Anaerobic cyanides oxidation with bimetallic modulation of biological toxicity and activity for nitrite reduction.

Cyanide is a typical toxic reducing agent prevailing in wastewater with a well-defined chemical mechanism, whereas its exploitation as an electron donor by microorganisms is currently understudied. Given that conventional denitrification requires additional electron donors, the cyanide and nitrogen can be eliminated simultaneously if the reducing HCN/CN- and its complexes are used as inorganic electron donors. Hence, this paper proposes anaerobic cyanides oxidation for nitrite reduction, whereby the biological toxicity and activity of cyanides are modulated by bimetallics. Performance tests illustrated that low toxicity equivalents of iron-copper composite cyanides provided higher denitrification loads with the release of cyanide ions and electrons from the complex structure by the bimetal. Both isotopic labeling and Density Functional Theory (DFT) demonstrated that CN--N supplied electrons for nitrite reduction. The superposition of chemical processes reduces the biotoxicity and enhances the biological activity of cyanides in the CN-/Fe3+/Cu2+/NO2- coexistence system, including complex detoxification of CN- by Fe3+, CN- release by Cu2+ from [Fe(CN)6]3-, and NO release by nitrite substitution of -CN groups. Cyanide is the smallest structural unit of C/N-containing compounds and serves as a probe to extend the electron-donating principle of anaerobic cyanides oxidation to more electron-donor microbial utilization.

A methodology for evaluating the relative pollution level of metal pollution in surface sediments of rivers based on the statistical results of relevant literatures covering world-wide rivers.

Due to the intervention of human activities, the background values of riverbed sediment exhibit spatiotemporal variability, which can affect the accuracy of risk assessment results. Using risk assessment that do not rely on background values is an executable alternative to avoid such problems. In this study, a relative pollution level assessment (RPLA) method which was based on the statistical results of relevant literatures was proposed. This method includes a four-step data processing procedure to extract the evaluation indexes of relative pollution degree of pollutants in environment and a series of relative pollution status assessment methods to evaluate the overall relative pollution level and regional difference of world-wide rivers. To demonstrate how to use RPLA method, 310 relevant literatures covering world-wide rivers were selected. And the ambient background value (x̅), the world-wide threshold values (WWTV) and the relative pollution grades (LEVEL I ∼ IV) of 9 target metals (Cr, Ni, Cu, Zn, As, Cd, Pb, Sb and Tl) in riverbed surface sediments of world-wide rivers were extracted and used for evaluation. Moreover, the stability and applicability of RPLA method were evaluated. Results show that the evaluation results of RPLA method are robust and comparable with traditional evaluation method.

A combined process model for wastewater treatment based on hydraulic retention time and toxicity inhibition.

Hydraulic retention time (HRT), as an important parameter in the wastewater treatment process, has a great impact on water quality and energy consumption. With the rapid advances in computer technology and deepened understanding of in microbial metabolism, a series of activated sludge models (ASMs) have been developed and applied in wastewater treatment. However, ASMs simulation based on the nexus of HRT, water treatment process, water quality and energy consumption has yet to be verified. In this study, HRT was creatively linked to water treatment process variation. And a novel combined process model (CPM) was developed based on the operational data and treatment performance data from 4 full-scale coking wastewater treatment processes. In the CPM, an array of biological treatment processes were represented by setting the HRT in respective treatment units of the anaerobic-oxic-hydrolytic & denitrification-oxic (A/O/H/O) process. The relationships between HRT, effluent quality and energy consumption were systematically analyzed. Results showed that: (i) for A/O/H/O process, the HRT of first oxic (O1) reactor has a key effect on the effluent water quality and energy consumption, while the impact of the anaerobic (A) reactor HRT was limited; (ii) the O/H/O process has a clear advantage in treating coking wastewater due to the carbon removal and detoxification function of O1 reactor; (iii) the lowest energy consumption (with the total system HRT below 210 h) to meet the biological effluent quality requirements (COD = 200 mg/L, TN = 50 mg/L) is 4.429 kWh/m3. Since the CPM could effectively work out the optimal process configuration and break the boundaries between HRT and process variation, it has enormous potential to be extended to the design of other wastewater treatment processes.

