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排序方式: 共有378条查询结果,搜索用时 15 毫秒
1.
2.
《Bioorganic & medicinal chemistry》2014,22(7):2320-2326
The therapeutic application of siRNA suffers from poor bioavailability caused by rapid degradation and elimination. The covalent attachment of PEG is a universal concept to increase molecular size and enhance the pharmacokinetic properties of biomacromolecules. We devised a facile approach for attachment of PEG molecules with a defined molecular weight, and successful purification of the resulting conjugates. We directly conjugated structurally defined PEG chains with twelve ethylene glycol units to the 3′-terminal hydroxyl group of both sense and antisense strands via an aminoalkyl linker. The conjugates were easily purified by HPLC and successful PEGylation and molecule integrity were confirmed by ESI-MS. The evaluation of in vitro gene knockdown of two different targets in MCF-7 breast cancer cells showed stable pharmacologic activity when combined with a standard transfection reagent. Sense strand PEGylation even increased the silencing potency of a CRCX4-siRNA which had modest activity in its wild-type form. The results indicate that PEG chains at the 3′-terminus of both strands of siRNA are well tolerated by the RNAi effector. The attachment of short, chemically defined PEG chains is a feasible approach to improve the pharmacokinetic properties of siRNA, and can be combined with other targeted and untargeted delivery vehicles. 相似文献
3.
An enzyme extract from apple(Pyrus malus Borb.) seeds which causes the disappearance of free indol-3-ylacetic acid (IAA) requires the presence of oxygen, but is not
inhibited by cyanide. Using 1-14C-IAA it has been demonstrated that the IAA transformation is not accompanied by its decarboxylation. Decarboxylating IAA
oxidase is absent during the whole period of apple seed cold stratification. Free IAA has not been detected in dormant apple
seeds and in seeds stratified at low temperature. It appears during stratification at 25 °C. Ethyl ester of IAA and indol-3-ylacetyl
aspartate have been identified in dormant and after-ripened seeds. Exogenous 1-14C IAA taken up by apple embryos is converted into conjugates with aspartate and short peptides containing an aspartate moiety. 相似文献
4.
Summary To elucidate the participation of fetal rat liver cells in the receptor-mediated internalization of low-density lipoproteins (LDL), rat fetuses were injected with either LDL-gold or albumin-gold conjugates. The degree of binding and uptake of LDL-gold and albumin-gold by parenchymal and sinusoidal cells of the fetal rat liver differs markedly. Endothelial cells exhibit low LDL-gold uptake. In contrast, parenchymal cells internalize LDL-gold more actively (45 ± 8 LDL conjugates/100 m2 cytoplasm within 60 min). Kupffer cells exceed this value by a factor of 20. The uptake of albumin-gold by endothelial and Kupffer cells is high, whereas it is extremely low in parenchymal cells. Estradiol pretreatment causes a significant doubling (p<0.05) of the LDL-gold particle density/100 m2 cytoplasm both in parenchymal and Kupffer cells, whereas estradiol has no effect on the albumin uptake. The results strongly indicate that LDL uptake by parenchymal and Kupffer cells in the fetal rat liver is mediated by estrogen-inducible receptors, which may correspond to B, E receptors in the adult liver. 相似文献
5.
Seeds from mature flowers of Heracleum laciniatum were collected locally (Tromsø, Norway). Seed coats were removed and the seeds were analyzed for their content of free, free plus ester-conjugate, and total indole-3-acetic acid (IAA) by quantitative gas chromatography-mass spectrometry. Seeds contained high levels of free and amide-linked IAA relative to other dicotyledonous seeds for which values have been published. The major amide conjugate in this material was identified as indole-3-acetylaspartate by gas chromatography-mass spectrometry of its bis-methyl ester. 相似文献
6.
