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Shaza M Elhusseiny,1 Taghrid S El-Mahdy,2 Nooran S Elleboudy,3 Ibrahim S Yahia,4,5 Mohamed MS Farag,6,7 Nasser SM Ismail,8 Mahmoud A Yassien,3 Khaled M Aboshanab3 1Department of Microbiology and Immunology, Faculty of Pharmacy, Ahram Canadian University (ACU), Cairo, 12566, Egypt; 2Department of Microbiology and Immunology, Faculty of Pharmacy, Helwan University, Cairo, Egypt; 3Department of Microbiology and Immunology, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt; 4Laboratory of Nano-Smart Materials for Science and Technology (LNSMST), Department of Physics, Faculty of Science, Research Center for Advanced Materials Science (RCAMS), King Khalid University, Abha, Saudi Arabia; 5Nanoscience Laboratory for Environmental and Bio-Medical Applications (NLEBA), Semiconductor Lab, Metallurgical Lab, Physics Department, Faculty of Education, Ain Shams University, Cairo, Egypt; 6Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Cairo, 11884, Egypt; 7Armed Forces College of Medicine (AFCM), Cairo, Egypt; 8Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Future University in Egypt, Cairo, 11835, EgyptCorrespondence: Khaled M Aboshanab, Department of Microbiology and Immunology, Faculty of Pharmacy, Ain Shams University, Organization of African Unity Street, Abbassia, Cairo, 11566, Egypt, Tel +20 1-0075-82620, Fax +20 224051107, Email aboshanab2012@pharma.asu.edu.egBackground: Fungi are rich source of biologically active metabolites aimed for the improvement of human health through the prevention of various diseases, including infections and inflammatory disorders.Aim: We aimed to in vitro examine the anti-SARS CoV-2 activity of the aqueous extract of each Pleurotus (P.) ostreatus, Lentinula (L.) edodes and Agaricus (A.) bisporus edible mushroom followed by docking analysis of certain metabolites against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-main protease (protease Mpro).Methods: Antiviral and cytotoxic effects were tested on hCoV-19/Egypt/NRC-3/2020/Vero-E6 cells and analyzed via (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide Assay (MTT) assay. Ligand-protein and protein-protein docking studies were performed to explore the interaction of different mushroom extracts at the binding site of protease Mpro. Molecular dynamics (MD) simulations were performed on the most promising ligand-target complexes to investigate their dynamic properties and confirm docking results.Results: Substantial antiviral activities with an IC50 of 39.19, 26.17, and 10.3.3 μg/mL and a selectivity index (SI) of 4.34, 3.44, and 1.5 for P. ostreatus, L. edodes and A. bisporus, were observed, respectively. Docking analysis revealed that, catechin from three mushroom isolates, chlorogenic acid from A. bisporus, kamperferol of P. ostreatus and quercetin from L. edodes, with a C-DOCKER interaction energy in the range of 22.8– 37.61 (Kcal/mol) with protease compared to boceprevir ligand of 41.6 (Kcal/mol). Docking of superoxide dismutase, catalase from the three mushrooms, tyrosinase from A. bisporus showed ligand contact surface area with the protein as 252.74 Å2 while receptor contact surface area was 267.23 Å2.Conclusion: P. ostreatus, L. edodes and A. bisporus have potential and remarkable in vitro antiviral activities against SARS-CoV-2. Quercetin from L. edodes, Kaempferol from P. ostreatus, chlorogenic acid and ascorbic acid, catechin, superoxide dismutase and catalase of the three mushrooms extracts were effectively bounded to Mpro of SARS-CoV-2 as conferred by docking analysis.Keywords: edible mushrooms, Pleurotus ostreatus, Lentinula edodes, Agaricus bisporus, SARS-CoV-2, cytotoxicity

