important roles in FM resistance. The primary-secondary metabolism interface and its potential contribution to FM resistance was investigated by targeted analyses of secondary metabolites. Both the seed coat and the pod have distinct but nonexclusive metabolic responses to FM, and these are functionally integrated into FM resistance mechanisms.

  12. Dietary Tributyrin Supplementation Attenuates Insulin Resistance and Abnormal Lipid Metabolism in Suckling Piglets with Intrauterine Growth Retardation

    He, Jintian; Dong, Li; Xu, Wen; Bai, Kaiwen; Lu, Changhui; Wu, Yanan; Huang, Qiang; Zhang, Lili; Wang, Tian

    2015-01-01

    Intrauterine growth retardation (IUGR) is associated with insulin resistance and lipid disorder. Tributyrin (TB), a pro-drug of butyrate, can attenuate dysfunctions in body metabolism. In this study, we investigated the effects of TB supplementation on insulin resistance and lipid metabolism in neonatal piglets with IUGR. Eight neonatal piglets with normal birth weight (NBW) and 16 neonatal piglets with IUGR were selected, weaned on the 7th day, and fed basic milk diets (NBW and IUGR groups) or basic milk diets supplemented with 0.1% tributyrin (IT group, IUGR piglets) until day 21 (n = 8). Relative parameters for lipid metabolism and mRNA expression were measured. Piglets with IUGR showed higher (P insulin in the serum, higher (P insulin, HOMA-IR, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol in the serum, and the concentrations of TG and NEFA in the liver, and increased (P insulin signal transduction pathway and hepatic lipogenic pathway (including transcription factors and nuclear factors) was significantly (P insulin resistance and abnormal lipid metabolism in IUGR piglets by increasing enzyme activities and upregulating mRNA expression, leading to an early improvement in the metabolic efficiency of IUGR piglets. PMID:26317832

  13. Ordovas-Oxidized LDL is associated with metabolic syndrome traits independently of central obesity and insulin resistance

    This study assesses whether oxidative stress, using oxidized LDL (ox-LDL) as a proxy, is associated with metabolic syndrome (MS), whether ox-LDL mediates the association between central obesity and MS, and whether insulin resistance mediates the association between ox-LDL and MS. We examined baselin...

  14. Association of Resistance Exercise, Independent of and Combined With Aerobic Exercise, With the Incidence of Metabolic Syndrome.

    Bakker, E.A.; Lee, D.C.; Sui, X.; Artero, E.G.; Ruiz, J.R.; Eijsvogels, T.M.H.; Lavie, C.J.; Blair, S.N.

    2017-01-01

    OBJECTIVE: To determine the association of resistance exercise, independent of and combined with aerobic exercise, with the risk of development of metabolic syndrome (MetS). PATIENTS AND METHODS: The study cohort included adults (mean +/- SD age, 46+/-9.5 years) who received comprehensive medical

  15. Insulin-resistance and metabolic syndrome are related to executive function in women in a large family-based study

    M. Schuur (Maaike); P. Henneman (Peter); J.C. van Swieten (John); M.C. Zillikens (Carola); I. de Koning (Inge); A.C.J.W. Janssens (Cécile); J.C.M. Witteman (Jacqueline); Y.S. Aulchenko (Yurii); R.R. Frants (Rune); B.A. Oostra (Ben); J.A.P. Willems van Dijk (Ko); C.M. van Duijn (Cornelia)

    2010-01-01

    textabstractWhile type 2 diabetes is well-known to be associated with poorer cognitive performance, few studies have reported on the association of metabolic syndrome (MetS) and contributing factors, such as insulin-resistance (HOMA-IR), low adiponectin-, and high C-reactive protein (CRP)- levels.

  16. Charge dividing mechanism on resistive electrode in position-sensitive detectors

    Radeka, V.; Rehak, P.

    1978-10-01

    A complete charge-division mechanism, including both the diffusion and the electromagnetic wave propagation on resistive electrodes, is presented. The charge injected into such a transmission line divides between the two ends according to the ratio of resistancies and independently of the value of the line resistance, of the propagation mechanism and of the distribution of inductance and capacitance along the line. The shortest charge division time is achieved for Rl = 2π (L/C) 1 / 2 , where R, L, C are resistance, inductance and capacitance per unit length and l is the length of the line

  17. Metabolism

    ... lin), which signals cells to increase their anabolic activities. Metabolism is a complicated chemical process, so it's not ... how those enzymes or hormones work. When the metabolism of body chemicals is ... Hyperthyroidism (pronounced: hi-per-THIGH-roy-dih-zum). Hyperthyroidism ...

  18. Molecular Mechanism of Terbinafine Resistance in Saccharomyces cerevisiae

    Leber, Regina; Fuchsbichler, Sandra; Klobučníková, Vlasta; Schweighofer, Natascha; Pitters, Eva; Wohlfarter, Kathrin; Lederer, Mojca; Landl, Karina; Ruckenstuhl, Christoph; Hapala, Ivan; Turnowsky, Friederike

    2003-01-01

    Ten mutants of the yeast Saccharomyces cerevisiae resistant to the antimycotic terbinafine were isolated after chemical or UV mutagenesis. Molecular analysis of these mutants revealed single base pair exchanges in the ERG1 gene coding for squalene epoxidase, the target of terbinafine. The mutants did not show cross-resistance to any of the substrates of various pleiotropic drug resistance efflux pumps tested. The ERG1 mRNA levels in the mutants did not differ from those in the wild-type parent strains. Terbinafine resistance was transmitted with the mutated alleles in gene replacement experiments, proving that single amino acid substitutions in the Erg1 protein were sufficient to confer the resistance phenotype. The amino acid changes caused by the point mutations were clustered in two regions of the Erg1 protein. Seven mutants carried the amino acid substitutions F402L (one mutant), F420L (one mutant), and P430S (five mutants) in the C-terminal part of the protein; and three mutants carried an L251F exchange in the central part of the protein. Interestingly, all exchanges identified involved amino acids which are conserved in the squalene epoxidases of yeasts and mammals. Two mutations that were generated by PCR mutagenesis of the ERG1 gene and that conferred terbinafine resistance mapped in the same regions of the Erg1 protein, with one resulting in an L251F exchange and the other resulting in an F433S exchange. The results strongly indicate that these regions are responsible for the interaction of yeast squalene epoxidase with terbinafine. PMID:14638499

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

    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.

  20. Mechanisms of redox metabolism and cancer cell survival during extracellular matrix detachment.

    Hawk, Mark A; Schafer, Zachary T

    2018-01-16

    Non-transformed cells that become detached from the extracellular matrix (ECM) undergo dysregulation of redox homeostasis and cell death. In contrast, cancer cells often acquire the ability to mitigate programmed cell death pathways and recalibrate the redox balance to survive after ECM detachment, facilitating metastatic dissemination. Accordingly, recent studies of the mechanisms by which cancer cells overcome ECM detachment-induced metabolic alterations have focused on mechanisms in redox homeostasis. The insights into these mechanisms may inform the development of therapeutics that manipulate redox homeostasis to eliminate ECM-detached cancer cells. Here, we review how ECM-detached cancer cells balance redox metabolism for survival. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Acaricide resistance and resistance mechanisms in Tetranychus urticae populations from rose greenhouses in the Netherlands

    Khajehali, J.; Van Nieuwenhuyse, P.; Demaeght, P.; Tirry, L.; Van Leeuwen, T.

    2011-01-01

    BACKGROUND: Spider mites are important crop pests that rapidly develop resistance to acaricides. To investigate whether acaricide resistance is a threat to greenhouse rose culture in the Netherlands, the susceptibility of 15 strains of Tetranychus urticae was tested to several currently used

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

    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.

  3. A Systems Biology Approach Reveals Converging Molecular Mechanisms that Link Different POPs to Common Metabolic Diseases.

    Ruiz, Patricia; Perlina, Ally; Mumtaz, Moiz; Fowler, Bruce A

    2016-07-01

    A number of epidemiological studies have identified statistical associations between persistent organic pollutants (POPs) and metabolic diseases, but testable hypotheses regarding underlying molecular mechanisms to explain these linkages have not been published. We assessed the underlying mechanisms of POPs that have been associated with metabolic diseases; three well-known POPs [2,3,7,8-tetrachlorodibenzodioxin (TCDD), 2,2´,4,4´,5,5´-hexachlorobiphenyl (PCB 153), and 4,4´-dichlorodiphenyldichloroethylene (p,p´-DDE)] were studied. We used advanced database search tools to delineate testable hypotheses and to guide laboratory-based research studies into underlying mechanisms by which this POP mixture could produce or exacerbate metabolic diseases. For our searches, we used proprietary systems biology software (MetaCore™/MetaDrug™) to conduct advanced search queries for the underlying interactions database, followed by directional network construction to identify common mechanisms for these POPs within two or fewer interaction steps downstream of their primary targets. These common downstream pathways belong to various cytokine and chemokine families with experimentally well-documented causal associations with type 2 diabetes. Our systems biology approach allowed identification of converging pathways leading to activation of common downstream targets. To our knowledge, this is the first study to propose an integrated global set of step-by-step molecular mechanisms for a combination of three common POPs using a systems biology approach, which may link POP exposure to diseases. Experimental evaluation of the proposed pathways may lead to development of predictive biomarkers of the effects of POPs, which could translate into disease prevention and effective clinical treatment strategies. Ruiz P, Perlina A, Mumtaz M, Fowler BA. 2016. A systems biology approach reveals converging molecular mechanisms that link different POPs to common metabolic diseases. Environ

  4. Mechanisms of quinolone resistance in Salmonella spp. / Mecanismos de resistência às quinolonas em Salmonella spp.

    Tereza Cristina Rocha Moreira de Oliveira

    2010-07-01

    Full Text Available Salmonellosis is a common and widespread zoonotic disease of humans and a frequent cause of foodborne disease. Treatment of severe and systemic salmonellosis is usually done with fluoroquinolones. In this review resistance mechanisms of Salmonella to quinolones are discussed. Single point mutations in the quinolone resistant determining region (QRDR of the gyrA gene may be sufficient to generate high levels of resistance to non-fluorated quinolones and also may decrease the fluoroquinolones susceptibility. Other resistance mechanisms that should be considered are mutations in parC gene, the possibility of acquiring resistance through plasmidial transference and hyper-expression of efflux pumps. Fluoroquinolones resistance is still relatively uncommon in Salmonella compared to other species belonging to the Enterobacteriaceae family. However, the more careful use of fluoroquinolones in veterinary and human medicine is essential to decrease the selective pressure which can avoid the emergence and spread of resistant clones and consequently maintain the clinical efficacy of this group of antibiotics.A salmonelose é uma zoonose de importância mundial e uma das mais freqüentes doenças de origem alimentar. As fluoroquinolonas são a principal opção para o tratamento de salmoneloses graves ou sistêmicas. Esta revisão de literatura teve como objetivo apresentar os principais mecanismos envolvidos na resistência de Salmonella spp a estes antimicrobianos. Mutações de ponto na Região Determinante de Resistência à Quinolona (QRDR do gene gyrA podem gerar altos níveis de resistência a quinolonas não-fluoradas, além de reduzir a suscetibilidade as fluoroquinolonas. Outros mecanismos de resistência que também precisam ser considerados são as mutações no gene parC, a possibilidade do envolvimento de plasmídios de resistência e o sistema de efluxo ativo. A resistência às fluoroquinolonas ainda é incomum em Salmonella spp., quando

  5. A non-traditional model of the metabolic syndrome: the adaptive significance of insulin resistance in fasting-adapted seals

    Dorian S Houser

    2013-11-01

    Full Text Available Insulin resistance in modern society is perceived as a pathological consequence of excess energy consumption and reduced physical activity. Its presence in relation to the development of cardiovascular risk factors has been termed the metabolic syndrome, which produces increased mortality and morbidity and which is rapidly increasing in human populations. Ironically, insulin resistance likely evolved to assist animals during food shortages by increasing the availability of endogenous lipid for catabolism while protecting protein from use in gluconeogenesis and eventual oxidation. Some species that incorporate fasting as a predictable component of their life history demonstrate physiological traits similar to the metabolic syndrome during prolonged fasts. One such species is the northern elephant seal (Mirounga angustirostris, which fasts from food and water for periods of up to three months. During this time, ~90% of the seals metabolic demands are met through fat oxidation and circulating non-esterified fatty acids are high (0.7-3.2 mM. All life history stages of elephant seal studied to date demonstrate insulin resistance and fasting hyperglycemia as well as variations in hormones and adipocytokines that reflect the metabolic syndrome to some degree. Elephant seals demonstrate some intriguing adaptations with the potential for medical advancement; for example, ketosis is negligible despite significant and prolonged fatty acid oxidation and investigation of this feature might provide insight into the treatment of diabetic ketoacidosis. The parallels to the metabolic syndrome are likely reflected to varying degrees in other marine mammals, most of which evolved on diets high in lipid and protein content but essentially devoid of carbohydrate. Utilization of these natural models of insulin resistance may further our understanding of the pathophysiology of the metabolic syndrome in humans and better assist the development of preventative measures

  6. A non-traditional model of the metabolic syndrome: the adaptive significance of insulin resistance in fasting-adapted seals.

