Long non-coding RNA DLEU1 promotes malignancy of breast cancer by acting as an indispensable coactivator for HIF-1α-induced transcription of CKAP2.

Earlier studies have suggested deleted in lymphocytic leukemia 1 (DLEU1), a long non-coding RNA, is a prognostic biomarker for breast cancer. Here we explored the malignant behaviors and underlying mechanisms regulated by DLEU1 in breast cancer. We demonstrated that up-regulation of DLEU1 was detected in breast cancer tissues and cells, particularly in tumors of higher malignancy. DLEU1 knockdown inhibited the growth and the motility of breast cancer cells. Mechanistically, DLEU1 interacted with HIF-1α to collectively activate the transcription of CKAP2. By activating ERK and STAT3 signaling, CKAP2 essentially mediated the pro-tumor activities of DLEU1. In vivo, depletion of DLEU1 inhibited xenograft growth and metastasis of breast cancer cells. Therefore, DLEU1, by acting as a coactivator for HIF-1α, up-regulates CKAP2 expression and promotes malignancy of breast cancer. Targeting DLEU1, HIF-1α, or CKAP2 may thus benefit breast cancer treatment.

Enhanced electrocatalytic performance of TiO2 nanoparticles by Pd doping toward ammonia synthesis under ambient conditions.

The traditional Haber-Bosch process in industry to produce NH3 leads to excessive CO2 emissions and a large amount of energy consumption. Ambient electrochemical N2 reduction is emerging as a green and sustainable alternative method to convert N2 to NH3, but is in sore need of efficient and stable electrocatalysts. Herein, we propose using Pd-doped TiO2 nanoparticles as a high-efficiency electrocatalyst to synthesize NH3 under ambient conditions. The Pd-TiO2 catalyst delivers a large NH3 yield (17.4 µg h-1 mgcat.-1) and a high faradaic efficiency (12.7%) at -0.50 V versus reversible hydrogen electrode in a neutral electrolyte, outperforming most Pd- and Ti-based electrocatalysts recently reported for N2 reduction. Most importantly, it also demonstrates extraordinary long-term electrochemical stability.

A new biflavonoids from Aster tataricus induced non-apoptotic cell death in A549 cells.

A new biflavonoids, (2R,2''R)-7-O-methyl-2,3,2'',3''-tetrahydrorobustaflavone (1), along with five known flavonoids (2-6) were isolated from the MeOH extract of Aster tataricus. Among them, compounds 1-2 were the C-3'-C-6'' type biflavonoids obtained from the genus Aster for the first time. The structures and absolute configurations of compound 1 was confirmed based on extensive spectroscopic and circular dichroism analyses. Compound 1 exhibited moderate cytotoxicity against seven human cancer A549, HepG2, PC3, DU145, MCF-7, LOVO and NCI-H1975 cell lines. Compound 1 remarkably inhibited the proliferation of A549 cancer cells with IC50 value of 5.4 µM. Further preliminary pharmacological study, 1 induces A549 cell death by non-apoptotic forms through flow cytometry and cell scratch assay data.

The prognostic value of MELD-XI in elderly patients with ST-segment elevation myocardial infarction: an observational study.

BACKGROUND: The model for end-stage liver disease excluding international normalized ratio (MELD-XI) is a simple score for risk assessment. However, the prognostic role of MELD-XI and its additional value to current risk assessment in elderly patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI) is uncertain. METHODS: In all, 1029 elderly patients with STEMI undergoing PCI were consecutively included and classified into three groups according to the TIMI risk score: low-risk (≤ 3, n = 251); moderate-risk (4-6, n = 509); and high-risk (≥ 7, n = 269) groups. Multivariate analysis was performed to identify risk factors for adverse events. RESULTS: The overall in-hospital mortality was 5.3% and was significantly higher in the high-risk group (1.2% vs. 3.3% vs. 13.0%, p < 0.001). The optimal cut-off of the TIMI risk score and MELD-XI for in-hospital death was 7 and 13, respectively. MELD-XI was associated with in-hospital (adjusted odds ratio = 1.09, 95% CI = 1.04-1.14, p = 0.001) and one-year (adjusted hazard ratio = 1.05, 95% CI = 1.01-1.08, p = 0.005) mortality independently of the TIMI risk score. Combining TIMI risk score and MELD-XI exhibited better predictive power for in-hospital death than TIMI risk score (area under the curve [AUC] = 0.810 vs. 0.753, p = 0.008) or MELD-XI alone (AUC = 0.810 vs. 0.750, p = 0.018). Patients with TIMI risk score ≥ 7 and MELD-XI ≥ 13 had the worst prognosis. CONCLUSION: MELD-XI could be considered as a risk-stratified tool for elderly patients with STEMI undergoing PCI. It had an additive prognostic value to TIMI risk score.

