Hypoxia occurs in chronic and acute vascular diseases and tumor formation. The ability of tumor cells to maintain a balance between an adaptation to hypoxia and cell death is regulated by a family of transcription factors called hypoxia-inducible factor 1 (HIF-1). Tumor hypoxia mediated by HIF-1 would facilitate the likelihood of resistance to chemotherapy and radiotherapy, proliferation, metastasis and the invasive potential; all of which culminate in a decrease in patient survival. And HIF-1 alpha subunit decides the activity of HIF-1, which is regulated by oxygen. So understanding the role of HIF in signal pathway, drug resistance mechanism and its feature is crucial for developing novel anticancer therapies. In recent years, more attentions have focused on HIF-1 alpha inhibitors. It is expected that development of more potent and selective HIF inhibitors will provide an effective treatment of cancer and other HIF-related diseases. So we will focus on the biological characteristics and mechanism of HIF-1 to review currently studied HIF-1 inhibitors.

Hypoxia is a general characteristic of most solid malignancies and intimately related to cancer progression. Homeostatic response to hypoxia is primarily mediated by hypoxia inducible factor-1alpha (HIF-1alpha) that elicits transcriptional activity through recruitment P300 coactivator. Targeting the interaction of HIF- alpha and P300 would thus constitute a novel approach for cancer treatment by suppressing tumor angiogenesis and metastasis. Here, a screening assay was developed for inhibitors targeting the interaction between HIF-1alpha and P300. The nucleotide sequence of human HIF-1alpha and P300 were cloned into pBIND and pACT vectors, named pBIND-HIF1alpha and pACT-P300. The interaction of HIF-1alpha and P300 was identified in HEK293 cell using mammalian two-hybrid system. And compound chetomin decreased their interaction in this mammalian two-hybrid system. We further verified HIF-1 inhibition effect of chetomin in U251-HRE cells. Therefore, we established a screening assay combined HIF-1alpha and P300 mammalian two-hybrid system and U251-HRE reporter assay for HIF-1 selective inhibitors.

Hypoxia occurs in chronic and acute vascular diseases and tumor formation. The ability of tumor cells to maintain a balance between an adaptation to hypoxia and cell death is regulated by a family of transcription factors called hypoxia-inducible factor 1 (HIF-1). Tumor hypoxia mediated by HIF-1 would facilitate the likelihood of resistance to chemotherapy and radiotherapy, proliferation, metastasis and the invasive potential; all of which culminate in a decrease in patient survival. And HIF-1 alpha subunit decides the activity of HIF-1, which is regulated by oxygen. So understanding the role of HIF in signal pathway, drug resistance mechanism and its feature is crucial for developing novel anticancer therapies. In recent years, more attentions have focused on HIF-1 alpha inhibitors. It is expected that development of more potent and selective HIF inhibitors will provide an effective treatment of cancer and other HIF-related diseases. So we will focus on the biological characteristics and mechanism of HIF-1 to review currently studied HIF-1 inhibitors.
Cell Death ; Humans ; Hypoxia-Inducible Factor 1 ; antagonists & inhibitors ; metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit ; antagonists & inhibitors ; metabolism ; Neoplasms ; drug therapy ; Oxygen ; metabolism ; Signal Transduction

Objective To quantitatively analyze radiation-induced trismus in patients with nasopha-ryngeal carcinoma (NPC) treated by intensity modulated radiation therapy (IMRT), and evaluate tem-poromandibular joint (TMJ) damage. Methods Between February 2001 and October 2004, 211 NPC pa-tients were treated by IMRT, with a total dose of 68 Gy, 2.27 Gy per fraction within 31 -86 days (median, 43 days). The distances between two dens incisivus medialis (DDIM) were measured before and 6 months after IMRT and then annually thereafter. Results The overall survival at 1-, 3-, and 5-year were 97.1%, 90.7% and 79. 1%, respectively. The mean irradiation doses to TMJ were 6.18 -51.36 Gy. Grade 1 TMJ damage was observed in 5.2% patients, and grade 2 occurred in one patients who had received the second course radiotherapy because of local relapse . No grade 3 or 4 TMJ toxicity was observed . Conclusions IMRT can spare the TMJ from high dose irradiation and markedly reduce severe TMJ damage.

Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor on hypoxia responses in mammalian tissues. HIF-1 plays as a positive factor in solid tumor and leads to hypoxia-driven responses that enhance its downstream gene expression for tumor growth and survival. LXY6099 was obtained by the structural modification and optimization of manassantin A (MA) as a high potent HIF-1 inhibitor. Antitumor activity of LXY6099 was observed in this study. LXY6099 with an IC50 value of 2.46 x 10(-10) mol x L(-1) showed more sensitive inhibition activity to HIF-1 than that of MA detected by reporter gene assay (> 100 folds). It showed strong inhibition on the growth of human solid tumor cell lines. Furthermore, LXY6099 exhibited significant antitumor activity against established human tumor xenografts in nu/nu mice with treatment of MX-1 breast cancer. Thus, LXY6099 as a novel HIF-1 inhibitor could be further developed into anti-cancer agents.

Objective To investigate the effect of HBV on the expression of fibrosis-related factors in hepatic stellate cells(HSC)and its relation with liver fibrosis.Methods HSCs were co-cultured with HepG2 or HepG2.2.15 in vitro and HSCs cultured alone served as the control.The mRNA expression of matrix metalloproteinase(MMP)-2 and tissue inhibitor of metalloproteinase(TIMP)-1 was detected by realtime PCR.The protein expression of MMP-2 and TIMp-1 was detected by Western-blot.Results Compared with the control and the HSCs co-cultured with HepG2,the expression of MMP-2 and TIMP-1 mRNA in HSCs co-cultured with HepG2.2.15 was increased remarkably and the most significant difference was found at 72 h(F=11.91,23.13;P=0.008,0.001);the expression of MMP-2 and TIMP-1 protein in HSCs co-cuhured with HepG2.2.15 was also increased remarkably and the most significant difference was found at 72 h(F=20.70,6.54;P=0.002,0.003)too.Conclusion The expression of fibrosis-related factors in HSCs increased significantly after co-cultured with HepG2.2.15,which suggests that HBV could promote liver fibrosis.

Hypoxia is a general characteristic of most solid malignancies and intimately related to cancer progression. Homeostatic response to hypoxia is primarily mediated by hypoxia inducible factor-1alpha (HIF-1alpha) that elicits transcriptional activity through recruitment P300 coactivator. Targeting the interaction of HIF- alpha and P300 would thus constitute a novel approach for cancer treatment by suppressing tumor angiogenesis and metastasis. Here, a screening assay was developed for inhibitors targeting the interaction between HIF-1alpha and P300. The nucleotide sequence of human HIF-1alpha and P300 were cloned into pBIND and pACT vectors, named pBIND-HIF1alpha and pACT-P300. The interaction of HIF-1alpha and P300 was identified in HEK293 cell using mammalian two-hybrid system. And compound chetomin decreased their interaction in this mammalian two-hybrid system. We further verified HIF-1 inhibition effect of chetomin in U251-HRE cells. Therefore, we established a screening assay combined HIF-1alpha and P300 mammalian two-hybrid system and U251-HRE reporter assay for HIF-1 selective inhibitors.
Cell Hypoxia ; Disulfides ; pharmacology ; Drug Screening Assays, Antitumor ; E1A-Associated p300 Protein ; antagonists & inhibitors ; HEK293 Cells ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit ; antagonists & inhibitors ; Indole Alkaloids ; pharmacology ; Two-Hybrid System Techniques

Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor on hypoxia responses in mammalian tissues. HIF-1 plays as a positive factor in solid tumor and leads to hypoxia-driven responses that enhance its downstream gene expression for tumor growth and survival. LXY6099 was obtained by the structural modification and optimization of manassantin A (MA) as a high potent HIF-1 inhibitor. Antitumor activity of LXY6099 was observed in this study. LXY6099 with an IC50 value of 2.46 x 10(-10) mol x L(-1) showed more sensitive inhibition activity to HIF-1 than that of MA detected by reporter gene assay (> 100 folds). It showed strong inhibition on the growth of human solid tumor cell lines. Furthermore, LXY6099 exhibited significant antitumor activity against established human tumor xenografts in nu/nu mice with treatment of MX-1 breast cancer. Thus, LXY6099 as a novel HIF-1 inhibitor could be further developed into anti-cancer agents.
Animals ; Antineoplastic Agents ; pharmacology ; Breast Neoplasms ; metabolism ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Heterografts ; Humans ; Hypoxia-Inducible Factor 1 ; metabolism ; Lignans ; pharmacology ; Mice, Nude