    Houser, Dorian S; Champagne, Cory D; Crocker, Daniel E

    2013-11-01

    Insulin resistance in modern society is perceived as a pathological consequence of excess energy consumption and reduced physical activity. Its presence in relation to the development of cardiovascular risk factors has been termed the metabolic syndrome, which produces increased mortality and morbidity and which is rapidly increasing in human populations. Ironically, insulin resistance likely evolved to assist animals during food shortages by increasing the availability of endogenous lipid for catabolism while protecting protein from use in gluconeogenesis and eventual oxidation. Some species that incorporate fasting as a predictable component of their life history demonstrate physiological traits similar to the metabolic syndrome during prolonged fasts. One such species is the northern elephant seal (Mirounga angustirostris), which fasts from food and water for periods of up to 4 months. During this time, ∼90% of the seals metabolic demands are met through fat oxidation and circulating non-esterified fatty acids are high (0.7-3.2 mM). All life history stages of elephant seal studied to date demonstrate insulin resistance and fasting hyperglycemia as well as variations in hormones and adipocytokines that reflect the metabolic syndrome to some degree. Elephant seals demonstrate some intriguing adaptations with the potential for medical advancement; for example, ketosis is negligible despite significant and prolonged fatty acid oxidation and investigation of this feature might provide insight into the treatment of diabetic ketoacidosis. The parallels to the metabolic syndrome are likely reflected to varying degrees in other marine mammals, most of which evolved on diets high in lipid and protein content but essentially devoid of carbohydrate. Utilization of these natural models of insulin resistance may further our understanding of the pathophysiology of the metabolic syndrome in humans and better assist the development of preventative measures and therapies.

  7. Etoxazole resistance in predatory mite Phytoseiulus persimilis A.-H. (Acari: Phytoseiidae): Cross-resistance, inheritance and biochemical resistance mechanisms.

    Yorulmaz Salman, Sibel; Aydınlı, Fatma; Ay, Recep

    2015-07-01

    Phytoseiulus persimilis of the family Phytoseiidae is an effective predatory mite species that is used to control pest mites. The LC50 and LC60 values of etoxazole were determined on P. persimilis using a leaf-disc method and spraying tower. A laboratory selection population designated ETO6 was found to have a 111.63-fold resistance to etoxazole following 6 selection cycles. This population developed low cross-resistance to spinosad, spiromesifen, acetamiprid, indoxacarb, chlorantraniliprole, milbemectin and moderate cross-resistance to deltamethrin. PBO, IBP and DEM synergised resistance 3.17-, 2.85- and 3.60-fold respectively. Crossing experiments revealed that etoxazole resistance in the ETO6 population was an intermediately dominant and polygenic. In addition, detoxifying enzyme activities were increased 2.71-fold for esterase, 3.09-fold for glutathione S-transferase (GST) and 2.76-fold for cytochrome P450 monooxygenase (P450) in the ETO6 population. Selection for etoxazole under laboratory conditions resulted in the development of etoxazole resistance in the predatory mite P. persimilis that are resistant to pesticides are considered valuable for use in resistance management programmes within integrated pest control strategies. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Evaluation the mechanisms of erythromycin and penicillin resistance ...

    user

    2012-01-12

    Jan 12, 2012 ... primer (Table 1) and 10 µl of DNA templates (Fukushima et al.,. 2008). PCR amplification was carried with the cycling parameters as follows: after an initial denaturation .... isolated from children in Japan. Mutations in pbp2x were observed in several strains presenting intermediate resistance to penicillin.

  9. Unravelling the resistance mechanism of lettuce against Nasonovia ribisnigri

    Broeke, ten C.J.M.

    2013-01-01

    Aphids are serious pests of crop plant species, and host plant resistance is often the most effective and environmentally friendly control strategy to control these pests. One of these aphid pests is the black currant - lettuce aphid, Nasonovia ribisnigri (Mosely), an economically

  10. Mechanism of Trypanosoma brucei gambiense resistance to human serum

    Uzureau, Pierrick; Uzureau, Sophie; Lecordier, Laurence

    2013-01-01

    GP), which prevents APOL1 toxicity and induces stiffening of membranes upon interaction with lipids. Two additional features contribute to resistance to TLFs: reduction of sensitivity to APOL1 requiring cysteine protease activity, and TbHpHbR inactivation due to a L210S substitution. According...

  11. Molecular mechanisms of insulin resistance | Pillay | South African ...

    This review discusses recent advances in understanding of the structure and function of the insulin receptor and insulin action, and how these relate to the clinical aspects of insulin resistance associated with non-insulin-dependent diabetes and other disorders. Improved understanding of the molecular basis of insulin ...

  12. Molecular Mechanisms of Antibiotic Resistance in Helicobacter pylori

    M.M. Gerrits (Monique)

    2004-01-01

    textabstractAn estimated 4 to 5 million individuals in the Netherlands are actively infected with Helicobacter pylori. Eradication of this bacterium becomes more difficult as the prevalence of antibiotic resistance is increasing worldwide. Most H. pylori infections are now diagnosed by

  13. A study on the mechanism of resistance to streptomycin in ...

    use

    2011-12-12

    1973), and the length of lesions on the inoculated leaf was measured after 15 days. DNA isolation. DNA was isolated from the wild-type isolate and resistant strains as described by Ausubel et al. (1987). After the bacteria were ...

  14. Emerging memories: resistive switching mechanisms and current status

    Jeong, Doo Seok; Thomas, Reji; Katiyar, R S; Scott, J F; Kohlstedt, H; Petraru, A; Hwang, Cheol Seong

    2012-01-01

    The resistance switching behaviour of several materials has recently attracted considerable attention for its application in non-volatile memory (NVM) devices, popularly described as resistive random access memories (RRAMs). RRAM is a type of NVM that uses a material(s) that changes the resistance when a voltage is applied. Resistive switching phenomena have been observed in many oxides: (i) binary transition metal oxides (TMOs), e.g. TiO 2 , Cr 2 O 3 , FeO x and NiO; (ii) perovskite-type complex TMOs that are variously functional, paraelectric, ferroelectric, multiferroic and magnetic, e.g. (Ba,Sr)TiO 3 , Pb(Zr x Ti 1−x )O 3 , BiFeO 3 and Pr x Ca 1−x MnO 3 ; (iii) large band gap high-k dielectrics, e.g. Al 2 O 3 and Gd 2 O 3 ; (iv) graphene oxides. In the non-oxide category, higher chalcogenides are front runners, e.g. In 2 Se 3 and In 2 Te 3 . Hence, the number of materials showing this technologically interesting behaviour for information storage is enormous. Resistive switching in these materials can form the basis for the next generation of NVM, i.e. RRAM, when current semiconductor memory technology reaches its limit in terms of density. RRAMs may be the high-density and low-cost NVMs of the future. A review on this topic is of importance to focus concentration on the most promising materials to accelerate application into the semiconductor industry. This review is a small effort to realize the ambitious goal of RRAMs. Its basic focus is on resistive switching in various materials with particular emphasis on binary TMOs. It also addresses the current understanding of resistive switching behaviour. Moreover, a brief comparison between RRAMs and memristors is included. The review ends with the current status of RRAMs in terms of stability, scalability and switching speed, which are three important aspects of integration onto semiconductors. (review article)

  15. Emerging memories: resistive switching mechanisms and current status

    Jeong, Doo Seok; Thomas, Reji; Katiyar, R. S.; Scott, J. F.; Kohlstedt, H.; Petraru, A.; Hwang, Cheol Seong

    2012-07-01

    The resistance switching behaviour of several materials has recently attracted considerable attention for its application in non-volatile memory (NVM) devices, popularly described as resistive random access memories (RRAMs). RRAM is a type of NVM that uses a material(s) that changes the resistance when a voltage is applied. Resistive switching phenomena have been observed in many oxides: (i) binary transition metal oxides (TMOs), e.g. TiO2, Cr2O3, FeOx and NiO; (ii) perovskite-type complex TMOs that are variously functional, paraelectric, ferroelectric, multiferroic and magnetic, e.g. (Ba,Sr)TiO3, Pb(Zrx Ti1-x)O3, BiFeO3 and PrxCa1-xMnO3 (iii) large band gap high-k dielectrics, e.g. Al2O3 and Gd2O3; (iv) graphene oxides. In the non-oxide category, higher chalcogenides are front runners, e.g. In2Se3 and In2Te3. Hence, the number of materials showing this technologically interesting behaviour for information storage is enormous. Resistive switching in these materials can form the basis for the next generation of NVM, i.e. RRAM, when current semiconductor memory technology reaches its limit in terms of density. RRAMs may be the high-density and low-cost NVMs of the future. A review on this topic is of importance to focus concentration on the most promising materials to accelerate application into the semiconductor industry. This review is a small effort to realize the ambitious goal of RRAMs. Its basic focus is on resistive switching in various materials with particular emphasis on binary TMOs. It also addresses the current understanding of resistive switching behaviour. Moreover, a brief comparison between RRAMs and memristors is included. The review ends with the current status of RRAMs in terms of stability, scalability and switching speed, which are three important aspects of integration onto semiconductors.

  16. Insulin resistance as a physiological defense against metabolic stress: implications for the management of subsets of type 2 diabetes.

    Nolan, Christopher J; Ruderman, Neil B; Kahn, Steven E; Pedersen, Oluf; Prentki, Marc

    2015-03-01

    Stratifying the management of type 2 diabetes (T2D) has to take into account marked variability in patient phenotype due to heterogeneity in its pathophysiology, different stages of the disease process, and multiple other patient factors including comorbidities. The focus here is on the very challenging subgroup of patients with T2D who are overweight or obese with insulin resistance (IR) and the most refractory hyperglycemia due to an inability to change lifestyle to reverse positive energy balance. For this subgroup of patients with T2D, we question the dogma that IR is primarily harmful to the body and should be counteracted at any cost. Instead we propose that IR, particularly in this high-risk subgroup, is a defense mechanism that protects critical tissues of the cardiovascular system from nutrient-induced injury. Overriding IR in an effort to lower plasma glucose levels, particularly with intensive insulin therapy, could therefore be harmful. Treatments that nutrient off-load to lower glucose are more likely to be beneficial. The concepts of "IR as an adaptive defense mechanism" and "insulin-induced metabolic stress" may provide explanation for some of the unexpected outcomes of recent major clinical trials in T2D. Potential molecular mechanisms underlying these concepts; their clinical implications for stratification of T2D management, particularly in overweight and obese patients with difficult glycemic control; and future research requirements are discussed. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  17. Inheritance and mechanism of resistance to herbicides inhibiting acetolactate synthase in Sonchus oleraceus L.

    Boutsalis, P; Powles, S B

    1995-07-01

    A biotype of Sonchus oleraceus L. (Compositae) has developed resistance to herbicides inhibiting acetolactate synthase (ALS) following field selection with chlorsulfuron for 8 consecutive years. The aim of this study was to determine the inheritance and mechanism of resistance in this biotype. Determination of ALS activity and inhibition kinetics revealed that Km and Vmax did not vary greatly between the resistant and susceptible biotypes. ALS extracted from the resistant biotype was resistant to five ALS-inhibiting herbicides in an in vitro assay. ALS activity from the resistant biotype was 14 19, 2, 3 and 3 times more resistant to inhibition by chlorsulfuron, sulfometuron, imazethapyr, imazapyr and flumetsulam, respectively, than the susceptible biotype. Hybrids between the resistant and a susceptible biotype were produced, and inheritance was followed through the F1, F2 and F3 generations. F1 hybrids displayed a uniform intermediate level of resistance between resistant and susceptible parents. Three distinct phenotypes, resistant, intermediate and susceptible, were identified in the F2 generation following chlorsulfuron application. A segregation ratio of 1∶2∶1 was observed, indicative of the action of a single, nuclear, incompletely dominant gene. F3 families, derived from intermediate F2 individuals, segregated in a similar manner. Resistance to herbicides inhibiting ALS in this biotype of S. oleraceus is due to the effect of a single gene coding for a resistant form of the target enzyme, ALS.