[Effect of Baicalin Derivative 02-036 on Burkitt Lymphoma Cell Line CA46 and Its Related Mechanisms].

OBJECTIVE: To investigate the effect of baicalin derivative 02-036 on proliferation and apoptosis human Burkitt lymphoma cell line CA46 and its related mechanisms. METHODS: The MTT assay and cell colony formation assay were used to measure the growth inhibition of CA46 cells after 02-036 treatment. The flow cytometry with AnnexinV-FITC/PI double staining was employed to detect the apoptosis induction effect of 02-036 on CA46 cells. Cell cycle distribution of CA46 cells was estimeted by using DNA ploid analysis. Western blot was used to determine the changes of apoptosis-related proteins, including C-MYC, BCL-2, Procaspase-9, Procaspase-3, PARP and Cleaved-PARP. RESULTS: Baicalin derivative 02-036 obviously inhibited the proliferation of CA46 cells, with dose- and time-dependent manner (r=0.963, r=0.992). The averaged IC50 value of CA46 cells was (6.04±0.11) µmol/L after 48-hour treatment. Low concentration of 02-036 could significantly inhibit the colony formation of CA46 cells. Flow cytometry analysis confirmed that 02-036 could effectively induce CA46 cell apoptosis. The apoptosis rate correlated with drug concentrations (r=0.959). Also, DNA ploid analysis showed that the cell cycle of CA46 was arrested in the S phase. The expression levels of BCL-2, Pro-caspase-9, Pro-caspase-3, PARP and C-MYC proteins decreased with a 02-036-dose dependent manner (r values were -0.990, -0.939, -0.971 and -0.967, respectively). In contrast, the expression level of cleaved-PARP increased with the same manner (r=0.920). CONCLUSION: Baicalin derivative 02-036 can effectively inhibit the proliferation and induce apoptosis of CA46 cells, and its related mechanisms may be correlated with the down-regulation of apoptosis-related molecule expression levels, such as BCL-2, Pro-caspase-9, Pro-caspase-3, PARP and C-MYC.

Synthesis and biological characterization of novel rose bengal derivatives with improved amphiphilicity for sono-photodynamic therapy.

Sono-Photodynamic therapy (SPDT) utilizing ultrasound and light has been demonstrated that this novel approach can lower dosage resulting in reduction of the potential side effects caused by sensitizers. Recently, a new formulation of rose bengal (RB) as an intralesional injection has completed clinical trials phase II for PDT treatment of melanoma cancer. However, the inherent unfavorable pharmacological properties of RB hindered its extensive clinical development. With the aim to identify new RB derivatives (RBDs) with enhanced photodynamic and sonodynamic anticancer efficiency, a series of amphiphilic RBDs have been designed, synthesized and biological characterized. Among them, RBD4 significantly improved cellular uptake and enhanced intracellular ROS generation efficiency upon light and ultrasound irradiation, resulting in dramatically improved anticancer potency. Notably, RBD4 has a relative potency similar to sinoporphyrin sodium (DVDMS), indicating its further potential application for SPDT.

Iron Nanoclusters as Template/Activator for the Synthesis of Nitrogen Doped Porous Carbon and Its CO2 Adsorption Application.

We propose a facile synthesis approach for nitrogen doped porous carbon and demonstrate a novel pore-forming method that iron nanoclusters act as a template or activator at different carbonization temperatures based on Fe3+-poly(4-vinyipyridine) (P4VP) coordination. P4VP will completely decompose even in an inert atmosphere, but under the coordination and catalysis of Fe3+, it can be converted to carbon at a very low temperature (400 °C). The aggregation of iron nanoclusters in the carbonization process showed different pore-forming methods at different temperatures. The as-prepared materials possess high specific surface area (up to 1211 m2 g-1), large pore volume (up to 0.96 cm3 g-1), narrow microporosity, and high N content (up to 9.9 wt %). Due to these unique features, the materials show high CO2 uptake capacity and excellent selectivity for CO2/N2 separation. The CO2 uptake capacity of NDPC-2-600 is up to 6.8 and 4.3 mmol g-1 at 0 and 25 °C; the CO2/N2 (0.15/0.85) selectivity at 0 and 25 °C also reaches 18.4 and 15.2, respectively.

