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1.
2.
Nirmal Mazumder Rodney K. Lyn Ragunath Singaravelu Andrew Ridsdale Douglas J. Moffatt Chih-Wei Hu Han-Ruei Tsai John McLauchlan Albert Stolow Fu-Jen Kao John Paul Pezacki 《PloS one》2013,8(6)
Hepatitis C virus (HCV) co-opts hepatic lipid pathways to facilitate its pathogenesis. The virus alters cellular lipid biosynthesis and trafficking, and causes an accumulation of lipid droplets (LDs) that gives rise to hepatic steatosis. Little is known about how these changes are controlled at the molecular level, and how they are related to the underlying metabolic states of the infected cell. The HCV core protein has previously been shown to independently induce alterations in hepatic lipid homeostasis. Herein, we demonstrate, using coherent anti-Stokes Raman scattering (CARS) microscopy, that expression of domain 2 of the HCV core protein (D2) fused to GFP is sufficient to induce an accumulation of larger lipid droplets (LDs) in the perinuclear region. Additionally, we performed fluorescence lifetime imaging of endogenous reduced nicotinamide adenine dinucleotides [NAD(P)H], a key coenzyme in cellular metabolic processes, to monitor changes in the cofactor’s abundance and conformational state in D2-GFP transfected cells. When expressed in Huh-7 human hepatoma cells, we observed that the D2-GFP induced accumulation of LDs correlated with an increase in total NAD(P)H fluorescence and an increase in the ratio of free to bound NAD(P)H. This is consistent with an approximate 10 fold increase in cellular NAD(P)H levels. Furthermore, the lifetimes of bound and free NAD(P)H were both significantly reduced – indicating viral protein-induced alterations in the cofactors’ binding and microenvironment. Interestingly, the D2-expressing cells showed a more diffuse localization of NAD(P)H fluorescence signal, consistent with an accumulation of the co-factor outside the mitochondria. These observations suggest that HCV causes a shift of metabolic control away from the use of the coenzyme in mitochondrial electron transport and towards glycolysis, lipid biosynthesis, and building of new biomass. Overall, our findings demonstrate that HCV induced alterations in hepatic metabolism is tightly linked to alterations in NAD(P)H functional states. 相似文献
3.
Cadmium (Cd) is a non-essential, highly toxic heavy metal and a ubiquitous environmental contaminant. Evidence exists that Cd can affect parameters which are of great importance in the response towards xenobiotics. However, there is a lack of information about the mechanisms that take place at the cellular and molecular levels upon dual exposure to Cd and other toxins. The purpose of the present work was therefore to examine the biochemical interactions between Cd and a well-known genotoxic hepatocarcinogen, 2-acetylaminofluorene (AAF) in isolated rat hepatocytes. The cells were incubated for 10 hr with a sub-cytotoxic concentration (0.22 M) of 109Cd. This was followed by a 10 hr exposure to 1 M [3H]AAF. Cellular distribution of Cd and 3H was determined. Sephadex G-75 elution profiles of the cytosol showed that Cd was almost entirely associated with the intermediate molecular weight (IMW) fractions containing metallothionein (MT) (>80%), and with high molecular weight proteins. In parallel, the highest proportion of 3H was found in the low molecular weight components. Further analysis of IMW fractions by DEAE A-25 anion-exchange chromatography revealed that, in addition to Cd, there was some 3H which coeluted along with MT-I and MT-II isoforms, but preferentially with MT-I. Moreover, Cd pretreatment caused a 1.6-fold increase in MT level, as measured by the silver-saturation assay. Under these conditions, there was a 17% lower binding of 3H to the DNA. This reduced binding was neither accompanied by diminished AAF uptake nor by inhibition of cytochrome P-450 activity. Taken together, these results suggest that Cd exposure has a protective effect against the genotoxicity of AAF. MT, whose synthesis is induced, could play a role in the Cd-AAF interaction through scavenging of reactive metabolites.Abbreviations AAF
2-acetylaminofluorene
- Cd
cadmium
- DMSO
dimethyl sulfoxide
- HBSS
Hank's balanced salt solution
- LDH
lactate dehydrogenase
- MT
metallothionein
- UDS
unscheduled DNA synthesis 相似文献
4.
