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排序方式: 共有164条查询结果,搜索用时 15 毫秒
101.
102.
Ramsson ES Covey DP Daberkow DP Litherland MT Juliano SA Garris PA 《Journal of neurochemistry》2011,117(6):937-948
Amphetamine (AMPH) is thought to disrupt normal patterns of action potential-dependent dopaminergic signaling by depleting dopamine (DA) vesicular stores and promoting non-exocytotic DA efflux. Voltammetry in brain slices concurrently demonstrates these key drug effects, along with competitive inhibition of neuronal DA uptake. Here, we perform comparable kinetic and voltammetric analyses in vivo to determine whether AMPH acts qualitatively and quantitatively similar in the intact brain. Fast-scan cyclic voltammetry measured extracellular DA in dorsal and ventral striata of urethane-anesthetized rats. Electrically evoked recordings were analyzed to determine K(m) and V(max) for DA uptake and vesicular DA release, while background voltammetric current indexed basal DA concentration. AMPH (0.5, 3, and 10 mg/kg i.p.) robustly increased evoked DA responses in both striatal subregions. The predominant contributor to these elevated levels was competitive uptake inhibition, as exocytotic release was unchanged in the ventral striatum and only modestly decreased in the dorsal striatum. Increases in basal DA levels were not detected. These results are consistent with AMPH augmenting action potential-dependent dopaminergic signaling in vivo across a wide, behaviorally relevant dose range. Future work should be directed at possible causes for the distinct in vitro and in vivo pharmacology of AMPH. 相似文献
103.
104.
Sara M. Peyrot Sigrid Nachtergaele Giovanni Luchetti Laurel K. Mydock-McGrane Hideji Fujiwara David Scherrer Andrew Jallouk Paul H. Schlesinger Daniel S. Ory Douglas F. Covey Rajat Rohatgi 《The Journal of biological chemistry》2014,289(16):11095-11110
Oxysterols, oxidized metabolites of cholesterol, are endogenous small molecules that regulate lipid metabolism, immune function, and developmental signaling. Although the cell biology of cholesterol has been intensively studied, fundamental questions about oxysterols, such as their subcellular distribution and trafficking pathways, remain unanswered. We have therefore developed a useful method to image intracellular 20(S)-hydroxycholesterol with both high sensitivity and spatial resolution using click chemistry and fluorescence microscopy. The metabolic labeling of cells with an alkynyl derivative of 20(S)-hydroxycholesterol has allowed us to directly visualize this oxysterol by attaching an azide fluorophore through cyclo-addition. Unexpectedly, we found that this oxysterol selectively accumulates in the Golgi membrane using a pathway that is sensitive to ATP levels, temperature, and lysosome function. Although previous models have proposed nonvesicular pathways for the rapid equilibration of oxysterols between membranes, direct imaging of oxysterols suggests that a vesicular pathway is responsible for differential accumulation of oxysterols in organelle membranes. More broadly, clickable alkynyl sterols may represent useful tools for sterol cell biology, both to investigate the functions of these important lipids and to decipher the pathways that determine their cellular itineraries. 相似文献
105.
Gibson S Kibiki Bert Mulder Wil MV Dolmans Jessica L de Beer Martin Boeree Noel Sam Dick van Soolingen Christophe Sola Adri GM van der Zanden 《BMC microbiology》2007,7(1):51
Background
Tuberculosis (TB) is a major health problem and HIV is the major cause of the increase in TB. Sub-Saharan Africa is endemic for both TB and HIV infection. Determination of the prevalence of M. tuberculosis strains and their drug susceptibility is important for TB control. 相似文献106.
Background
Suicide has been associated with smoking/tobacco use but its association of and change in smoking/tobacco use status with suicide attempt (SA) is not well established.Methods
We investigated whether persistent, former tobacco use, initiation, quitting tobacco use, relapse to tobacco use, and DSM-IV nicotine dependence predict independently SA using Wave 1 and 2 data of the National Epidemiologic Survey of Alcohol and Related Conditions. Data from 34,653 US adults interviewed at Wave 1 (2001-02) and Wave 2 (2004-05) were analyzed. The main outcome measure was SA between Wave 1 and Wave 2 as reported at Wave 2.Results
Among the 1,673 respondents reporting lifetime SA at Wave 2, 328 individuals reported SA between Wave 1 and Wave 2. Current and former tobacco use at Wave 1 predicted Wave 2 SA independently of socio-demographic characteristics, psychiatric history, and prior SA (Adjusted Odds Ratio (AOR): 1.49; 95% CI: 1.13-1.95, AOR: 1.31; 95% CI:1.01-1.69, respectively versus never tobacco users). The strongest association with SA was observed among former tobacco users who relapsed after Wave 1 (AOR: 4.66; 95% CI: 3.49-6.24) and among tobacco use initiators after Wave 1 (AOR: 3.16; 95% CI: 2.23-4.49). Persistent tobacco use (current tobacco use at both Wave 1 and Wave 2) also had an increased risk of SA (AOR: 1.89; 95% CI: 1.47-2.42). However, former tobacco users in both Waves 1 and 2 did not show a significantly elevated risk for SA in Wave 2 (AOR:1.09, 95% CI: 0.78-1.52) suggesting that the risk resided mainly in Wave 1 former tobacco users who relapsed to tobacco use by Wave 2. DSM-IV nicotine dependence did not predict SA at Wave 2.Conclusion
In a representative sample of US adults, relapse, tobacco use initiation, and persistent tobacco use, which are amenable to intervention, were associated with risk of SA. 相似文献107.