S L Monfort S Jayaraman S E Shideler B L Lasley A G Hendrickx 《Journal of medical primatology》1986,15(1):17-26
Investigations were undertaken to determine the applicability of recently reported specific radioimmunoassays for urinary estrone conjugates and progesterone metabolites for monitoring ovarian function in the cynomolgus macaque (Macaca fasciularis) and other macaque species. Mean estrone conjugate measurements appear to accurately reflect the preovulatory estrogen peak in both conceptive (n = 5) and nonconceptive (n = 6) cycles, as well as to indicate early pregnancy through increases which are significantly elevated by Day + 15 (p less than 0.049) post estrone conjugates peak. The mean luteal phase levels of these progesterone metabolites are significantly elevated by Day + 14 (p less than 0.012) in conceptive cycles when compared to the mean values for nonconceptive cycles. 相似文献
7.
Masaji Koshioka Alan Jones Mayumi N. Koshioka Richard P. Pharis 《Phytochemistry》1983,22(7):1585-1590
The native gibberellin A4 (GA4), in radioactive form ([1,2-3H]GA4, 1.06 Ci/mmol), was fed to carrot somatic cell cultures (suspension and immobilized cell systems) and its metabolism over a 48 hr period was investigated. It was found that the [3H]GA4 was metabolized to at least two GAs, [3H]GA1 and [3H]GA8, six GA glucosyl conjugates, [3H]GA1-0(3)-glucoside, [3H]GA1-0(13)-glucoside, [3H]GA1-glucosyl ester, [3H]GA4-glucoside, [3H]GA4-glucosyl ester, a [3H]GA8 glucosyl conjugate(s) and a previously unknown [3H]GA1 glucosyl conjugate ([3H]GA1-0(3,13)-diglucoside-like compound). The GA1-diglucoside-like compound was found only in extracts of cells and was present in significant amounts (33 % of total extractable radioactivity). All other metabolites were present in both cells and medium. For extracts of the medium, no differences between the suspension and immobilized cultures existed in types of [3H]GA4 metabolites although quantitative differences were apparent. 相似文献
8.
Jeffery J. Feigenbaum Milind D. Choubal David S. Crumrine Jeffrey R. Kanofsky Kemal Payza 《Peptides》1996,17(8):1279-1284
Three neuropeptide analogues of FMRFamide (FMRFa) were covalently attached to a tethered derivative of methylene blue to form dye-neuropeptide conjugates. The comparative binding of the latter to FMRFa receptors was subsequently examined in both Helix aspersa (circumesophageal ganglia) and squid (optic lobe membrane). In Helix, the FMRFa analogue CFMRFamide (CFMRFa) inhibited the specific binding of the FMRFa ligand [125I]daYFnLRFa in a dose-dependent manner. Az-CFMRFa, one of the dye-neuropeptide conjugates, also dose-dependently inhibited the specific binding of [125I]daYFnLRFa. Moreover, their potencies equaled or exceeded that of FMRFamide. In squid, the binding of CFMRFa and FMRFa was similar. However, the dye-neuropeptide conjugate (IC50 of 14 nM) was about 44-fold less potent than FMRFa. The conjugates were synthesized as part of a study seeking to target and inactivate preselected receptors with heretofore unattainable selectivity and permanence. 相似文献
9.