  18. Chemotherapeutics-resistance "arms" race: An update on mechanisms involved in resistance limiting EGFR inhibitors in lung cancer.

    Singh, Pankaj Kumar; Silakari, Om

    2017-10-01

    Clinical reports suggest that EGFR-mutated lung cancer usually respond significantly towards small molecule tyrosine kinase inhibitors. Same studies also report the eventual development of acquired resistance within a median time interval of 9 to 14months. One of the major mechanisms involved in this acquired resistance was found to be a secondary point mutation at gate-keeper residue, EGFR T790M. However, there are other recent studies which disclose the role of few other novel key players such as, ZEB1, TOPK etc., in the development of tolerance towards the EGFR TKI's, along with other commonly known mechanisms, such as amplification of signalling pathways such as, c-MET, Erbb2, AXL, additional acquired secondary mutations (PIK3CA, BRAF), or phenotypic transformation (small cell or epithelial to mesenchymal transitions). Interestingly, a recent study showed development of resistance via another point mutation, C797S, in case of tumors which were previously resistant and were administered agents capable of overcoming T790M gatekeeper mutation based resistance. Thus, raising serious concern over the direction of drug development involving tyrosine kinases such as EGFR. Current approaches focussing on development of third generation inhibitors, dual inhibitors or inhibitors of HSP90 have shown significant activity but do not answer the long term question of resistance. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Elucidation of Mechanisms of Ceftazidime Resistance among Clinical Isolates of Pseudomonas aeruginosa by Using Genomic Data.

    Kos, Veronica N; McLaughlin, Robert E; Gardner, Humphrey A

    2016-06-01

    Ceftazidime is one of the few cephalosporins with activity against Pseudomonas aeruginosa Using whole-genome comparative analysis, we set out to determine the prevalent mechanism(s) of resistance to ceftazidime (CAZ) using a set of 181 clinical isolates. These isolates represented various multilocus sequence types that consisted of both ceftazidime-susceptible and -resistant populations. A presumptive resistance mechanism against ceftazidime was identified in 88% of the nonsusceptible isolates using this approach. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

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

    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.

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

    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.

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

    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).

  3. Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors.

    Winyoo Chowanadisai

    Full Text Available The majority of ovarian tumors eventually recur in a drug resistant form. Using cisplatin sensitive and resistant cell lines assembled into 3D spheroids we profiled gene expression and identified candidate mechanisms and biological pathways associated with cisplatin resistance. OVCAR-8 human ovarian carcinoma cells were exposed to sub-lethal concentrations of cisplatin to create a matched cisplatin-resistant cell line, OVCAR-8R. Genome-wide gene expression profiling of sensitive and resistant ovarian cancer spheroids identified 3,331 significantly differentially expressed probesets coding for 3,139 distinct protein-coding genes (Fc >2, FDR < 0.05 (S2 Table. Despite significant expression changes in some transporters including MDR1, cisplatin resistance was not associated with differences in intracellular cisplatin concentration. Cisplatin resistant cells were significantly enriched for a mesenchymal gene expression signature. OVCAR-8R resistance derived gene sets were significantly more biased to patients with shorter survival. From the most differentially expressed genes, we derived a 17-gene expression signature that identifies ovarian cancer patients with shorter overall survival in three independent datasets. We propose that the use of cisplatin resistant cell lines in 3D spheroid models is a viable approach to gain insight into resistance mechanisms relevant to ovarian tumors in patients. Our data support the emerging concept that ovarian cancers can acquire drug resistance through an epithelial-to-mesenchymal transition.

  4. Clinical implications of adipocytokines and newly emerging metabolic factors with relation to insulin resistance and cardiovascular health

    Sung Hee eChoi

    2013-08-01

    Full Text Available Adipose tissue is known to secrete hormones actively and produces many biologically active proteins called adipocytokines. Typically, obesity is followed by low-grade inflammation, which is characterized by increased circulating levels of pro-inflammatory cytokines. Macrophages play a role in the inflammatory process by secreting many cytokines such as tumour necrosis factor-alpha, interleukin-6, resistin and retinol binding protein-4. These cytokines and chemokines participate in low grade pro-inflammatory processes leading to insulin resistance, metabolic impairment and cardiovascular diseases. More metabolic regulators, such as fibroblast growth factor (FGF21, FGF19, FGF1, vaspin and visfatin have now been discovered but their exact roles in human diseases are still unclear. This review focuses on recent research regarding the role of adipokines and new metabolic factors in metabolic derangement or cardiovascular disease.

  5. Quantitative proteomic studies in resistance mechanisms of Eimeria tenella against polyether ionophores.

    Thabet, Ahmed; Honscha, Walther; Daugschies, Arwid; Bangoura, Berit

    2017-05-01

    Polyether ionophores are widely used to treat and control coccidiosis in chickens. Widespread use of anticoccidials resulted in worldwide resistance. Mechanisms of resistance development and expansion are complex and poorly understood. Relative proteomic quantification using LC-MS/MS was used to compare sensitive reference strains (Ref-1, Ref-2) with putatively resistant and moderately sensitive field strains (FS-R, FS-mS) of Eimeria tenella after isotopic labelling with tandem mass tags (TMT). Ninety-seven proteins were identified, and 25 of them were regulated. Actin was significantly upregulated in resistant strains in comparison with their sensitive counterparts. On the other hand, microneme protein (MIC4) was downregulated in resistant strains. Optimization of labelling E. tenella sporozoites by TMT might identify further proteins that play a role in the obvious complex mechanism leading to resistance against Monensin.

  6. Novel drug-resistance mechanisms of pemetrexed-treated non-small cell lung cancer.

    Tanino, Ryosuke; Tsubata, Yukari; Harashima, Nanae; Harada, Mamoru; Isobe, Takeshi

    2018-03-30

    Pemetrexed (PEM) improves the overall survival of patients with advanced non-small cell lung cancer (NSCLC) when administered as maintenance therapy. However, PEM resistance often appears during the therapy. Although thymidylate synthase is known to be responsible for PEM resistance, no other mechanisms have been investigated in detail. In this study, we explored new drug resistance mechanisms of PEM-treated NSCLC using two combinations of parental and PEM-resistant NSCLC cell lines from PC-9 and A549. PEM increased the apoptosis cells in parental PC-9 and the senescent cells in parental A549. However, such changes were not observed in the respective PEM-resistant cell lines. Quantitative RT-PCR analysis revealed that, besides an increased gene expression of thymidylate synthase in PEM-resistant PC-9 cells, the solute carrier family 19 member1 ( SLC19A1) gene expression was markedly decreased in PEM-resistant A549 cells. The siRNA-mediated knockdown of SLC19A1 endowed the parental cell lines with PEM resistance. Conversely, PEM-resistant PC-9 cells carrying an epidermal growth factor receptor (EGFR) mutation acquired resistance to a tyrosine kinase inhibitor erlotinib. Although erlotinib can inhibit the phosphorylation of EGFR and Erk, it is unable to suppress the phosphorylation of Akt in PEM-resistant PC-9 cells. Additionally, PEM-resistant PC-9 cells were less sensitive to the PI3K inhibitor LY294002 than parental PC-9 cells. These results indicate that SLC19A1 negatively regulates PEM resistance in NSCLC, and that EGFR-tyrosine-kinase-inhibitor resistance was acquired with PEM resistance through Akt activation in NSCLC harboring EGFR mutations.

  7. Metabolic acidosis as an underlying mechanism of respiratory distress in children with severe acute asthma.

    Meert, Kathleen L; Clark, Jeff; Sarnaik, Ashok P

    2007-11-01

    1) To alert the clinician that increasing rate and depth of breathing during treatment of acute asthma may be a manifestation of metabolic acidosis with hyperventilation rather than worsening airway obstruction; and 2) to describe the frequency of metabolic acidosis with hyperventilation in children with severe acute asthma admitted to our pediatric intensive care unit. Retrospective medical record review. University-affiliated children's hospital. All patients admitted to the pediatric intensive care unit with a diagnosis of asthma between January 1, 2005, and December 31, 2005. None. Fifty-three patients with asthma (median age 7.8 yrs, range 0.7-17.9 yrs; 35 [66%] male; 46 [87%] black and 7 [13%] white) were admitted to the pediatric intensive care unit during the study period. Fifteen (28%) patients developed metabolic acidosis with hyperventilation (pH 120 mg/dL [6.7 mmol/L]). Patients who developed metabolic acidosis with hyperventilation received asthma therapy similar to that received by patients who did not develop the disorder. Metabolic acidosis resolved contemporaneously with tapering of beta2-adrenergic agonists and administration of supportive care. All patients survived. Metabolic acidosis with hyperventilation manifesting as respiratory distress can occur in children with severe acute asthma. A pathophysiologic rationale exists for the contribution of beta2-adrenergic agents to the development of this acid-base disorder. Failure to recognize metabolic acidosis as the underlying mechanism of respiratory distress may lead to inappropriate intensification of bronchodilator therapy. Supportive care and tapering of beta2-adrenergic agents are recommended to resolve this condition.

  8. Synthesis, Characterization, and Preclinical Evaluation of New Thiazolidin-4-ones Substituted with p-Chlorophenoxy Acetic Acid and Clofibric Acid against Insulin Resistance and Metabolic Disorder

    Vasantharaju S. Gowdra

    2014-01-01

    Full Text Available We synthesized twenty thiazolidin-4-one derivatives, which were then characterized by standard chromatographic and spectroscopic methods. From the in vitro glucose uptake assay, two compounds behaved as insulin sensitizers, where they enhanced glucose uptake in isolated rat diaphragm. In high-carbohydrate diet-induced insulin resistant mice, these two thiazolidin-4-ones attenuated hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and glucose intolerance. They raised the plasma leptin but did not reverse the diabetes-induced hypoadiponectinemia. Additionally, compound 3a reduced adiposity. The test compounds were also able to reverse the disturbed liver antioxidant milieu. To conclude, these two novel thiazolidin-4-ones modulated multiple mechanisms involved in metabolic disorders, reversing insulin resistance and thus preventing the development of type-2 diabetes.

  9. Synthesis, characterization, and preclinical evaluation of new thiazolidin-4-ones substituted with p-chlorophenoxy acetic acid and clofibric acid against insulin resistance and metabolic disorder.

    Gowdra, Vasantharaju S; Mudgal, Jayesh; Bansal, Punit; Nayak, Pawan G; Manohara Reddy, Seethappa A; Shenoy, Gautham G; Valiathan, Manna; Chamallamudi, Mallikarjuna R; Nampurath, Gopalan K

    2014-01-01

    We synthesized twenty thiazolidin-4-one derivatives, which were then characterized by standard chromatographic and spectroscopic methods. From the in vitro glucose uptake assay, two compounds behaved as insulin sensitizers, where they enhanced glucose uptake in isolated rat diaphragm. In high-carbohydrate diet-induced insulin resistant mice, these two thiazolidin-4-ones attenuated hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and glucose intolerance. They raised the plasma leptin but did not reverse the diabetes-induced hypoadiponectinemia. Additionally, compound 3a reduced adiposity. The test compounds were also able to reverse the disturbed liver antioxidant milieu. To conclude, these two novel thiazolidin-4-ones modulated multiple mechanisms involved in metabolic disorders, reversing insulin resistance and thus preventing the development of type-2 diabetes.

