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961.
Motomura M Kwon KM Suh SJ Lee YC Kim YK Lee IS Kim MS Kwon DY Suzuki I Kim CH 《Environmental toxicology and pharmacology》2008,26(1):61-67
We investigated mechanism(s) where propolis induces apoptosis in human leukemic U937 cells. Propolis inhibited the proliferation of U937 cells in a dose-dependent manner by inducing apoptosis and blocking cell cycle progression in the G2/M phase. Western blot analysis showed that propolis increases the expression of p21 and p27 proteins, and decreases the levels of cyclin B1, cyclin A, Cdk2 and Cdc2, thereby contributing to cell cycle arrest. DAPI staining assay revealed typical morphology features of apoptotic cells. Propolis-induced apoptosis was also confirmed by assays with annexin V-FITC, PI-labeling and DNA fragmentation assay. The increase in apoptosis level induced by propolis was associated with down-regulation of Bcl-2 and activation of caspase-3, but not with Bax. These results suggests that propolis-induced apoptosis is related to the selective activation of caspase-3 and induction of Bcl-2/Bax regulation. 相似文献
962.
Lysophosphatidic acid (LPA), a potent bioactive phospholipid, mediates diverse cellular responses by binding to specific G
protein-coupled receptors (GPCRs). We investigated the signaling mechanisms underlying LPA-induced COX-2 expression in primary
cultures of feline esophageal epithelial cells. The identity of the cultures was confirmed by immunocytochemistry using a
cytokeratin antibody. Western blot analysis revealed a concentration-and time-dependent induction of COX-2 in response to
LPA. Of the three major MAPKs, only ERK1/2 was activated by LPA in a time-dependent manner. LPA-induced COX-2 expression was
significantly attenuated by the MEK inhibitor, PD98059, but not by the JNK inhibitor, SP600125, or the p38 MAPK inhibitor,
SB212090. LPA-induced COX-2 expression was repressed by pertussis toxin, GF109204X, and Ki16425, indicating the involvements
of PTX-sensitive Gi/o protein, PKC, and the LPA1/3 receptor, respectively. Our data suggest that in esophageal epithelial cells, LPA-induced COX-2 expression requires activation
of PKC and ERK1/2 downstream of the LPA1/3 receptor, Understanding the regulation of COX-2 expression induced by LPA in esophageal epithelial cells might provide a
new therapeutic strategy for esophageal inflammatory diseases. 相似文献
963.
Novel cationic cholesterol derivative-based liposomes for serum-enhanced delivery of siRNA 总被引:1,自引:0,他引:1
Han SE Kang H Shim GY Suh MS Kim SJ Kim JS Oh YK 《International journal of pharmaceutics》2008,353(1-2):260-269
Most cationic liposomes used for gene delivery suffer from reduced transfection efficiency in the presence of serum. In this study, we report serum-enhanced delivery efficiency of siRNA via the use of newly synthesized liposomes that contain cationic lipids. Two cholesterol derivatives, cholesteryloxypropan-1-amine (COPA) and cholesteryl-2-aminoethylcarbamate (CAEC), were synthesized. A fluorescein label was then used to visualize cellular uptake of small interfering RNA (siRNA) via COPA or CAEC-based liposomes. The presence of serum had different effects on the cellular delivery of siRNA when siRNA was complexed to different cationic liposomes. CAEC-based liposomes showed significantly reduced cellular delivery of siRNA in serum-containing media as compared to serum-free media. Conversely, COPA-based liposomes (COPA-L) provided serum-enhanced delivery of siRNA in Hepa1-6, A549, and Hela cell lines. Following delivery of the oncogene survivin-specific siRNA, COPA-L reduced the mRNA expression levels of the target gene more efficiently than did Lipofectamine 2000. The delivery of green fluorescent protein-specific siRNA with COPA-L reduced the expression of green fluorescent protein in 293T stable cell lines. The apoptosis of Hepa1-6 significantly increased by delivery of survivin-specific siRNA by COPA-L. Additionally, Hepa1-6, A549, and Hela cells were >80% viable after treatment with COPA-L. These results suggest that the newly synthesized cholesterol derivative, COPA-L, could be further developed as a serum-enhanced delivery system of siRNA. 相似文献
964.
