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

Public hospital reform pilots have been initiated recently and it is necessary to clarify some key issues. To this end, thispaper touches upon six fundamental issues, discussing the generality and value for the existence of public hospitals, differences between reforms of public hospital and those of state-owned enterprise, the public financing for and regulation on public hospitals, relationship with the private sector, as well as service and function positioning of public hospitals.

AIM: To investigate the effect of cultured limbal stem cells on proliferating of vascular endothelial cells and validate the theory of limbal stem cells.

METHODS: The limbal stem cells and epithelium cells of bulbar conjunctiva were cultured and determined by immunohistochemistry staining with AE-5. The supernatant was collected and added into the cultured human umbilical vein endothelium cells(ECV-304). The negative control was set up. After 24h, MTT was done to detect endothelium cell proliferation. The statistical analysis was done by analysis of Variance.

RESULTS: Negative stain of AE-5 can be seen in limbal stem cells and positive stain can be seen in conjunctiva cells. The ratio of MTT added by limbal stem cell supernatant, conjunctiva epithelium cell and negative control were 2.097±0.079, 1.981±0.034 and 1.990±0.044, respectively. There were significant difference among the three groups(F=9.169, P=0.000). The proliferate activity of vascular endothelial cells added by supernatant of limbal stem cells was higher than the other two groups(P=0.005 and P=0.007, respectively).

CONCLUSION:The supernatant of limbal stem cells can improve the proliferation of vascular endothelium cell. This may be the unique characteristics of limbal stem cells. This study provides more evidences for the theory of limbal stem cells by determining the functional methods.

A new compound and five known compounds were isolated from the ethanolic extract of the leaves of Ilex pernyi Franch. Their structures were established on the basis of spectral analysis and identified as trans-isoeugenyl-alpha-L-arabinopynosyl (1 --> 6) -beta-D-glucopyranoside (1) , kaempferol-3-O-sambubioside (2), quercetin-3-O-sambubioside (3), isoquercitrin (4), (+) -syringaresinol-O-beta-D-glucopyranoside (5), amarantholidoside IV (6). Among them, compound 1 is a new phenolic glycoside, named as ilexperphenoside A, and compounds 2-6 were isolated from this plant for the first time.
Glucosides ; chemistry ; isolation & purification ; Glycosides ; chemistry ; isolation & purification ; Ilex ; chemistry ; Molecular Structure ; Plant Leaves ; chemistry ; Plants, Medicinal ; chemistry ; Quercetin ; analogs & derivatives ; chemistry ; isolation & purification

OBJECTIVETo investigate the effects of alpha-linolenic acid (ALA) on inflammation and oxidative stress in the diabetic rats.

METHODSAn experimental type 2 diabetes mellitus model was induced by feeding male SD rats with diet of high fat for 4 weeks and then injected them intraperitoneally with streptozocin (STZ) at 30 mg/kg. Then the animals were randomly divided into three groups (n = 10): control group, diabetic group and ALA group. Four weeks later, tumor necrosis factor (TNF)-a, soluble P-selectin (sP-selectin), soluble intercellular adhesion molecule-1 (sICAM-1), nitric oxide (NO) production, malondialdehyde (MDA), superoxide dismutase (SOD) and catalase (CAT) in the serum were determined.

RESULTSInflammatory agents including TNF-alpha, sP-selectin and sICAM-1 increased in diabetic rats to compare with control group. Treatment with ALA significantly decreased TNF-alpha, sP-selectin and slCAM-1 to compare with diabetic group. Furthermore, compared with control group, serum MDA production increased whereas NO production, SOD and CAT activities decreased in diabetic rats. Treatment with ALA reduced MDA production, increased NO production, promoted SOD and CAT activities compared with diabetic group.

CONCLUSIONThese results indicate that diet rich in ALA exerted the anti-inflammatory and anti-oxidative effects in diabetic rats, which may be beneficial to the prevention and treatment of diabetes.

Animals ; Diabetes Mellitus, Experimental ; drug therapy ; metabolism ; Diabetes Mellitus, Type 2 ; drug therapy ; metabolism ; Inflammation ; Male ; Malondialdehyde ; blood ; Oxidative Stress ; drug effects ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase ; blood ; Tumor Necrosis Factor-alpha ; blood ; alpha-Linolenic Acid ; pharmacology ; therapeutic use