Metabolism of Benzyladenine is Impaired in a Mutant of Arabidopsis thaliana Lacking Adenine Phosphoribosyltransferase Activity 总被引:2,自引:0,他引:2 下载免费PDF全文
Formation of the riboside-5′-monophosphate is a general feature of the metabolism of cytokinins in plants. As part of a study of the biological significance of the nucleotide form of cytokinins, we analyzed a mutant of Arabidopsis thaliana deficient in adenine phosphoribosyltransferase (APRT) activity for its ability to metabolize N6-benzyladenine (BA). Formation of N6-benzyladenosine-5′-monophosphate (BAMP) was assayed in vivo, by feeding tritiated BA to wild-type and mutant plantlets, and in crude plantlet extracts. Metabolites were separated by high performance liquid chromatography and quantitated by on-line liquid scintillation spectrometry. BA was rapidly absorbed by A. thaliana plantlets and primarily converted to BAMP and to BA 7- and 9-glucosides. BA was also rapidly absorbed by APRT-deficient plantlets, but its conversion to BAMP was strongly reduced. Formation of BAMP from N6-benzyladenosine was not affected in the mutant plantlets. In vitro conversion of BA to its nucleoside-5′-monophosphate was detected in crude extracts of wild-type plantlets, but not in extracts of APRT-deficient plantlets. Therefore, results of both assays indicate that APRT-deficient tissue does not convert BA to BAMP to a significant extent. Further, nondenaturing isoelectric focusing analysis of APRT activity in leaf extracts indicated that the enzyme activities which metabolize adenine and BA into their corresponding riboside-5′-monophosphate in extracts of wild-type plantlets have the same apparent isoelectric point. These activities were not detected in extracts prepared from APRT-deficient plantlets. Thus, these results demonstrate that APRT is the main enzyme which converts BA to its nucleotide form in young A. thaliana plants and that the ribophosphorylation of BA is not a prerequisite of its absorption by the plantlets. 相似文献
5.
On Day 5 of pregnancy, before the blastocyst migrates to the uterus, one uterine horn was ligated to restrict the trophoblast to the lumen ipsilateral to the corpus luteum. The numbers of placentomes (caruncles and cotyledons) were reduced by half, but neither at 120 nor at 140 days of pregnancy (term 147 days) did the weights of placentae and fetuses of treated ewes differ significantly from those of control ewes. Amongst uterus-ligated animals prepared for chronic study, the rate of uterine blood flow (electromagnetic flow transducer, ml/min) to the pregnant horn was higher than in control ewes, as was the concentration of progestagens in maternal peripheral blood. There may be a compensatory response that causes hypertrophy of placentomes and that increases blood flow to the uterine horn containing placental tissue. 相似文献
6.
Hardies SC; Martin SL; Voliva CF; Hutchison CA d; Edgell MH 《Molecular biology and evolution》1986,3(2):109-125
7.
A 330 bp region of the spinach nitrite reductase gene promoter directs nitrate-inducible tissue-specific expression in transgenic tobacco 总被引:4,自引:0,他引:4
8.