Fate and distribution of phosphorus in coking wastewater treatment: From sludge to its derived biochar.

Due to the phosphorus (P) deficiency in coking wastewater, sufficient P needs to be provided in the treatment process to maintain biotic activity. However, most of the dosed P sources are transferred to the sludge phase out of the chemical equilibrium. After an in-depth investigation of P morphology changes in coking wastewater treatment, it is found that above 71.6 % P applied to the full-scale O/H/H/O (oxic-hydrolytic & denitrification-hydrolytic & denitrification-oxic) process for coking wastewater treatment is ended up in the sludge phase of the aerobic reactors in the forms of non-apatite inorganic phosphorus (NAIP). Theoretical simulations suggest that the P forms precipitates such as FePO4·2H2O, AlPO4·2H2O, MnHPO4 at pH < 7, and Ca5(PO4)3OH at pH > 7. Microbial utilization of P in coking wastewater treatment is swayed by precipitation, pH and sludge retention time (SRT). By pyrolysis treatment of the waste sludge at 700 °C, phosphoric substances in coking sludge are enriched and converted into Ca5(PO4)3OH, Ca5(PO4)3Cl, Ca3(PO4)2, etc. with apatite phosphorus (AP) accounting for 65.7 % of total phosphorus. Moreover, the heavy metals in biochar were below the national standard limits for discharge. This study shows that hazardous waste (coking sludge) can be transformed into bioavailable products (P-rich biochar) through comprehensive management of the fate of P. Combined with the O/H/H/O process, the mechanisms of phosphorus consumption in coking wastewater treatment are revealed for the first time, which will facilitate a reduced consumption of phosphorus and provide a demonstration for other phosphorus-deficient industrial wastewater treatment.

Bivalent BET Bromodomain Inhibitors Confer Increased Potency and Selectivity for BRDT via Protein Conformational Plasticity.

Bromodomain and extraterminal domain (BET) proteins are important regulators of gene transcription and chromatin remodeling. BET family members BRD4 and BRDT are validated targets for cancer and male contraceptive drug development, respectively. Due to the high structural similarity of the acetyl-lysine binding sites, most reported inhibitors lack intra-BET selectivity. We surmised that protein-protein interactions induced by bivalent inhibitors may differ between BRD4 and BRDT, conferring an altered selectivity profile. Starting from nonselective monovalent inhibitors, we developed cell-active bivalent BET inhibitors with increased activity and selectivity for BRDT. X-ray crystallographic and solution studies revealed unique structural states of BRDT and BRD4 upon interaction with bivalent inhibitors. Varying spacer lengths and symmetric vs unsymmetric connections resulted in the same dimeric states, whereas different chemotypes induced different dimers. The findings indicate that the increased intra-BET selectivity of bivalent inhibitors is due to the differential plasticity of BET bromodomains upon inhibitor-induced dimerization.

Small molecule-drug conjugates: A novel strategy for cancer-targeted treatment.

Targeted therapy has become an effective strategy of precision medicine for improving cancer treatment. Selectivity improvement is always popular in modern oncology because of decreased side effects in conventional cancer chemotherapy. The use of antibody-drug conjugates (ADC), a robust strategy for targeted therapy, applies antibodies to selectively deliver a potent cytotoxic compound to tumor cells and thus improve the therapeutic efficacy of the chemotherapeutic agents. Three ADC products (trastuzumab emtansine, brentuximab vedotin and inotuzumab ozogamicin) are already on the market, and several compounds are in clinical trials. Compared with ADCs, small molecule-drug conjugates (SMDCs) provide a new, less established perspective for targeted delivery. Nevertheless, SMDCs have several strengths: they have 1) a non-immunogenic nature, 2) much more manageable synthesis, 3) lower molecular weights, which confer a high potential for good cell penetration in solid tumors. SMDCs might therefore be a promising alternative with similar efficacy to ADCs. In this article, we highlight the medicinal chemistry aspects of SMDC design. SMDC targeting ligands, linkers and small-molecule payloads will be discussed. Successful cases of SMDCs used as therapeutic agents and other applications of SMDC will also be included.