The purpose of this study is to investigate the activity and mechanism of a new anti-tumor agent T03. MTT and colony formation assay were performed to determine anti-proliferation activity of T03 in vitro. Antitumor activity was observed by Renca xenograft model in vivo. The effect of T03 on cell cycle and apoptosis were measured by FCM analysis. Western blotting was performed to investigate the expression level of proteins in HepG2 cell lines treated with T03. T03 had anti-tumor activity by inhibiting tumor cell growth and colony formation in vitro, especially on hepatocellular carcinoma cells (HCC). At the concentration of 10 micromol x L(-1), T03 induced cell apoptosis and cell cycle arrest in HCC. Moreover, it proved that T03 reduced the tumor weight with the rate of 42.30% without any obviously side effect in Renca xenograft model. At the concentration of 2.0 micromol x L(-1), T03 was able to reduce the level of p-c-Raf (Ser259), and thus blocked Raf/MEK/ERK and AKT signaling in HepG2 cell lines. The result suggested that T03 has the potential to inhibit cell proliferation and induce cell apoptosis both in vitro and in vivo, particularly active against HCC, indicating T03 and its analogues may serve as a new anti-cancer drug against hepatocellular carcinoma.
Animals ; Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Carcinoma, Hepatocellular ; pathology ; Cell Cycle Checkpoints ; drug effects ; Cell Proliferation ; drug effects ; Hep G2 Cells ; drug effects ; Humans ; Liver Neoplasms ; pathology ; Signal Transduction ; drug effects ; Xenograft Model Antitumor Assays

Objective To investigate the epidemiological condition of the sub-health status of the young and middle-aged persons in urban and rural areas of Hubei province, and to explore the relationships among personality, quality of sleep and sub-health status. Methods Purposive sampling method and Personal Health Status Questionnaire developed by Chinese Academy of Medical Sciences were used to investigate the sub-healthy status of 3187 subjects aged 18-55 and evaluate the relationships among sub-health status, personality and the quality of sleep with structural equation model. Results Gender, education, marriage, age and occupation were factors influencing the status of sub-health. Among all of the subjects, sub-health status of females were more serious than that of males (P＜0.0001 of all). The divorced, separated and widowed ones were more likely to experience sub-health than other status of marriage (P= 0.0006, P=0.0102). The sub-health status of the subjects aged 30-55 in the urban (P=0.0197)and low-literacy residents in rural (P=0.0003)were among the worst. The condition of the sub-health in migrant workers and professional were worse compared to other occupational groups (P=0.0043). Structural equation model analysis revealed that sub-health status associated with the quality of sleep and the type of characteristics (P＜0.01 ). Conclusion Sub-health status did exist among the young and middle-aged persons and was influenced by the quality of sleep and personality. However, it could be adjusted by improving the quality of sleep and personality to prevent sub-health.

Objective To investigate the characteristics of microbial isolates and the positive rate from bile cultures taken from obstructive jaundice patients, then compare the antimicrobial sensitivities to guide the rational choice and use of antibiotics. Methods Bile cultures from 322 patients from January 2012 to April 2016 were reviewed. Specimens were obtained from patients that were diagnosed obstructive jaundice. The bile specimens were examined for pathogenic respectively. At the same time, the empirical antibiotics of the 322 cases prior to operation were also analyzed. Results Bile culture was positive in 246 among322 cases, the positive culture rate was 76.40%. A total of 267 pathogens were isolated in bile culture: 208 Gram-negative bacteria, 48 Gram-positive bacteria and 11 fungus. The most common pathogens in all were Escherichia coli (208 strains, 53.18%), Enterococcus faecium (28 strains, 10.49%), Klebsiella pneumoniae (27 strains, 10.11%). The most sensitive antibiotics against Gram-negative bacteria were imipenem and meropenem (with susceptibility rate for 98.08%, respectively). The more sensitive antibiotics against Gram-negative bacteria were efoperazone/sulbactam, amikacin, piperacillin/tazobactam (susceptibility 92.31%, 88.46% and 85.58%). The lowest susceptibility rate of Gram-negative to twelve kings of antimicrobial agents were levofloxacin, andaztreonam (susceptibility 29.81%, 28.37%). The most sensitive antibiotics against Gram-positive bacteria were linezolid, teicoplanin and vancomycin(with susceptibility rate for 100.00%, respectively). The more sensitive antibiotics against Gram-positive bacteria was chloromycrtin (susceptibility 88.89%). The lower susceptibility rate of Gram-positive were levofloxacin (susceptibility 25.00%). 281 cases of patients before surgery empirical use of antimicrobial drugs. Monotherapy was used in 219 cases. The main drug was levofloxacin (86/219), the second was cefoperazone/sulbactam (70/219). The dual therapy was used in 62 cases, the mainly was cefoperazone/sulbactam plus ornidazole or metrornidazole(27/62), the second was levofloxacin plus ornidazole or metrornidazole (12/62). Conclusions Gram negative bacteria were the predominant bile pathogens found in patients with obstructive jaundice. And the most prominent Gram-negative pathogens were Escherichia coli. The sensitive rates of cefoperazone/sulbactam, amikacin and piperacillin/tazobactam were higher, which could be used as the preferred antimicrobial agents. Imipenem and meropenem should remain the last alternative when all other therapies fail or serious infection; The empirical antibiotics's pertinence was not very suitable, levofloxacin's resistance rates in obstructive jaundice was higher. It should be avoided to choose during empirical antimicrobial therapy.