Achintya K. Bandyopadhyaya Brad D. Manion Ann Benz Amanda Taylor Nigam P. Rath Alex S. Evers Charles F. Zorumski Steven Mennerick Douglas F. Covey 《Bioorganic & medicinal chemistry letters》2010,20(22):6680-6684
Alphaxalone, a neuroactive steroid containing a 17β-acetyl group, has potent anesthetic activity in humans. This pharmacological activity is attributed to this steroid’s enhancement of γ-amino butyric acid-mediated chloride currents at γ-amino butyric acid type A receptors. The conversion of alphaxalone into Δ16-alphaxalone produces an analogue that lacks anesthetic activity in humans and that has greatly diminished receptor actions. By contrast, the corresponding 17β-carbonitrile analogue of alphaxalone and the Δ16-17-carbonitrile analogue both have potent anesthetic and receptor actions. The differential effect of the Δ16-double bond on the actions of alphaxalone and the 17β-carbonitrile analogue is accounted for by a differential effect on the orientation of the 17-acetyl and 17-carbonitrile substituents. 相似文献
108.
109.
Sneitz N Krishnan K Covey DF Finel M 《The Journal of steroid biochemistry and molecular biology》2011,127(3-5):282-288
Steroids enantiomers are interesting compounds for detailed exploration of drug metabolizing enzymes, such as the UDP-glucuronosyltransferases (UGTs). We have now studied the glucuronidation of the enantiomers of estradiol, androsterone and etiocholanolone by the 19 human UGTs of subfamilies 1A, 2A and 2B. The results reveal that the pattern of human UGTs of subfamily 2B that glucuronidate ent-17β-estradiol, particularly 2B15 and 2B17, resembles the glucuronidation of epiestradiol (17α-estradiol) rather than 17β-estradiol, the main physiological estrogen. The UGTs of subfamilies 1A and 2A exhibit higher degree of regioselectivity than enantioselectivity in the conjugation of these estradiols, regardless of whether the activity is primarily toward the non-chiral site, 3-OH (UGT1A1, UGT1A3, UGT1A7, UGT1A8 and, above all, UGT1A10), or the 17-OH (UGT1A4). In the cases of etiocholanolone and androsterone, glucuronidation of the ent-androgens, like the conjugation of the natural androgens, is mainly catalyzed by UGTs of subfamilies 2A and 2B. Nevertheless, the glucuronidation of ent-etiocholanolone and ent-androsterone by both UGT2B7 and UGT2B17 differs considerably from their respective activity toward the corresponding endogenous androgens, whereas UGT2A1-catalyzed conjugation is much less affected by the stereochemistry differences. Kinetic analyses reveal that the K(m) value of UGT2A1 for ent-estradiol is much higher than the corresponding value in the other two high activity enzymes, UGT1A10 and UGT2B7. Taken together, the results highlight large enantioselectivity differences between individual UGTs, particularly those of subfamily 2B. 相似文献
110.
Bryson W. Katona Shrikant Anant Douglas F. Covey William F. Stenson 《The Journal of biological chemistry》2009,284(5):3354-3364
Bile acids are steroid detergents that are toxic to mammalian cells at high
concentrations; increased exposure to these steroids is pertinent in the
pathogenesis of cholestatic disease and colon cancer. Understanding the
mechanisms of bile acid toxicity and apoptosis, which could include
nonspecific detergent effects and/or specific receptor activation, has
potential therapeutic significance. In this report we investigate the ability
of synthetic enantiomers of lithocholic acid (ent-LCA),
chenodeoxycholic acid (ent-CDCA), and deoxycholic acid
(ent-DCA) to induce toxicity and apoptosis in HT-29 and HCT-116
cells. Natural bile acids were found to induce more apoptotic nuclear
morphology, cause increased cellular detachment, and lead to greater capase-3
and -9 cleavage compared with enantiomeric bile acids in both cell lines. In
contrast, natural and enantiomeric bile acids showed similar effects on
cellular proliferation. These data show that bile acid-induced apoptosis in
HT-29 and HCT-116 cells is enantiospecific, hence correlated with the absolute
configuration of the bile steroid rather than its detergent properties. The
mechanism of LCA- and ent-LCA-induced apoptosis was also investigated
in HT-29 and HCT-116 cells. These bile acids differentially activate initiator
caspases-2 and -8 and induce cleavage of full-length Bid. LCA and
ent-LCA mediated apoptosis was inhibited by both pan-caspase and
selective caspase-8 inhibitors, whereas a selective caspase-2 inhibitor
provided no protection. LCA also induced increased CD95 localization to the
plasma membrane and generated increased reactive oxygen species compared with
ent-LCA. This suggests that LCA/ent-LCA induce apoptosis
enantioselectively through CD95 activation, likely because of increased
reactive oxygen species generation, with resulting procaspase-8 cleavage.Bile acids are physiologic steroids that are necessary for the proper
absorption of fats and fat-soluble vitamins. Their ability to aid in these
processes is largely due to their amphipathic nature and thus their ability to
act as detergents. Despite the beneficial effects, high concentrations of bile
acids are toxic to cells
(1-11).