  10. The Physiological and Biochemical Mechanisms Providing the Increased Constitutive Cold Resistance in the Potato Plants, Expressing the Yeast SUC2 Gene Encoding Apoplastic Invertase

    A.N. Deryabin

    2016-05-01

    Full Text Available The expression of heterologous genes in plants is an effective method to improve our understanding of plant resistance mechanisms. The purpose of this work was to investigate the involvement of cell-wall invertase and apoplastic sugars into constitutive cold resistance of potato (Solanum tuberosum L., cv. Dйsirйe plants, which expressed the yeast SUC2 gene encoding apoplastic invertase. WT-plants of a potato served as the control. The increase in the essential cell-wall invertase activity in the leaves of transformed plants indicates significant changes in the cellular carbohydrate metabolism and regulatory function of this enzyme. The activity of yeast invertase changed the composition of intracellular sugars in the leaves of the transformed potato plant. The total content of sugars (sucrose, glucose, fructose in the leaves and apoplast was higher in the transformants, in comparison by WT-plants. Our data indicate higher constitutive resistance of transformants to severe hypothermia conditions compared to WT-plants. This fact allows us to consider cell-wall invertase as a enzyme of carbohydrate metabolism playing an important regulatory role in the metabolic signaling upon forming increased plant resistance to low temperature. Thus, the potato line with the integrated SUC2 gene is a convenient tool to study the role of the apoplastic invertase and the products of its activity during growth, development and formation constitutive resistance to hypothermia.

  11. The relationship of thioredoxin-1 and cisplatin resistance: its impact on ROS and oxidative metabolism in lung cancer cells.

    Wangpaichitr, Medhi; Sullivan, Elizabeth J; Theodoropoulos, George; Wu, Chunjing; You, Min; Feun, Lynn G; Lampidis, Theodore J; Kuo, Macus T; Savaraj, Niramol

    2012-03-01

    Elimination of cisplatin-resistant lung cancer cells remains a major obstacle. We have shown that cisplatin-resistant tumors have higher reactive oxygen species (ROS) levels and can be exploited for targeted therapy. Here, we show that increased secretion of the antioxidant thioredoxin-1 (TRX1) resulted in lowered intracellular TRX1 and contributed to higher ROS in cisplatin-resistant tumors in vivo and in vitro. By reconstituting TRX1 protein in cisplatin-resistant cells, we increased sensitivity to cisplatin but decreased sensitivity to elesclomol (ROS inducer). Conversely, decreased TRX1 protein in parental cells reduced the sensitivity to cisplatin but increased sensitivity to elesclomol. Cisplatin-resistant cells had increased endogenous oxygen consumption and mitochondrial activity but decreased lactic acid production. They also exhibited higher levels of argininosuccinate synthetase (ASS) and fumarase mRNA, which contributed to oxidative metabolism (OXMET) when compared with parental cells. Restoring intracellular TRX1 protein in cisplatin-resistant cells resulted in lowering ASS and fumarase mRNAs, which in turn sensitized them to arginine deprivation. Interestingly, cisplatin-resistant cells also had significantly higher basal levels of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). Overexpressing TRX1 lowered ACC and FAS proteins expressions in cisplatin-resistant cells. Chemical inhibition and short interfering RNA of ACC resulted in significant cell death in cisplatin-resistant compared with parental cells. Conversely, TRX1 overexpressed cisplatin-resistant cells resisted 5-(tetradecyloxy)-2-furoic acid (TOFA)-induced death. Collectively, lowering TRX1 expression through increased secretion leads cisplatin-resistant cells to higher ROS production and increased dependency on OXMET. These changes raise an intriguing therapeutic potential for future therapy in cisplatin-resistant lung cancer.

  12. Impact of Roux-en-Y Gastric Bypass on Metabolic Syndrome and Insulin Resistance Parameters

    Gestic, Martinho Antonio; Utrini, Murillo Pimentel; Machado, Ricardo Rossetto; Geloneze, Bruno; Pareja, José Carlos; Chaim, Elinton Adami

    2014-01-01

    Abstract Background: Metabolic syndrome (MetS) is a complex association of clustering metabolic factors that increase risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease. Surgical treatment has become an important tool to achieve its control. The aim of this study was to evaluate the impact of Roux-en-Y gastric bypass (RYGB) on MetS and its individual components, clinical characteristics, and biochemical features. Subjects and Methods: The study is a retrospective cohort of 96 subjects with MetS who underwent RYGB and were evaluated at baseline and after surgery. Clinical and biochemical features were analyzed. Results: After surgery, significant rates of resolution for MetS (88.5%), T2DM (90.6%), hypertension (85.6%), and dyslipidemias (54.2%) were found. Significant decreases in levels of fasting glucose, fasting insulin, hemoglobin A1c, low-density lipoprotein, and triglycerides and an increase in high-density lipoprotein level were also shown. The decrease in insulin resistance evaluated by homeostasis model assessment (HOMA-IR) was consistent. MetS resolution was associated with postoperative glycemic control, decreases in levels of fasting glucose, hemoglobin A1c, HOMA-IR, and triglycerides and in antihypertensive usage, and percentage weight loss. Conclusions: This study found high rates of resolution for MetS, T2DM, hypertension, and dyslipidemias after RYGB in obese patients. This finding was consistent with current literature. Hence RYGB should be largely indicated for this group of subjects as it is a safe and powerful tool to achieve MetS control. PMID:24299427

  13. The molecular changing mechanism of Ampicillin-Sulbactam resistant Staphylococcus aureus towards Methicillin resistant Staphylococcus aureus

    Mieke Hemiawati Satari

    2005-12-01

    Full Text Available The aim of this study was to determine the molecular changing of S.aureus, which is resistant to Ampicillin-Sulbactam and then become resistant to Methicillin as a result of improper dosage. The study was conducted by isolating Ampicillin-Sulbactam resistant and Methicillin Resistant S.aureus (MRSA, afterwards an amplification process was performed by PCR (Polymerase Chain Reaction. to isolate the betalactamase enzyme regulator and PBP 2a genes. The result of this research showed that there were a deletion of few amino acids from the regulator gene, and a suspicion that the DNA sequence had been substituted from PBP 2 gene into PBP 2a (gen mec. This process had formed MRSA.

  14. Mechanisms of resistance to quinolones: target alterations, decreased accumulation and DNA gyrase protection.

    Ruiz, Joaquim

    2003-05-01

    Quinolones are broad-spectrum antibacterial agents, commonly used in both clinical and veterinary medicine. Their extensive use has resulted in bacteria rapidly developing resistance to these agents. Two mechanisms of quinolone resistance have been established to date: alterations in the targets of quinolones, and decreased accumulation due to impermeability of the membrane and/or an overexpression of efflux pump systems. Recently, mobile elements have also been described, carrying the qnr gene, which confers resistance to quinolones.

  15. Effects of a diet rich in arabinoxylan and resistant starch compared with a diet rich in refined carbohydrates on postprandial metabolism and features of the metabolic syndrome.

    Schioldan, Anne Grethe; Gregersen, Søren; Hald, Stine; Bjørnshave, Ann; Bohl, Mette; Hartmann, Bolette; Holst, Jens Juul; Stødkilde-Jørgensen, Hans; Hermansen, Kjeld

    2018-03-01

    Low intake of dietary fibre is associated with the development of type 2 diabetes. Dyslipidaemia plays a key role in the pathogenesis of type 2 diabetes. Knowledge of the impact of dietary fibres on postprandial lipaemia is, however, sparse. This study aimed in subjects with metabolic syndrome to assess the impact on postprandial lipaemia and features of the metabolic syndrome of a healthy carbohydrate diet (HCD) rich in cereal fibre, arabinoxylan and resistant starch compared to a refined-carbohydrate western-style diet (WSD). Nineteen subjects completed the randomised, crossover study with HCD and WCD for 4-week. Postprandial metabolism was evaluated by a meal-challenge test and insulin sensitivity was assessed by HOMA-IR and Matsuda index. Furthermore, fasting cholesterols, serum-fructosamine, circulating inflammatory markers, ambulatory blood pressure and intrahepatic lipid content were measured. We found no diet effects on postprandial lipaemia. However, there was a significant diet × statin interaction on total cholesterol (P = 0.02) and LDL cholesterol (P = 0.002). HCD decreased total cholesterol (-0.72 mmol/l, 95% CI (-1.29; -0.14) P = 0.03) and LDL cholesterol (-0.61 mmol/l, 95% CI (-0.86; -0.36) P = 0.002) compared with WSD in subjects on but not without statin treatment. We detected no other significant diet effects. In subjects with metabolic syndrome on statins a 4-week diet rich in arabinoxylan and resistant starch improved fasting LDL and total cholesterol compared to subjects not being on statins. However, we observed no diet related impact on postprandial lipaemia or features of the metabolic syndrome. The dietary fibre x statin interaction deserves further elucidation.

  16. Relationship of hypovitaminosis d and insulin resistance in patients with coronary heart disease and metabolic syndrome

    V. F. Orlovsky

    2013-08-01

    Full Text Available BACKGROUND: Insulin resistance (IR - is one of the predictors of cardiovascular disease and progression of atherosclerosis, regardless of major classical risk factors. IR has become a global epidemic. Experimental data indicate that low concentration of vitamin D associated with IR, diabetes mellitus type 2, by reducing the sensitivity of peripheral tissues to insulin and dysfunction of β-pancreatic cells. Randomized studies showed that vitamin D supplements have a preventive role in the development of type 2 diabetes mellitus (DM. The present study aims to examine the association between serum vitamin D concentrations and indicators of carbohydrate metabolism, indexes of insulin resistance and insulin sensitivity in the patients with coronary artery disease. METHODS: This study included 135 patients with CHD stable angina pectoris class II – III. The mean age was 64,7±0,97 years, 40% were women (n = 54. Patients were divided into two groups: I – with isolated CHD (70 patients and II - CHD combined with MS (65 patients. MS was diagnosed according to the criteria of the International Diabetes Federation (IDF, 2005. The study did not include patients who received vitamin D2, D3 and multivitamins containing these vitamins for last 6 months, patients with malabsorption fat syndrome, acute and chronic liver disease, chronic renal failure, nephrotic syndrome, urolithiasis, and primary hyperparathyroidism. Also excluded from the study were patients with DM type 1 and type 2 taking glucose-lowering drugs. Serum 25(OHD and insulin were measured by enzyme immunoassay (25-OH Vitamin D Immunodiagnostics Systems Limited (UK; DRG (USA. RESULT: Vitamin D deficiency or insufficiency was present in 91,9 % of the tested patients. Among subnormal values prevailed insufficiency in 51,9 % (70 pers., deficit diagnosed in 40.0% of patients (54 pers.. Established that patients with CHD associated with MS have a significantly more pronounced hypovitaminosis D

  17. Ectopic brown adipose tissue in muscle provides a mechanism for differences in risk of metabolic syndrome in mice.

    Almind, Katrine; Manieri, Monia; Sivitz, William I; Cinti, Saverio; Kahn, C Ronald

    2007-02-13

    C57BL/6 (B6) mice subjected to a high-fat diet develop metabolic syndrome with obesity, hyperglycemia, and insulin resistance, whereas 129S6/SvEvTac (129) mice are relatively protected from this disorder because of differences in higher basal energy expenditure in 129 mice, leading to lower weight gain. At a molecular level, this difference correlates with a marked higher expression of uncoupling protein 1 (UCP1) and a higher degree of uncoupling in vitro in mitochondria isolated from muscle of 129 versus B6 mice. Detailed histological examination, however, reveals that this UCP1 is in mitochondria of brown adipocytes interspersed between muscle bundles. Indeed, the number of UCP1-positive brown fat cells in intermuscular fat in 129 mice is >700-fold higher than in B6 mice. These brown fat cells are subject to further up-regulation of UCP1 after stimulation with a beta3-adrenergic receptor agonist. Thus, ectopic deposits of brown adipose tissue in intermuscular depots with regulatable expression of UCP1 provide a genetically based mechanism of protection from weight gain and metabolic syndrome between strains of mice.