Davit BM Conner DP Fabian-Fritsch B Haidar SH Jiang X Patel DT Seo PR Suh K Thompson CL Yu LX 《The AAPS journal》2008,10(1):148-156
Introduction
It is widely believed that acceptable bioequivalence studies of drugs with high within-subject pharmacokinetic variability must enroll higher numbers of subjects than studies of drugs with lower variability. We studied the scope of this issue within US generic drug regulatory submissions.Materials and Methods
We collected data from all in vivo bioequivalence studies reviewed at FDA’s Office of Generic Drugs (OGD) from 2003–2005. We used the ANOVA root mean square error (RMSE) from bioequivalence statistical analyses to estimate within-subject variability. A drug was considered highly variable if its RMSE for C max and/or AUC was ≥0.3. To identify factors contributing to high variability, we evaluated drug substance pharmacokinetic characteristics and drug product dissolution performance.Results and Discussion
In 2003–2005, the OGD reviewed 1,010 acceptable bioequivalence studies of 180 different drugs, of which 31% (57/180) were highly variable. Of these highly variable drugs, 51%, 10%, and 39% were either consistently, borderline, or inconsistently highly variable, respectively. We observed that most of the consistent and borderline highly variable drugs underwent extensive first pass metabolism. Drug product dissolution variability was high for about half of the inconsistently highly variable drugs. We could not identify factors causing variability for the other half. Studies of highly variable drugs generally used more subjects than studies of lower variability drugs.Conclusion
About 60% of the highly variable drugs we surveyed were highly variable due to drug substance pharmacokinetic characteristics. For about 20% of the highly variable drugs, it appeared that formulation performance contributed to the high variability. 相似文献965.
Although, numerous studies have attempted to reduce the oxygen radical injury induced by the antioxidants in paraquat intoxication, these antioxidant therapies have showed few survival benefits. Ethyl pyruvate (EP) may function as an effective scavenger of oxygen radicals, an anti-inflammatory agent and an energy source in many ischemia reperfusion models. The aim of this study was to evaluate the antioxidant and anti-inflammatory effects of EP on the lung and the liver tissues in paraquat-intoxicated rats. Rats were randomly given either a low (2 mg/kg i.p.) or high (40 mg/kg i.p.) EP dose, 30 min before or 1 h after paraquat (50 mg/kg i.p.) administration, and subsequently killed at 6 and 24 h. Glutathione (GSH) and malondialdehyde (MDA) levels of the lungs and the livers, and plasma nitric oxide (NO) concentrations were measured. Pretreatment of EP significantly decreased the MDA level in the lung and the liver tissues. EP also significantly decreased plasma NO concentrations at 6 h. EP pretreatment, however, failed to show significant change in GSH concentration. In post-treatment of EP, MDA levels in the lung tissue and plasma NO levels were significantly decreased. In conclusion, EP decreased the lipid peroxidation and seemed to exert an anti-inflammatory action in the paraquat intoxication rat model. 相似文献
966.
A systematic structure-activity relationship of 3beta-hydroxy-27- P- E-coumaroyloxyurs-12-en-28-oic acid ( 7), a triterpene ester isolated from UNCARIA RHYNCHOPHYLLA as a phospholipase Cgamma1 inhibitor, was undertaken with a view toward elucidating its chemical mode of action on PLCgamma1. Related derivatives and analogues of 7 were synthesized and their inhibitory activities against PLCgamma1 were evaluated IN VITRO. The results indicate that 3-OH and 27-esterification may be essential, and that 28-COOH and the 2' double bond appear to be important for activity. Furthermore, the compound possessing a P-coumaroyloxy at position 27 rather than at the 3 and 28 positions shows the greatest inhibitory activity against PLCgamma1. Therefore, this inhibitor will be providing a chemical lead for the further development of cancer chemopreventive or cancer chemotherapeutic agents that have lower toxicity against normal tissues. 相似文献
967.
Pettinati HM Kampman KM Lynch KG Suh JJ Dackis CA Oslin DW O'Brien CP 《Journal of substance abuse treatment》2008,34(4):378-390
This is a randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy of a higher-than-typical daily dose of naltrexone (150 mg/day), taken for 12 weeks, in 164 patients (n = 116 men and n = 48 women) with co-occurring cocaine and alcohol dependence. Patients were stratified by gender and then randomly assigned to either naltrexone or placebo, and to either cognitive–behavioral therapy or a type of medical management. The two primary outcomes were cocaine use and alcohol use. Significant Gender × Medication interactions were found for cocaine use via urine drug screens (three way, with time) and self-reports (two way) for drug severity (two way) and alcohol use (two way). The type of psychosocial treatment did not affect outcomes. Thus, 150 mg/day naltrexone added to a psychosocial treatment resulted in reductions in cocaine and alcohol use and drug severity in men, compared to higher rates of cocaine and alcohol use and drug severity in women. 相似文献
968.
