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11.
多聚胺阳离子脂质体转染效率及细胞毒性的评价 总被引:4,自引:1,他引:3
目的评估四种多聚胺阳离子脂质体的转染效率及细胞毒性,筛选高效低毒的阳离子脂质体。方法多聚胺阳离子脂质TC-Chol、DC-Chol与中性磷脂DOPE分别以1:1、3:1摩尔比制备多聚胺阳离子脂质体,转染以增强型绿色荧光蛋白为报告基因的质粒PIRES2-EGFP入Hela细胞、Hep2细胞,倒置荧光显微镜下检测转染细胞的报告基因表达,筛选出高效的阳离子脂质体,通过MTT法检测转染细胞毒性,从而筛选相对高效低毒的阳离子脂质体。结果所制备的多聚胺阳离子脂质体在透射电镜下呈圆形、椭圆形囊泡样结构,少数呈管状、不规则状,粒径50-200nm,可将质粒PIRES2-EGFP有效转染入Hela细胞、Hep2细胞,其中多聚胺阳离子脂质TC-Chol与DOPE以3:1摩尔比制备的多聚胺阳离子脂质体是一种相对高效低毒的阳离子脂质体,转染效率39.5%~42.1%。结论多聚胺阳离子脂质TC-Chol、DC-Chol与中性磷脂DOPE以一定的摩尔比可制备高效低毒的多聚胺阳离子脂质体,其转染效率和细胞毒性与阳离子脂质的结构和中性磷脂DOPE的比例有关,在基因转染和基因治疗方面具有较广阔的应用前景。 相似文献
12.
《Clinical and experimental hypertension (New York, N.Y. : 1993)》2013,35(8):1197-1217
The impact of the antineoplastic polyamine analogues N1N14-diethylhomospermine (DEHSPM) and N1N11-diethylnorspermine (DENSPM) on the blood pressure and heart rate of normotensive and hypertensive rats are described. DEHSPM was administered to both normotensive and spontaneously hypertensive rats (SHR), while the DENSPM analogue was given only to the normotensive animals. The intravenous administration of DEHSPM a t doses of 5 or 10 mg/kg resulted in a profound and long-lasting drop in the test animals' blood pressure, with no appreciable change in their heart rate. This was true for both the normotensive and the hypertensive animals. When administered at equivalent molar dosages, DENSPM was one fifth as effective as DEHSPM at reducing blood pressure. The impact of NG-nitro-L-arginine- methyl ester (L-NAME) and L-arginine on the analogues' activity is consistent with the involvement of nitric oxide. 相似文献
13.
Laura T. Mkitie Kristiina Kanerva Tuomo Polvikoski Anders Paetau Leif C. Andersson 《Brain pathology (Zurich, Switzerland)》2010,20(3):571
Polyamines are small cationic molecules that in adult brain are connected to neuronal signaling by regulating inward‐rectifier K+‐channels and different glutamate receptors. Antizyme inhibitors (AZINs) regulate the cellular uptake of polyamines and activate ornithine decarboxylase (ODC), the rate‐limiting enzyme of polyamine synthesis. Elevated levels of ODC activity and polyamines are detected in various brain disorders including stroke and Alzheimer''s disease (AD).We originally reported a novel brain‐ and testis‐specific AZIN, called AZIN2, the distribution of which we have now studied in normal and diseased human brain by in situ hybridization and immunohistochemistry. We found the highest accumulation of AZIN2 in a pearl‐on‐the‐string‐like distribution along the axons in both the white and gray matter. AZIN2 was also detected in a vesicle‐like distribution in the somas of selected cortical pyramidal neurons. Double‐immunofluorescence staining revealed co‐localization of AZIN2 and N‐methyl D‐aspartate‐type glutamate receptors (NMDARs) in pyramidal neurons of the cortex. Moreover, we found accumulation of AZIN2 in brains affected by AD, but not by other neurodegenerative disorders (CADASIL or Lewy body disease). ODC activity is mostly linked to cell proliferation, whereas its regulation by AZIN2 in post‐mitotically differentiated neurons of the brain apparently serves different purposes. The subcellular distribution of AZIN2 suggests a role in vesicular trafficking. 相似文献
14.
