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Hongwei Tian,
Shengyong Liu,
Junfeng Zhang,
Shuang Zhang,
Lin Cheng,
Can Li,
Xiaomei Zhang,
Lixia Dail, Ping Fan,
Lei Dai,
Nv Yan,
Ruibo Wang,
Yuquan Wei,
Hongxin Deng
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ABSTRACT: Survivin, a member of the inhibitor of apoptosis protein (IAP) family, is abundantly expressed in a variety of cancer cells, including lung cancer cells, resulting in low sensitivity of these cells to various apoptotic stimuli; Cisplatin (CDDP), a commonly used chemotherapeutic agent of several cancers, has a major limitation because of its toxicity at high concentration. In the present study, we constructed a plasmid encoding Survivin shRNA to knockdown survivin with low dose DDP both in vitro and in vivo. The specificity and potency of the shRNA were validated by western blot, flow cytometric and MTT in H292 lung cancers cells. In vivo, therapy experiments were conducted on nude mice bearing H292 xenograft tumors. The Survivin shRNA expression plasmid was administered systemically in combination with low-dose CDDP on a frequent basis. Assessments of angiogenesis, cell proliferation and apoptosis were performed by using immunohistochemistry against CD31, Ki67 and TUNEL assays, respectively. The results revealed that treatment with the Survivin shRNA plus low-dose CDDP reduced volume by approximately 83.13% compared with the blank control (P < 0.01), accompanied with angiogenesis inhibition (p < 0.01), tumor cell proliferation suppression (p < 0.05) and apoptosis induction (p < 0.01). Moreover, combination treatment also significantly reduced the mean tumor volume compared with other treatment alone (p < 0.05). Taken together, our study suggested that silencing of survivin sensitized H292 lung cancer cells to chemotherapy of CDDP, suggesting potential applications of the combined approach in the treatment of lung cancer.
Journal of Biomedical Nanotechnology 08/2012; 8(4):633-41. · 4.22 Impact Factor
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Nv Yan,
Shuang Zhang,
Yang Yang,
Lin Cheng,
Can Li,
Lixia Dai,
Lei Dai,
Xiaomei Zhang, Ping Fan,
Hongwei Tian,
Ruibo Wang,
Xiaolei Chen,
Xiaolan Su,
Yiming Li,
Junfeng Zhang,
Tao Du,
Yuquan Wei,
Hongxin Deng
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ABSTRACT: Class A scavenger receptor member 5 (SCARA5) is a new member of the Class A scavenger receptors that has been proposed recently as a novel candidate tumor suppressor gene in human hepatocellular carcinoma. In the present study, we found that SCARA5 expression was frequently downregulated in various cancer cell lines and tumor samples. In addition, upregulation of SCARA5 expression in human cancer cell line (U251) led to a significant decrease in cell proliferation, clone formation, migration, and invasion in vitro. Furthermore, systemic treatment of tumor-bearing mice with SCARA5-cationic liposome complex not only reduced the growth of subcutaneous human glioma tumors, but also markedly suppressed the spontaneous formation of lung metastases. Similar results were obtained in another experiment using mice bearing experimental A549 lung metastases. Compared with the untreated control group, mice treated with SCARA5 exhibited reductions in both spontaneous U251 and experimental A549 lung metastases rates of 77.3% and 70.2%, respectively. Western blot analysis was used to explore the molecular mechanisms involved and revealed that SCARA5 physically associated with focal adhesion kinase. Interestingly, upregulation of SCARA5 inactivated signal transducer and activator of transcription 3, as well as downstream signaling including cyclinB1, cyclinD1, AKT, survivin, matrix metalloproteinase-9 and vascular endothelial growth factor-A. Overall, the findings of the present study provide the first evidence that SCARA5 might be a promising target for the development of new antimetastatic agents for the gene therapy of cancer.
Cancer Science 05/2012; 103(9):1631-9. · 3.33 Impact Factor
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ABSTRACT: To clarify the dose-response effects of troglitazone on insulin sensitivity and β-cell function, we examined the effects of
high-dose troglitazone (100 mg/day per animal, administered as a food admixture) on glucose and insulin metabolism in hyperinsulinemic
Watanabe heritable hyperlipidemic (WHHL) rabbits, and compared the results with our previous results with low-dose troglitazone
(10 mg/day per animal). Materials and Methods: Glucose and insulin metabolism were quantitatively characterized by a minimal
model technique as reported previously. Results: When troglitazone was administrated at a high dose for 6 months, it reduced
hyperinsulinemia as reflected by a reduced basal (steady-state) insulin concentration Ib and the insulin response to a glucose
load, improved β-cell function as reflected by decreased second-phase post-hepatic insulin delivery to glucose Ø2, and reduced
insulin resistance as reflected by increased insulin sensitivity to glucose disposal Si, without affecting glucose tolerance as reflected by an unchanged rate of glucose utilization Kg or insulin-independent glucose
disposal Sg. The reductions in Ib and Ø2 and the increases in Si in WHHL rabbits treated with a high dose of troglitazone were greater (p<0.05) than those
observed in WHHL rabbits treated with a low dose of troglitazone, as assessed by a two-way repeated measures analysis of variance
and the Wilcoxon-Mann-Whitney test. Conclusion: In WHHL rabbits, troglitazone dose-dependently reduced hyperinsulinemia, improved
β-cell function, and increased insulin sensitivity.