A major difference between the divergence patterns within the lines-1 families in mice and voles 总被引:3,自引:0,他引:3
Vanlerberghe F; Bonhomme F; Hutchison CA d; Edgell MH 《Molecular biology and evolution》1993,10(4):719-731
L1 retroposons are represented in mice by subfamilies of interspersed
sequences of varied abundance. Previous analyses have indicated that
subfamilies are generated by duplicative transposition of a small number of
members of the L1 family, the progeny of which then become a major
component of the murine L1 population, and are not due to any active
processes generating homology within preexisting groups of elements in a
particular species. In mice, more than a third of the L1 elements belong to
a clade that became active approximately 5 Mya and whose elements are >
or = 95% identical. We have collected sequence information from 13 L1
elements isolated from two species of voles (Rodentia: Microtinae: Microtus
and Arvicola) and have found that divergence within the vole L1 population
is quite different from that in mice, in that there is no abundant
subfamily of homologous elements. Individual L1 elements from voles are
very divergent from one another and belong to a clade that began a period
of elevated duplicative transposition approximately 13 Mya. Sequence
analyses of portions of these divergent L1 elements (approximately 250 bp
each) gave no evidence for concerted evolution having acted on the vole L1
elements since the split of the two vole lineages approximately 3.5 Mya;
that is, the observed interspecific divergence (6.7%-24.7%) is not larger
than the intraspecific divergence (7.9%-27.2%), and phylogenetic analyses
showed no clustering into Arvicola and Microtus clades.
相似文献
9.
Molecular phylogeny and divergence times of drosophilid species 总被引:32,自引:15,他引:17
The phylogenetic relationships and divergence times of 39 drosophilid
species were studied by using the coding region of the Adh gene. Four
genera--Scaptodrosophila, Zaprionus, Drosophila, and Scaptomyza (from
Hawaii)--and three Drosophila subgenera--Drosophila, Engiscaptomyza, and
Sophophora--were included. After conducting statistical analyses of the
nucleotide sequences of the Adh, Adhr (Adh-related gene), and nuclear rRNA
genes and a 905-bp segment of mitochondrial DNA, we used Scaptodrosophila
as the outgroup. The phylogenetic tree obtained showed that the first major
division of drosophilid species occurs between subgenus Sophophora (genus
Drosophila) and the group including subgenera Drosophila and Engiscaptomyza
plus the genera Zaprionus and Scaptomyza. Subgenus Sophophora is then
divided into D. willistoni and the clade of D. obscura and D. melanogaster
species groups. In the other major drosophilid group, Zaprionus first
separates from the other species, and then D. immigrans leaves the
remaining group of species. This remaining group then splits into the D.
repleta group and the Hawaiian drosophilid cluster (Hawaiian Drosophila,
Engiscaptomyza, and Scaptomyza). Engiscaptomyza and Scaptomyza are tightly
clustered. Each of the D. repleta, D. obscura, and D. melanogaster groups
is monophyletic. The splitting of subgenera Drosophila and Sophophora
apparently occurred about 40 Mya, whereas the D. repleta group and the
Hawaiian drosophilid cluster separated about 32 Mya. By contrast, the
splitting of Engiscaptomyza and Scaptomyza occurred only about 11 Mya,
suggesting that Scaptomyza experienced a rapid morphological evolution. The
D. obscura and D. melanogaster groups apparently diverged about 25 Mya.
Many of the D. repleta group species studied here have two functional Adh
genes (Adh-1 and Adh-2), and these duplicated genes can be explained by two
duplication events.
相似文献
10.
Addition of iodine and methanol to N6,N6-dibenzoyl-9(2,3-O-carbonyl-5-deoxy-β-d-erythro-pent-4-enofuranosyl)adenine (4) selectively gives N6,N6-dibenzoyl-2′,3′-O-carbonyl-5′-deoxy-5′-iodo-4′-methoxyadenosine (5). Compound 5 can be converted into 4′-methoxyadenosine via hydrolysis of the carbonate followed by benzoylation, displacement of the 5′-iodo function by benzoate ion, and hydrolysis with ammonia. Configurational assignments are based upon comparisons of 1H- and 13C-n.m.r. spectra with those of previously characterised analogues in the uracil series and by borate electrophoresis. Intermediates in the above scheme have also been converted into 5′-amino-5′-deoxy-4′-methoxyadenosine, 4′-methoxy-5′-O-sulfamoyladenosine, and ethyl 4′-methoxyadenosine-5′-carboxylate, each of which is a 4′-methoxy analogue of biologically active derivatives of adenosine. 相似文献