There are well-described sexually dimorphic differences both in the electrocardiogram and in the propensity to develop drug-induced arrhythmias. The QT interval and the risk of ventricular proarrhythmia are reduced in males compared with females. Inward rectifier potassium current (IK(1)) is a primary determinant of the ventricular resting membrane potential, and an important contributor to myocardial excitability.Methods and results: Using the whole-cell patch-clamp technique, we evaluated the effects of dihydrotestosterone (DHT) on IK(1) in ventricular myocytes from castrated rabbits that were treated with either replacement DHT or vehicle-control for 3 weeks. Compared with the DHT-treated group, myocytes from the control animals had a significant reduction in inward IK(1) conductance (p < 0.005) and rectification ratio (RR) (p < 0.04) with no significant change in peak outward current. Acute DHT superfusion of the myocytes increased inward IK(1) conductance from baseline (p < 0.05) and increased the RR (p < 0.05). Testosterone has been reported to increase intracellular ornithine decarboxylase activity in ventricular tissue, which would increase intracellular polyamines, known modulators of IK(1) rectification. We found that inclusion of the intracellular polyamines spermidine and putrescine in the pipette solution caused a decrease in inward IK(1), accompanied by an increase in peak outward current and a reduction in the RR. Conclusion: In summary, DHT modulates IK(1) in a chronic, as well as, an acute fashion. These effects are not because of altered intracellular polyamines. DHT may modulate myocardial excitability through effects on IK(1). 相似文献
15.
Background:
Background: Polyamines, which are contained in many foods, play an important role in the growth and differentiation of the enterocyte,
but their role in glucose transport is unclear. Using isolated rat small intestine and a nonrecirculating perfusion system,
we studied the effect of luminal polyamines on glucose uptake and on the concentration of sodium-glucose transporter 1 (SGLT1)
and glucose transporter 5 (GLUT5) proteins.
Methods: In the control group, 300 mg glucose solution was administered through the jejunum, and the glucose concentration in the
portal vein was measured for 15 min. In treatment groups, various concentrations of polyamine (putrescine [Put] or spermine
[Spm]) were administered simultaneously with the glucose. At the end of the perfusion period, the amount of SGLT1, GLUT5,
and aminopeptidase N (APN) in the brush border membrane was subjected to Western blot analysis.
Results: Glucose concentration in the portal vein increased after the simultaneous administration of glucose and polyamines, and the
area under the curve (AUC) after the 15-min perfusion was enhandced to 188%, 196%, 132%, and 192% by 0.5 mM Spm, 4 mM Spm,
1 mM Put, and 8 mM Put, respectively. The brush border membrane concentration of SGLT1 protein 15 min after polyamine administration
was also enhanced in all treatment groups, and it correlated with the AUC. The concentration of GLUT5, on the other hand,
was reduced by 4 mM Spm, and the concentra-tion of APN was not affected by polyamine administration.
Conclusions: Luminal polyamines increase glucose absorption in the small intestine via the rapid enhancement of SGLT1 protein in the brush
border membrane.
Received: May 31, 2001 / Accepted: November 2, 2001 相似文献
16.
Subtype-specific pharmacological compounds represent important tools to identify the molecular components of synaptically activated glutamate receptors in central neurones. Here, we utilized a collection of subtype-specific antagonists and modulators to investigate the functional profile of glutamate receptors in identified synapses in thin slices of the cerebellum, hippocampus and brain stem. During whole-cell patch-clamp recordings α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate/kainate (AMPA/KA) receptor-mediated synaptic currents (EPSCs) in cerebellar Purkinje cells were (i) prolonged by 100 μm cyclothiazide, (ii) not significantly changed after preincubation in 10 μm concanavalin A, (iii) not affected by 1 μm Evans Blue or polyamine toxin analogue N-(4-hydroxyphenylpropanolyl)-spermine (NHPPS), but (iv) significantly reduced by high (≥ 100 μm ) concentrations of Evans Blue. These pharmacological properties were distinct from those observed in hippocampal granule cells and brain stem interneurones and markedly different from those of recombinant glutamate receptor channels GluR1–GluR6 previously investigated in heterologous expression systems. 相似文献
17.
