共查询到20条相似文献,搜索用时 31 毫秒
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Immunity and metabolism are intimately linked; manipulating metabolism, either through diet or genetics, has the power to alter survival during infection. However, despite metabolism''s powerful ability to alter the course of infections, little is known about what being “sick” means metabolically. Here we describe the metabolic changes occurring in a model system when Listeria monocytogenes causes a lethal infection in Drosophila melanogaster. L. monocytogenes infection alters energy metabolism; the flies gradually lose both of their energy stores, triglycerides and glycogen, and show decreases in both intermediate metabolites and enzyme message for the two main energy pathways, beta-oxidation and glycolysis. L. monocytogenes infection also causes enzymatic reduction in the anti-oxidant uric acid, and knocking out the enzyme uric oxidase has a complicated effect on immunity. Free amino acid levels also change during infection, including a drop in tyrosine levels which may be due to robust L. monocytogenes induced melanization. 相似文献
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B-cell lymphoma 2 (Bcl-2) family proteins regulate survival, mitochondria morphology dynamics and metabolism in many cell types including neurons. Huntington''s disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat tract in the IT15 gene that encodes for the protein huntingtin (htt). In vitro and in vivo models of HD and HD patients'' tissues show abnormal mitochondrial function and increased cell death rates associated with alterations in Bcl-2 family protein expression and localization. This review aims to draw together the information related to Bcl-2 family protein alterations in HD to decipher their potential role in mutated htt-related cell death and mitochondrial dysfunction. 相似文献
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Georgeta Crivat Vladimir A. Lizunov Caroline R. Li Karin G. Stenkula Joshua Zimmerberg Samuel W. Cushman Leslie Pick 《PloS one》2013,8(11)
The fruit fly Drosophila melanogaster is an excellent model system for studies of genes controlling development and disease. However, its applicability to physiological systems is less clear because of metabolic differences between insects and mammals. Insulin signaling has been studied in mammals because of relevance to diabetes and other diseases but there are many parallels between mammalian and insect pathways. For example, deletion of Drosophila Insulin-Like Peptides resulted in ‘diabetic’ flies with elevated circulating sugar levels. Whether this situation reflects failure of sugar uptake into peripheral tissues as seen in mammals is unclear and depends upon whether flies harbor the machinery to mount mammalian-like insulin-dependent sugar uptake responses. Here we asked whether Drosophila fat cells are competent to respond to insulin with mammalian-like regulated trafficking of sugar transporters. Transgenic Drosophila expressing human glucose transporter-4 (GLUT4), the sugar transporter expressed primarily in insulin-responsive tissues, were generated. After expression in fat bodies, GLUT4 intracellular trafficking and localization were monitored by confocal and total internal reflection fluorescence microscopy (TIRFM). We found that fat body cells responded to insulin with increased GLUT4 trafficking and translocation to the plasma membrane. While the amplitude of these responses was relatively weak in animals reared on a standard diet, it was greatly enhanced in animals reared on sugar-restricted diets, suggesting that flies fed standard diets are insulin resistant. Our findings demonstrate that flies are competent to mobilize translocation of sugar transporters to the cell surface in response to insulin. They suggest that Drosophila fat cells are primed for a response to insulin and that these pathways are down-regulated when animals are exposed to constant, high levels of sugar. Finally, these studies are the first to use TIRFM to monitor insulin-signaling pathways in Drosophila, demonstrating the utility of TIRFM of tagged sugar transporters to monitor signaling pathways in insects. 相似文献
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Andriy S. Yatsenko April K. Marrone Mariya M. Kucherenko Halyna R. Shcherbata 《Journal of visualized experiments : JoVE》2014,(88)