Background: Sunitinib, a multitargeted tyrosine-kinase inhibitor, which is approved by both US and European Commission regulatory agencies for clinical use, extends survival of patients with metastatic renal-cell carcinoma and gastrointestinal stromal tumours, but concerns have arisen about its cardiac safety. We therefore assessed the cardiovascular risk associated with sunitinib in patients with metastatic gastrointestinal stromal tumours.Methods: We retrospectively reviewed all cardiovascular events in 75 patients with imatinib-resistant, metastatic, gastrointestinal stromal tumours who had been enrolled in a phase I/II trial investigating the efficacy of sunitinib. The composite cardiovascular endpoint was cardiac death, myocardial infarction, and congestive heart failure. We also examined sunitinib's effects on left ventricular ejection fraction (LVEF) and blood pressure. We investigated potential mechanisms of sunitinib-associated cardiac effects by studies in isolated rat cardiomyocytes and in mice.Findings: Eight of 75 (11%) patients given repeating cycles of sunitinib in the phase I/II trial had a cardiovascular event, with congestive heart failure recorded in six of 75 (8%). Ten of 36 (28%) patients treated at the approved sunitinib dose had absolute LVEF reductions in ejection fraction (EF) of at least 10%, and seven of 36 (19%) had LVEF reductions of 15 EF% or more. Sunitinib induced increases in mean systolic and diastolic blood pressure, and 35 of 75 (47%) individuals developed hypertension (>150/100 mm Hg). Congestive heart failure and left ventricular dysfunction generally responded to sunitinib being withheld and institution of medical management. Sunitinib caused mitochondrial injury and cardiomyocyte apoptosis in mice and in cultured rat cardiomyocytes.Interpretation: Left ventricular dysfunction might be due, in part, to direct cardiomyocyte toxicity, exacerbated by hypertension. Patients treated with sunitinib should be closely monitored for hypertension and LVEF reduction, especially those with a history of coronary artery disease or cardiac risk factors. [ABSTRACT FROM AUTHOR]

Background: Ocular trauma is the leading cause of monocular blindness in children. This study aimed to identify and compare pediatric ocular injuries at two national university hospitals: Benha University Hospital (BUH) and South Valley University Hospital (SVUH) while evaluating the predictive utility of the Ocular Trauma Score (OTS) for post-traumatic permanent visual infirmity., Design and Methods: This multicenter observational study enrolled children under 18 years at BUH and SVUH Ophthalmology Departments from May 31 to December 31, 2022. Comprehensive medical histories and detailed data on eye trauma were obtained, with each undergoing thorough eye examinations at the initial presentation and during the 6-month follow-up period. The final visual outcome was permanent visual infirmity that was defined as the Best Corrected Visual Acuity in the better eye worse than 3/60 or near vision worse than N6 according to the International Classification of Diseases 11., Results: The study included 120 cases evenly distributed between the two hospitals, with a mean age of 10.03 (±3.30) years, 74.17% male and 51.67% urban residents. Blunt, sharp, and foreign objects were the most common causes (39.17%, 33.33%, and 11.67%, respectively). Closed-globe injuries prevailed at BUH (83.33%) than SVUH (40.0%). Most injuries were accidental and outdoors, with an average interval of 9.93 (±23.57) hours to seek medical care. Lack of education, open-globe injuries, poor initial visual acuity, longer intervals from admission to intervention, and lower OTS were associated with visual impairment., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Two rapid, precise, and sensitive stability-indicating high performance chromatographic methods for the measurement of Teriflunomide in its degradation products' existence were developed. These were RP-HPLC and HPTLC using UV detector. HPLC separation was accomplished utilizing Thermo BDS hypercil C18 column (250 × 4.6 mm, 5 μm) and acetonitrile: 0.03 M potassium dihydrogen phosphate: triethylamine (50:50:0.1%, by volume) as mobile phase at flow rate of 1mL/min. The separated peaks were detected at 250.0 nm. The densitometric approach was conducted utilizing HPTLC 60 F254 silica gel plates, and a developing system of benzene: ethanol: acetic acid (7.5:1:0.25, by volume) and detection was done at 250.0 nm. The developed approaches were evaluated regarding the International Conference on Harmonization (ICH) instructions. The calibration curves of both techniques were constructed with linearity ranges of (5-100) µg/mL and (2-10) µg /band, for HPLC and densitometric determination, consecutively. Teriflunomide was exposed to base and acid hydrolysis, oxidation using H 2 O 2 and finally, thermal degradation as stated in ICH guidelines. The degradation product structures' elucidation was achieved through LC-MS., (© 2024. The Author(s).)

Background: 5α-Reductase type II (5αR2) inhibition is a promising strategy for benign prostatic hyperplasia treatment. A computational approach including virtual screening, ligand-based 3D pharmacophore modeling, 2D quantitative structure-activity relationship and molecular docking simulations were adopted to develop novel inhibitors. Results: Hits were first filtered via the validated pharmacophore and 2D quantitative structure-activity relationship models. Docking on the recently determined cocrystallized structure of 5αR2 showed three promising hits. Visual inspection results were compared with finasteride ligand and dihydrotestosterone as reference, to explain the role of binding to Glu57 and Tyr91 for 5αR2 selective inhibition. Conclusion: Alignment between Hit 2 and finasteride in the binding pocket showed similar binding modes. The biological activity prediction showed antitumor and androgen targeting activity of the new hits.

