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排序方式: 共有171条查询结果,搜索用时 31 毫秒
21.
Ramya TN Surolia N Surolia A 《Biochemical and biophysical research communications》2006,348(2):579-584
We demonstrate, for the first time, a functional polyamine biosynthetic pathway in the malaria parasite Plasmodium falciparum that culminates in the synthesis of spermine. Additionally, we also report putrescine and spermidine salvage in the malaria parasite. Putrescine and spermidine transport in P. falciparum infected red blood cells is a highly specific, carrier mediated and active process, mediated by new transporters that differ from the transporters of uninfected red blood cells in their kinetic parameters, Vmax and km, as well as in their activation energy. 相似文献
22.
Microrchidia 2 (MORC2) is an emerging chromatin modifier with a role in chromatin remodeling and epigenetic regulation. MORC2 is found to be upregulated in most cancers, playing a significant role in tumorigenesis and tumor metastasis. Recent studies have demonstrated that MORC2 is a scaffolding protein, which interacts with the proteins involved in DNA repair, chromatin remodeling, lipogenesis, and glucose metabolism. In this review, we discuss the domain architecture and cellular and subcellular localization of MORC2. Further, we highlight MORC2-specific interacting partners involved in metabolic reprogramming and other pathological functions such as cancer progression and metastasis. 相似文献
23.
Philippe Labrune Anne Myara Michèle Hadchouel Flavio Ronchi Olivier Bernard François Trivin Namita Roy Chowdhury Jayanta Roy Chowdhury Arnold Munnich Michel Odièvre 《Human genetics》1994,94(6):693-697
Crigler-Najjar syndrome type I (CN-I) is an autosomal recessive condition characterized by severe unconjugated hyperbilirubinemia caused by the lack of bilirubin-UDP-glucuronosyltransferase (B-UGT) activity in the liver. Two B-UGTs are coded for by a gene complex (UGT1) that maps to chromosome 2q37 and that also encodes two phenol-UDP-glucuronosyltransferases. Here, we report eleven mutations (including nine novel mutations) of the B-UGT1 gene in a large series of 14 unrelated CN-I children of various geographic origins: France (seven patients: A401P, Q357X, W335X, A368T, 1223insG, A291V, K426E, K437X); Portugal (two patients: G308E); Tunisia (two patients: Q357R); Turkey (one patient: S381R); Italy (two siblings: S381R). Interestingly, 6/14 mutant alleles carried by unrelated probands of French ancestry bore the A401P mutation, indicating a founder effect; this effect is probably also present in Portugal, Turkey, and Tunisia. Since mutations occurred in exons 2-5 shared by all mRNAs species of the gene, a combined deficiency of B-UGT and P-UGT was observed in the liver of five patients in whom these activities were measured. The present study confirms that CN-I is genetically heterogeneous and suggests that different founder effects are involved in Western Europe, the Middle East, and North Africa.These results were presented in part at the American Association for the Study of Liver Diseases, Chicago, November 4–7, 1993 相似文献
24.
Mow Yee Foo Namita Sawant Ellen Overholtzer Maureen D. Donovan 《AAPS PharmSciTech》2018,19(7):2767-2777
A mathematical approach was developed to estimate spray deposition patterns in the nasal cavity based on the geometric relationships between the emitted spray plume and the anatomical dimensions of the nasal valve region of the nasal cavity. Spray plumes were assumed to be spherical cones and the nasal valve region was approximated as an ellipse. The effect of spray plume angle (15–85°) on the fraction of the spray able to pass through the nasal valve (deposition fraction) was tested for a variety of nasal valve (ellipse) shapes and cross-sectional areas based on measured dimensions from pediatric and adult nasal cavities. The effect of the distances between the tip of the nasal spray device and the nasal valve (0.2–1.9 cm) on the deposition fraction was also tested. Simulation results show that (1) decreasing spray plume angles resulted in higher deposition fractions, (2) deposition fraction was inversely proportional to the spray distance and the nasal valve (ellipse) major/minor axis ratio, and (3) for fixed major/minor axis ratios, improved deposition occurred with larger nasal valve cross-sectional areas. For a typical adult nasal valve, plume angles of less than 40° emitted from a distance of 1 cm resulted depositions greater than 90% within the main nasal cavity, whereas for a 12-year-old child, only the most narrow plume angles (<?20°) administered resulted in significant deposition beyond the nasal valve. 相似文献
25.
Imipramine and clorgyline, at concentrations of 0.002 M, inhibit the respiration of brain tissue by 82 and 71 per cent respectively, while chloropromazine and tranylcypromine, at concentrations of 0.01 M, inhibit it about 25 per cent. Deprenyl and amphetamine at a concentration of 0.002 M inhibit brain tissue respiration by 12 and 18 per cent respectively. Respiration in brain is least affected by lithium chloride (only 5 per cent inhibition). 相似文献
26.