Effect of a hepatitis B virus inhibitor, NZ-4, on capsid formation.

During the hepatitis B virus (HBV) life cycle, nucleocapsid assembly is essential for HBV replication. Both RNA reverse transcription and DNA replication occur within the HBV nucleocapsid. HBV nucleocapsid is consisted of core protein (HBcAg), whose carboxy-terminal domain (CTD) contains an Arg-rich domain (ARD). The ARD of HBcAg does contribute to the encapsidation of pregenomic RNA (pgRNA). Previously, we reported a small-molecule, NZ-4, which dramatically reduced the HBV DNA level in an in vitro cell setting. Here, we explore the possible mechanisms by which NZ-4 inhibits HBV function. As an HBV inhibitor, NZ-4 leads to the formation of genome-free capsids, including a new population of capsid that runs faster on agarose gels. NZ-4's activity was dependent on the presence of the ARD I, containing at least one positively charged amino acid. NZ-4 might provide a new option for further development of HBV therapeutics for the treatment of chronic hepatitis B.

Potential sonodynamic anticancer activities of artemether and liposome-encapsulated artemether.

The potential application of artemether as a novel sonosensitizer for sonodynamic therapy (SDT) was explored and illustrated for the first time. In addition, liposome-encapsulated artemether exhibited significantly enhanced sonodynamic anticancer activity. Our findings indicated that artemisinin derivatives may serve as a new kind of sonosensitizer for SDT.

Preparation and sonodynamic activities of water-soluble tetra-α-(3-carboxyphenoxyl) zinc(II) phthalocyanine and its bovine serum albumin conjugate.

Sonodynamic therapy (SDT) is a new approach for cancer treatment, involving the synergistic effect of ultrasound and certain chemical compounds termed as sonosensitizers. A water-soluble phthalocyanine, namely tetra-α-(3-carboxyphenoxyl) zinc(II) phthalocyanine (ZnPcC4), has been prepared and characterized. The interactions between ZnPcC4 and bovine serum albumin (BSA) were also investigated by absorption and fluorescence spectroscopy. It was found that there were strong interactions between ZnPcC4 and BSA with a binding constant of 6.83×10(7)M(-1). A non-covalent BSA conjugate of ZnPcC4 (ZnPcC4-BSA) was prepared. Both ZnPcC4 and ZnPcC4-BSA exhibited efficient sonodynamic activities against HepG2 human hepatocarcinoma cells. Compared with ZnPcC4, conjugate ZnPcC4-BSA showed a higher sonodynamic activity with an IC50 value of 7.5µM. Upon illumination with ultrasound, ZnPcC4-BSA can induce an increase of intracellular reactive oxygen species (ROS) level, resulting in cellular apoptosis. The results suggest that the albumin conjugates of zinc(II) phthalocyanines functionalized with carboxyls can serve as promising sonosensitizers for sonodynamic therapy.

Nevirapine versus efavirenz for patients co-infected with HIV and tuberculosis: a systematic review and meta-analysis.

OBJECTIVES: Antiretroviral therapy (ART) reduces the morbidity and mortality of patients infected with HIV. Standard ART includes either nevirapine or efavirenz, however the efficacy of these drugs is limited in patients receiving rifampin treatment for tuberculosis (TB). We compared the efficacy and safety of nevirapine- and efavirenz-based ART regimens in patients co-infected with both HIV and TB through a systematic review and meta-analysis. METHODS: A comprehensive search of the literature was carried out to identify clinical trials comparing the efficacy and safety of nevirapine- and efavirenz-based ART regimens in HIV-associated TB. Eligible clinical studies included at least one primary or secondary event; the primary event was virological response and secondary events were TB treatment outcomes, mortality, and safety profile. RESULTS: This meta-analysis compared five randomized clinical trials and four retrospective clinical trials. Both included patients co-infected with HIV and TB; 833 received nevirapine, while 1424 received efavirenz. The proportion of patients achieving a virological response by the end of the follow-up was higher in the efavirenz group: plasma viral load <400 copies/ml, risk ratio (RR) 1.10, 95% confidence interval (CI) 1.03-1.17 (p = 0.004); plasma viral load<50 copies/ml, RR 1.07, 95% CI 0.98-1.16 (p = 0.146). No significant differences were found in either mortality (RR 0.70, 95% CI 0.44-1.13, p = 0.142) or TB treatment outcomes (RR 1.01, 95% CI 0.96-1.06, p = 0.766). Due to adverse advents, nevirapine-based regimens significantly increased the risk of discontinuation of assigned ART (RR 0.43, 95% CI 0.23-0.81, p = 0.009). CONCLUSIONS: Although efavirenz-based ART was associated with more satisfactory virological outcomes, nevirapine-based ART could be considered an acceptable alternative for patients for whom efavirenz cannot be administered.