Objectives . To evaluate carotid artery intima-media thickness (CIMT) and lipid profile in children with epilepsy on long-term antiepileptic drug (AED) monotherapy. Methods . We included 60 children with epilepsy receiving valproate, carbamazepine, or levetiracetam monotherapy and 60 controls. A high-resolution B-mode ultrasound was used to measure (CIMT). Measurement of serum lipids was done. Results . Patients on valproate (0.44 ± 0.03, P  ≤ .001), carbamazepine (0.43 ± 0.03with P  ≤ .001), and levetiracetam (0.44 ± 0.02 with P  ≤ .001) monotherapy showed significantly higher CIMT compared to controls. CIMT was correlated with age ( P  = .041, r  = .112) AEDs{valproate ( P  = .005, r  = .731), carbamazepine ( P  = .038, r  = .365), and levetiracetam ( P  = .036, r  = .155)}, duration of treatment ( P  = .001, r  = .313), TC( P  = .001, r  = .192), TG ( P  = .014, r  = .018), and LDL ( P  = .001, r  = .219). HDL ( P  = .003, r  = -.126). Seizure severity and Apo A1 were insignificantly involved. Conclusion . Long-term monotherapy with valproate, carbamazepine, and levetiracetam in epileptic children was associated with significant abnormalities in CIMT., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Three smart carbon paste electrodes were fabricated to quantify dorzolamide hydrochloride DRZ, including conventional carbon paste I, modified carbon paste embedding Silica II, and modified carbon paste embedding β-cyclodextrin III. This study is based on the insertion of DRZ with phosphomolybdic acid to create an electroactive moiety dorzolamide-phosphomolybdate ion exchanger using a solvent mediator dibutyl phthalate. The three constructed carbon paste electrodes displayed Nernstian responses and linear concentration ranges with lower detection limits. The vital performance of the created electrodes was verified in relation to various parameters. The electrodes enhance the selective determination of DRZ in the presence of inorganic ions, a co-formulated drug in the dosage form timolol maleate, and the excipient benzalkonium chloride. The modified carbon paste electrode including Silica was utilized to detect DRZ in ophthalmic eye drop form utilizing the direct calibration curve and potentiometric titration methods. Satisfactory findings were achieved by comparing them to other reported methods., (© 2023. Springer Nature Switzerland AG.)

Microplastics (MPs) pollution is a newly emerging environmental issue. MPs can accumulate within animals and humans, which can pose a serious health threat. Petroleum-based polyethylene (PE) is one of the most popular plastics. Accordingly, its exposure rates have steadily increased over the years. This study aimed to analyze the effects of PE-MPs on the hematological system of albino rats and the epigenetic effect. Five groups of adult male eight-weeks-old rats received either distilled water, corn oil, 3.75 mg/kg PE-MPs, 15 mg/kg PE-MPs, or 60 mg/kg of PE-MPs, daily by oral gavage for 35 days. PE-MPs significantly increased the body weights of the rats and lipid peroxidation, with concomitant reduction of superoxide dismutase activity and depletion of reduced glutathione, thus adversely affecting oxidants/antioxidants balance. Moreover, PE-MPs increased the % of abnormal RBCs, irregular cells, tear drop cells, Schistocyte cells, and folded cells. The genotoxic effects on DNA were evident by increased DNA damage, confirmed by the comet assay, in addition to increased DNA methylation. The effects of PE-MPs have been shown to be dose correlated. In conclusion, this study provides evidence of dose-related PE-MPs-induced hematological, genotoxic, and epigenetic effects in mammals, and thus emphasizes the potentially hazardous health effects of environmental PE-MPs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Alzheimer's disease is a neurological disorder that causes brain cells to shrink and die. Aim: Thirteen novel 'oxathiolanyl', 'pyrazolyl' and 'pyrimidinyl' indole derivatives were designed and synthesized as anti-Alzheimer's disease treatment. Method: In vitro enzyme assay was performed against both AChE and BChE enzymes. In addition, antioxidant assay and cytotoxicity on a normal cell line were determined. Molecular docking and dynamic simulations were conducted to confirm the binding mode in both esterases' active sites. In silico absorption, distribution, metabolism, excretion and toxicity studies were also carried out. Results & conclusion: Compounds 5 , 7 and 11 exhibited superior inhibitory activity against acetylcholinesterase and butyrylcholinesterase, with IC 50 values of 0.042 and 3.003 μM, 2.54 and 0.207 μM and 0.052 and 2.529 μM, respectively, compared with donepezil.