Metabolic disorders are a frequent problem affecting human health. Therefore, understanding the mechanisms that regulate metabolism is a crucial scientific task. Many disease causing genes in humans have a fly homologue, making Drosophila a good model to study signaling pathways involved in the development of different disorders. Additionally, the tractability of Drosophila simplifies genetic screens to aid in identifying novel therapeutic targets that may regulate metabolism. In order to perform such a screen a simple and fast method to identify changes in the metabolic state of flies is necessary. In general, carbon dioxide production is a good indicator of substrate oxidation and energy expenditure providing information about metabolic state. In this protocol we introduce a simple method to measure CO2 output from flies. This technique can potentially aid in the identification of genetic perturbations affecting metabolic rate. 相似文献
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Mochel F Charles P Seguin F Barritault J Coussieu C Perin L Le Bouc Y Gervais C Carcelain G Vassault A Feingold J Rabier D Durr A 《PloS one》2007,2(7):e647
Huntington disease (HD) is a fatal neurodegenerative disorder, with no effective treatment. The pathogenic mechanisms underlying HD has not been elucidated, but weight loss, associated with chorea and cognitive decline, is a characteristic feature of the disease that is accessible to investigation. We, therefore, performed a multiparametric study exploring body weight and the mechanisms of its loss in 32 presymptomatic carriers and HD patients in the early stages of the disease, compared to 21 controls. We combined this study with a multivariate statistical analysis of plasma components quantified by proton nuclear magnetic resonance ((1)H NMR) spectroscopy. We report evidence of an early hypermetabolic state in HD. Weight loss was observed in the HD group even in presymptomatic carriers, although their caloric intake was higher than that of controls. Inflammatory processes and primary hormonal dysfunction were excluded. (1)H NMR spectroscopy on plasma did, however, distinguish HD patients at different stages of the disease and presymptomatic carriers from controls. This distinction was attributable to low levels of the branched chain amino acids (BCAA), valine, leucine and isoleucine. BCAA levels were correlated with weight loss and, importantly, with disease progression and abnormal triplet repeat expansion size in the HD1 gene. Levels of IGF1, which is regulated by BCAA, were also significantly lower in the HD group. Therefore, early weight loss in HD is associated with a systemic metabolic defect, and BCAA levels may be used as a biomarker, indicative of disease onset and early progression. The decreased plasma levels of BCAA may correspond to a critical need for Krebs cycle energy substrates in the brain that increased metabolism in the periphery is trying to provide. 相似文献
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Agavni Petrosyan I-Hui Hsieh John P. Phillips Kourosh Saberi 《Genetics and molecular biology》2015,38(1):107-114
Mutation of the human gene superoxide dismutase (hSOD1) is
associated with the fatal neurodegenerative disease familial amyotrophic lateral
sclerosis (Lou Gehrig’s disease). Selective overexpression of hSOD1
in Drosophila motorneurons increases lifespan to 140% of normal. The
current study was designed to determine resistance to lifespan decline and failure of
sensorimotor functions by overexpressing hSOD1 in
Drosophila‘s motorneurons. First, we measured the ability to
maintain continuous flight and wingbeat frequency (WBF) as a function of age (5 to 50
days). Flies overexpressing hSOD1 under the D42-GAL4 activator were
able to sustain flight significantly longer than controls, with the largest effect
observed in the middle stages of life. The hSOD1-expressed line also
had, on average, slower wingbeat frequencies in late, but not early life relative to
age-matched controls. Second, we examined locomotor (exploratory walking) behavior in
late life when flies had lost the ability to fly (age ≥ 60 d).
hSOD1-expressed flies showed significantly more robust walking
activity relative to controls. Findings show patterns of functional decline
dissimilar to those reported for other life-extended lines, and suggest that the
hSOD1 gene not only delays death but enhances sensorimotor
abilities critical to survival even in late life. 相似文献
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Carlos H Ni?o Nicolás Forero-Baena Luis E Contreras Diana Sánchez-Lancheros Katherine Figarella María H Ramírez 《Memórias do Instituto Oswaldo Cruz》2015,110(7):890-897
The intracellular parasite Trypanosoma cruzi is the aetiological
agent of Chagas disease, a public health concern with an increasing incidence rate.