KeywordsWHHL rabbits-troglitazone-insulin sensitivity-high-dose-minimal model-β-cell function
European Journal of Drug Metabolism and Pharmacokinetics 04/2012; 26(3):185-192. · 0.36 Impact Factor
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ABSTRACT: Capillary isotachophoresis (cITP) is a technique for characterizing plasma lipoprotein subfractions according to their electrophoretic charges. We used this technique to examine the mechanism by which apoA-I/phosphatidylcholine (POPC) discs increase pre-beta HDL.
The cITP analysis was performed using plasma prestained with a lipophilic dye on a Beckman P/ACE MDQ system. Plasma from a patient with lecithin:cholesterol acyltransferase (LCAT) deficiency who had increased apoE-containing HDL was used to characterize the charge distribution of apoA-I/POPC discs. cITP analysis of apoB- and E-depleted plasma of the patient in the presence of apoA-I/POPC discs indicated two major subfractions of apoA-I/POPC discs with mobilities of triglyceride-rich lipoproteins (fast and slow apoA-I). Incubation of whole plasma from a normolipidemic subject in the presence of apoA-I/POPC discs caused a reduction in cITP fast (f)- and intermediate (i)-migrating HDL, and fast and slow apoA-I, and an increase in slow (s)-migrating HDL. The changes in cITP lipoprotein subfractions were not affected by the inhibition of LCAT activity. ApoA-I/POPC discs increased the fractional esterification rate of cholesterol in apoB-depleted plasma.
ApoA-I/POPC discs remodeled cITP fHDL and iHDL to sHDL independent of LCAT activity.
Atherosclerosis 10/2006; 188(1):95-101. · 3.79 Impact Factor
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ABSTRACT: Platelet-activating factor acetylhydrolyse (PAF-AH) is an enzyme that degrades PAF and bioactive oxidized lipids. However, it has been reported to be a risk factor for coronary heart disease. The present study examined the effects of cholesterol feeding and simvastatin treatment on plasma PAF-AH activity.
Japanese White rabbits (n=22) were fed a diet containing 0.3% cholesterol and 3% corn oil for 1 month, and then divided into two groups that continued to receive this diet with (treated) or without (control) treatment with simvastatin (0.01%) for another 2 months.
Cholesterol feeding increased and simvastatin treatment decreased apolipoprotein (apo) B-containing lipoprotein subfractions as characterized by capillary isotachophoresis, serum levels of total cholesterol, phospholipids, LDL-C, apoE, plasma and LDL-associated PAF-AH (LDL-PAF-AH) activities, and plasma lyso-PC concentration. Cholesterol feeding also increased apoB levels but decreased the LDL-PAF-AH/LDL-C ratio and did not change the plasma PAF-AH/lyso-PC ratio. Simvastatin treatment did not affect apoB levels and only slightly increased the LDL-PAF-AH/LDL-C ratio. Secretion of PAF-AH activity from monocyte-derived macrophages was increased by cholesterol feeding but not affected by simvastatin treatment. These results indicate that PAF-AH activity is increased by cholesterol feeding due to increased secretion of PAF-AH activity from macrophages and that PAF-AH activity is decreased by simvastatin due to increased removal of lipid and enzyme contents of LDL particles.
Cholesterol elevation by cholesterol feeding and cholesterol-lowering by simvastatin modulate plasma PAF-AH activity by different mechanisms.
Atherosclerosis 07/2006; 186(2):291-301. · 3.79 Impact Factor
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Bo Zhang,
Naoko Shono, Ping Fan,
Setsuko Ando,
Huali Xu,
Shiro Jimi,
Shin-ichiro Miura,
Koichiro Kumagai,
Khin Mimi Win,
Akira Matsunaga,
Hiroshi Iwasaski,
Keijiro Saku
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ABSTRACT: We examined the histochemical characteristics of soleus muscle in the angiotensin-converting enzyme (ACE) gene (Ace in mice, ACE in humans) knockout mice. Serial sections of soleus muscle of wild-type (Ace+/+, n=20) and heterozygous mutant (Ace+/-, n=24) mice were stained for myosin adenosine triphosphatase activity to identify different muscle fiber types. Capillaries were visualized by amylase-periodic acid-Schiff staining. ACE activity in the serum and gastrocnemius muscle was higher in male mice than in female mice. Female and male Ace+/- mice had markedly lower ACE activity in the serum and the gastrocnemius muscle than did female and male Ace+/+ mice, respectively. In both male and female mice, the composition of fiber types (type I and IIa) did not differ significantly between Ace+/+ and Ace+/- mice. There was no significant gender difference in capillary density. Ace+/- mice had significantly more capillaries around type IIa fibers (5.44 +/- 0.18 vs. 5.01 +/- 0.13, p<0.05) than Ace+/+ mice. The differences in the number of capillaries around type I fibers and in the number of capillaries around per fiber (capillary:fiber ratio) between Ace+/- and Ace+/+ mice were not significant (p<0.1). There was no significant difference in the mean cross-sectional area occupied by one capillary and the number of capillaries per fiber area between Ace+/+ and Ace+/- mice. In conclusion, knockout of the Ace gene in mice increased capillary density, as expressed by the mean number of capillaries around type IIa fibers. This finding suggests a possible mechanism for the cardioprotective effects of ACE inhibitors.