The use of electrochemical sensors offers a simple, affordable solution with great reliability. Magnesium is a mineral that the body requires to function properly. It encourages preserving a stable pulse, strong bones, and healthy blood pressure. Herein, a novel ion-selective electrode using esomeprazole magnesium trihydrate as an ion-association complex was developed for magnesium(ii) ion determination in mineral water, drug substances, and pharmaceutical formulations. The electrode response was optimized in terms of plasticizer type, ion exchanger concentration, and membrane composition. To find the best sensor combination, the initial optimization research was performed using eight different sensors. A membrane containing 20% esomeprazole magnesium trihydrate, 36% carbon, and 44% o -Nitrophenyl Octyl Ether (NPOE) as a plasticizer yielded the best potentiometric response. The developed sensor demonstrated a Nernstian response with a slope of 29.93 ± 0.1 mV per decade in the concentration range of 1.41 × 10 -5 mol L -1 to 1 × 10 -2 mol L -1 . Within a pH range of 5-8, it had a low detection limit of 4.13 × 10 -6 mol L -1 . When compared to the official method, there are no statistically significant differences., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Treatment wetlands utilize various physical and biological processes to reduce levels of organic contaminants, metals, bacteria, and suspended solids. Silver nanoparticles (AgNPs) are one type of contaminant that can enter treatment wetlands and impact the overall treatment efficacy. Grazing by filter-feeding zooplankton, such as Daphnia magna, is critical to treatment wetland functioning; but the effects of AgNPs on zooplankton are not fully understood, especially at environmentally relevant concentrations. We characterized the bioaccumulation kinetics of dissolved and nanoparticulate (citrate-coated) 109 Ag in D. magna exposed to environmentally relevant 109 Ag concentrations (i.e., 0.2-23 nmol L -1 Ag) using a stable isotope as a tracer of Ag. Both aqueous and nanoparticulate forms of 109 Ag were bioavailable to D. magna after exposure. Water chemistry affected 109 Ag influx from 109 AgNP but not from 109 AgNO 3 . Silver retention was greater for citrate-coated 109 AgNP than dissolved 109 Ag, indicating a greater potential for bioaccumulation from nanoparticulate Ag. Feeding inhibition was observed at higher dietary 109 Ag concentrations, which could lead to reduced treatment wetland performance. Our results illustrate the importance of using environmentally relevant concentrations and media compositions when predicting Ag bioaccumulation and provide insight into potential effects on filter feeders critical to the function of treatment wetlands. Environ Toxicol Chem 2022;41:726-738. © 2021 SETAC., (© 2021 SETAC.)

Waterborne viruses are responsible for numerous diseases and are abundant in aquatic systems. Understanding the fate of viruses in natural systems has important implications for human health. This research quantifies the uptake of the bacteriophage T4 and the enteric virus echovirus 11 when exposed to the filter feeders Tetrahymena pyriformis and Daphnia magna , and also examines the potential of viral transfer due to trophic interactions. Experiments co-incubating each species with the viruses over 72-96 h showed up to a 4 log virus removal for T. pyriformis , while direct viral uptake by D. magna was not observed. However, viral uptake by D. magna occurred indirectly by viral transfer from prey to predator, through D. magna feeding on virus-loaded T. pyriformis . This prey-predator interaction resulted in a 1 log additional virus removal compared to removal by T. pyriformis alone. Incomplete viral inactivation by D. magna was observed through recovery of infective viruses from the daphnid tissue. This research furthers our understanding of the impacts of zooplankton filter feeding on viral inactivation and shows the potential for viral transfer through the food chain. The viral-zooplankton interactions observed in these studies indicate that zooplankton may improve water quality through viral uptake or may serve as vectors for infection by accumulating viruses.