The effect of the selective inhibitor of Na(+)/Ca(2+) exchanger (NCX), KB-R7943, on large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels was examined in cultured human umbilical vein endothelial cells (HUVECs) and freshly isolated mouse aortic smooth muscle cells (MASMCs). In voltage-clamped cells, KB-R7943 reversibly activated BK(Ca) currents in HUVECs and MASMCs. The EC(50) of KB-R7943 for BK(Ca) current activation in HUVECs was determined to be 6.78+/-0.7 microM. In inside-out and outside-out patches, KB-R7943 markedly increased BK(Ca) channel activity and slightly decreased single channel current amplitudes. In inside-out patches, KB-R7943 shifted the relationship between [Ca(2+)](i) and open probability (P(o)) to the left; the [Ca(2+)](i) required to evoke half-maximal activation changed from 1220+/-68 nM (in the absence of KB-R7943) to 620+/-199 nM (in the presence of 10 microM KB-R7943). In addition, KB-R7943 shifted the relationship between membrane potential and P(o) to the left; the membrane potential to evoke half-maximal activation changed from 76.86+/-1.09 mV (in the absence of KB-R7943) to 49.62+/-2.55 mV (in the presence of 10 microM KB-R7943). In conclusion, KB-R7943 was found to act as a potent BK(Ca) channel activator, which increases the sensitivity of BK(Ca) channels to cytosolic free Ca(2+) and membrane potential, and thereby BK(Ca) channel activity. These results should be considered when KB-R7943 is used as NCX blocker. 相似文献
969.
C. Jung W. Yoon S.J. Ahn B.S. Choi J.H. Kim S.H. Suh 《AJNR. American journal of neuroradiology》2016,37(2):285
BACKGROUND AND PURPOSE:Although various revascularization scales are used in the angiographic evaluation of acute ischemic stroke, observer reliability tests of these scales have been rarely performed for posterior circulation stroke. We aimed to evaluate inter- and intraobserver variability of 2 scales, the modified Treatment in Cerebral Ischemia and the Arterial Occlusive Lesion, in posterior circulation stroke.MATERIALS AND METHODS:Three independent readers interpreted pre- and postthrombolytic angiographies of 62 patients with posterior circulation stroke by using the modified Treatment in Cerebral Ischemia and Arterial Occlusive Lesion scales. The κ statistic was used to measure observer agreement for both scales, and κ > 0.6 was considered substantial agreement.RESULTS:For the Arterial Occlusive Lesion scale, inter- and intraobserver agreement was >0.6. While intraobserver agreement of the modified Treatment in Cerebral Ischemia scale was >0.6 except for 1 reader, interobserver agreement was lower in dichotomized and original scales. In 49 cases with solely basilar artery occlusion, inter- and intraobserver agreement of both scales was similar to that in all 62 patients with posterior circulation stroke. In 2 consecutive readings, there was a significant decrease in the proportion of mTICI 2a reads (22.58% in the first versus 13.44% in the second session, P < .03) and a reciprocal increase in the sum of proportions for modified Treatment in Cerebral Ischemia 2b and modified Treatment in Cerebral Ischemia 3 reads (62.37% in the first versus 72.58% in the second session, P < .046).CONCLUSIONS:In angiographic assessment of posterior circulation stroke, inter- and intraobserver agreement for the Arterial Occlusive Lesion scale was reliable, while the modified Treatment in Cerebral Ischemia failed to achieve substantial interobserver agreement. The clinical impact of this result needs to be validated in future studies.In the treatment of acute ischemic stroke with large intracranial arterial occlusion, endovascular techniques are becoming the mainstream with higher revascularization rates.1–3 While various grading schemes, such as the Thrombolysis in Myocardial Infarction (TIMI) or Thrombolysis in Cerebral Infarction (TICI), are widespread, their reliability in angiographic assessment of anterior circulation stroke remains controversial.4–8 Recently, the modified Treatment in Cerebral Ischemia (mTICI) and the Arterial Occlusive Lesion (AOL) scales were strongly recommended as standards of reperfusion and recanalization in the angiographic evaluation of anterior circulation stroke.9Despite applying similar scales to the posterior circulation, it is also unclear which scales might be reliably implemented for the vertebrobasilar territory. Recently, Gerber et al10 questioned whether it is right to use the TIMI or TICI scale in posterior circulation stroke and demonstrated that interobserver variability tests of these scales had never been performed in case of posterior circulation stroke.Therefore, we aimed to evaluate intra- and interobserver agreement of the mTICI and AOL scales in the angiographic evaluation of posterior circulation stroke. 相似文献
970.