  18. NEW METABOLIC INDEX USE POTENTIALITIES IN EVALUATION OF INSULIN RESISTANCE IN CLINICAL PRACTICE

    G. E. Roytberg

    2015-09-01

    Full Text Available Early diagnostics of insulin resistance (IR is one of the methods of primary prevention of cardio-vascular diseases and type 2 diabetes mellitus. The HOMA-IR index and ratio of plasma triglyceride to high-density lipoprotein cholesterol concentration are the most frequently used indices in clinical and epidemiological scientific research. Prognostic value and efficacy of these tests as a screening method are not high. What method of IR detection should be used in clinical practice and how to interpret received values of the indices is still a matter of dispute.Aim. To evaluate informative value, sensitivity and specificity of a new metabolic index (MI for IR estimation in comparison with the calculated HOMA-IR index.Material and methods. A total of 845 patients (298 men, 547 women were enrolled into the further study after an outpatient regular medical check-up of 2,615 persons. Mean age of the patients was 45.77±12.18 years, body mass index – 28.95±1.44 kg/m2. To evaluate lipid and carbohydrate metabolism blood chemistry parameters were assessed. IR was determined by the Homeostasis Model Assessment (HOMA-IR and an oblique calculated index based on lipid metabolism parameters. In accordance with the developed screening method of IR detection (invention patent № 2493566 MI considering carbohydrate and lipid changes was proposed.Results. Calculation of MI and its threshold level was performed by analysis of a characteristic curve. Graphical dependence between sensitivity and specificity of the proposed index was demonstrated: sensitivity of the test was 75.7%, specificity – 89.1%. Probability of IR at MI value >7.0 was 63.5% (positive predictive value, probability of IR absence at the index value ≤7.0 was 93.6% (negative predictive value. The general accuracy of the test, which is characterized by the area under the characteristic curve, was 0.881 with 95%-confidence interval within 0.854-0.905.Conclusion. The importance of negative

  19. NEW METABOLIC INDEX USE POTENTIALITIES IN EVALUATION OF INSULIN RESISTANCE IN CLINICAL PRACTICE

    G. E. Roytberg

    2014-01-01

    Full Text Available Early diagnostics of insulin resistance (IR is one of the methods of primary prevention of cardio-vascular diseases and type 2 diabetes mellitus. The HOMA-IR index and ratio of plasma triglyceride to high-density lipoprotein cholesterol concentration are the most frequently used indices in clinical and epidemiological scientific research. Prognostic value and efficacy of these tests as a screening method are not high. What method of IR detection should be used in clinical practice and how to interpret received values of the indices is still a matter of dispute.Aim. To evaluate informative value, sensitivity and specificity of a new metabolic index (MI for IR estimation in comparison with the calculated HOMA-IR index.Material and methods. A total of 845 patients (298 men, 547 women were enrolled into the further study after an outpatient regular medical check-up of 2,615 persons. Mean age of the patients was 45.77±12.18 years, body mass index – 28.95±1.44 kg/m2. To evaluate lipid and carbohydrate metabolism blood chemistry parameters were assessed. IR was determined by the Homeostasis Model Assessment (HOMA-IR and an oblique calculated index based on lipid metabolism parameters. In accordance with the developed screening method of IR detection (invention patent № 2493566 MI considering carbohydrate and lipid changes was proposed.Results. Calculation of MI and its threshold level was performed by analysis of a characteristic curve. Graphical dependence between sensitivity and specificity of the proposed index was demonstrated: sensitivity of the test was 75.7%, specificity – 89.1%. Probability of IR at MI value >7.0 was 63.5% (positive predictive value, probability of IR absence at the index value ≤7.0 was 93.6% (negative predictive value. The general accuracy of the test, which is characterized by the area under the characteristic curve, was 0.881 with 95%-confidence interval within 0.854-0.905.Conclusion. The importance of negative

  20. The effects of resistance exercise training on arterial stiffness in metabolic syndrome.

    DeVallance, E; Fournier, S; Lemaster, K; Moore, C; Asano, S; Bonner, D; Donley, D; Olfert, I M; Chantler, P D

    2016-05-01

    Arterial stiffness is a strong independent risk factor for cardiovascular disease and is elevated in individuals with metabolic syndrome (MetS). Resistance training is a popular form of exercise that has beneficial effects on muscle mass, strength, balance and glucose control. However, it is unknown whether resistance exercise training (RT) can lower arterial stiffness in patients with MetS. Thus, the aim of this study was to examine whether a progressive RT program would improve arterial stiffness in MetS. A total of 57 subjects (28 healthy sedentary subjects; 29 MetS) were evaluated for arterial structure and function, including pulse wave velocity (cfPWV: arterial stiffness), before and after an 8-week period of RT or continuation of sedentary lifestyle. We found that 8 weeks of progressive RT increased skeletal muscle strength in both Con and MetS, but did not change arterial stiffness in either MetS (cfPWV; Pre 7.9 ± 0.4 m/s vs. Post 7.7 ± 0.4 m/s) or healthy controls (cfPWV; Pre 6.9 ± 0.3 m/s vs. Post 7.0 ± 0.3 m/s). However, when cfPWV is considered as a continuous variable, high baseline measures of cfPWV tended to show a decrease in cfPWV following RT. Eight weeks of progressive RT did not decrease the group mean values of arterial stiffness in individuals with MetS or healthy controls.

  1. A review of mechanisms of circumvention and modulation of chemotherapeutic drug resistance.

    O'Connor, R

    2009-05-01

    Drug resistance is a serious limitation to the effective treatment of a number of common malignancies. Thirty years of laboratory and clinical research have greatly defined the molecular alterations underlying many drug resistance processes in cancer. Based on this knowledge, strategies to overcome the impact of resistance and increase the efficacy of cancer treatment have been translated from laboratory models to clinical trials. This article reviews laboratory and, in particular, clinical attempts at drug resistance circumvention from early forays in the inhibition of cellular efflux pump-mediated drug resistance through to more selective circumvention agent strategies and into inhibition of the other important mechanisms which can allow cancer cells to survive therapy, such as apoptosis resistance. Despite some promising results to date, resistance inhibition strategies have largely failed due to poor understanding of the pharmacology, dynamics and complexity of the resistance phenotype. With the realisation that new molecularly-targeted agents can also be rendered ineffectual by the actions of resistance mechanisms, a major focus is once again emerging on identifying new strategies/pharmaceuticals which can augment the activity of the arsenal of more conventional cytotoxics and newer targeted anti-cancer drugs. Future tactical directions where old and new resistance strategies may merge to overcome this challenge are discussed.

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

    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

  3. Defining the Adipose Tissue Proteome of Dairy Cows to Reveal Biomarkers Related to Peripartum Insulin Resistance and Metabolic Status.

    Zachut, Maya

    2015-07-02

    Adipose tissue is a central regulator of metabolism in dairy cows; however, little is known about the association between various proteins in adipose tissue and the metabolic status of peripartum cows. Therefore, the objectives were to (1) examine total protein expression in adipose tissue of dairy cows and (2) identify biomarkers in adipose that are linked to insulin resistance and to cows' metabolic status. Adipose tissue biopsies were obtained from eight multiparous cows at -17 and +4 days relative to parturition. Proteins were analyzed by intensity-based, label-free, quantitative shotgun proteomics (nanoLC-MS/MS). Cows were divided into groups with insulin-resistant (IR) and insulin-sensitive (IS) adipose according to protein kinase B phosphorylation following insulin stimulation. Cows with IR adipose lost more body weight postpartum compared with IS cows. Differential expression of 143 out of 586 proteins was detected in prepartum versus postpartum adipose. Comparing IR to IS adipose revealed differential expression of 18.9% of the proteins; those related to lipolysis (hormone-sensitive lipase, perilipin, monoglycerol lipase) were increased in IR adipose. In conclusion, we found novel biomarkers related to IR in adipose and to metabolic status that could be used to characterize high-yielding dairy cows that are better adapted to peripartum metabolic stress.

  4. Nucleus geometry and mechanical properties of resistance spot ...

    Department of Mechanical Engineering, Engineering Faculty, Mersin University, 33343 Ciftlikkoy, Mersin, Turkey; Metallurgy Materials Engineering Department, Engineering Faculty, Karabuk University Baliklarkayasi, Karabuk, Turkey; Faculty of Tarsus Technical Education, Mersin University, 33480 Tarsus, Turkey ...

  5. Production of sintered alumina from powder; optimization of the sinterized parameters for the maximum mechanical resistence

    Rocha, J.C. da.

    1981-02-01

    Pure, sinterized alumina and the optimization of the parameters of sinterization in order to obtain the highest mechanical resistence are discussed. Test materials are sinterized from a fine powder of pure alumina (Al 2 O 3 ), α phase, at different temperatures and times, in air. The microstructures are analysed concerning porosity and grain size. Depending on the temperature or the time of sinterization, there is a maximum for the mechanical resistence. (A.R.H.) [pt

  6. HYDRO-ABRASIVE RESISTANCE AND MECHANICAL PROPERTIES OF CONCRETE WITH ADDED FLY ASH

    Ristić, Nenad; Grdić, Zoran; Topličić-Ćurčić, Gordana

    2015-01-01

    The durability of hydraulic engineering structures mostly depends on the resistance of their concrete surfaces to mechanical abrasion. In this paper, we study the hydro-abrasive resistance and mechanical properties of concrete in which cement is partially replaced with fly ash in various proportions. To evaluate these concretes, we measured their compressive strength, flexural strength, static modulus of elasticity, ultrasound velocity through concrete, and sclerometer rebound. The hydro-abra...

  7. Dissecting the Mechanisms of Drug Resistance in BRCA1/2-Mutant Breast Cancers

    2017-10-01

    AWARD NUMBER: W81XWH-16-1-0600 TITLE: Dissecting the Mechanisms of Drug Resistance in BRCA1/2-Mutant Breast Cancers PRINCIPAL INVESTIGATOR: Dr...2017 4. TITLE AND SUBTITLE Dissecting the Mechanisms of Drug Resistance in BRCA1/2- Mutant Breast Cancers 5a. CONTRACT NUMBER W81XWH-16-1-0600 5b...therapeutic modality for targeting homologous recombination (HR) deficient tumors such as BRCA1 and BRCA2-mutated triple negative breast cancers

  8. Mapping insecticide resistance and characterization of resistance mechanisms in Anopheles arabiensis (Diptera: Culicidae) in Ethiopia.

    Alemayehu, Eba; Asale, Abebe; Eba, Kasahun; Getahun, Kefelegn; Tushune, Kora; Bryon, Astrid; Morou, Evangelia; Vontas, John; Van Leeuwen, Thomas; Duchateau, Luc; Yewhalaw, Delenasaw

    2017-09-02

    The emergence and spread of insecticide resistance in the major African malaria vectors Anopheles gambiae (s.s.) and An. arabiensis may compromise the current vector control interventions and threatens the global malaria control and elimination efforts. Insecticide resistance was monitored in several study sites in Ethiopia from 2013 to 2015 using papers impregnated with discriminating concentrations of DDT, deltamethrin, bendiocarb, propoxur, malathion, fenitrothion and pirimiphos-methyl, following the WHO insecticide susceptibility test procedure. Mosquitoes sampled from different localities for WHO bioassay were morphologically identified as An. gambiae (s.l.) using standard taxonomic keys. Samples were identified to species using species-specific polymerase chain reaction (PCR) and screened for the presence of target site mutations L1014F, L1014S and N1575Y in the voltage gated sodium channel (VGSC) gene and G119S in the acethylcholinesterase (AChE) gene using allele-specific PCR. Biochemical assays were performed to assess elevated levels of acetylcholinesterases, carboxylcholinesterases, glutathione-S-transferases (GSTs) and cytochrome P450s monooxygenases in wild populations of An. arabiensis, compared to the fully susceptible Sekoru An. arabiensis laboratory strain. Populations of An. arabiensis were resistant to DDT and deltamethrin but were susceptible to fenitrothion in all the study sites. Reduced susceptibility to malathion, pirimiphos-methyl, propoxur and bendiocarb was observed in some of the study sites. Knockdown resistance (kdr L1014F) was detected in all mosquito populations with allele frequency ranging from 42 to 91%. Elevated levels of glutathione-S-transferases (GSTs) were detected in some of the mosquito populations. However, no elevated levels of monooxygenases and esterases were detected in any of the populations assessed. Anopheles arabiensis populations from all surveyed sites in Ethiopia exhibited resistance against DDT and pyrethroids

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

    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.

