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

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

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

OBJECTIVETo measure the stability of Evans procedure and Chrisman-Snook technique in the treatment of II degree lateral collateral ligament of ankle joint, and provide basis for treatment and prognosis.

METHODSFrom July 2008 to June 2009,18 frozen corpes were collected, including 10 males and 8 females, with an average age of fresh 39.3 +/- 11.2 years. The frozen corpes were randomly divided into three group, including normal controls(group A), Evans procedure (group B) and Chrisman-Snook technique ( group C), 6 specimens in each group. Anterior talofibular ligament and calcaneofibular ligament were cut off to cause II degree lateral collateral ligament in group B and C. Evans procedure or Chrisman-Snook technique were applied to restore lateral collateral ligament, and measure biomechnics. The displacement of tibiotalar joint and subtalar joint were observed.

RESULTS(1) The lateral stress results of tibiotalar joint showed the displacement by Evans procedure (group B) was greater than other groups (P < 0.0001). There were no significant differences between group A and C (P > 0.05). (2) The lateral stress results of subtalar joint showed the displacement by Evans procedure (group B) was greater than other groups (P< 0.0001). There were no significant differences between group A and C (P > 0.05).

CONCLUSIONAnkle instability is caused by ankle joint lateral collateral ligament injury. Chrisman-Snook technique is better than Evans procedure in stability on the early stage of ankle joint restoration, and conform to principle of biomechanics.

Adult ; Ankle Joint ; Biomechanical Phenomena ; Female ; Humans ; Lateral Ligament, Ankle ; diagnostic imaging ; injuries ; surgery ; Male ; Mechanical Phenomena ; Prognosis ; Radiography ; Reconstructive Surgical Procedures ; methods

OBJECTIVETo observe the association between plasma endothelin (ET) concentration and blood pressure level in essential hypertensive (EH) patients with or without complications and possible impact of statins on ET concentration.

METHODSFrom Sep 2007 to Mar 2009, 149 patients with EH were analyzed [44 EH, 40 EH complicated by left ventricular hypertrophy (EH-LVH), 36 EH complicated by atrial fibrillation (EH-AF), and 29 EH complicated by lacunar infarction (EH-LI)], 30 healthy persons were selected as controls. EH patients were randomly divided into routine treatment group (calcium antagonists, ACEI, diuretics, beta-receptor blocker for 8 weeks) and simvastatin intervention group (routine treatment + simvastatin 40 mg/d for 8 weeks), plasma ET concentrations before and after drug intervention were measured.

RESULTS(1) ET concentration was higher in EH group than that in control group [(71.42 +/- 6.62) pg/ml vs. (45.52 +/- 8.28) pg/ml, P < 0.01]. ET concentration was higher in EH-LVH group, EH-AF group and EH-LI group than that in EH group [(97.67 +/- 10.53) pg/ml, (102.15 +/- 12.96) pg/ml, (103.49 +/- 9.91) pg/ml vs. (71.42 +/- 6.62) pg/ml, P <0.01]. The degrees of elevated blood pressure was positively correlated with ET concentrations(all P < 0.001). (2) The left atrial diameters of EH-AF group were positively correlated with ET concentration (r = 0.684, P < 0.001). The left ventricular mass index of EH-LVH group were positively correlated with ET concentration (r = 0.545, P < 0.001). (3) The percentages of class 3 hypertension in EH-LVH group, EH-AF group and EH-LI group were higher than that in EH group (57.5%, 50.0%, 62.1% vs. 25.0%, all P < 0.05). (4) Blood pressure in class 3 hypertension patient treated with simvastatin decreased more significantly than that in routine treatment group (P < 0.05). (5) ET concentration of class 2 hypertension patient treated with simvastatin decreased significantly than that in routine treatment group (P < 0.05). ET concentrations of class 3 hypertension patient treated with simvastatin and routine treatment patient decreased significantly after treatment (P < 0.05), and the former was lower (P < 0.05).