Hypertension Research 08/2005; 28(8):681-8. · 2.58 Impact Factor
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ABSTRACT: The effect of pitavastatin on the mRNA levels of apolipoprotein (apo) A-I, peroxisome proliferator-activated receptor alpha (PPARalpha), cholesterol 7alpha-hydroxylase (CYP7A1), and farnesoid X receptor (FXR) in HepG2 cells was examined to establish whether pitavastatin affects bile acid synthesis and if so, to determine a possible molecular mechanism.
HepG2 cells were cultured in serum-free Dulbecco's modified Eagle medium for 18 h before drug treatment. Total RNA was extracted at set times and mRNA levels were quantified by reverse transcription-real time polymerase chain reaction. Pitavastatin at 0.1, 1, 5, and 10 micromol/L increased the mRNA levels of apo A-I, PPARalpha, CYP7A1, and FXR in a dose-dependent manner. The mRNA levels of apo A-I, PPAR alpha, CYP7A1, and FXR similarly increased with increasing doses of pitavastatin. Coincubation of mevalonate (4 mmol/L) with pitavastatin (5 micromol/L) reversed the inductive effects of pitavastatin on the mRNA levels of these genes, indicating that the inductive effects of pitavastatin were related to its inhibition of HMG-CoA reductase.
Pitavastatin increased the mRNA levels of CYP7A1 in HepG2 cells, suggesting that increased conversion of cholesterol to bile acids may be the mechanism for its potent low-density lipoprotein cholesterol-lowering effects.
Circulation Journal 12/2004; 68(11):1061-6. · 3.77 Impact Factor
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ABSTRACT: Inhibition of cholesteryl ester transfer protein (CETP) is an efficient way to increase high-density lipoprotein (HDL) levels in humans. We investigated the effects of the inhibition of CETP activity by a CETP inhibitor, JTT-705, on the function and composition of HDL particles.
Japanese white rabbits were fed either normal rabbit chow LRC-4 (n=10) or a food admixture of LRC-4 and 0.75% JTT-705 (n=10) for 7 months. JTT-705 significantly inhibited CETP activities, increased HDL cholesterol (HDL-C) levels and the ratio of HDL2-C/HDL3-C, and decreased the fractional esterification rate of cholesterol in HDL, indicating preferentially increased large HDL particles. Treatment with JTT-705 increased all of the 3 charge-based HDL subfractions as determined by capillary isotachophoresis: fast-migrating, intermediate-migrating, and slow-migrating HDL. The percentage of slow HDL, ie, apolipoprotein E (apoE)-containing HDL and levels of apoE in HDL fraction, was also increased. JTT-705 treatment increased serum paraoxonase activity and HDL-associated platelet-activating factor acetylhydrolase activity, but decreased the plasma lysophosphatidylcholine concentration.
Inhibition of CETP activity by JTT-705 not only increased the quantity of HDL, including HDL-C levels and charge-based HDL subfractions, but also favorably affected the size distribution of HDL subpopulations and the apolipoprotein and enzyme composition of HDL in rabbits.
Arteriosclerosis Thrombosis and Vascular Biology 11/2004; 24(10):1910-5. · 6.37 Impact Factor
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ABSTRACT: Inhibition of cholesteryl ester transfer protein (CETP) is an effective way to increase HDL levels in animals and humans. The effects of a CETP inhibitor, JTT-705, on the in vivo kinetics of apolipoprotein (apo) A-I and apo A-I gene expression in the liver and intestine were investigated.
Japanese White rabbits were randomly fed normal rabbit chow LRC-4 (n=10, control) or a food admixture of LRC-4 and 0.75% JTT-705 (n=10, treated) for 7 months. An in vivo kinetics study of apo A-I was performed by injecting rabbit 125I-apo A-I, and apo A-I mRNA levels were quantified by RT-PCR.
JTT-705 significantly inhibited CETP activities, increased serum levels of HDL-cholesterol (C), HDL2-C, HDL-phospholipid, and apo A-I, and decreased HDL-triglyceride levels. The synthetic rate of apo A-I was higher in the treated rabbits than in control rabbits (13.7 +/- 2.6 versus 9.5 +/- 1.3 mg/kg per day, P < 0.05), while the fractional catabolic rate was similar in the two groups. JTT-705 increased apo A-I mRNA levels in the liver without affecting those in the intestine.
Inhibition of CETP activity by JTT-705 increases HDL levels by increasing the synthesis of apo A-I, suggesting that it could be a promising therapeutic approach for atherosclerosis.
Atherosclerosis 02/2004; 172(2):247-57. · 3.79 Impact Factor