  10. INFLUENCE OF HERBAL EXTRACTS ON METABOLIC DISTURBANCES IN DIABETES MELLITUS AND INSULIN RESISTANCE MODEL

    T. V. Yakimova

    2015-01-01

    Full Text Available The aim of this research was to assess the influence on metabolic processes of herbal extracts, used in diets with different fat content, in diabetes mellitus and insulin resistance model.Material and methods. The experiments were performing on 90 noninbred male albino rats. Diabetes mellitus was modeling with twice-repeated intraperitoneal streptozotocine (30 mg/kg injections. For the insulin resistance formation animals were fad meal with 30% fat content. Against the background rats were administering into the stomach nettle leafs (Urtica dioica L., 100 mg/kg, burdock roots (Arctium lappa L., 25 mg/kg extracts or intraperitoneal insulin preparation Actrapide HM Penfill (3 mg/kg daily during 10 days. During period of agents introduction one-half of animals continued to receive food with high fat content, the other half received diet with 8% fat content. The third rats group received only food with low fat content without extracts or insulin administration. In blood was measured the glucose, glycosylated hemoglobin, creatinine, urea, uric acid content, in liver homogenates – glycogen, protein content, aminotransferases and glucose-6phosphatase activity, in muscle homogenates – glycogen and protein content.Results. After streptozotocine injections and diet with 30% fat content the blood glucose level became by 4.0–5.3 fold more than level of intact animals, increased the hemoglobin glycosylation, also creatinine, urea, uric acid blood content, in liver and muscle homogenates raised glycogen content, decreased protein quantity, in liver homogenates increased aminotranferases and glucose-6-phosphatase activity. In animals only feeding with 8% fat diminished hyperglycemia, creatinine blood retention, the liver glycogen content and recovered its protein resources. The nettle or burdock extracts administrating to animals that continued to receive high fat meal decreased the blood glucose, glycosylated hemoglobin and creatinine content, the liver

  11. Metabolism by conjugation appears to confer resistance to paracetamol (acetaminophen) hepatotoxicity in the cynomolgus monkey.

    Yu, Hong; Barrass, Nigel; Gales, Sonya; Lenz, Eva; Parry, Tony; Powell, Helen; Thurman, Dale; Hutchison, Michael; Wilson, Ian D; Bi, Luke; Qiao, Junwen; Qin, Qiuping; Ren, Jin

    2015-03-01

    1. Paracetamol overdose remains the leading cause of acute liver failure in humans. This study was undertaken in cynomolgus monkeys to study the pharmacokinetics, metabolism and the potential for hepatotoxic insult from paracetamol administration as a possible model for human toxicity. 2. No adverse effects were observed for doses of up to 900 mg/kg/d for 14 d. Only minor sporadic increases in alanine aminotransferase, aspartate aminotransferase and glutamate dehydrogenase in a number of animals were observed, with no clear dose response. 3. Toxicokinetic analysis showed good plasma exposure, albeit with less than proportional rises in Cmax and AUC, with increasing dose. The Cmax values in monkey were up to 3.5 times those associated with human liver toxicity and the AUC approx. 1000 times those associated with liver enzyme changes in 31-44% of human subjects. 4. Metabolite profiling of urine by (1)H NMR spectroscopy revealed paracetamol and its glucuronide and sulphate metabolites. Glutathione-derived metabolites, e.g. the cysteinyl conjugate, were only present in very low concentrations whilst the mercapturate was not detected. 5. These in vivo observations demonstrated that the cynomolgus monkey is remarkably resistant to paracetamol-induced toxicity and a poor model for investigating paracetamol-related hepatotoxicity in humans.

  12. Mechanisms of Acquired Resistance to Trastuzumab Emtansine in Breast Cancer Cells.

    Li, Guangmin; Guo, Jun; Shen, Ben-Quan; Bumbaca Yadav, Daniela; Sliwkowski, Mark X; Crocker, Lisa M; Lacap, Jennifer A; Lewis Phillips, Gail D

    2018-04-25

    The receptor tyrosine kinase HER2 is overexpressed in approximately 20% of breast cancer, and its amplification is associated with reduced survival. Trastuzumab emtansine (Kadcyla®, T-DM1), an antibody-drug conjugate that is comprised of trastuzumab covalently linked to the anti-mitotic agent DM1 through a stable linker, was designed to selectively deliver DM1 to HER2-overexpressing tumor cells. T-DM1 is approved for the treatment of patients with HER2-positive metastatic breast cancer following progression on trastuzumab and a taxane. Despite the improvement in clinical outcome, many patients who initially respond to T-DM1 treatment eventually develop progressive disease. The mechanisms that contribute to T-DM1 resistance are not fully understood. To this end, we developed T-DM1-resistant in vitro models to examine the mechanisms of acquired T-DM1 resistance. We demonstrate that decreased HER2 and up-regulation of MDR1 contribute to T-DM1 resistance in KPL-4 T-DM1 resistant cells. In contrast, both loss of SLC46A3 and PTEN deficiency play a role in conferring resistance in BT-474M1 T-DM1 resistant cells. Our data suggest that these two cell lines acquire resistance through distinct mechanisms. Furthermore, we show that the KPL-4 T-DM1 resistance can be overcome by treatment with an inhibitor of MDR1, whereas a PI3K inhibitor can rescue PTEN loss-induced resistance in T-DM1-resistant BT-474M1 cells. Our results provide a rationale for developing therapeutic strategies to enhance T-DM1 clinical efficacy by combining T-DM1 and other inhibitors that target signaling transduction or resistance pathways. Copyright ©2018, American Association for Cancer Research.

  13. Prevalence of insulin resistance and its association with metabolic syndrome criteria among Bolivian children and adolescents with obesity

    Rodriguez Susana

    2008-08-01

    Full Text Available Abstract Background Obesity is a one of the most common nutritional disorder worldwide, clearly associated with the metabolic syndrome, condition with implications for the development of many chronic diseases. In the poorest countries of Latin America, malnourishment is still the most prevalent nutritional problem, but obesity is emerging in alarming rates over the last 10 years without a predictable association with metabolic syndrome. The objective of our study was to determine the association between insulin-resistance and components of the metabolic syndrome in a group of Bolivian obese children and adolescents. The second objective was determining the relation of acanthosis nigricans and insulin-resistance. Methods We studied 61 obese children and adolescents aged between 5 and 18 years old. All children underwent an oral glucose tolerance test and fasting blood sample was also obtained to measure insulin, HDL, LDL and triglycerides serum level. The diagnosis of metabolic syndrome was defined according to National Cholesterol Education Program-Adult Treatment Panel (NCEP-ATP III criteria adapted for children. Results Metabolic syndrome was found in 36% of the children, with a higher rate among males (40% than females (32.2% (p = 0.599. The prevalence of each of the components was 8.2% in impaired glucose tolerance, 42.6% for high triglyceride level, 55.7% for low levels of high-density lipoprotein cholesterol, and 24.5% for high blood pressure. Insulin resistance (HOMA-IR > 3.5 was found in 39.4% of the children, with a higher rate in males (50% than females (29%. A strong correlation was found between insulin resistance and high blood pressure (p = 0.0148 and high triglycerides (p = 0.002. No statistical significance was found between the presence of acanthosis nigricans and insulin resistance. Conclusion Metabolic syndrome has a prevalence of 36% in children and adolescent population in the study. Insulin resistance was very common among

  14. Antiangiogenic Therapy and Mechanisms of Tumor Resistance in Malignant Glioma

    Ruman Rahman

    2010-01-01

    Full Text Available Despite advances in surgery, radiation therapy, and chemotherapeutics, patients with malignant glioma have a dismal prognosis. The formations of aberrant tumour vasculature and glioma cell invasion are major obstacles for effective treatment. Angiogenesis is a key event in the progression of malignant gliomas, a process involving endothelial cell proliferation, migration, reorganization of extracellular matrix and tube formation. Such processes are regulated by the homeostatic balance between proangiogenic and antiangiogenic factors, most notably vascular endothelial growth factors (VEGFs produced by glioma cells. Current strategies targeting VEGF-VEGF receptor signal transduction pathways, though effective in normalizing abnormal tumor vasculature, eventually result in tumor resistance whereby a highly infiltrative and invasive phenotype may be adopted. Here we review recent anti-angiogenic therapy for malignant glioma and highlight implantable devices and nano/microparticles as next-generation methods for chemotherapeutic delivery. Intrinsic and adaptive modes of glioma resistance to anti-angiogenic therapy will be discussed with particular focus on the glioma stem cell paradigm.

  15. Mechanisms and management of diuretic resistance in congestive heart failure.

    De Bruyne, L K M

    2003-05-01

    Diuretic drugs are used almost universally in patients with congestive heart failure, most frequently the potent loop diuretics. Despite their unproven effect on survival, their indisputable efficacy in relieving congestive symptoms makes them first line therapy for most patients. In the treatment of more advanced stages of heart failure diuretics may fail to control salt and water retention despite the use of appropriate doses. Diuretic resistance may be caused by decreased renal function and reduced and delayed peak concentrations of loop diuretics in the tubular fluid, but it can also be observed in the absence of these pharmacokinetic abnormalities. When the effect of a short acting diuretic has worn off, postdiuretic salt retention will occur during the rest of the day. Chronic treatment with a loop diuretic results in compensatory hypertrophy of epithelial cells downstream from the thick ascending limb and consequently its diuretic effect will be blunted. Strategies to overcome diuretic resistance include restriction of sodium intake, changes in dose, changes in timing, and combination diuretic therapy.

  16. Novel adiponectin-resistin (AR and insulin resistance (IRAR indexes are useful integrated diagnostic biomarkers for insulin resistance, type 2 diabetes and metabolic syndrome: a case control study

    Muniandy Sekaran

    2011-01-01

    Full Text Available Abstract Background Adiponectin and resistin are adipokines which modulate insulin action, energy, glucose and lipid homeostasis. Meta-analyses showed that hypoadiponectinemia and hyperresistinemia are strongly associated with increased risk of insulin resistance, type 2 diabetes (T2DM, metabolic syndrome (MS and cardiovascular disease. The aim of this study was to propose a novel adiponectin-resistin (AR index by taking into account both adiponectin and resistin levels to povide a better indicator of the metabolic homeostasis and metabolic disorders. In addition, a novel insulin resistance (IRAR index was proposed by integration of the AR index into an existing insulin resistance index to provide an improved diagnostic biomarker of insulin sensitivity. Methods In this case control study, anthropometric clinical and metabolic parameters including fasting serum total adiponectin and resistin levels were determined in 809 Malaysian men (208 controls, 174 MS without T2DM, 171 T2DM without MS, 256 T2DM with MS whose ages ranged between 40-70 years old. Significant differences in continuous variables among subject groups were confirmed by ANCOVA or MANCOVA test using 1,000 stratified bootstrap samples with bias corrected and accelerated (BCa 95% CI. Spearman's rho rank correlation test was used to test the correlation between two variables. Results The AR index was formulated as 1+log10(R0-log10(A0. The AR index was more strongly associated with increased risk of T2DM and MS than hypoadiponectinemia and hyperresistinemia alone. The AR index was more strongly correlated with the insulin resistance indexes and key metabolic endpoints of T2DM and MS than adiponectin and resistin levels alone. The AR index was also correlated with a higher number of MS components than adiponectin and resistin levels alone. The IRAR index was formulated as log10(I0G0+log10(I0G0log10(R0/A0. The normal reference range of the IRAR index for insulin sensitive individuals was

  17. Genetically Determined Insulin Resistance is Characterized by Down-Regulation of Mitochondrial Oxidative Metabolism in Human Skeletal Muscle

    Kristensen, Jonas M; Skov, Vibe; Wojtaszewski, Jørgen

    2010-01-01

    Transcriptional profiling of skeletal muscle from patients with type 2 diabetes and high-risk individuals have demonstrated a co-ordinated down-regulation of oxidative phosphorylation (OxPhos) genes, suggesting a link between insulin resistance and mitochondrial dysfunction. However, whether...... mitochondrial dysfunction is a cause or consequence of insulin resistance remains to be clarified. In the present study, we tested the hypothesis that mitochondrial oxidative metabolism was down-regulated in skeletal muscle of patients with genetically determined insulin resistance. Skeletal muscle biopsies.......02), and complex V (ATP5B; p=0.005). Our data demonstrate that genetically determined insulin resistance is associated with a co-ordinated down-regulation of OxPhos components both at the transcriptional and translational level. These findings suggest that an impaired biological response to insulin in skeletal...