N.J. Lee M.S. Chung S.C. Jung H.S. Kim C.-G. Choi S.J. Kim D.H. Lee D.C. Suh S.U. Kwon D.-W. Kang J.S. Kim 《AJNR. American journal of neuroradiology》2016,37(12):2245
BACKGROUND AND PURPOSE:High-resolution MR imaging has recently been introduced as a promising diagnostic modality in intracranial artery disease. Our aim was to compare high-resolution MR imaging with digital subtraction angiography for the characterization and diagnosis of various intracranial artery diseases.MATERIALS AND METHODS:Thirty-seven patients who had undergone both high-resolution MR imaging and DSA for intracranial artery disease were enrolled in our study (August 2011 to April 2014). The time interval between the high-resolution MR imaging and DSA was within 1 month. The degree of stenosis and the minimal luminal diameter were independently measured by 2 observers in both DSA and high-resolution MR imaging, and the results were compared. Two observers independently diagnosed intracranial artery diseases on DSA and high-resolution MR imaging. The time interval between the diagnoses on DSA and high-resolution MR imaging was 2 weeks. Interobserver diagnostic agreement for each technique and intermodality diagnostic agreement for each observer were acquired.RESULTS:High-resolution MR imaging showed moderate-to-excellent agreement (interclass correlation coefficient = 0.892–0.949; κ = 0.548–0.614) and significant correlations (R = 0.766–892) with DSA on the degree of stenosis and minimal luminal diameter. The interobserver diagnostic agreement was good for DSA (κ = 0.643) and excellent for high-resolution MR imaging (κ = 0.818). The intermodality diagnostic agreement was good (κ = 0.704) for observer 1 and moderate (κ = 0.579) for observer 2, respectively.CONCLUSIONS:High-resolution MR imaging may be an imaging method comparable with DSA for the characterization and diagnosis of various intracranial artery diseases.Intracranial artery disease (ICAD) is one of the major causes of ischemic stroke and neurologic symptoms.1–3 ICAD generally presents with intracranial artery stenosis on luminal evaluation, even though it includes various ICADs, such as atherosclerosis, dissection, Moyamoya disease, and vasculitis. The degree of stenosis has been the most common and important characteristic for evaluating ICAD and determining the treatment options.4,5Luminal angiography, such as digital subtraction angiography, CT angiography, and MR angiography, has been widely used and has functioned successfully for the evaluation of stenosis and the diagnosis of ICAD. Among these methods, DSA is thought to be the criterion standard tool compared with the other modalities because it depicts luminal geometric shapes and hemodynamic information with higher resolution.6–8 However, DSA has several limitations. It only depicts the luminal morphology and not the vessel walls directly, and many diseases share nonspecific luminal findings. Because DSA is also an invasive procedure with the risk of neurologic complications and radiation exposure, it is not suitable for screening or serial examinations.9–11 Accordingly, CTA and MRA have been commonly used as the minimally invasive method to diagnose and differentiate intracranial artery disease in the clinical field, though they have more drawbacks in the luminal evaluation to DSA.High-resolution MR imaging (HR-MR) has recently been introduced as a minimally invasive and promising advanced imaging technique for directly depicting the intracranial arterial wall.12,13Although HR-MR evaluates and differentiates various ICADs with the direct depiction of arterial walls and multicontrast images6,14–20 that may correlate with luminal angiography,8,21,22 the usefulness and value of HR-MR compared with luminal angiography are still unclear. Only a few studies presented a comparison or correlation between DSA and HR-MR,8,13,23 and these studies showed a good correlation regarding the degree of stenosis8,23 and HR-MR features beyond DSA.13 However, the observations were based on single vascular pathology or a single cerebral artery (middle cerebral artery, basilar artery) or a small sample size (n = 9).In our study, we compared HR-MR with DSA in the characterization and diagnosis of various ICADs. We hypothesized that HR-MR may be an imaging method comparable with DSA for the characterization and diagnosis of ICAD. 相似文献