Background: This is the fastest work in obtaining the metabolic profiles of Pseudomonas aeruginosa in order to combat the infection diseases which leads to high morbidity and mortality rates. Pseudomonas aeruginosa is a high versatility of gram-negative bacteria that can undergo aerobic and anaerobic respiration. Capabilities in deploying different carbon sources, energy metabolism and regulatory system, ensure the survival of this microorganism in the diverse environment condition. Determination of differences in carbon sources utilization among biofilm and non-biofilm of Pseudomonas aeruginosa provides a platform in understanding the metabolic activity of the microorganism., Methods: The study was carried out from September 2017 to February 2019. Four archive isolates forming strong and intermediate biofilm and non-biofilms producer were subcultured from archive isolates. ATCC 27853 P. aeruginosa was used as a negative control or non-biofilm producing microorganism. Biofilm formation was confirmed by Crystal Violet Assay (CVA) and Congo Red Agar (CRA). Metabolic profiles of the biofilm and non-biofilms isolates were determined by phenotype microarrays (Biolog Omnilog)., Results and Discussion: In this study, Pseudomonas aeruginosa biofilm isolates utilized uridine, L-threonine and L-serine while non-biofilm utilized adenosine, inosine, monomethyl, sorbic acid and succinamic acid., Conclusion: The outcome of this result will be used for future studies to improve detection or inhibit the growth of P. aeruginosa biofilm and non-biofilm respectively., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The fecal indicator bacterial species Escherichia coli is an important measure of water quality and a leading cause of impaired surface waters. We investigated the impact of the filter-feeding metazooplankton Daphnia magna on the inactivation of E. coli The E. coli clearance rates of these daphnids were calculated from a series of batch experiments conducted under variable environmental conditions. Batch system experiments of 24 to 48 h in duration were completed to test the impacts of bacterial concentration, organism density, temperature, and water type. The maximum clearance rate for adult D. magna organisms was 2 ml h -1 organism -1 Less than 5% of E. coli removed from water by daphnids was recoverable from excretions. Sorption of E. coli on daphnid carapaces was not observed. As a comparison, the clearance rates of the freshwater rotifer Branchionus calyciflorus were also calculated for select conditions. The maximum clearance rate for B. calyciflorus was 6 × 10 -4  ml h -1 organism -1 This research furthers our understanding of the impacts of metazooplankton predation on E. coli inactivation and the effects of environmental variables on filter feeding. Based on our results, metazooplankton can play an important role in the reduction of E. coli in natural treatment systems under environmentally relevant conditions. IMPORTANCE Escherichia coli is a fecal indicator bacterial species monitored by the U.S. Environmental Protection Agency to assess microbial water quality. Due to the potential human health implications linked to high levels of E. coli , it is important to understand the inactivation or reduction mechanisms in surface waters. Our research examines the capacities of two types of widespread filter-feeding freshwater metazooplankton, Daphnia magna and Brachionus calyciflorus , to reduce E. coli concentrations. We examine the impacts of different environmentally relevant conditions on the clearance rates. Our results contribute to a better understanding of the importance of metazooplankton in controlling E. coli concentrations and what conditions will reduce or increase grazing. These results provide baseline data to support future efforts to develop a quantitative model relating zooplankton uptake rates to relevant environmental variables., (Copyright © 2019 American Society for Microbiology.)

Background: Few stability-indicating chromatographic methods were published for determination of daclatasvir. All used UV detection. Objective: This work aimed to develop rapid, specific, and novel stability-indicating methods using HPLC with fluorescence detection and ultra performance liquid chromatography (UPLC) with UV detection for the determination of daclatasvir in bulk powder and in its dosage form. Methods: The drug was subjected to hydrolysis (acidic and alkaline) as per International Conference on Harmonization (ICH) guidelines. The fragmentation pattern of the drug was studied using LC-MS. Separation was carried out first by HPLC using Thermo BDS Hypersil Phenyl (300 mm × 4 mm, 5 μm) column and a mobile phase consisting of ammonium phosphate buffer (0.02 M) pH 3-methanol (40+60, v/v) at flow rate 1 mL/min. Quantitation was achieved by fluorescence detection at 305 and 457 nm for excitation and emission, respectively. The second method used UPLC equipped with diode-array detector. Acquity BEH C 18 (50 mm × 2.1 mm, 1.7 μm) column was used with the same mobile phase at flow rate 0.4 mL/min and detection wavelength at 305 nm. ICH guidelines were used for validation. Results: The mean percentage recovery ± SD values for tablet assay were found to be 101.12 ± 0.655 and 99.78 ± 0.632 by HPLC and UPLC methods, respectively. The assay results showed a good agreement with the reported method. Conclusions: The developed HPLC and UPLC methods provide simple, accurate, and reproducible analysis of daclatasvir without interference from degradates. Highlights: This is the first research using fluorescence detection in a stability-indicating chromatographic method for determination of daclatasvir.