This increase is due, among other reasons, to the parasite''s drug resistance
mechanisms, which require nicotinamide adenine dinucleotide (NAD+).
Furthermore, this molecule is involved in metabolic and intracellular signalling
processes necessary for the survival of T. cruzi throughout its life
cycle. NAD+ biosynthesis is performed by de novo and
salvage pathways, which converge on the step that is catalysed by the enzyme
nicotinamide mononucleotide adenylyltransferase (NMNAT) (enzyme commission
number: 2.7.7.1). The identification of the NMNAT of T.
cruzi is important for the development of future therapeutic strategies
to treat Chagas disease. In this study, a hypothetical open reading frame (ORF) for
NMNAT was identified in the genome of T. cruzi. The corresponding
putative protein was analysed by simulating structural models. The ORF was amplified
from genomic DNA by polymerase chain reaction and was further used for the
construction of a corresponding recombinant expression vector. The expressed
recombinant protein was partially purified and its activity was evaluated using
enzymatic assays. These results comprise the first identification of an NMNAT in
T. cruzi using bioinformatics and experimental tools and hence
represent the first step to understanding NAD+ metabolism in these
parasites. 相似文献
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Elisabeth Kemter Petra Prückl Birgit Rathkolb Kateryna Micklich Thure Adler Lore Becker Johannes Beckers Dirk H. Busch Alexander A. G?tz Wolfgang Hans Marion Horsch Boris Ivandic Martin Klingenspor Thomas Klopstock Jan Rozman Anja Schrewe Holger Schulz Helmut Fuchs Valérie Gailus-Durner Martin Hrabé de Angelis Eckhard Wolf Bernhard Aigner 《PloS one》2013,8(10)
Uromodulin-associated kidney disease (UAKD) summarizes different clinical features of an autosomal dominant heritable disease syndrome in humans with a proven uromodulin (UMOD) mutation involved. It is often characterized by hyperuricemia, gout, alteration of urine concentrating ability, as well as a variable rate of disease progression inconstantly leading to renal failure and histological alterations of the kidneys. We recently established the two Umod mutant mouse lines Umod
C93F and Umod
A227T on the C3H inbred genetic background both showing kidney defects analogous to those found in human UAKD patients. In addition, disease symptoms were revealed that were not yet described in other published mouse models of UAKD. To examine if further organ systems and/or metabolic pathways are affected by Umod mutations as primary or secondary effects, we describe a standardized, systemic phenotypic analysis of the two mutant mouse lines Umod
A227T and Umod
C93F in the German Mouse Clinic. Different genotypes as well as different ages were tested. Beside the already published changes in body weight, body composition and bone metabolism, the influence of the Umod mutation on energy metabolism was confirmed. Hematological analysis revealed a moderate microcytic and erythropenic anemia in older Umod mutant mice. Data of the other analyses in 7-10 month-old mutant mice showed single small additional effects. 相似文献
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Melanocortin 4 receptor (MC4R), which is associated with inherited human
obesity, is involoved in food intake and body weight of mammals. To study the
relationships between MC4R gene polymorphism and body weight in Beagle
dogs, we detected and compared the nucleotide sequence of the whole coding region and 3′-
and 5′- flanking regions of the dog MC4R gene (1214 bp). In 120 Beagle
dogs, two SNPs (A420C, C895T) were identified and their relation with body weight was
analyzed with RFLP-PCR method. The results showed that the SNP at A420C was significantly
associated with canine body weight trait when it changed amino acid 101 of the
MC4R protein from asparagine to threonine,while canine body weight
variations were significant in female dogs when MC4R nonsense mutation at
C895T. It suggested that the two SNPs might affect the MC4R gene’s
function which was relative to body weight in Beagle dogs. Therefore,
MC4R was a candidate gene for selecting different size dogs with the
MC4R SNPs (A420C, C895T) being potentially valuable as a genetic
