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 identify the difference of CA IX and P-gp expression level between laryngeal squamous cell carcinoma (LSCC) and benign tissues, evaluate the relationship of these two proteins in LSCC, and their correlation with clinical and pathological features. METHOD: Immunohistochemical detection of CA IX and P-gp were performed in 47 cases of LSCC and 20 cases of vocal cord polyps. RESULT: Overexpression of CA IX and P-gp both in LSCC and in vocal cord polyp (P < 0.05) were confirmed, with a correlation between the two proteins in LSCC (r = 0.324, P < 0.05). The expression of CA IX was related to clinical staging and lymph node metastasis in LSCC (P < 0.05). While P-gp was related to clinical staging and histological grading in LSCC (P < 0.05). CONCLUSION The overexpression of CA IX and P-gp may play a role in LSCC progression.
ATP Binding Cassette Transporter, Subfamily B ; metabolism ; Antigens, Neoplasm ; metabolism ; Carbonic Anhydrase IX ; Carbonic Anhydrases ; metabolism ; Carcinoma, Squamous Cell ; metabolism ; pathology ; Humans ; Laryngeal Neoplasms ; metabolism ; pathology ; Lymphatic Metastasis ; Neoplasm Grading ; Neoplasm Staging ; Polyps ; metabolism ; Vocal Cords ; metabolism ; pathology

Fermentation conditions for the production of spores of Bacillus mucilaginosus mutant 021120 were optimized through the single factor and orthogonal experiments.The results showed that the biomass and formation of spores were obviously affected by carbonate,followed by nitrogen.Addition of CaCO3 and enhancing air flux notably promoted the formation of spores.The optimal culture medium was composed of 2% starch,0.4% Yeast,0.1% K2HPO4,0.1% MgSO4?7H20 and 0.5 %CaCO3,pH7.5.6% of the inoculum prepared with two-stage extensive culture was inoculated into a 70L fermentor.The fermentation was carried out with 2.0~2.5 vvm of air flux at 32℃ for 38~42h,and the spores of 9.80?108 cfu ml-1 was obtained.Under these optimal fermentation conditions,the capsule was successfully controled and the formation of the spores was effectively improved,thus the satisfying bacteial product was obtained.

Objective To evaluate the effects of tumor-associated macrophages on the proliferation,invasion and migration of human cutaneous malignant melanoma cells.Methods Cultured U937 human monocytic cells at logarithmic phase were classified into three groups to be pretreated with phorbol ester for 48 hours followed by 48-hour activation by phorbol ester (M polarization),lipopolysaccharide (LPS) at 25 mg/L (M1 polarization),and interleukin (IL)-4 at 15 μg/L (M2 polarization) respectively.Then,enzyme-linked immunosorbent assay (ELISA) was performed to determine the levels of IL-12p70 and IL-10 in the supernatant of these activated cells.A375 human malignant melanoma cells were divided into four groups to be cultured alone or with M-,M1-and M2-polarized macrophages respectively.After additional culture for different durations (24,48 and 72 hours),methyl thiazolyl tetrazolium (MTT) assay was conducted to estimate the proliferative activity,and Transwell assay to evaluate the invasion and migration activity,of the A375 cells.Results The proliferation of A375 cells was accelerated by coculture with M-and M2-polarized macrophages,but inhibited by that with M1-polarized macrophages,with significant differences among the four groups in the proliferative activity at 48 and 72 hours (all P ＜ 0.05),but not at 24 hours (P ＞ 0.05).Invasion assay showed that the number of A375 cells that migrated through Transwell chambers was significantly larger in M2 and M groups (147.00 ± 7.92 and 113.22 ± 8.15 respectively),but smaller in the M1 group (56.44 ± 7.55),than in the control group (84.11 ± 6.07,all P ＜ 0.05).Similarly,migration assay revealed a significant increase in the number of A375 cells that migrated through Transwell chambers in the M2 and M(p) groups (198.33 ± 8.22 and 156.00 ± 8.83 respectively),but a significant decrease in the M1 group (97.11 ± 6.75) as compared with the control group (123.89 ± 7.01,all P＜ 0.05).Conclusions The proliferation,invasion and migration of A375 cells can be accelerated by IL-4-activated M2-polarized macrophages,but decelerated by LPS-activated M1-polarized macrophages.Phorbol ester tends to induce monocytic cells to differentiate into M2-polarized macrophages.

Facing the background of "team spirit"in constructing harmonious society and the development of relief medicine,the article analyzed the current situation of "team spirit education"and the dilemma of relief medical teaching,and put forward the suggestion of developing "team spirit education"in relief medical teaching.