Background: Oxyclozanide (OXY) is a veterinary medicine used for control of fascioliasis in farm animals. Literature review shows absence of sufficient information regarding its stability. Such information is important as it affects many stages of a drug's life cycle, from pharmaceutical manufacturing to its environmental fate understanding of the degradation of the drug once it is placed in the environment. Objective: An HPLC method was developed to address the impact of different stress conditions on OXY's stability. Methods: OXY's stability was investigated by exposure to forced acid and alkaline hydrolysis, thermal, oxidative and photolytic degradation, which are different stress conditions applied to the forced degradation study. Separation was performed on Eurosphere C18 analytical column (125 × 4.6 mm, 5 μm particle size) using 50 mM sodium acetate trihydrate (pH 4.5) and acetonitrile (50:50, v/v) as mobile phase and UV detection at 254 nm. A photolytic kinetics study was conducted by monitoring OXY photolysis under monochromatic and polychromatic light sources (UV lamp at 366 nm and natural sunlight) in aqueous buffers of different pHs (5, 7, and 9). LC-MS was used to identify the major photolytic degradate. Results: OXY was quantified over a concentration range of 1-80 μg/mL with mean recovery of 99.32 ± 1.80%. The drug was susceptible to oxidative and photolytic degradation. The photolytic kinetics were pH dependent. The LC-MS result supported photo-dehalogenation degradation mechanism. Conclusions: The developed method could be used in OXY stability testing. The results of the photolytic kinetics study can address OXY aquatic photo-transformation, thereby predicting its environmental fate and risks imposed on the ecosystem. Highlights: An HPLC method was developed for monitoring OXY degradation behavior and studying its photolytic kinetics with identification of its photodegradate.

Aim: Imatinib possesses various mechanisms for combating cancer, making the development of imatinib analogs an attractive target for cancer research., Method: Two series of analogs were designed and synthesized, maintaining the essential pharmacophoric features in imatinib structure. The synthesized compounds were subjected to cell-based antiproliferative assays against nonsmall lung (A549) and colon cancer cell lines. In addition, flow cytometry cell cycle and caspase-3 colorimetric assays were performed., Results: Most compounds showed potent anticancer activity against both cell lines with IC 50  = 0.14-5.07 μM. Three compounds demonstrated ability to reinforce cell cycle arrest at G1 stage in a manner similar to imatinib. In addition, they induced apoptosis via activation of caspase-3.

Fecal indicator bacteria (FIB) are leading causes of impaired surface waters. Innovative and environmentally appropriate best management practices are needed to reduce FIB concentrations and associated risk. This study examines the ability of the native freshwater mussel Anodonta californiensis and an invasive freshwater clam Corbicula fluminea to reduce concentrations of the FIB Escherichia coli in natural waters. Laboratory batch experiments were used to show bivalve species-specific E. coli removal capabilities and to develop a relationship between bivalve size and clearance rates. A field survey within an impaired coastal river containing both species of bivalves in an agricultural- and grazing-dominated area of the central coast of California showed a significant inverse correlation between E. coli concentration and bivalve density. An in situ field spiking and sampling study showed filtration by freshwater bivalves resulting in 1-1.5 log 10 reduction of E. coli over 24 h, and calculated clearance rates ranged from 1.2 to 7.4 L hr -1 bivalve -1 . Results of this study show the importance of freshwater bivalves for improving water quality through the removal of E. coli. While both native and invasive bivalves can reduce E. coli levels, the use of native bivalves through integration into best management practices is recommended as a way to improve water quality and protect and encourage re-establishment of native bivalve species that are in decline.

Quinoxaline derivatives, also called benzopyrazines, are an important class of heterocyclic compounds. Quinoxalines have drawn great attention due to their wide spectrum of biological activities. They are considered as an important basis for anticancer drugs due to their potential activity as protein kinase inhibitors. In this review, we focus on the chemistry of the quinoxaline derivatives, the strategies for their synthesis, their potential activities against various tyrosine kinases, and on the structure-activity relationship studies reported to date., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This study evaluates secondary environmental impacts of various remedial alternatives for sediment contaminated with hydrophobic organic contaminants using life cycle assessment (LCA). Three alternatives including two conventional methods, dredge-and-fill and capping, and an innovative sediment treatment technique, in-situ activated carbon (AC) amendment, are compared for secondary environmental impacts by a case study for a site at Hunters Point Shipyard, San Francisco, CA. The LCA results show that capping generates substantially smaller impacts than dredge-and-fill and in-situ amendment using coal-based virgin AC. The secondary impacts from in-situ AC amendment can be reduced effectively by using recycled or wood-based virgin AC as production of these materials causes much smaller impacts than coal-based virgin AC. The secondary environmental impacts are highly sensitive to the dredged amount and the distance to a disposal site for dredging, the capping thickness and the distance to the cap materials for capping, and the AC dose for in-situ AC amendment. Based on the analysis, this study identifies strategies to minimize secondary impacts caused by different remediation activities: optimize the dredged amount, the capping thickness, or the AC dose by extensive site assessments, obtain source materials from local sites, and use recycled or bio-based AC., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A sensitive and highly selective stability-indicating gradient HPLC method was developed and validated for simultaneous determination of clorsulon (CLO) and ivermectin (IVM) in the presence of their degradation products. The drugs were subjected to different stress conditions, including acid and alkaline hydrolysis, oxidative, thermal, and photolytic forced degradation. The robustness of the proposed method was assessed using the Plackett-Burman experimental design, the factors affecting system performance were defined, and nonsignificant intervals for the significant factors were determined. The separation was carried out on a ZORBAX SB phenyl analytical column (250 × 4.6 mm id, 5 μm particle size), with gradient elution utilizing 10 mM sodium dihydrogen phosphate and acetonitrile as mobile phase. UV detection was performed for CLO and IVM at 254 nm over a concentration range of 4-140 and 5-50 μg/mL, respectively, with mean percentage recoveries of 99.90 ± 1.30 and 98.59 ± 1.16%, respectively. The proposed method was successfully applied to a pharmaceutical dosage form containing the investigated drugs. The results were statistically compared with the official HPLC methods, and no significant differences were found.