  18. Comparative physiological, metabolomic, and transcriptomic analyses reveal mechanisms of improved abiotic stress resistance in bermudagrass [Cynodon dactylon (L). Pers.] by exogenous melatonin

    Shi, Haitao; Jiang, Chuan; Ye, Tiantian; Tan, Dun-xian; Reiter, Russel J.; Zhang, Heng; Liu, Renyi; Chan, Zhulong

    2015-01-01

    Melatonin (N-acetyl-5-methoxytryptamine), a well-known animal hormone, is also involved in plant development and abiotic stress responses. In this study, it is shown that exogenous application of melatonin conferred improved salt, drought, and cold stress resistances in bermudagrass. Moreover, exogenous melatonin treatment alleviated reactive oxygen species (ROS) burst and cell damage induced by abiotic stress; this involved activation of several antioxidants. Additionally, melatonin-pre-treated plants exhibited higher concentrations of 54 metabolites, including amino acids, organic acids, sugars, and sugar alcohols, than non-treated plants under abiotic stress conditions. Genome-wide transcriptomic profiling identified 3933 transcripts (2361 up-regulated and 1572 down-regulated) that were differentially expressed in melatonin-treated plants versus controls. Pathway and gene ontology (GO) term enrichment analyses revealed that genes involved in nitrogen metabolism, major carbohydrate metabolism, tricarboxylic acid (TCA)/org transformation, transport, hormone metabolism, metal handling, redox, and secondary metabolism were over-represented after melatonin pre-treatment. Taken together, this study provides the first evidence of the protective roles of exogenous melatonin in the bermudagrass response to abiotic stresses, partially via activation of antioxidants and modulation of metabolic homeostasis. Notably, metabolic and transcriptomic analyses showed that the underlying mechanisms of melatonin could involve major reorientation of photorespiratory and carbohydrate and nitrogen metabolism. PMID:25225478

  19. Comparative physiological, metabolomic, and transcriptomic analyses reveal mechanisms of improved abiotic stress resistance in bermudagrass [Cynodon dactylon (L). Pers.] by exogenous melatonin.

    Shi, Haitao; Jiang, Chuan; Ye, Tiantian; Tan, Dun-Xian; Reiter, Russel J; Zhang, Heng; Liu, Renyi; Chan, Zhulong

    2015-02-01

    Melatonin (N-acetyl-5-methoxytryptamine), a well-known animal hormone, is also involved in plant development and abiotic stress responses. In this study, it is shown that exogenous application of melatonin conferred improved salt, drought, and cold stress resistances in bermudagrass. Moreover, exogenous melatonin treatment alleviated reactive oxygen species (ROS) burst and cell damage induced by abiotic stress; this involved activation of several antioxidants. Additionally, melatonin-pre-treated plants exhibited higher concentrations of 54 metabolites, including amino acids, organic acids, sugars, and sugar alcohols, than non-treated plants under abiotic stress conditions. Genome-wide transcriptomic profiling identified 3933 transcripts (2361 up-regulated and 1572 down-regulated) that were differentially expressed in melatonin-treated plants versus controls. Pathway and gene ontology (GO) term enrichment analyses revealed that genes involved in nitrogen metabolism, major carbohydrate metabolism, tricarboxylic acid (TCA)/org transformation, transport, hormone metabolism, metal handling, redox, and secondary metabolism were over-represented after melatonin pre-treatment. Taken together, this study provides the first evidence of the protective roles of exogenous melatonin in the bermudagrass response to abiotic stresses, partially via activation of antioxidants and modulation of metabolic homeostasis. Notably, metabolic and transcriptomic analyses showed that the underlying mechanisms of melatonin could involve major reorientation of photorespiratory and carbohydrate and nitrogen metabolism. © The Author 2014. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  20. Role of reduced insulin-stimulated bone blood flow in the pathogenesis of metabolic insulin resistance and diabetic bone fragility.

    Hinton, Pamela S

    2016-08-01

    Worldwide, 387 million adults live with type 2 diabetes (T2D) and an additional 205 million cases are projected by 2035. Because T2D has numerous complications, there is significant morbidity and mortality associated with the disease. Identification of early events in the pathogenesis of insulin resistance and T2D might lead to more effective treatments that would mitigate health and monetary costs. Here, we present our hypothesis that impaired bone blood flow is an early event in the pathogenesis of whole-body metabolic insulin resistance that ultimately leads to T2D. Two recent developments in different fields form the basis for this hypothesis. First, reduced vascular function has been identified as an early event in the development of T2D. In particular, before the onset of tissue or whole body metabolic insulin resistance, insulin-stimulated, endothelium-mediated skeletal muscle blood flow is impaired. Insulin resistance of the vascular endothelium reduces delivery of insulin and glucose to skeletal muscle, which leads to tissue and whole-body metabolic insulin resistance. Second is the paradigm-shifting discovery that the skeleton has an endocrine function that is essential for maintenance of whole-body glucose homeostasis. Specifically, in response to insulin signaling, osteoblasts secret osteocalcin, which stimulates pancreatic insulin production and enhances insulin sensitivity in skeletal muscle, adipose, and liver. Furthermore, the skeleton is not metabolically inert, but contributes to whole-body glucose utilization, consuming 20% that of skeletal muscle and 50% that of white adipose tissue. Without insulin signaling or without osteocalcin activity, experimental animals become hyperglycemic and insulin resistant. Currently, it is not known if insulin-stimulated, endothelium-mediated blood flow to bone plays a role in the development of whole body metabolic insulin resistance. We hypothesize that it is a key, early event. Microvascular dysfunction is a

  1. Obesity, metabolic dysfunction and cardiac fibrosis: pathophysiologic pathways, molecular mechanisms and therapeutic opportunities

    Cavalera, Michele; Wang, Junhong; Frangogiannis, Nikolaos G

    2014-01-01

    Cardiac fibrosis is strongly associated with obesity and metabolic dysfunction and may contribute to the increased incidence of heart failure, atrial arrhythmias and sudden cardiac death in obese subjects. Our review discusses the evidence linking obesity and myocardial fibrosis in animal models and human patients, focusing on the fundamental pathophysiologic alterations that may trigger fibrogenic signaling, the cellular effectors of fibrosis and the molecular signals that may regulate the fibrotic response. Obesity is associated with a wide range of pathophysiologic alterations (such as pressure and volume overload, metabolic dysregulation, neurohumoral activation and systemic inflammation); their relative role in mediating cardiac fibrosis is poorly defined. Activation of fibroblasts likely plays a major role in obesity-associated fibrosis; however, inflammatory cells, cardiomyocytes and vascular cells may also contribute to fibrogenic signaling. Several molecular processes have been implicated in regulation of the fibrotic response in obesity. Activation of the Renin-Angiotensin-Aldosterone System, induction of Transforming Growth Factor-β, oxidative stress, advanced glycation end-products (AGEs), endothelin-1, Rho-kinase signaling, leptin-mediated actions and upregulation of matricellular proteins (such as thrombospondin-1) may play a role in the development of fibrosis in models of obesity and metabolic dysfunction. Moreover, experimental evidence suggests that obesity and insulin resistance profoundly affect the fibrotic and remodeling response following cardiac injury. Understanding the pathways implicated in obesity-associated fibrosis may lead to development of novel therapies to prevent heart failure and to attenuate post-infarction cardiac remodeling in obese patients. PMID:24880146

  2. Genomic sequencing of a strain of Acinetobacter baumannii and potential mechanisms to antibiotics resistance.

    Zhao, Lei; Li, Hongru; Zhu, Ziwen; Wakefield, Mark R; Fang, Yujiang; Ye, Ying

    2017-06-01

    Acinetobacter baumannii has been becoming a great challenge to clinicians due to their resistance to almost all available antibiotics. In this study, we sequenced the genome from a multiple antibiotics resistant Acinetobacter baumannii stain which was named A. baumannii-1isolated from China by SMRT sequencing technology to explore its potential mechanisms to antibiotic resistance. We found that several mechanisms might contribute to the antibiotic resistance of Acinetobacter baumannii. Specifically, we found that SNP in genes associated with nucleotide excision repair and ABC transporter might contribute to its resistance to multiple antibiotics; we also found that specific genes associated with bacterial DNA integration and recombination, DNA-mediated transposition and response to antibiotics might contribute to its resistance to multiple antibiotics; Furthermore, specific genes associated with penicillin and cephalosporin biosynthetic pathway and specific genes associated with CHDL and MBL β-lactamase genes might contribute to its resistance to multiple antibiotics. Thus, the detailed mechanisms by which Acinetobacter baumannii show extensive resistance to multiple antibiotics are very complicated. Such a study might be helpful to develop new strategies to control Acinetobacter baumannii infection. Copyright © 2017 Elsevier B.V. All rights reserved.

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

    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.

  4. BAD-Dependent Regulation of Fuel Metabolism and KATP Channel Activity Confers Resistance to Epileptic Seizures

    Giménez-Cassina, Alfredo; Martínez-François, Juan Ramón; Fisher, Jill K.; Szlyk, Benjamin; Polak, Klaudia; Wiwczar, Jessica; Tanner, Geoffrey R.; Lutas, Andrew; Yellen, Gary; Danial, Nika N.

    2012-01-01

    Neuronal excitation can be substantially modulated by alterations in metabolism, as evident from the anticonvulsant effect of diets that reduce glucose utilization and promote ketone body metabolism. We provide genetic evidence that BAD, a protein with dual functions in apoptosis and glucose metabolism, imparts reciprocal effects on metabolism of glucose and ketone bodies in brain cells. These effects involve phospho-regulation of BAD and are independent of its apoptotic function. BAD modific...

  5. Lincosamides: Chemical structure, biosynthesis, mechanism of action, resistance, and applications

    Spížek, Jaroslav; Řezanka, Tomáš

    2017-01-01

    Roč. 133, June 1 SI (2017), s. 20-28 ISSN 0006-2952 Institutional support: RVO:61388971 Keywords : Lincosamides * Chemical structure * Biosynthesis and mechanism of action Subject RIV: EE - Microbiology, Virology OBOR OECD: Microbiology Impact factor: 4.581, year: 2016

  6. New insights into Vinca alkaloids resistance mechanism and circumvention in lung cancer.

    Zhang, Ying; Yang, Shao-Hui; Guo, Xiu-Li

    2017-12-01

    Nowadays, lung cancer, as a health problem in worldwide, has high mortality both in men and women. Despite advances in diagnosis and surgical techniques of lung cancer in recent decades, chemotherapy is still a fundamentally and extensively useful strategy. Vinca alkaloids are a class of important and widely used drugs in the treatment of lung cancer, targeting on the Vinca binding site at the exterior of microtubule plus ends. Either intrinsic or acquired resistance to chemotherapy of Vinca alkaloids has been a major obstacle to the treatment of lung cancer, which arose great interests in studies of understanding and overcoming resistance. In this review, we focused on the application and resistance mechanisms of the Vinca alkaloids such as vinblastine, vincristine, vinorelbine and vinflunine in lung cancer. We reviewed characteristic resistance mechanisms in lung cancer including over-expression of ATP-binding cassette (ABC) transporters P-glycoprotein and structural, functional or expression alterations of β-tubulin (βII, βIII, βIV) which may devote to the development of acquired resistance to the Vinca alkaloids; multidrug-resistance proteins (MRP1, MRP2, MRP3) and RLIP76 protein have also been identified that probably play a significant role in intrinsic resistance. Lung resistance-related protein (LRP) is contributed to lung cancer therapy resistance, but is not deal with the Vinca alkaloids resistance in lung cancer. Understanding the principle of the Vinca alkaloids in clinical application and mechanisms of drug resistance will support individualized lung cancer therapy and improve future therapies. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  7. Contact resistance at ceramic interfaces and its dependence on mechanical load

    Koch, Søren; Hendriksen, P.V.

    2004-01-01

    Low contact resistance between individual components is important for solid oxide fuel cell stacks if high performance is to be achieved. Several mechanisms may result in high contact resistance, e.g., current constriction due to low area of contact and formation of resistive phases between...... the components. In this study, the importance of current constriction due to limited area of contact at an interface is investigated by comparing the characteristics of contacts between LSM pellets with different surface finish. The load behaviour of the contact resistance has been investigated and a power law...... of the contact resistance was calculated using a simple model describing the variation of the contact area with load based on the measured surface roughness. Good agreement between the calculations and the experimentally observed resistances was found. (C) 2004 Elsevier B.V. All rights reserved....