27.
The present study investigates the effect of pH and intermediate products formation on biological hydrogen production using Enterobacter cloacae IIT-BT 08. Initial pH was found to have a profound effect on hydrogen production potential, while regulating the pH 6.5 throughout the fermentation was found to increase the cumulative hydrogen production rate and yield significantly. Modified Gompertz equation was used to fit the cumulative hydrogen production curves to obtain the hydrogen production potential P, the hydrogen production rate R and lag phase λ. At regulated pH 6.5, higher H(2) yield (3.1molH(2)mol(-1) glucose), specific hydrogen production potential (798.1mL/g) and specific rate of H(2) production (72.1mLL(-1)h(-1)g(-1)) were obtained. The volatile fatty acid profile showed butyrate, ethanol and acetate as the major end metabolites of fermentation under the operating pH conditions tested; however, their pattern of distribution was pH dependent. At the optimum pH of 6.5, the acetate to butyrate ratio (A/B ratio) was found to be higher than that at any other pH. The study also investigates the effect of sodium ions on biohydrogen production potential. It was also found that sodium ion concentration up to 250mM enhanced the hydrogen production potential; however, any further increase in the metal ion concentration had an inhibitory effect. 相似文献
28.
Bromo-benzothiophene carboxamide derivatives have been shown in the preceding article to inhibit Plasmodium falciparum Enoyl-ACP reductase. Here, we report bromo-benzothiophene carboxamide derivatives as potent inhibitors of Plasmodium asexual blood-stages in vitro as well as in vivo in the mouse model. These compounds specifically impair the development of metabolically active trophozoite stage of intraerythrocytic cycle and the intravenous administration of 3-bromo-N-(4-fluorobenzyl)-benzo[b]thiophene-2-carboxamide (compound 6) enhances the longevity of P. berghei infected mice by 2 weeks compared to disease control animals thereby preventing the onset of ataxia and convulsions in treated mice. These compounds thus hold promise for the development of potent antimalarials. 相似文献
29.
J. Shawn Goodwin Gaynor A. Larson Jarod Swant Namita Sen Jonathan A. Javitch Nancy R. Zahniser Louis J. De Felice Habibeh Khoshbouei 《The Journal of biological chemistry》2009,284(5):2978-2989
The psychostimulants d-amphetamine (AMPH) and methamphetamine
(METH) release excess dopamine (DA) into the synaptic clefts of dopaminergic
neurons. Abnormal DA release is thought to occur by reverse transport through
the DA transporter (DAT), and it is believed to underlie the severe behavioral
effects of these drugs. Here we compare structurally similar AMPH and METH on
DAT function in a heterologous expression system and in an animal model. In
the in vitro expression system, DAT-mediated whole-cell currents were
greater for METH stimulation than for AMPH. At the same voltage and
concentration, METH released five times more DA than AMPH and did so at
physiological membrane potentials. At maximally effective concentrations, METH
released twice as much [Ca2+]i from internal
stores compared with AMPH. [Ca2+]i responses to
both drugs were independent of membrane voltage but inhibited by DAT
antagonists. Intact phosphorylation sites in the N-terminal domain of DAT were
required for the AMPH- and METH-induced increase in
[Ca2+]i and for the enhanced effects of METH on
[Ca2+]i elevation. Calmodulin-dependent protein
kinase II and protein kinase C inhibitors alone or in combination also blocked
AMPH- or METH-induced Ca2+ responses. Finally, in the rat nucleus
accumbens, in vivo voltammetry showed that systemic application of
METH inhibited DAT-mediated DA clearance more efficiently than AMPH, resulting
in excess external DA. Together these data demonstrate that METH has a
stronger effect on DAT-mediated cell physiology than AMPH, which may
contribute to the euphoric and addictive properties of METH compared with
AMPH.The dopamine transporter
(DAT)3 is a main
target for psychostimulants, such as d-amphetamine (AMPH),
methamphetamine (METH), cocaine (COC), and methylphenidate (Ritalin®). DAT
is the major clearance mechanism for synaptic dopamine (DA)
(1) and thereby regulates the
strength and duration of dopaminergic signaling. AMPH and METH are substrates
for DAT and competitively inhibit DA uptake
(2,
3) and release DA through
reverse transport
(4–9).
AMPH- and METH-induced elevations in extracellular DA result in complex
neurochemical changes and profound psychiatric effects
(2,
10–16).
Despite their structural and pharmacokinetic similarities, a recent National
Institute on Drug Abuse report describes METH as a more potent stimulant than
AMPH with longer lasting effects at comparable doses
(17). Although the route of
METH administration and its availability must contribute to the almost four
times higher lifetime nonmedical use of METH compared with AMPH
(18), there may also be
differences in the mechanisms that underlie the actions of these two drugs on
the dopamine transporter.Recent studies by Joyce et al.
