ABSTRACT
Tyrosine phosphatase SHP2 is a promising drug target in cancer immunotherapy due to its bidirectional role in both tumor growth promotion and T-cell inactivation. Its allosteric inhibitor SHP099 is known to inhibit cancer cell growth both and . However, whether SHP099-mediated SHP2 inhibition retards tumor growth anti-tumor immunity remains elusive. To address this, a CT-26 colon cancer xenograft model was established in mice since this cell line is insensitive to SHP099. Consequently, SHP099 minimally affected CT-26 tumor growth in immuno-deficient nude mice, but significantly decreased the tumor burden in CT-26 tumor-bearing mice with intact immune system. SHP099 augmented anti-tumor immunity, as shown by the elevated proportion of CD8IFN- T cells and the upregulation of cytotoxic T-cell related genes including , which decreased the tumor load. In addition, tumor growth in mice with SHP2-deficient T-cells was markedly slowed down because of enhanced anti-tumor responses. Finally, the combination of SHP099 and anti-PD-1 antibody showed a higher therapeutic efficacy than either monotherapy in controlling tumor growth in two colon cancer xenograft models, indicating that these agents complement each other. Our study suggests that SHP2 inhibitor SHP099 is a promising candidate drug for cancer immunotherapy.
ABSTRACT
Notch signaling, a highly conserved pathway, is wide-ly found in invertebrates and vertebrates. By mediating cell com-munication, it can regulate many physiological and pathological processes in various kinds of cells, including cell proliferation, differentiation and apoptosis in multi-cellular organism. Accu-mulating evidence shows that abnormality in Notch signaling is highly related to diabetes mellitus and its complications. Accord-ingly, this paper reviews the molecular basis of Notch signaling and the relations between its abnormal expression and diabetes mellitus, and focuses on the impact of key elements in the Notch signaling pathway on diabetic complications as well as correlative mechanisms.
ABSTRACT
Aim To investigate the protective effect of Panax Notoginseng Saponins ( PNS ) on Aβ25-35-in-duced apoptosis in PC12 cells and molecular mecha-nism. Methods The cell viability of PC12 cells was detected by MTT assay. The levels of LDH leakage, ROS,MDA,Caspase-3 activity and antioxidant enzyme activities of SOD, CAT, and GSH-Px activity were de-termined by respective kits. The apoptosis of cells was decteced by Western blot. Results PNS could signifi-cantly inhibit the decrease of cell viability and LDH leakage, reduce the production of MDA and ROS( P<0. 01), increase the activity of SOD,CAT and GSH-Px ( P <0. 01 ) , and the mitochondrial membrane poten-tial, inhibit the activation of caspase-3 ( P <0. 01 ) in PC12 cells which were induced by Aβ25-35 . PNS could incrase nuclear Nrf2 and up-regulate HO-1 . The neu-roprotective of PNS could be inhibited by HO-1 inhibi-tor ZnPP. Conclusion PNS may inhibit Aβ25-35-in-duced oxidative stress and apoptosis in PC12 cells by activating Nrf2/HO-1 signaling pathway.
ABSTRACT
This study is to report the study of protective effects of myricitrin against oxidative stress-induced apoptosis of vascular endothelial cells and the investigation of the possible mechanisms of action of myricitrin. The model of H2O2-induced apoptosis of vascular endothelial cells was used to determine the protective effects of myricitrin. The levels of LDH, MDA and the activities of SOD, NO were measured using the respective kits. The H2O2-induced apoptosis of vascular endothelial cells was detected using MTT reduction, TUNEL assay, JC-1 and ROS staining. The activation of Caspase-3 was also measured by fluorometry. The expression of apoptosis-related proteins was determined with Western blotting assay. Myricitrin had significant protective effects against H2O2-induced apoptosis of vascular endothelial cells in a time- and dose-dependent manner. The results show that myricitrin could attenuate H2O2-induced decrease in the activities of SOD (P < 0.01). Myricitrin could decrease the levels of LDH, MDA and increase cell viability and the mitochondrial membrane potential (P < 0.01). Myricitrin had protective effects in a dose-dependent manner between 32 micromol x L(-1) to 64 micromol x L(-1). Myricitrin pretreatment could attenuate H2O2-induced increase of p-ERK. Moreover, myricitrin pretreatment could up-regulate the expression of the anti-apoptotic protein Bcl-2, down-regulate the expression of the pro-apoptotic protein Bax, and decrease the expression of Caspase-3, 9. In conclusion, myricitrin had significant protective effects against H2O2-induced apoptosis of vascular endothelial cells. Myricitrin can enhance the activities of anti-oxidative enzymes and decrease the production of free radicals. The possible mechanisms of action of myricitrin are due to myricitrin-mediated inhibition of phosphorylation of the apoptosis signaling pathways-related kinase ERK, up-regulation of the expression of the anti-apoptotic protein, and down-regulation of the expression of the pro-apoptotic protein.
ABSTRACT
Objective To study the mechanism of senile escaping of benign prostatic hyperplasia(BPH) condition. Methods With polymerase chain reaction based telomeric repeat amplification protocol assay(TRAP),telomerase activity was examined in 13 normal prostate tissues,35 benign prostatic hyperplasia tissues,33 hyperplastic tubercle and diaphragm. Results Telomerase activity was detected in 2 of 13(15%)normal prostate tissues,17 of 35(49%)benign hyperplasia tissues,14 of 33(42%)hyperplastic tubercle tissues and 1 of 33(3%)diaphragm tissues.The positive rate of telomerase in BPH is higher than normal prostate (P