Victor D. Ramirez Jianbiao Zheng Khawar M. Siddique 《Cellular and molecular neurobiology》1996,16(2):175-198
Summary 1. There are numerous circumstantial evidence supporting the concept that steroid hormones control cellular function by means other than the nuclear receptor steroid binding mechanism. It is the intent of this report to present evidence indicating that steroids bind to specific sites in neuronal membranes.2. Some of the criteria to define steroid membrane receptors using steroid-BSA conjugates that can be radioiodinated to desired specific activity have been fulfilled for each of the three sex steroids using crude synaptosomal membrane preparations (P2 fractions) from the CNS of female and male rats. Ligand binding for each of the three steroids indicate high-affinity and high-capacity sites with distinct brain selectivity and stereospecificity. For example, 17-E-6-[125I]BSA binds hypothalamic P2 fractions (HYP-P2) with an estimatedK
d of about 3±0.7 nM (X ± SE;n=3), whereas the cerebellum P2 (CB-P2) fractions bind the ligand with aK
d of 34±7 nM and, aB
max of 3 and 42 pmol/mg protein, respectively. Estrogen and testosterone binding fit best a one-single site, while progesterone binding sites can be best represented by a two-binding site, one high-affinity (K
d=1–2 nM) and one low affinity (K
d=62 nM), in CB-P2 fractions from intact adult female rat brain. Kinetics studies for T-3-[125I]BSA indicate that the estimatedK
d of 30±2 nM for the olfactory bulb P2 fractions (OB-P2) from male rats is in good agreement withK
d values computed from Scatchard-derived data using the LIGAND algorithm.3. 17-E-6-[125I]BSA binding sites are stereospecific and appears to be present as early as 5 days of age in both the OB- and the CB-P2 fractions without changes during development. In contrast, P-6-[125I]BSA binding sites are practically absent during days 5 and 12 and appear by day 22.4. Finally, membrane receptor molecules for estrogen and progesterone have been isolated and purified by affinity chromatography and characterized by PAGE and Western blot. Microsequencing of one of the membrane estrogen binding proteins indicates that the high-affinity site corresponds to the OSCP subunit of the proton ATP synthase.5. It remains to be determined if P and T also bind to this complex enzyme or if they bind to other subunits of the family of proton ATPases. Overall the data indicate that steroid hormones conjugated to BSA are important tools to study the reality of membrane steroid receptors. 相似文献
10.
Kelem Kassahun Pei Hu Mark P. Grillo Margaret R. Davis Lixia Jin Thomas A. Baillie 《Chemico-biological interactions》1994,90(3):253-275
The ability of 2-n-propyl-4-pentenoic acid (Δ4-VPA) and 2-n-propyl-2(E)-pentenoic acid ([E]-Δ2-VPA), two unsaturated metabolites of valproic acid (VPA), to form reactive intermediates, deplete hepatic glutathione (GSH) and cause accumulation of liver triglycerides was investigated in the rat. With the aid of ionspray liquid chromatography-tandem mass spectrometry (LC-MS/MS), three GSH adducts were detected in the bile of Δ4-VPA-treated animals and were identified as 4-hydroxy-5-glutathion-S-yl-VPA-γ-lactone, 5-glutathion-S-yl-(E)-Δ3-VPA and 3-oxo-5-glutathion-S-yl-VPA. A fourth conjugate was identified tentatively as 4-glutathion-S-yl-5-hydroxy-VPA. Quantitative analysis of the corresponding N-acetylcysteine (NAC) conjugates in urine indicated that metabolism of Δ4-VPA via the GSH-dependent pathways accounted for approximately 20% of an acute dose (100 mg kg−1 i.p.). In contrast, when rats were given an equivalent dose of (E)-Δ2-VPA, only one GSH adduct (5-glutathion-S-yl-(E)-Δ3-VPA) was detected at low concentrations in bile. In vitro experiments with rat liver mitochondria demonstrated that Δ4-VPA undergoes coenzyme A- and ATP-dependent metabolic activation in this organelle via the β-oxidation pathway to intermediates which bind covalently to proteins. When liver homogenates and hepatic mitochondria from rats injected with Δ4-VPA, (E)-Δ2-VPA or VPA were analyzed for GSH content, it was found that only Δ4-VPA depleted GSH pools significantly. Treatment of rats with Δ4-VPA and (to a lesser extent) VPA led to an accumulation of liver triglycerides, whereas (E)-Δ2-VPA had no measurable effect. It is concluded that Δ4-VPA undergoes metabolic activation by both microsomal cytochrome P-450-dependent and mitochondrial coenzyme A-dependent processes, and that the resulting electrophilic intermediates, which are trapped in part by GSH, may mediate the hepatotoxic effects of this compound. In contrast, (E)-Δ2-VPA is not transformed to any appreciable extent to reactive metabolites, which thus accounts for the apparent lack of hepatotoxicity of this positional isomer in the rat. 相似文献