Three simple, precise, accurate and validated derivative spectrophotometric methods have been developed for the simultaneous determination of levocetirizine dihydrochloride (LCD) and ambroxol hydrochloride (ABH) in bulk powder and in pharmaceutical formulations. The first method is a first derivative spectrophotometric method ((1)D) using a zero-crossing technique of measurement at 210.4 nm for LCD and at 220.0 nm for ABH. The second method employs a second derivative spectrophotometry ((2)D) where the measurements were carried out at 242.0 and 224.4 nm for LCD and ABH, respectively. In the third method, the first derivative of the ratio spectra was calculated and the first derivative of the ratio amplitudes at 222.8 and 247.2 nm was selected for the determination of LCD and ABH, respectively. Calibration graphs were established in the ranges of 1.0-20.0 μg mL(-1) for LCD and 4.0-20.0 μg mL(-1) for ABH using derivative and ratio first derivative spectrophotometric methods with good correlation coefficients. The developed methods have been successfully applied to the simultaneous determination of both drugs in commercial tablet dosage form., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Previously, we reported the identification of a thiazolidinedione-based adenosine monophosphate activated protein kinase (AMPK) activator, compound 1 (N-[4-({3-[(1-methylcyclohexyl)methyl]-2,4-dioxothiazolidin-5-ylidene}methyl)phenyl]-4-nitro-3-(trifluoromethyl)benzenesulfonamide), which provided a proof of concept to delineate the intricate role of AMPK in regulating oncogenic signaling pathways associated with cell proliferation and epithelial-mesenchymal transition (EMT) in cancer cells. In this study, we used 1 as a scaffold to conduct lead optimization, which generated a series of derivatives. Analysis of the antiproliferative and AMPK-activating activities of individual derivatives revealed a distinct structure-activity relationship and identified 59 (N-(3-nitrophenyl)-N'-{4-[(3-{[3,5-bis(trifluoromethyl)phenyl]methyl}-2,4-dioxothiazolidin-5-ylidene)methyl]phenyl}urea) as the optimal agent. Relative to 1, compound 59 exhibits multifold higher potency in upregulating AMPK phosphorylation in various cell lines irrespective of their liver kinase B1 (LKB1) functional status, accompanied by parallel changes in the phosphorylation/expression levels of p70S6K, Akt, Foxo3a, and EMT-associated markers. Consistent with its predicted activity against tumors with activated Akt status, orally administered 59 was efficacious in suppressing the growth of phosphatase and tensin homologue (PTEN)-null PC-3 xenograft tumors in nude mice. Together, these findings suggest that 59 has clinical value in therapeutic strategies for PTEN-negative cancer and warrants continued investigation in this regard., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Novel curcumin analogs with 4-piperidone ring were designed, synthesized, and evaluated for their cytotoxic activities against five different cancer cell lines. 3,5-bis(4-Hydroxy-3-methoxybenzylidene)-4-oxo-N-phenylpiperidine-1-carbothioamide (XIIe) exhibited considerable cytotoxic activity with IC50 values in 1-2.5 μm range. In silico and in vitro, studies were also performed to predict the binding affinity of the target compounds to the β-chain of tubulin receptor (PDB code 1SA1) and their abilities to affect microtubules polymerization cycle. 3,5-bis(3-Iodo-5-methoxy-4-propoxybenzylidene)-N-acetylpiperidin-4-one (VIIa) was found to exert 93.3% inhibition of tubulin and destabilization of microtubules in vitro compared to vincristine while, 3,5-bis(3,4,5-trimethoxybenzylidene)-N-benzoylpiperidin-4-one (XIIc) showed high potency in a different way where it exerted 94.8% stabilization of microtubules in vitro compared to positive control paclitaxel., (© 2014 John Wiley & Sons A/S.)