Synthesis and biological evaluation of novel bis-aromatic amides as novel PTP1B inhibitors.

A series of bis-aromatic amides was designed, synthesized, and evaluated as a new class of inhibitors with IC50 values in the micromolar range against protein tyrosine phosphatase 1B (PTP1B). Among them, compound 15 displayed an IC50 value of 2.34±0.08 µM with 5-fold preference over TCPTP. More importantly, the treatment of CHO/HIR cells with compound 15 resulted in increased phosphorylation of insulin receptor (IR), which suggested extensive cellular activity of compound 15. These results provided novel lead compounds for the design of inhibitors of PTP1B as well as other PTPs.

Isothiafludine, a novel non-nucleoside compound, inhibits hepatitis B virus replication through blocking pregenomic RNA encapsidation.

AIM: To investigate the action of isothiafludine (NZ-4), a derivative of bis-heterocycle tandem pairs from the natural product leucamide A, on the replication cycle of hepatitis B virus (HBV) in vitro and in vivo. METHODS: HBV replication cycle was monitored in HepG2.2.15 cells using qPCR, qRT-PCR, and Southern and Northern blotting. HBV protein expression and capsid assembly were detected using Western blotting and native agarose gel electrophoresis analysis. The interaction of pregenomic RNA (pgRNA) and the core protein was investigated by RNA immunoprecipitation. To evaluate the anti-HBV effect of NZ-4 in vivo, DHBV-infected ducks were orally administered NZ-4 (25, 50 or 100 mg·kg⁻¹·d⁻¹) for 15 d. RESULTS: NZ-4 suppressed intracellular HBV replication in HepG2.2.15 cells with an IC50 value of 1.33 µmol/L, whereas the compound inhibited the cell viability with an IC50 value of 50.4 µmol/L. Furthermore, NZ-4 was active against the replication of various drug-resistant HBV mutants, including 3TC/ETV-dual-resistant and ADV-resistant HBV mutants. NZ-4 (5, 10, 20 µmol/L) concentration-dependently reduced the encapsidated HBV pgRNA, resulting in the assembly of replication-deficient capsids in HepG2.2.15 cells. Oral administration of NZ-4 dose-dependently inhibited DHBV DNA replication in the DHBV-infected ducks. CONCLUSION: NZ-4 inhibits HBV replication by interfering with the interaction between pgRNA and HBcAg in the capsid assembly process, thus increasing the replication-deficient HBV capsids. Such mechanism of action might provide a new therapeutic strategy to combat HBV infection.

1H-2,3-dihydroperimidine derivatives: a new class of potent protein tyrosine phosphatase 1B inhibitors.

A series of 1H-2,3-dihydroperimidine derivatives was designed, synthesized, and evaluated as a new class of inhibitors of protein tyrosine phosphatase 1B (PTP1B) with IC50 values in the micromolar range. Compounds 46 and 49 showed submicromolar inhibitory activity against PTP1B, and good selectivity (3.48-fold and 2.10-fold respectively) over T-cell protein tyrosine phosphatases (TCPTP). These results have provided novel lead compounds for the design of inhibitors of PTP1B as well as other PTPs.

Expression of huCdc7 in colorectal cancer.

