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  • Author: Jun Ren x
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Meng Ren, Qingbo Guan, Xia Zhong, Bendi Gong, Ying Sun, Wei Xin, Jun Guo, Hai Wang, Ling Gao and Jiajun Zhao

It is known that decreased apoptosis of thyrocytes may be involved in the formation of goiters in patients with Graves’ disease, and growth factors are involved in regulating the size of the thyroid gland. The purpose of our study was to investigate mRNA and protein levels of an antiapoptotic protein, namely, Fas-associated death domain-like interleukin-1-converting enzyme (FLICE)-inhibitory protein (FLIP). The results showed that in FRTL thyroid cells, treatment with IGF-I upregulated mRNA and protein levels of FLIP in a dose-dependant manner. While a specific nuclear factor-κB (NF-κB) inhibitor, BAY11-7082, blocked this effect. Further study demonstrated that IGF-I induced the DNA-binding activity of NF-κB in association with decreased expression of the NF-κB inhibitory protein IκBα . These findings implied that IGF-I increased FLIP expression by enhancing the activation of NF-κB in FRTL thyroid cells. Using a specific phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, we also found that PI3K was involved in the pathway by which IGF-I activated NF-κB and increased FLIP expression. When treated with IGF-I and LY294002, decreased NF-κB DNA binding activity and increased expression of IκBα protein were detected in cultured thyroid cells, which further confirmed that NF-κB was under the control of the PI3K pathway. Taken together, our results suggest that IGF-I regulates the expression of FLIP in FRTL cells by activating the PI3K/NF-κB cascade.

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He-jun Zhao, Xia Jiang, Li-juan Hu, Lei Yang, Lian-dong Deng, Ya-ping Wang and Zhi-peng Ren

This study aimed to determine whether and how the glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide affects the chemoresistance and chemosensitivity of pancreatic cancer cells to gemcitabine in vitro and in vivo. The GLP-1R and protein kinase A (PKA) levels were compared between the human pancreatic cancer cell line PANC-1 and the gemcitabine-resistant cell line PANC-GR. The in vitro effects of liraglutide on the cell proliferation and apoptosis as well as the nuclear factor-kappa B NF-κB expression levels of PANC-GR cells were evaluated. In addition, a mouse xenograft model of human pancreatic cancer was established by s.c. injection of PANC-1 cells, and the effects of liraglutide on the chemosensitivity were evaluated in vitro and in vivo. In contrast to PANC-1 cells, PANC-GR cells exhibited lower expression levels of GLP-1R and PKA. Incubation with liraglutide dose dependently inhibited the growth, promoted the apoptosis, and increased the expression of GLP-1R and PKA of PANC-GR cells. Similar effects of liraglutide were observed in another human pancreatic cancer cell line MiaPaCa-2/MiaPaCa-2-GR. Either the GLP-1R antagonist Ex-9, the PKA inhibitor H89, or the NF-κB activator lipopolysaccharide (LPS) could abolish the antiproliferative and proapoptotic activities of liraglutide. Additionally, each of these agents could reverse the expression of NF-κB and ABCG2, which was decreased by liraglutide treatment. Furthermore, liraglutide treatment increased the chemosensitivity of pancreatic cancer cells to gemcitabine, as evidenced by in vitro and in vivo experiments. Thus, GLP-1R agonists are safe and beneficial for patients complicated with pancreatic cancer and diabetes, especially for gemcitabine-resistant pancreatic cancer.

Free access

Ying Chen, Hua Ni, Xing-Hong Ma, Shi-Jun Hu, Li-Ming Luan, Gang Ren, Yue-Chao Zhao, Shi-Jie Li, Hong-Lu Diao, Xiu Xu, Zhen-Ao Zhao and Zeng-Ming Yang

Although implantation types differ between species, the interaction between blastocyst trophectoderm and apical surface of the uterine epithelium is a common event during the implantation process. In this study, uterine luminal epithelium at implantation and inter-implantation sites was isolated by enzymatic digestion and used for microarray analysis. In a mouse microarray containing 12 345 unigenes, we found 136 genes upregulated more than twofold at the implantation site, while 223 genes were downregulated by at least twofold. Reverse transcription-PCR was used to verify the differential expression of seven upregulated and six downregulated genes chosen randomly from our microarray analysis, and the expression trends were similar. The differential expression patterns of eight upregulated genes were verified by in situ hybridization. Compared with the inter-implantation site on day 5 of pregnancy and the uterus on day 5 of pseudopregnancy, protease, serine, 12 neurotrypsin, endothelin-1, γ-glutamyl hydrolase, Ras homolog gene family, member U, T-cell immunoglobulin, and mucin domain containing 2, proline–serine–threonine phosphatase-interacting protein 2, 3-monooxgenase/tryptophan 5-monooxgenase activation protein, γ-polypeptide, and cysteine-rich protein 61 (Cyr61) were upregulated in the luminal epithelium at implantation site on day 5 of pregnancy. These genes may be related to embryo apposition and adhesion during embryo implantation. Cyr61, a gene upregulated at the implantation site, was chosen to examine its expression and regulation during the periimplantation period by in situ hybridization. Cyr61 mRNA was specifically localized in the luminal epithelium surrounding the implanting blastocyst at day 4 midnight and on day 5 of pregnancy, and in the activated uterus, but not expressed in inter-implantation sites and under delayed implantation, suggesting a role for Cyr61 in mediating embryonic–uterine dialog during embryo attachment. Our data could be a valuable source for future study on embryo implantation.

Open access

Kamran Ullah, Tanzil Ur Rahman, Hai-Tao Pan, Meng-Xi Guo, Xin-Yan Dong, Juan Liu, Lu-Yang Jin, Yi Cheng, Zhang-Hong Ke, Jun Ren, Xian-Hua Lin, Xiao-Xiao Qiu, Ting-Ting Wang, He-Feng Huang and Jian-Zhong Sheng

Previous studies have shown that increasing estradiol concentrations had a toxic effect on the embryo and were deleterious to embryo adhesion. In this study, we evaluated the physiological impact of estradiol concentrations on endometrial cells to reveal that serum estradiol levels probably targeted the endometrium in controlled ovarian hyperstimulation (COH) protocols. An attachment model of human choriocarcinoma (JAr) cell spheroids to receptive-phase endometrial epithelial cells and Ishikawa cells treated with different estradiol (10−9 M or 10−7 M) concentrations was developed. Differentially expressed protein profiling of the Ishikawa cells was performed by proteomic analysis. Estradiol at 10−7 M demonstrated a high attachment rate of JAr spheroids to the endometrial cell monolayers. Using iTRAQ coupled with LC–MS/MS, we identified 45 differentially expressed proteins containing 43 significantly upregulated and 2 downregulated proteins in Ishikawa cells treated with 10−7 M estradiol. Differential expression of C3, plasminogen and kininogen-1 by Western blot confirmed the proteomic results. C3, plasminogen and kininogen-1 localization in human receptive endometrial luminal epithelium highlighted the key proteins as possible targets for endometrial receptivity and interception. Ingenuity pathway analysis of differentially expressed proteins exhibited a variety of signaling pathways, including LXR/RXR activation pathway and acute-phase response signaling and upstream regulators (TNF, IL6, Hmgn3 and miR-140-3p) associated with endometrial receptivity. The observed estrogenic effect on differential proteome dynamics in Ishikawa cells indicates that the human endometrium is the probable target for serum estradiol levels in COH cycles. The findings are also important for future functional studies with the identified proteins that may influence embryo implantation.