Design, Synthesis, and Characterization of a Fluorescence Polarization Pan-BET Bromodomain Probe.

Several chemical probes have been developed for use in fluorescence polarization screening assays to aid in drug discovery for the bromodomain and extra-terminal domain (BET) proteins. However, few of those have been characterized in the literature. We have designed, synthesized, and thoroughly characterized a novel fluorescence polarization pan-BET chemical probe suitable for high-throughput screening, structure-activity relationships, and hit-to-lead potency and selectivity assays to identify and characterize BET bromodomain inhibitors.

Design, Synthesis and Evaluation of Indene Derivatives as Retinoic Acid Receptor α Agonists.

A series of novel indene-derived retinoic acid receptor α (RARα) agonists have been designed and synthesized. The use of receptor binding, cell proliferation and cell differentiation assays demonstrated that most of these compounds exhibited moderate RARα binding activity and potent antiproliferative activity. In particular, 4-((3-isopropoxy-2,3-dihydro-1H-inden-5-yl)-carbamoyl)benzoic acid (36d), which showed a moderate binding affinity, exhibited a great potential to induce the differentiation of NB4 cells (68.88% at 5 µM). Importantly, our work established indene as a promising skeleton for the development of novel RARα agonists.

Active Ankle Movements Prevent Formation of Lower-Extremity Deep Venous Thrombosis After Orthopedic Surgery.

BACKGROUND The aim of this study was to assess the preventive value of active ankle movements in the formation of lower-extremity deep venous thrombosis (DVT), attempting to develop a new method for rehabilitation nursing after orthopedic surgery. MATERIAL AND METHODS We randomly assigned 193 patients undergoing orthopedic surgery in the lower limbs into a case group (n=96) and a control group (n=97). The control group received routine nursing while the case group performed active ankle movements in addition to receiving routine nursing. Maximum venous outflow (MVO), maximum venous capacity (MVC), and blood rheology were measured and the incidence of DVT was recorded. RESULTS On the 11th and 14th days of the experiment, the case group had significantly higher MVO and MVC than the control group (all P<0.05). The whole-blood viscosity at high shear rate and the plasma viscosity were significantly lower in the case group than in the control group on the 14th day (both P<0.05). During the experiment, a significantly higher overall DVT incidence was recorded in the control group (8 with asymptomatic DVT) compared with the case group (1 with asymptomatic DVT) (P=0.034). During follow-up, the case group presented a significantly lower DVT incidence (1 with symptomatic DVT and 4 with asymptomatic DVT) than in the control group (5 with symptomatic DVT and 10 with asymptomatic DVT) (P=0.031). CONCLUSIONS Through increasing MVO and MVC and reducing blood rheology, active ankle movements may prevent the formation of lower-extremity DVT after orthopedic surgery.

miR-137 regulates the migration of human umbilical vein endothelial cells by targeting ephrin-type A receptor 7.

MicroRNAs (miRNAs) are short non-coding RNAs, which negatively regulate gene expression. Post­transcriptional regulation by miRNAs is important for organism development. In addition, endothelial cells are key regulators of angiogenesis. By using the 3-(4,5-dimethylthiazol-2-yl)­2,5­diphenyltetrazolium bromide (MTT), migration and gelatin sponge-chorioallantoic membrane assays, it was demonstrated that when miR-137 was overexpressed, cell viability and migration decreased. In addition, it was observed that blocking endogenous miR-137 increased cell viability and migration. Bioinformatics analysis indicated that the 3'­untranslated region (3'UTR) of the ephrin type-A receptor 7 (EPHA7) has a putative binding site for miR-137. miR-137 is able to directly bind to the EPHA7 3'UTR and negatively regulate the expression of EPHA7. miR-137 is also able to decrease the growth and migration of human umbilical vein endothelial cells (HUVECs). The identification of the function of miR-137 and its target gene EPHA7 in HUVECs may provide novel insights into the mechanisms of angiogenesis.

Imidazoline derivatives: a patent review (2006--present).