AIM: To detect the expression of huCdc7 in colorectal cancer. METHODS: The mRNA and protein expression of huCdc7 in 39 colorectal cancer tissue specimens and matched tumor-adjacent normal colorectal tissue specimens was detected by reverse transcription-polymerase chain reaction and immunohistochemistry, respectively. RESULTS: The relative expression level of huCdc7 mRNA in colorectal cancer was significantly higher than that in tumor-adjacent normal colorectal tissues (0.03675 ± 1.00 vs 0.01199 ± 0.44, P < 0.05). huCdc7-positive cells displayed brown granules in the nucleus. Tumor tissues contained many huCdc7-positive cells, whereas normal colorectal tissues contained very few positive cells. CONCLUSION: huCdc7 may play an important role in the development and progression of colorectal cancer.

Synthesis and antiviral activity of conformational analogues of leucamide A.

In order to study the effect of heterocyclic core conformational state of leucamide A on its anti-influenza virus A activity, five conformational analogues were prepared by replacing the Pro-Leu dipeptide in the molecule with various amino acids. The amino acids used were of 2 to 6 carbons. The results showed that these replacements not only changed the conformational relationship between the 4,2-bisheterocycle tandem pair and the third heterocycle, but also had dramatic effect on its activity against influenza virus A.

[A correlation study of Tei index and N-terminal pro-brain natriuretic peptide in patients with high-altitude heart disease].

OBJECTIVE: To explore the diagnostic value of Tei index of right ventricle and serum level of NT-proBNP in patients with high-altitude heart disease (HAHD). METHODS: Right ventricle Tei index and serum NT-proBN level were calculated and tested in 32 local healthy volunteers and 34 cases of HAHD patients hospitalized in our hospital in Golmud city (2808 meters above sea level) from 2008 to 2010, and a correlation study was conducted thereafter. RESULTS: The pulmonary arterial systolic pressure and right ventricle Tei index, elevated significantly in HAHD patients compared with the control group [(86.61 vs 9.72) mm Hg (1 mm Hg = 0.133 kPa) and (0.90 vs 0.33) respectively, P < 0.05]. Patients diagnosed as mild pulmonary hypertension without alteration in cardiac structure showed higher pulmonary arterial systolic pressure and the Tei index compared with the control group [(57.1 vs 9.72) mm Hg and (0.78 vs 0.33) respectively, P < 0.05]. In addition, the level of serum NT-proBNP was significantly higher in HAHD group than that of control group [(1246.8 ± 512.6) ng/L and (98.6 ± 21.7) ng/L respectively, P < 0.05]. CONCLUSION: Right ventricle Tei index and serum NT-proBNP level are sensitive indicators for right ventricular function and thus of favorable clinical significance for the diagnosis of HAHD.

Discovery and structural optimization of pyrazole derivatives as novel inhibitors of Cdc25B.

Structural optimization and preliminary structure-activity relationship studies of a series of N-substituted maleimide fused-pyrazole analogues with Cdc25B inhibitory activity, starting from a high-throughput screening hit, are illustrated. A simplified 3,5-diacyl pyrazole analogue was obtained as the most potent compound (118, IC(50)=0.12 microM) with a 270-fold increase in potency.

Periplocoside A, a pregnane glycoside from Periploca sepium Bge, prevents concanavalin A-induced mice hepatitis through inhibiting NKT-derived inflammatory cytokine productions.

Periploca sepium Bge, a traditional Chinese herb medicine, is widely used for treating rheumatoid arthritis in china. Periplocoside A (PSA), a pregnane glycoside, is a new nature product compound isolated from P. sepium Bge. We examined the protective effects of PSA, on concanavaline A (ConA)-induced hepatitis. Pretreatment with PSA dramatically ameliorated ConA-induced liver injury, which was characterized by reducing serum alanine transaminase (ALT), pathogenic cytokines of interleukin (IL)-4 and interferon (IFN)-gamma levels, impeding the liver necrosis, and thus elevating the survival rate. In vitro, PSA inhibited IL-4 and IFN-gamma productions of alpha-galactosylceramide (alpha-GalCer) or anti-CD3-activated Natural killer T (NKT) cells. Enzyme Linked Immunosorbent Assay (ELISA) and Reverse Transcription Polymerase Chain Reaction (RT-PCR) assays revealed PSA suppressed IL-4 transcription and IFN-gamma translation. In conclusion, PSA had significantly preventative effect on ConA-induced hepatitis, which was closely associated with inhibition of NKT-derived inflammatory cytokine productions. These findings suggested that PSA has the therapeutic potential for treatment of human autoimmune-related hepatitis.