Objective To study the effect of endothelial progenitor cells (EPCs) transplantation on CCl4 induced hepatic cirrhosis in rats. Methods Eight male SD rats were used as normal control. Thirty rats were induced liver cirrhosis by feeding with 25% CCl4/olive oil for 12 weeks, and then were subdivided into cirrhosis group (n = 10), EPCs transplanted group (n = 10) and saline control group (n = 10). EPCs were transplanted into the portal vein for 4 weeks in EPCs transplanted group. Rats in EPCs nontransplanted group were sacrificed at the beginning of the 12th week. Rats in EPCs transplanted group and saline control group were killed at the beginning of 16th week. Serum biochemical parameters were examined. The degree of liver cirrhosis was evaluated by Masson staining and by detecting the expression of α-SMA, Collagen Ⅲ and Ki67. Results The volumes of liver in cirrhosis group were twice as much as that in normal rats. 12 weeks after CCl4 administration, compared with saline control group, in EPCs transplanted group, hepatic activity index (HAI) ( F = 75. 062, P < 0. 01 ), the levels of ALT( F = 29. 942, P<0.05), AST(F=16.618,P<0.05) and TBIL(F=9.911 ,P<0.05) in serum decreased, the level of Alb ( F = 4. 944, P < 0. 05 ) and Ki67 ( F = 45. 966, P < 0. 01 ) was increased, the expression of α-SM A ( F = 7.86,P<0.05) and collagen Ⅲ (F = 135.787,P <0.01) decreased (P <0.05). Compared with untransplanted group, in EPCs transplanted group, the levels of ALT, AST and TBIL in serum were lower; In saline control group, the levels of ALT, AST and TBIL in serum were higher, the level of Alb and Ki67was lower, the expression of α-SMA and collagen Ⅲ were higher( P < 0. 05 ). Compared with normal rats, in saline control group, the levels of INR were higher (P < 0. 05 ). Conclusion EPCs transplantation improves hepatocye regeneration and ameliorates established hepatic cirrhosis.

Purpose To explore the predictive value of myocardial perfusion in assessing myocardial systolic function recovery after primary percutaneous coronary intervention (PPCI),in order to improve poor prognosis by early detection of myocardial no-reflow.Materials and Methods Forty nine patients with acute myocardial infarction (AMI) who had received PPCI were chosen as subjects.All the patients underwent two-dimensional strain (2DS) images and resting real-time myocardial contrast echocardiography (MCE) within one week after surgery,and 2DS measurement was repeated after three months.2DS imaging was used to acquire longitudinal peak systolic strain (LPSS) at all myocardial segments.Based on the graphs of LPSS,left ventricular myocardium was divided into normal contractile function myocardium (red) and impaired contractile function myocardium (light red,blue).According to the myocardial perfusion scores (MPS) qualitatively assessed by MCE visual interpretation,the myocardia with impaired systolic function were categorized into three groups with different perfusion level.The changes of LPSS within one week and three months after surgery (△ LPSS) among the three groups were analyzed.The correlation between MPS and LPSS within one week and three months after PPCI was also analyzed respectively.Results The △ LPSS increased significantly among the three groups with the improvement of myocardial perfusion level [(-5.78±6.23)％ vs.(-4.37±6.60)％ vs.(-1.21 ±4.77)％,all P＜0.05].The MPS measured one week after PPCI was both positively correlated with the LPSS detected within one week after surgery and that after three months (r=0.47,0.58,P＜0.001).The consistence of myocardial perfusion scores given by two evaluators was good (Kappa=0.785,P＜0.05).Conclusion The level of myocardial perfusion after PPCI in patients with AMI is closely related to regional myocardial systolic function,and the improvement of myocardial perfusion can forecast the recovery of regional systolic function.