CONCLUSIONThe level of ET were positively correlated with the severity of EH. Simvastatin could decrease the ET levels of patients with EH and blood pressure levels of patients with class 3 hypertension. It suggested that therapeutic alliance of antihypertensive drugs and statins could be benefit to patients with EH.

Aged ; Aged, 80 and over ; Antihypertensive Agents ; therapeutic use ; Blood Pressure ; Endothelins ; blood ; Female ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; therapeutic use ; Hypertension ; blood ; complications ; drug therapy ; Male ; Middle Aged ; Simvastatin ; therapeutic use

OBJECTIVETo investigate the clinicopathological significance of positive CK7 expression in human colorectal carcinoma (HCC).

METHODSImmunohistochemistry was used to detect CK7 and CK20 protein expressions in 68 cases of HCC, 20 cases of canalicular adenoma (CA), 5 cases of serrated adenoma (SA) and 20 cases of hyperplastic polyps (HP).

RESULTSThe positivity rate of CK20 expression was 89.7% in HCC, and 100% in CA, SA and HP. In HCC, the expression rate of CK7 (39.7%) was not correlated with Dukes' classification, differentiation and tumor location. CK7 positivity rate in colon cancer was 35.7% (15/52) and 42.3% (11/26) in rectal cancer. CK7 expression was negative in CA. CK7 positivity rate in SA was 49% and 30% in HP.

CONCLUSIONCK7 is a possible marker for colorectal carcinogenesis from HP to SA, and ultimately to HCC, and examination of the colorectal polypoid lesions for CK7 expression can be significant for estimating the colorectal polypous cancerization.

Colorectal Neoplasms ; genetics ; metabolism ; pathology ; Cytoplasm ; metabolism ; pathology ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Immunohistochemistry ; Intestinal Mucosa ; metabolism ; pathology ; Keratin-7 ; metabolism ; Male ; Middle Aged

OBJECTIVETo investigate the value of application of mandibular outer cortex as bone graft by comparing its bone absorption with cranial outer cortex.

METHODS8 minitype grown-up pigs at the age of 8 - 12 months underwent surgery of taking out the same size (2.5 cm x 1.0 cm) of outer cortex from mandible and craninium. The volume of the outer cortex was measured by volume-displacement method. Then the outer cortex of mandible and cranium were onlay grafted to the each side of the pig snout, respectively. 12 weeks later, 2 pigs were randomly selected for histological examination. The other 6 pigs were killed 24 weeks after surgery for measurement of the bone graft volume and histologic examination.

RESULTSThe bone graft absorption rate was (41 +/- 5)% for mandibular outer cortex and (46 +/- 12)% for cranial outer cortex, showing no significant difference between them (P = 0.51). The histologic examination results also had no marked difference in the bony healing and reforming between the two graft.

CONCLUSIONSMandibular outer cortex is a good donor site for onlay bone graft in craniofacial region.

Animals ; Bone Plates ; Bone Regeneration ; Bone Transplantation ; methods ; Female ; Male ; Mandible ; transplantation ; Skull ; transplantation ; Swine ; Swine, Miniature

BACKGROUNDTobacco-specific 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is the most important carcinogen in cigarette. Models induced by NNK are widely used in investigations about the mechanisms of pulmonary neoplasia and chemoprevention studies. The aim of this study is to explore the pulmonary precancerous lesions induced by NNK and its possible mechanisms.

METHODSFifteen Wistar rats were divided into two trial groups, in which the high-dose group was instilled with iodized oil including 10 mg (50 mg/kg) NNK into the left lower lobar bronchus, and the low-dose group received 5mg ( 25mg/kg) NNK. Another 15 Wistar rats were instilled only with iodized oil as control group. All rats were examined immediately after instillation and followed up periodically by pulmogram. The pulmonary tissues of rats were pathologically examined, and the expression of AE1/AE3, PCNA and p53 was detected by immunohistochemical method.