marker. 相似文献
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Audrey M. Neyrinck Maud Alligier Patrick B. Memvanga Elodie Névraumont Yvan Larondelle Véronique Préat Patrice D. Cani Nathalie M. Delzenne 《PloS one》2013,8(11)
Background
Supra-nutritional doses of curcumin, derived from the spice Curcuma longa, have been proposed as a potential treatment of inflammation and metabolic disorders related to obesity. The aim of the present study was to test whether Curcuma longa extract rich in curcumin and associated with white pepper (Curcuma-P®), at doses compatible with human use, could modulate systemic inflammation in diet-induced obese mice. We questioned the potential relevance of changes in adiposity and gut microbiota in the effect of Curcuma-P® in obesity.Methodology/Principal Findings
Mice were fed either a control diet (CT), a high fat (HF) diet or a HF diet containing Curcuma longa extract (0.1 % of curcumin in the HF diet) associated with white pepper (0.01 %) for four weeks. Curcumin has been usually combined with white pepper, which contain piperine, in order to improve its bioavailability. This combination did not significantly modify body weight gain, glycemia, insulinemia, serum lipids and intestinal inflammatory markers. Tetrahydrocurcumin, but not curcumin accumulated in the subcutaneous adipose tissue. Importantly, the co-supplementation in curcuma extract and white pepper decreased HF-induced pro-inflammatory cytokines expression in the subcutaneous adipose tissue, an effect independent of adiposity, immune cells recruitment, angiogenesis, or modulation of gut bacteria controlling inflammation.Conclusions/Significance
These findings support that nutritional doses of Curcuma longa, associated with white pepper, is able to decrease inflammatory cytokines expression in the adipose tissue and this effect could be rather linked to a direct effect of bioactive metabolites reaching the adipose tissue, than from changes in the gut microbiota composition. 相似文献14.
Genome-scale models of metabolism have only been analyzed with the constraint-based modelling philosophy and there have been several genome-scale gene-protein-reaction models. But research on the modelling for energy metabolism of organisms just began in recent years and research on metabolic weighted complex network are rare in literature. We have made three research based on the complete model of E. coli’s energy metabolism. We first constructed a metabolic weighted network using the rates of free energy consumption within metabolic reactions as the weights. We then analyzed some structural characters of the metabolic weighted network that we constructed. We found that the distribution of the weight values was uneven, that most of the weight values were zero while reactions with abstract large weight values were rare and that the relationship between w (weight values) and v (flux values) was not of linear correlation. At last, we have done some research on the equilibrium of free energy for the energy metabolism system of E. coli. We found that (free energy rate input from the environment) can meet the demand of (free energy rate dissipated by chemical process) and that chemical process plays a great role in the dissipation of free energy in cells. By these research and to a certain extend, we can understand more about the energy metabolism of E. coli. 相似文献
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Wei-Hua Lee Vijesh J Bhute Hitoshi Higuchi Sakae Ikeda Sean P Palecek Akihiro Ikeda 《Experimental biology and medicine (Maywood, N.J.)》2020,245(17):1571
Mitochondria are dynamic organelles that undergo fission and fusion. While they are essential for cellular metabolism, the effect of dysregulated mitochondrial dynamics on cellular metabolism is not fully understood. We previously found that transmembrane protein 135 (Tmem135) plays a role in the regulation of mitochondrial dynamics in mice. Mice homozygous for a Tmem135 mutation (Tmem135FUN025/FUN025) display accelerated aging and age-related disease pathologies in the retina including the retinal pigment epithelium (RPE). We also generated a transgenic mouse line globally overexpressing the Tmem135 gene (Tmem135 TG). In several