INTRODUCTION: Recent decades have witnessed the growing interest in the development of imidazoline derivatives in drug discovery due to increased knowledge in pathogenesis of many diseases. Imidazoline structure has been one of the most sought-after scaffolds employed in developing various agents with different kinds of pharmacological activities. During 2006 - 2012, imidazoline structures have been found in numerous patented compounds for the treatment of neurodegenerative diseases and cancer. AREAS COVERED: This paper provides a general review of patented imidazoline derivatives from 2006 to 2012. Information from articles published in international peer-reviewed journals has also been included to give a more exhaustive overview. EXPERT OPINION: With the uncovering of the molecular mechanisms related to neurodegenerative diseases and cancer, the use of classical and novel imidazoline structures has been more frequently noted in recent (2006 - 2012) patented agents for the treatment of neurodegenerative diseases and cancer instead of agents for the treatment of cardiovascular disease noticed earlier.

Identification of novel piperazinylquinoxaline derivatives as potent phosphoinositide 3-kinase (PI3K) inhibitors.

BACKGROUND: Development of small-molecule inhibitors targeting phosphoinositide 3-kinase (PI3K) has been an appealing strategy for the treatment of various types of cancers. METHODOLOGY/PRINCIPAL FINDING: Our approach was to perform structural modification and optimization based on previously identified morpholinoquinoxaline derivative WR1 and piperidinylquinoxaline derivative WR23 with a total of forty-five novel piperazinylquinoxaline derivatives synthesized. Most target compounds showed low micromolar to nanomolar antiproliferative potency against five human cancer cell lines using MTT method. Selected compounds showed potent PI3Kα inhibitory activity in a competitive fluorescent polarization assay, such as compound 22 (IC(50) 40 nM) and 41 (IC(50): 24 nM), which induced apoptosis in PC3 cells. Molecular docking analysis was performed to explore possible binding modes between target compounds and PI3K. CONCLUSIONS/SIGNIFICANCE: The identified novel piperazinylquinoxaline derivatives that showed potent PI3Kα inhibitory activity and cellular antiproliferative potency may be promising agents for potential applications in cancer treatment.

Synthesis and biological evaluation of new 4ß-anilino-4'-O-demethyl-4-desoxypodophyllotoxin derivatives as potential antitumor agents.

A series of new 4ß-anilino-4'-O-demethyl-4-desoxypodophyllotoxin derivatives were prepared and evaluated for their cytotoxicities against four human cancer cell lines including KB, KB/VCR, A549 and 95D. Most compounds showed better growth-inhibition activities against tested cell lines than that of etoposide (VP-16). Preliminary structure-activity relationships (SARs) were concluded and it indicated that the side chains substituted at 4ß position of podophyllotoxin significantly influenced the cytotoxic activity, especially for the drug resistance profile. In vivo studies of compound 26c on highly metastatic human lung cancer xenograft in nude mice showed that it can significantly inhibit tumor growth with administrating by oral route.

[The diagnostic value of platelet glycoprotein-specific autoantibody detection in idiopathic thrombocytopenic purpura].

To detect levels of platelet glycoprotein-specific autoantibody in idiopathic thrombocytopenic purpura (ITP), chronic aplastic anemia (CAA), hematologic malignancies and healthy volunteers, and evaluate the clinical significance of platelet glycoprotein-specific autoantibody level in diagnosis for ITP, anti-GPIb/IX, anti-GPIIb/IIIa, anti-GPIV and anti-GPV auto-antibodies were detected contemporaneously by a modified monoclonal antibody immobilization of platelet antigen assay (modified MAIPA). The results showed that the total positive rate of antibodies against platelet GPIb/IX, GPIIb/IIIa, GPIV, GPV were 69.99%, 10%, 20% and 0% in ITP, CAA, hematologic malignancy group and healthy volunteers respectively. There was significant difference between ITP and CAA (chi(2) = 20.71, P < 0.005), between ITP and hematologic malignancy group (chi(2) = 12.22, P < 0. 005). There was no positive finding in the healthy control. It is concluded that platelet glycoprotein-specific autoantibody has high value for the diagnosis of ITP,many kinds of antibodies detection at one time can enhance sensitivity, MAIPA is a specific assay for the diagnosis of idiopathic thrombocytopenic purpura.