(19) have shown that compared
with d-AMPH alone, the combination of d- and
l-AMPH in Adderall® significantly prolonged the time course of
extracellular DA in vivo. These experiments demonstrate that subtle
structural features of AMPH, such as chirality, can affect its action on
dopamine transporters. Here we investigate whether METH, a more lipophilic
analog of AMPH, affects DAT differently than AMPH, particularly in regard to
stimulated DA efflux.METH and AMPH have been reported as equally effective in increasing
extracellular DA levels in rodent dorsal striatum (dSTR), nucleus accumbens
(NAc) (10,
14,
20), striatal synaptosomes,
and DAT-expressing cells in vitro
(3,
6). John and Jones
(21), however, have recently
shown in mouse striatal and substantia nigra slices, that AMPH is a more
potent inhibitor of DA uptake than METH. On the other hand, in synaptosomes
METH inhibits DA uptake three times more effectively than AMPH
(14), and in DAT-expressing
COS-7 cells, METH releases DA more potently than AMPH (EC50 = 0.2
μm for METH versus EC50 = 1.7
μm for AMPH) (5).
However, these differences do not hold up under all conditions. For example,
in a study utilizing C6 cells, the disparity between AMPH and METH was not
found (12).The variations in AMPH and METH data extend to animal models. AMPH- and
METH-mediated behavior has been reported as similar
(22), lower
(20), or higher
(23) for AMPH compared with
METH. Furthermore, although the maximal locomotor activation response was less
for METH than for AMPH at a lower dose (2 mg/kg, intraperitoneal), both drugs
decreased locomotor activity at a higher dose (4 mg/kg)
(20). In contrast, in the
presence of a salient stimuli, METH is more potent in increasing the overall
magnitude of locomotor activity in rats yet is equipotent with AMPH in the
absence of these stimuli
(23).The simultaneous regulation of DA uptake and efflux by DAT substrates such
as AMPH and METH, as well as the voltage dependence of DAT
(24), may confound the
interpretation of existing data describing the action of these drugs. Our
biophysical approaches allowed us to significantly decrease the contribution
of DA uptake and more accurately determine DAT-mediated DA efflux with
millisecond time resolution. We have thus exploited time-resolved, whole-cell
voltage clamp in combination with in vitro and in vivo
microamperometry and Ca2+ imaging to compare the impact of METH and
AMPH on DAT function and determine the consequence of these interactions on
cell physiology.We find that near the resting potential, METH is more effective than AMPH
in stimulating DAT to release DA. In addition, at efficacious concentrations
METH generates more current, greater DA efflux, and higher Ca2+
release from internal stores than AMPH. Both METH-induced or the lesser
AMPH-induced increase in intracellular Ca2+ are independent of
membrane potential. The additional Ca2+ response induced by METH
requires intact phosphorylation sites in the N-terminal domain of DAT.
Finally, our in vivo voltammetry data indicate that METH inhibits
clearance of locally applied DA more effectively than AMPH in the rat nucleus
accumbens, which plays an important role in reward and addiction, but not in
the dorsal striatum, which is involved in a variety of cognitive functions.
Taken together these data imply that AMPH and METH have distinguishable
effects on DAT that can be shown both at the molecular level and in
vivo, and are likely to be implicated in the relative euphoric and
addictive properties of these two psychostimulants. 相似文献
30.
Balance of signals generated from the engaged activating and inhibitory surface receptors regulates mature NK cell activities. The inhibitory receptors signal through immunoreceptor tyrosine based inhibitory motifs (ITIM), and recruit phosphatases such as SHP-1 to inhibit NK cell activation. To directly examine the importance of SHP-1 in regulating activities and cell fate of mature NK cells, we used our established lentiviral-based engineering protocol to knock down the SHP-1 protein expression in primary C57BL/6NCrl cells. Gene silencing of the SHP-1 in primary NK cells abrogated the ability of ITIM-containing NK inhibitory receptors to suppress the activation signals induced by NK1.1 activating receptors. We followed the fates of stably transduced SHP-1 silenced primary NK cells over a longer period of time in IL-2 containing cultures. We observed an impaired IL-2 induced proliferation in the SHP-1 knockdown NK cells. More interestingly, these "de-regulated" SHP-1 knockdown NK cells mediated specific self-killing in a real-time live cell microscopic imaging system we developed to study NK cell cytotoxicity in vitro. Selective target recognition of the SHP-1 knockdown NK cells revealed also possible involvement of the SHP-1 phosphatase in regulating other NK functions in mature NK cells. 相似文献