tissues and cells that we studied such as the retina, heart, and fibroblast cells, we observed that the Tmem135 mutation causes elongated mitochondria, while overexpression of Tmem135 results in fragmented mitochondria. To investigate how abnormal mitochondrial dynamics affect metabolic signatures of tissues and cells, we identified metabolic changes in primary RPE cell cultures as well as heart, cerebellum, and hippocampus isolated from Tmem135FUN025/FUN025 mice (fusion > fission) and Tmem135 TG mice (fusion < fission) using nuclear magnetic resonance spectroscopy. Metabolomics analysis revealed a tissue-dependent response to Tmem135 alterations, whereby significant metabolic changes were observed in the heart of both Tmem135 mutant and TG mice as compared to wild-type, while negligible effects were observed in the cerebellum and hippocampus. We also observed changes in Tmem135FUN025/FUN025 and Tmem135 TG RPE cells associated with osmosis and glucose and phospholipid metabolism. We observed depletion of NAD+ in both Tmem135FUN025/FUN025 and Tmem135 TG RPE cells, indicating that imbalance in mitochondrial dynamics to both directions lowers the cellular NAD+ level. Metabolic changes identified in this study might be associated with imbalanced mitochondrial dynamics in heart tissue and RPE cells which can likely lead to functional abnormalities.Impact statementMitochondria are dynamic organelles undergoing fission and fusion. Proper regulation of this process is important for healthy aging process, as aberrant mitochondrial dynamics are associated with several age-related diseases/pathologies. However, it is not well understood how imbalanced mitochondrial dynamics may lead to those diseases and pathologies. Here, we aimed to determine metabolic alterations in tissues and cells from mouse models with over-fused (fusion > fission) and over-fragmented (fusion < fission) mitochondria that display age-related disease pathologies. Our results indicated tissue-dependent sensitivity to these mitochondrial changes, and metabolic pathways likely affected by aberrant mitochondrial dynamics. This study provides new insights into how dysregulated mitochondrial dynamics could lead to functional abnormalities of tissues and cells. 相似文献
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Age‐related memory impairment (AMI) occurs in many species, including humans. The underlying mechanisms are not fully understood. In wild‐type Drosophila (w1118 ), AMI appears in the form of a decrease in learning (3‐min memory) from middle age (30 days after eclosion [DAE]). We performed in vivo, DNA microarray, and behavioral screen studies to identify genes controlling both lifespan and AMI and selected mitochondrial Acon1 (mAcon1). mAcon1 expression in the head of w1118 decreased with age. Neuronal overexpression of mAcon1 extended its lifespan and improved AMI. Neuronal or mushroom body expression of mAcon1 regulated the learning of young (10 DAE) and middle‐aged flies. Interestingly, acetyl‐CoA and citrate levels increased in the heads of middle‐aged and neuronal mAcon1 knockdown flies. Acetyl‐CoA, as a cellular energy sensor, is related to autophagy. Autophagy activity and efficacy determined by the positive and negative changes in the expression levels of Atg8a‐II and p62 were proportional to the expression level of mAcon1. Levels of the presynaptic active zone scaffold protein Bruchpilot were inversely proportional to neuronal mAcon1 levels in the whole brain. Furthermore, mAcon1 overexpression in Kenyon cells induced mitophagy labeled with mt‐Keima and improved learning ability. Both processes were blocked by pink1 knockdown. Taken together, our results imply that the regulation of learning and AMI by mAcon1 occurs via autophagy/mitophagy‐mediated neural plasticity. 相似文献
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Yu Jin Hwang Seung Jae Hyeon Younghee Kim Sungsu Lim Min Young Lee Jieun Kim Ashwini M. Londhe Lizaveta Gotina Yunha Kim Ae Nim Pae Yong Seo Cho Jihye Seong Hyemyung Seo Yun Kyung Kim Hyunah Choo Hoon Ryu Sun-Joon Min 《Journal of enzyme inhibition and medicinal chemistry》2021,36(1):856