  8. Insulin Resistance and the Polycystic Ovary Syndrome Revisited: An Update on Mechanisms and Implications

    Diamanti-Kandarakis, Evanthia

    2012-01-01

    Polycystic ovary syndrome (PCOS) is now recognized as an important metabolic as well as reproductive disorder conferring substantially increased risk for type 2 diabetes. Affected women have marked insulin resistance, independent of obesity. This article summarizes the state of the science since we last reviewed the field in the Endocrine Reviews in 1997. There is general agreement that obese women with PCOS are insulin resistant, but some groups of lean affected women may have normal insulin sensitivity. There is a post-binding defect in receptor signaling likely due to increased receptor and insulin receptor substrate-1 serine phosphorylation that selectively affects metabolic but not mitogenic pathways in classic insulin target tissues and in the ovary. Constitutive activation of serine kinases in the MAPK-ERK pathway may contribute to resistance to insulin's metabolic actions in skeletal muscle. Insulin functions as a co-gonadotropin through its cognate receptor to modulate ovarian steroidogenesis. Genetic disruption of insulin signaling in the brain has indicated that this pathway is important for ovulation and body weight regulation. These insights have been directly translated into a novel therapy for PCOS with insulin-sensitizing drugs. Furthermore, androgens contribute to insulin resistance in PCOS. PCOS may also have developmental origins due to androgen exposure at critical periods or to intrauterine growth restriction. PCOS is a complex genetic disease, and first-degree relatives have reproductive and metabolic phenotypes. Several PCOS genetic susceptibility loci have been mapped and replicated. Some of the same susceptibility genes contribute to disease risk in Chinese and European PCOS populations, suggesting that PCOS is an ancient trait. PMID:23065822

  9. A mechanism of acquired resistance to complement-mediated lysis by Entamoeba histolytica.

    Gutiérrez-Kobeh, L; Cabrera, N; Pérez-Montfort, R

    1997-04-01

    Some Entamoeba histolytica strains resist complement-mediated lysis by serum. Susceptible and resistant strains activate the complement system equivalently, but resistant amebas evade killing by membrane attack complexes. Our objective was to determine the mechanism by which trophozoites of E. histolytica resist lysis by human serum. Amebas were made resistant to lysis by incubation with increasing concentrations of normal human serum. The possibility that resistant cells ingest membrane attack complexes was explored by subcellular fractionation of susceptible and resistant trophozoites treated with sublytic concentrations of human serum containing radiolabeled C9. In both cases, most of the label was in the fractions containing plasma membrane. The susceptible strain consistently showed more label associated with these fractions than the resistant strain. Thus, the possibility that the membrane attack complexes were released to the medium was explored. Both resistant and susceptible trophozoites release to the medium similar amounts of material excluded by Sepharose CL-2B in the presence or absence of normal human serum. Labeled C9 elutes together with the main bulk of proteins from the medium: this indicates that it is not in vesicles or high molecular weight aggregates. Coincubation of susceptible amebas with lysates of resistant trophozoites confers resistance to susceptible cells within 30 min. Resistance to lysis by serum can also be acquired by susceptible amebas after coincubation with lysates from human erythrocytes or after feeding them with whole human red blood cells. Resistant but not susceptible trophozoites show intense immunofluorescent staining on their surface with anti-human erythrocytic membrane antibody. These results suggest that amebas acquire resistance to lysis by serum by incorporating into their membranes complement regulatory proteins.

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

    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.

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

    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.

  12. Glucokinase regulatory protein genetic variant interacts with omega-3 PUFA to influence insulin resistance and inflammation in metabolic syndrome.

    Pablo Perez-Martinez

    Full Text Available Glucokinase Regulatory Protein (GCKR plays a central role regulating both hepatic triglyceride and glucose metabolism. Fatty acids are key metabolic regulators, which interact with genetic factors and influence glucose metabolism and other metabolic traits. Omega-3 polyunsaturated fatty acids (n-3 PUFA have been of considerable interest, due to their potential to reduce metabolic syndrome (MetS risk.To examine whether genetic variability at the GCKR gene locus was associated with the degree of insulin resistance, plasma concentrations of C-reactive protein (CRP and n-3 PUFA in MetS subjects.Homeostasis model assessment of insulin resistance (HOMA-IR, HOMA-B, plasma concentrations of C-peptide, CRP, fatty acid composition and the GCKR rs1260326-P446L polymorphism, were determined in a cross-sectional analysis of 379 subjects with MetS participating in the LIPGENE dietary cohort.Among subjects with n-3 PUFA levels below the population median, carriers of the common C/C genotype had higher plasma concentrations of fasting insulin (P = 0.019, C-peptide (P = 0.004, HOMA-IR (P = 0.008 and CRP (P = 0.032 as compared with subjects carrying the minor T-allele (Leu446. In contrast, homozygous C/C carriers with n-3 PUFA levels above the median showed lower plasma concentrations of fasting insulin, peptide C, HOMA-IR and CRP, as compared with individuals with the T-allele.We have demonstrated a significant interaction between the GCKR rs1260326-P446L polymorphism and plasma n-3 PUFA levels modulating insulin resistance and inflammatory markers in MetS subjects. Further studies are needed to confirm this gene-diet interaction in the general population and whether targeted dietary recommendations can prevent MetS in genetically susceptible individuals.ClinicalTrials.gov NCT00429195.

  13. Functional Characterization of Bacteria Isolated from Ancient Arctic Soil Exposes Diverse Resistance Mechanisms to Modern Antibiotics

    Perron, Gabriel G.; Whyte, Lyle; Turnbaugh, Peter J.; Goordial, Jacqueline; Hanage, William P.; Dantas, Gautam; Desai, Michael M.

    2015-01-01

    Using functional metagenomics to study the resistomes of bacterial communities isolated from different layers of the Canadian high Arctic permafrost, we show that microbial communities harbored diverse resistance mechanisms at least 5,000 years ago. Among bacteria sampled from the ancient layers of a permafrost core, we isolated eight genes conferring clinical levels of resistance against aminoglycoside, β-lactam and tetracycline antibiotics that are naturally produced by microorganisms. Among these resistance genes, four also conferred resistance against amikacin, a modern semi-synthetic antibiotic that does not naturally occur in microorganisms. In bacteria sampled from the overlaying active layer, we isolated ten different genes conferring resistance to all six antibiotics tested in this study, including aminoglycoside, β-lactam and tetracycline variants that are naturally produced by microorganisms as well as semi-synthetic variants produced in the laboratory. On average, we found that resistance genes found in permafrost bacteria conferred lower levels of resistance against clinically relevant antibiotics than resistance genes sampled from the active layer. Our results demonstrate that antibiotic resistance genes were functionally diverse prior to the anthropogenic use of antibiotics, contributing to the evolution of natural reservoirs of resistance genes. PMID:25807523

  14. Reduced expression of p27 is a novel mechanism of docetaxel resistance in breast cancer cells

    Brown, Iain; Shalli, Kawan; McDonald, Sarah L; Moir, Susan E; Hutcheon, Andrew W; Heys, Steven D; Schofield, Andrew C

    2004-01-01

    Docetaxel is one of the most effective chemotherapeutic agents in the treatment of breast cancer. Breast cancers can have an inherent or acquired resistance to docetaxel but the causes of this resistance remain unclear. However, apoptosis and cell cycle regulation are key mechanisms by which most chemotherapeutic agents exert their cytotoxic effects. We created two docetaxel-resistant human breast cancer cell lines (MCF-7 and MDA-MB-231) and performed cDNA microarray analysis to identify candidate genes associated with docetaxel resistance. Gene expression changes were validated at the RNA and protein levels by reverse transcription PCR and western analysis, respectively. Gene expression cDNA microarray analysis demonstrated reduced p27 expression in docetaxel-resistant breast cancer cells. Although p27 mRNA expression was found to be reduced only in MCF-7 docetaxel-resistant sublines (2.47-fold), reduced expression of p27 protein was noted in both MCF-7 and MDA-MB-231 docetaxel-resistant breast cancer cells (2.83-fold and 3.80-fold, respectively). This study demonstrates that reduced expression of p27 is associated with acquired resistance to docetaxel in breast cancer cells. An understanding of the genes that are involved in resistance to chemotherapy may allow further development in modulating drug resistance, and may permit selection of those patients who are most likely to benefit from such therapies

  15. The mechanics of tessellations - bioinspired strategies for fracture resistance.

    Fratzl, Peter; Kolednik, Otmar; Fischer, F Dieter; Dean, Mason N

    2016-01-21

    Faced with a comparatively limited palette of minerals and organic polymers as building materials, evolution has arrived repeatedly on structural solutions that rely on clever geometric arrangements to avoid mechanical trade-offs in stiffness, strength and flexibility. In this tutorial review, we highlight the concept of tessellation, a structural motif that involves periodic soft and hard elements arranged in series and that appears in a vast array of invertebrate and vertebrate animal biomaterials. We start from basic mechanics principles on the effects of material heterogeneities in hypothetical structures, to derive common concepts from a diversity of natural examples of one-, two- and three-dimensional tilings/layerings. We show that the tessellation of a hard, continuous surface - its atomization into discrete elements connected by a softer phase - can theoretically result in maximization of material toughness, with little expense to stiffness or strength. Moreover, the arrangement of soft/flexible and hard/stiff elements into particular geometries can permit surprising functions, such as signal filtering or 'stretch and catch' responses, where the constrained flexibility of systems allows a built-in safety mechanism for ensuring that both compressive and tensile loads are managed well. Our analysis unites examples ranging from exoskeletal materials (fish scales, arthropod cuticle, turtle shell) to endoskeletal materials (bone, shark cartilage, sponge spicules) to attachment devices (mussel byssal threads), from both invertebrate and vertebrate animals, while spotlighting success and potential for bio-inspired manmade applications.

  16. Biomechanical walking mechanisms underlying the metabolic reduction caused by an autonomous exoskeleton.

    Mooney, Luke M; Herr, Hugh M

    2016-01-28

    Ankle exoskeletons can now reduce the metabolic cost of walking in humans without leg disability, but the biomechanical mechanisms that underlie this augmentation are not fully understood. In this study, we analyze the energetics and lower limb mechanics of human study participants walking with and without an active autonomous ankle exoskeleton previously shown to reduce the metabolic cost of walking. We measured the metabolic, kinetic and kinematic effects of wearing a battery powered bilateral ankle exoskeleton. Six participants walked on a level treadmill at 1.4 m/s under three conditions: exoskeleton not worn, exoskeleton worn in a powered-on state, and exoskeleton worn in a powered-off state. Metabolic rates were measured with a portable pulmonary gas exchange unit, body marker positions with a motion capture system, and ground reaction forces with a force-plate instrumented treadmill. Inverse dynamics were then used to estimate ankle, knee and hip torques and mechanical powers. The active ankle exoskeleton provided a mean positive power of 0.105 ± 0.008 W/kg per leg during the push-off region of stance phase. The net metabolic cost of walking with the active exoskeleton (3.28 ± 0.10 W/kg) was an 11 ± 4 % (p = 0.019) reduction compared to the cost of walking without the exoskeleton (3.71 ± 0.14 W/kg). Wearing the ankle exoskeleton significantly reduced the mean positive power of the ankle joint by 0.033 ± 0.006 W/kg (p = 0.007), the knee joint by 0.042 ± 0.015 W/kg (p = 0.020), and the hip joint by 0.034 ± 0.009 W/kg (p = 0.006). This study shows that the ankle exoskeleton does not exclusively reduce positive mechanical power at the ankle joint, but also mitigates positive power at the knee and hip. Furthermore, the active ankle exoskeleton did not simply replace biological ankle function in walking, but rather augmented the total (biological + exoskeletal) ankle moment and power. This study

  17. Characterization of resistance mechanisms and genetic relatedness of carbapenem-resistant Acinetobacter baumannii isolated from blood, Italy.

    Migliavacca, Roberta; Espinal, Paula; Principe, Luigi; Drago, Monica; Fugazza, Giulia; Roca, Ignasi; Nucleo, Elisabetta; Bracco, Silvia; Vila, Jordi; Pagani, Laura; Luzzaro, Francesco

    2013-02-01

    The aim of this study was to characterize the resistance mechanisms and genetic relatedness of 21 carbapenem-resistant Acinetobacter baumannii blood isolates collected in Italy during a 1-year multicenter prospective surveillance study. Genes coding for carbapenemase production were identified by polymerase chain reaction (PCR) and sequencing. Pulsed-field gel electrophoresis (PFGE), multiplex PCRs for group identification, and multilocus sequence typing (MLST) were used to determine genetic relationships. Carbapenem resistance was consistently related to the production of oxacillinases, mostly the plasmid-mediated OXA-58 enzyme. Strains producing the OXA-23 enzyme (chromosomally mediated) were also detected. Seven PFGE clones were identified, some of which being related to international (ICL- I and ICL-II) or national clonal lineages. Multiplex PCRs identified 4 different groups (group 2 being dominant), further distinguishable in 6 sequence types by MLST. The heterogeneity of profiles highlights the diffusion of international and national clonal lineages in Italy. Continuous surveillance is needed for monitoring the spread of these worrisome strains equipped with multiple drug resistance mechanisms. Copyright © 2013 Elsevier Inc. All rights reserved.

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

    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.