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ABSTRACT: Recent studies have indicated that Toll-like receptors (TLRs) are implicated in the development of chemoresistance in cancer cells. TLR4 has been shown to be highly expressed in prostate cancer cells and contributes to tumor cell survival and invasion. In this study, we aimed to investigate the role of TLR4 signaling in the chemoresistance of prostate cancer cells. We showed that ligation of TLR4 with lipopolysaccharide (LPS) abrogated docetaxel-induced growth suppression in PC-3 prostate cancer cells, with an increase in the half-maximal inhibitory concentration. Downregulation of TLR4 using small-interference RNA sensitized PC-3 cells to docetaxel-induced apoptosis as determined by annexin V staining and poly (ADP-ribose) polymerase cleavage, which was coupled with increased Bax expression and decreased Bcl-2. TLR4 ligation resulted in a marked increase in the phosphorylation of phosphatidylinositol 3-kinase (PI3-K) and Akt. The pretreatment with a PI3-K inhibitor LY294002 reduced LPS-mediated resistance to docetaxel, significantly decreasing the viability of PC-3 cells. Our data show that TLR4 ligation contributes to the chemosensitivity of prostate cancer cells, which at least partially involves the activation of the PI3-K/Akt pathway. Therefore, TLR4 signaling may represent a promising target for the improvement of chemotherapeutic efficacy in prostate cancer.
Cell Biology and Toxicology 06/2012; 28(4):269-77. · 2.51 Impact Factor
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Fei Liu,
Liping Yao,
Jianlin Yuan,
Heliang Liu, Xiaojian Yang,
Weijun Qin,
Guojun Wu,
Lijun Yang,
He Wang,
Norio Takahashi,
Osamu Yamaguchi
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ABSTRACT: To evaluate the protective effects of inosine on bladder dysfunction, nerve density, and oxidative damage after partial bladder outlet obstruction in rats.
A total of 60 adult male Sprague-Dawley rats were divided into 5 groups. Groups 1-4 underwent bladder outlet obstruction. Groups 1-3 were treated with inosine at 100, 150, or 225 mg/kg/d intraperitoneally and group 4 with saline. Group 5 consisted of sham-operated control rats. At 21 days postoperatively, cystometry were performed in 30 rats (6 per group). In the remaining 30 rats (6 per group), the bladders were excised and used for contractile responses to various stimulations, immunohistochemical examination for protein gene product 9.5 (a neuronal marker) and evaluation of superoxide dismutase activity and thiobarbituric acid reductase substance level.
Inosine administration resulted in dose-dependent protective effects on the contractile responses to both field stimulation and carbachol, although the protective responses to KCl was restricted to a greater dose of inosine. A dose-dependent reduction in residual volume was noted in inosine-treated groups at different dosages compared with the saline-treated group. In addition, the protein gene product 9.5-positive nerve density decreased in the saline-treated group but significantly increased in the inosine-treated (225 mg/kg/d) group. Compared with the saline-treated group, significantly enhanced superoxide dismutase activity and a reduced thiobarbituric acid reductase substance level were observed in the inosine-treated group at 150 and 225 mg/kg/d.
These results suggest that inosine has a potential protective effect against partial bladder outlet obstruction-induced bladder dysfunction and oxidative injury in rats.
Urology 05/2009; 73(6):1417-22. · 2.43 Impact Factor
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Geng Zhang,
He Wang,
Fuli Wang,
Lei Yu, Xiaojian Yang,
Junhua Meng,
Weijun Qin,
Guojun Wu,
Jianhua Li,
Angang Yang,
Yu Zhou,
Rui Zhang
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ABSTRACT: Steroid refractory acute rejection (SRAR) is a major vital factor in renal transplantation recipients. The pathogenesis of SRAR may involve both immune and non-immune mechanisms. A decreased renal allograft function has also been associated with increased activity of renin-angiotensin-aldosterone system (RAS), which may be genetically determined. A total 206 renal transplant recipients, 116 males and 90 females, were included. The effects of gene polymorphisms of the four components of RAS including angiotensinogen (AGT), angiotensin-converting enzyme (ACE), angiotensin type 1 receptor (AT1R), and aldosterone synthase (CYP11B2) were investigated in 19 cases of renal transplant patients with SRAR. The association between SRAR and the activating antibodies targeting the AT1R were also investigated. Genotyping was performed for the M235T-AGT, the I/D-ACE, the A1166C-AT1R, and the -344T/C-CYP11B2 gene polymorphisms using polymerase chain reaction. Our results showed that renal allograft recipients with SRAR had significantly higher occurrences of the DD genotype of ACE and CC genotype of AT1R than recipients without SRAR. The other genetic polymorphisms of the RAS were not associated with SRAR. Activating antibodies targeting the AT1R were detected in the sera from 14 SRAR victims with malignant hypertension and without anti-HLA antibodies. This study provides evidence that determination before transplantation of the polymorphism of the gene encoding components of RAS may help identify patients who are at risk for SRAR. The detection of the antibodies of AT1R may contribute to the prevention of SRAR.
The Tohoku Journal of Experimental Medicine 12/2007; 213(3):203-14. · 1.24 Impact Factor