The present study describes evaluation of epigenetic regulation by a small molecule as the therapeutic potential for treatment of Huntington’s disease (HD). We identified 5-allyloxy-2-(pyrrolidin-1-yl)quinoline (APQ) as a novel SETDB1/ESET inhibitor using a combined in silico and in vitro cell based screening system. APQ reduced SETDB1 activity and H3K9me3 levels in a HD cell line model. In particular, not only APQ reduced H3K9me3 levels in the striatum but it also improved motor function and neuropathological symptoms such as neuronal size and activity in HD transgenic (YAC128) mice with minimal toxicity. Using H3K9me3-ChIP and genome-wide sequencing, we also confirmed that APQ modulates H3K9me3-landscaped epigenomes in YAC128 mice. These data provide that APQ, a novel small molecule SETDB1 inhibitor, coordinates H3K9me-dependent heterochromatin remodelling and can be an epigenetic drug for treating HD, leading with hope in clinical trials of HD. 相似文献
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Liang Guo Fangfang Ma Fang Wei Brian Fanella Doug K. Allen Xuemin Wang 《The Plant cell》2014,26(7):3023-3035
The cytosolic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPC) catalyzes a key
reaction in glycolysis, but its contribution to plant metabolism and growth are not
well defined. Here, we show that two cytosolic GAPCs play important roles in cellular
metabolism and seed oil accumulation. Knockout or overexpression of
GAPCs caused significant changes in the level of intermediates in
the glycolytic pathway and the ratios of ATP/ADP and NAD(P)H/NAD(P). Two double
knockout seeds had ∼3% of dry weight decrease in oil content compared with
that of the wild type. In transgenic seeds under the constitutive 35S promoter, oil
content was increased up to 42% of dry weight compared with 36% in the wild type and
the fatty acid composition was altered; however, these transgenic lines exhibited
decreased fertility. Seed-specific overexpression lines had >3% increase in seed
oil without compromised seed yield or fecundity. The results demonstrate that
GAPC levels play important roles in the overall cellular
production of reductants, energy, and carbohydrate metabolites and that
GAPC levels are directly correlated with seed oil accumulation.
Changes in cellular metabolites and cofactor levels highlight the complexity and
tolerance of Arabidopsis thaliana cells to the metabolic
perturbation. Further implications for metabolic engineering of seed oil production
are discussed. 相似文献
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Kara Y. Chan Xueying Li Janice Ortega Liya Gu Guo-Min Li 《The Journal of biological chemistry》2021,297(4)
Huntington''s disease (HD), a neurodegenerative disease characterized by progressive dementia, psychiatric problems, and chorea, is known to be caused by CAG repeat expansions in the HD gene HTT. However, the mechanism of this pathology is not fully understood. The translesion DNA polymerase θ (Polθ) carries a large insertion sequence in its catalytic domain, which has been shown to allow DNA loop-outs in the primer strand. As a result of high levels of oxidative DNA damage in neural cells and Polθ''s subsequent involvement in base excision repair of oxidative DNA damage, we hypothesized that Polθ contributes to CAG repeat expansion while repairing oxidative damage within HTT. Here, we performed Polθ-catalyzed in vitro DNA synthesis using various CAG•CTG repeat DNA substrates that are similar to base excision repair intermediates. We show that Polθ efficiently extends (CAG)n•(CTG)n hairpin primers, resulting in hairpin retention and repeat expansion. Polθ also triggers repeat expansions to pass the threshold for HD when the DNA template contains 35 repeats upward. Strikingly, Polθ depleted of the catalytic insertion fails to induce repeat expansions regardless of primers and templates used, indicating that the insertion sequence is responsible for Polθ''s error-causing activity. In addition, the level of chromatin-bound Polθ in HD cells is significantly higher than in non-HD cells and exactly correlates with the degree of CAG repeat expansion, implying Polθ''s involvement in triplet repeat instability. Therefore, we have identified Polθ as a potent factor that promotes CAG•CTG repeat expansions in HD and other neurodegenerative disorders. 相似文献