RESULTSThe pulmograms showed that the iodized oil localized at the bottom of left lobe and disappeared 107 days later. In trial group, 10 of 15 rats (67%) had nodus at the bottom of left lobe. All of rats in trial group (15/15) displayed atypical hyperplasia in alveolar region, showing single or multiple layers of proliferative epithelial cells along intact alveolar septa with irregular and non-discrete margins of lesion, but continuous alveolar spaces were not obliterated by proliferative epithelial cells. Ten of 15 rats in trial group showed severe atypical hyperplasia of glandular epithelium with occasional infiltrating to muscular layer. All of those atypical hyperplasia cells showed positive AE1/AE3 expression. The positive rate of PCNA was 90% (9/10) and 100% (5/5) in low-dose group and high-dose group respectively, which was significantly higher than that in control group (13%, 2/15) (P=0.000, P=0.001). The positive rate of p53 expression was 50% (5/10) and 60% (3/5) in low-dose group and high-dose group respectively, which was significantly higher than that in control group (0) (P=0.005, P=0.009). However, there was no remarkable difference in PCNA and p53 expression between low-dose group and high-dose group (P > 0.05).

CONCLUSIONSTransbronchial instillation of iodized oil including tobacco-specific NNK can induce pulmonary lesions as atypical hyperplasia of alveolar cell and glandular epithelium in Wistar rats. This model can be used in experimental studies about tobacco-related lung cancer.

OBJECTIVETo study the clinical characteristics of male urethral duplication infection and offer some guidelines for the diagnosis and treatment of the disease.

METHODSWe analyzed the pathological types, clinical characteristics, therapeutic processes and follow-up results of 9 cases of male urethral duplication.

RESULTSAmong the 9 cases of urethral duplication, 7 turned out to be of Type I, 1 Type II A2 and 1 Type II B. The disease courses varied from 2 to 420 days, with an average of 77.2 +/- 141.5 days. Four cases with longer disease duration were identified with a history of repeated use of various antibiotics for treatment. Their clinical manifestations varied, with the outflow of excretions or pus from the duplicate or normal urethra as the cardinal symptoms. The pathogens detected from the secretions were mainly Neisseria gonorrhoeae, Ureaplasma urealyticum, and Chlamydia trachomatis. The consistency rate of the same pathogens detected in the vaginal or cervical secretions from the sex partners of the patients was 87.5%. All the symptoms disappeared after a sufficient-course treatment with sensitive antibiotics, and the patients' sex partners received the same medication simultaneously. No recurrence was found during a 3-month follow-up.

CONCLUSIONUrethral duplication infection has various clinical manifestations, and thus is easily missed in diagnosis. Sufficient-course treatment with sensitive antibiotics is recommended for those that prefer conservative therapy, and their sex partners should be treated simultaneously.

Adult ; Humans ; Male ; Middle Aged ; Urethra ; microbiology ; Urethral Diseases ; diagnosis ; drug therapy ; microbiology ; Young Adult

OBJECTIVETo study the association of transforming growth factor-alpha (TGF-alpha gene polymorphism and environment factors with nonsyndromic cleft lip with or without cleft palate (NSCLP) in Han nationality.

METHODSData related to infection, drug intake and folic acid supplement during pregnancy were gained through investigation of mothers. Polymerase chain reaction combined with restrict enzyme digestion was used to detect the target gene variation in 199 patients with NSCL/P and 203 healthy controls. Analysis was carried on the genotype and infection,drug intake and folic acid supplement.

RESULTSThe C2 allele frequency in patients with NSCL/P was significantly higher than that in healthy controls. There was a significant increase of patients with NSCL/P in pregnant women exposed to infection, drug intake and folic acid deficiency. There was an interaction between C1C2 genetype and infection, drug intake and folic acid supplement.

CONCLUSIONTGF-alpha gene polymorphism is associated with NSCL/P. Infection, drug intake and folic acid supplement during pregnancy were associated with the occurrence of NSCL/P. Individuals containing C2 allele were more sensitive to infection, drug intake and folic acid deficiency.

Alleles ; Cleft Lip ; Cleft Palate ; Ethnic Groups ; Female ; Gene Frequency ; Genotype ; Humans ; Polymerase Chain Reaction ; Polymorphism, Genetic ; Pregnancy ; Transforming Growth Factors