High fat western diets induce extensive recirculation of the bile acid pool,
resulting in increased exposure of the colonic epithelial cells to these toxic
steroids (12,
13). A high fat diet is also a
risk factor for colon carcinogenesis; increased bile acid exposure is
responsible for some of this risk. Bile acids can contribute to both colon
cancer formation and progression, and their effects on colonic proliferation
and apoptosis aid this process by disrupting the balance between cell growth
and cell death, as well as helping to select for bile acid-resistant cells
(14,
15).In colonocyte-derived cell lines bile acid-induced apoptosis is thought to
proceed through mitochondrial destabilization with resulting mitochondrial
permeability transition formation and cytochrome c release as well as
generation of oxidative stress
(1,
9-11).
Bile acid-induced apoptosis has also been extensively explored in hepatocyte
derived cell lines with mechanisms including mitochondria dysfunction
(16-23),
endoplasmic reticulum stress
(24), ligand-independent
activation of death receptor pathways
(18,
25-28),
and modulation of cellular apoptotic and anti-apoptotic Bcl-2 family proteins
(29).Although ample evidence exists for multiple mechanisms of bile acid-induced
apoptosis, the precise interactions responsible for initiating these apoptotic
pathways are still unclear. Bile acids have been shown to interact directly
with specific receptors (30,
31). These steroids can also
initiate cellular signaling through nonspecific membrane perturbations
(32), and evidence exists
showing that other simple detergents (i.e. Triton X-100) are capable
of inducing caspase cleavage nonspecifically with resultant apoptosis
(33). Therefore, hydrophobic
bile acids may interact nonspecifically with cell membranes to alter their
physical properties, bind to receptors specific for these steroids, or utilize
a combination of both specific and nonspecific interactions to induce
apoptosis.Bile acid enantiomers could be useful tools for elucidating mechanisms of
bile acid toxicity and apoptosis. These enantiomers, known as
ent-bile acids, are synthetic nonsuperimposable mirror images of
natural bile acids with identical physical properties except for optical
rotation. Because bile acids are only made in one absolute configuration
naturally, ent-bile acids must be constructed using a total synthetic
approach. Recently we reported the first synthesis of three enantiomeric bile
acids: ent-lithocholic acid
(ent-LCA),2
ent-chenodeoxycholic acid (ent-CDCA), and
ent-deoxycholic acid (ent-DCA)
(Fig. 1)
(34,
35). Enantiomeric bile acids
have unique farnesoid X receptor, vitamin D receptor, pregnane X receptor, and
TGR5 receptor activation profiles compared with the corresponding natural bile
acids (34). This illustrates
that natural and enantiomeric bile acids interact differently within chiral
environments because of their distinct three-dimensional configurations
(Fig. 1). Despite these
differences in chiral interactions, ent-bile acids have physical
properties identical to those of their natural counterparts including
solubility and critical micelle concentrations
(34,
35). With different receptor
interaction profiles and identical physical properties compared with natural
bile acids, ent-bile acids are ideal compounds to differentiate
between the receptor-mediated and the non-receptor-mediated functions of
natural bile acids.Open in a separate windowFIGURE 1.Natural and enantiomeric bile acids. Structures and
three-dimensional projection views of natural LCA, CDCA, DCA, and their
enantiomers (ent-LCA, ent-CDCA, and ent-DCA). The
three-dimensional ent-steroid structure is rotated 180° around
the long axis for easier comparison with the natural steroid.In this study we explore the enantioselectivity of LCA-, CDCA-, and
DCA-mediated toxicity and apoptosis in two human colon adenocarcinoma cell
lines, HT-29 and HCT-116. Because the mechanism of natural LCA induced
apoptosis has never been characterized, we then examined in more detail LCA-
and ent-LCA-mediated apoptosis in colon cancer cells. These studies
will not only explore the LCA apoptotic mechanism but will also determine
whether ent-LCA signals through similar cellular pathways. 相似文献