Resveratrol analog (Z)-3,5,4'-trimethoxystilbene is a potent anti-mitotic drug inhibiting tubulin polymerization 总被引:6,自引:0,他引:6
Schneider Y Chabert P Stutzmann J Coelho D Fougerousse A Gossé F Launay JF Brouillard R Raul F 《International journal of cancer. Journal international du cancer》2003,107(2):189-196
Resveratrol (3,5,4'-trihydroxystilbene) a natural polyphenol present in medicinal plants, grapes and wines, has potent chemopreventive properties on intestinal carcinogenesis. A methylated derivative (Z-3,5,4'-trimethoxystilbene: R3) was synthesized. R3 at 0.3 microM exerted a 80% growth inhibition of human colon cancer Caco-2 cells and arrested growth completely at 0.4 microM (R3 was 100-fold more active than resveratrol). The cis conformation of R3 was also 100-fold more potent than the trans isomer. R3 (0.3 microM) caused cell cycle arrest at the G2/M phase transition. The drug inhibited tubulin polymerization in a dose-dependent manner (IC50=4 microM), and it reduced also by 2-fold ornithine decarboxylase and s-adenosylmethionine decarboxylase activities. This caused the depletion of the polyamines, putrescine and spermidine, which are growth factors for cancer cells. R3 inhibited partially colchicine binding to its binding site on tubulin, indicating that R3 either partially overlaps with colchicine binding or that R3 binds to a specific site of tubulin that is not identical with the colchicine binding site modifying colchicine binding by allosteric influences. The resveratrol derivative (Z)-3,5,4'-trimethoxystilbene (R3) is an interesting anti-mitotic drug that exerts cytotoxic effects by depleting the intracellular pool of polyamines and by altering microtubule polymerization. Such a drug may be useful for the treatment of neoplastic diseases. 相似文献
18.
Anne-Marie Maddox Michael J. Keating Emil J. Freireich Mari K Haddox 《Investigational new drugs》1989,7(2-3):119-129
Summary Fourteen patients with acute leukemia in relapse were treated with difluoromethylornithine (DFMO) alone or in combination with methylglyoxal-bis(guanylhydrazone) (MGBG) as part of Phase I studies. Five patients included in the trial exhibited morphologic evidence of cellular differentiation during the course of treatment. In one patient who exhibited no blasts and a normal white blood cell differential at the end of treatment the mononuclear cell content of all three polyamines declined after an initial increase in spermidine and spermine content. In the other patients in whom the cellular maturation was less pronounced the mononuclear cell polyamine levels remained stable or increased over the treatment time. No absolute difference was apparent between the cellular polyamine levels detected in patients at the times of the greatest increase in per cent circulating neutrophils as compared to the cellular levels present in patients whose circulating mononuclear cell number were increasing. Circulating mononuclear cell putrescine, spermidine, and spermine levels varied over two orders of magnitude from patient to patient and the range of values detected in each state completely overlapped those present in the other. It does not appear from the present study that there is a consistent human leukemic cell polyamine content at which cellular differentiation occurs. 相似文献
19.
A circadian rhythm in cellular polyamine levels was detected in the liver, pineal gland, anterior pituitary gland, Harderian gland, and testicular seminiferous tubules of male rats fed ad libitum and maintained in a light:dark cycle of LD 12:12 (lights on at 07:00). Liver putrescine content was highest at 24:00, showing a sixfold increase over 12:00 levels. Pineal spermidine and spermine contents reached a maximum at 06:00, late in the dark phase. A similar pattern was also detected in the Harderian gland. In the anterior pituitary, the polyamines putrescine, spermidine and spermine were highest at 18:00, late in the light phase. However, the increase in putrescine was not statistically significant. The three polyamine contents decreased late in the dark phase. In testicular seminiferous tubules putrescine, on the contrary, was highest (about a twofold increase) late in the dark phase. 相似文献
20.
Ornithine decar☐ylase (ODC) activity was studied in dorsal root ganglia (DRG) of regenerating frog sciatic nerve. There was a significant increase in activity two days after a crush lesion of the nerve 2.5 cm distal to the DRG. The increase reached a maximum after 7 days, then declined but remained above control levels for at least 9 days. An endoneural injection of vinblastine, a potent inhibitor of retrograde and orthograde axonal transport, between the DRG and the crush inhibited the increase in ODC. In contrast, injections of vinblastine into undamaged nerves failed to affect ODC. The increase in ODC and also the regenerative properties of the nerve could be prevented by daily i.p. injections of α-difluoromethyl ornithine. We suggest that a signal is formed at the site of injury in the sciatic nerve. This signal is conveyed to the DRG by retrograde axonal transport where it initiates the events leading to an increase in ODC. This increase appears to be necessary for the regeneration of sensory fibers in the frog sciatic nerve. 相似文献