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 Toll-like receptor ( TLR) gene family is the most important pathogen recognition receptor and animal experiment have found TLR4 mice is inclined to infect aspergillosis ( IA) .The study was to investigate the variation of TLR4 gene in Chinese Han nationality and its relation with the susceptibility of IA. Methods 25 patients diagnosed with proven IA from June 2011 to December 2012 in our hospital were enrolled, among which 17 were males.Their average age was 52.4 ±12.3, and 12 pa-tients had underlying diseases, the others had no underlying diseases.The control group consisted of 103 normal persons, among which 70 were males.Their average age was 56.0 ±17.2.All of the subjects were Chinese Han population.DNA was extracted from periph-eral blood.Polymerase chain reaction ( PCR) was applied to amplify the coding sequence of TLR4 gene followed by sequencing.The sequencing result was compared with TLR4 coding sequence in NCBI GenBank along with the analysis on amino acid change caused by genetic mutation and its effect on protein function.Comparison analysis was made on genetic mutation rate between IA group and con-trol group. Results Two missense mutations,TLR4 219 C>G and 1420 C>T, were identified in TLR4.The prediction result of protein structure showed 219 C>G resulted in the change of functional area for TLR4 to recognize pathogen and 1420 C>T caused no change in domains.The variation rate of TLR4 in IA group was 8%( 2/25 ) and both the patients had no underlying diseases. No mutation has been founded in control group and the difference between two groups was of statistical significance (P=0.037). Conclusion Two missense mutations (219 C>G and 1420 C>T) have been detec-ted in encoding area of TLR4 gene of IA patients.Variation in the cod-ing region of TLR4 gene may increase the susceptibility to IA.

Objective To investigate the characteristics of health related quality of life(HR-QOL) in Chinese patients with early Parkinson' s disease(PD), to identify the motor and non-motor factors that are associated with a poorer quality of life in patients with early PD. Methods All 391 patients with early PD were identified in a clinical-based study. Motor functions were measured by Unified Parkinson' s Disease Rating Scale (UPDRS) and Hoehn-Yabr Scale. Non-motor variables were assessed by Center of Epidemiological Survey Depression Scale (CES-D) for depressive symptoms, Pittsburg Sleep Quality Index (PSQI) for sleep disturbance, Fatigue Severity Scale (FSS) for fatigue, Alzheimer' s Disease Assessment Scale-Cognitive Sections (ADAS-Cng) for cognitive function, and Constipation Severity Scale for constipation. HR-QOL was measured by SF-36. Motor and non-motor variables were collected at the baseline assessment of a clinical trial and determined during a structured interview and by clinical examination by movement disorder specialists. The results were compared with those in healthy elderly people. Multiple regression analyses were used to determine which variables were strongly associated with lower levels of quality of life. Results Patients with early PD had a lower score on all dimensions of SF-36, except bodily pain dimension. Motor factors, particular physical disability and disease severity, contributed to decreased HR-QOL, but to a lesser extent. The motor score of the UPDRS (23. 8±11.8), Hoehn-Yahr stage(2. 0± 0.7), together with the rigidity score (4.4 ± 3.1), only accounted for 18.9 % (R2=0. 189) of the variance of SF-36 total score. The variables that most strongly predicted a low total SF-36 score were non-motor factors, particularly depressive symptoms, sleep disorders and fatigue. When the CES-D, FSS, and PSQI score were included in the model, the R2 increased from 0. 189 to 0.617, indicating that 61.7% of the variance in HR-QOL could be explained if additional CES-D, FSS and PSQI scores were known. Depressive symptoms, as measured by CES-D, had an overwhelming impact on HR-QOL. When CES-D score was included, the R2 change was 0.433, which indicated that additional 43.3% of the variability in HR-QOL could be explained by adding depressive symptoms. Conclusions PD has a substantial impact on HR-QOL, even if in its early stage. Depressive symptoms, sleep disorders and fatigue correlated strongly with lower quality of life. Depressive symptoms appeared to be the strongest determinant of HR-QOL in early PD patients. Every effort should be made to recognize and treat these conditions, thus improving all aspects of PD and giving these patients as good a quality of life as possible.

[ ABSTRACT] AIM:To study the effect of interleukin-1β( IL-1β) on neuron activation during the process of me-dial temporal lobe epilepsy ( MTLE ) .METHODS: IL-1β, rapamycin [ an inhibitor of mammalian target of rapamycin (mTOR)]and lentiviral transfection to knockdown PI3K-p85 were used to pre-treat the neurons.The protein levels of PI3K-p85, p-Akt, p-p70S6K and MAP2 were detected and the relationship among the tested cytokines was analyzed.The neuron endocytosis was observed in each group.RESULTS:IL-1βincreased the protein levels of PI3K-p85, p-Akt and p-p70S6K, up-regulated the expression of PI3K-p85 binding with IL-1RI in the neurons, and increased the neuron endocyto-sis compared with control group (P<0.05) .These processes were inhibited by rapamycin and silence of PI3K-p85 (P<0.05).Inhibition of the PI3K-p85 binding to IL-1RI decreased the protein levels of p-Akt, p-p70S6K and MAP2 which were increased by IL-1βstimulation (P<0.05).CONCLUSION: IL-1βactivates PI3K-p85 by binding with IL-1RI to promote the activation and proliferation of neuron synapses via PI3K/Akt/mTOR signaling pathway, which might be one of the mechanisms in MTLE chronic progress.