3D-pharmacophore and 2D-QSAR modeling studies describe the anti-oncological properties of spiro-alkaloids. The dispiro[2H-indene-2,3'-pyrrolidine-2',3''-[3H]indole]-1,2''(1''H, 3H)-diones 20-38 were prepared via 1,3-dipolar cycloaddition reactions of azomethine ylides (generated in situ via decarboxylative condensation of isatins 7-9 with sarcosine 10) and 2-(arylmethylidene)-2,3-dihydro-1H-inden-1-ones 11-19 in refluxing ethanol. Some of the spiro-alkaloids (21, 22, 29 and 37) revealed potent antitumor properties against melanoma carcinoma cell lines (GaLa, LuPiCi and LuCa) utilizing the in vitro SRB standard method exhibiting potency close to that of the standard reference doxorubicin.

QSAR study describes the anti-neoplastic spiro-alkaloids with relevant molecular descriptors using CODESSA III software. The dispiro[3H-indole-3,2'-pyrrolidine-3',3"-piperidines] 24-48 were synthesized via [3 + 2]-cycloaddition reaction of azomethine ylides, (generated in situ via decarboxylative condensation of isatins 21-23 with sarcosine) and 3E,5E-1-alkyl-3,5-bis(arylmethylidene)-4-piperidones 10-20. Some of the synthesized analogues exhibited promising antitumor properties against HELA (cervical), HEPG2 (liver), T-47D, MCF7 (breast), and HCT116 (colon) human tumor cell lines, demonstrating activity close to or even better than the standard Doxorubicin, based on in vitro Sulfo-Rhodamine-B bio-assay.

High levels of fecal indicator bacteria, such as Escherichia coli, can be indicative of poor water quality. The use of shellfish to reduce eutrophication has been proposed, but application of bivalves to reduce bacterial levels has not been extensively reported. Removal of E. coli by the native freshwater mussel Anodonta californiensis was studied using laboratory batch systems and field-based flow-through systems. Batch systems were utilized to determine the fate and inactivation of E. coli after uptake by the mussel. Batch experiments demonstrated that uptake patterns followed first order kinetics and E. coli was inactivated with less than 5% of the initial colonies recoverable in fecal matter or tissue. Flow-through systems located at an urban impaired lake in San Francisco, CA were utilized to determine uptake kinetics under environmentally relevant conditions. The bivalves maintained a 1-log removal of E. coli for the duration of exposure. The calculated uptake rates can be used in conjunction with hydrologic models to determine the number of bivalves needed to maintain removal of E. coli in different freshwater systems. The outcomes of this study support the use of native freshwater bivalves to achieve the co-benefits of rehabilitating a freshwater ecosystem and improving water quality via reduction of E. coli in contaminated freshwater systems.

A novel series of quinzoline based compounds (IIIa-d, VIa-f, IXa-f) were designed, synthesized and screened for their inhibitory activity towards the PDE4B isoform. The in vivo anti-inflammatory effect of the titled compounds (IIIa-d, VIa-f, IXa-f) as well as their effect on the level of tumor necrosis factor (TNF-α) were evaluated. Among all of the synthesized compounds, IXb, IXd and IXf, exhibited good inhibitory activity against PDE4B enzyme with inhibition percentages of 42, 62 and 68%, respectively. Most of the tested compounds showed potent anti-inflammatory activity compared to indomethacin with a marked decrease in TNF-α level. The ulcerogenic effect of the tested compounds was also examined. The gastric mucosa of the tested animals remained intact after oral administration of the hit compounds. Additionally, docking study was used to explore the possible binding mode of the active compounds on the PDE4B enzyme as well as to illustrate the selectivity of the active hits on the PDE4B isoform.

In an effort to develop ATP-competitive VEGFR-2 selective inhibitors, a series of new quinoxaline-based derivatives was designed and synthesized. The target compounds were biologically evaluated for their inhibitory activity against VEGFR-2. The design of the target compounds was accomplished after a profound study of the structure activity relationship (SAR) of type-II VEGFR-2 inhibitors. Among the synthesized compounds, 1-(2-((4-methoxyphenyl)amino)-3-oxo-3,4 dihydroquinoxalin-6-yl)-3-phenylurea (VIIa) displayed the highest inhibitory activity against VEGFR-2. Molecular modeling study involving molecular docking and field alignment was implemented to interpret the variable inhibitory activity of the newly synthesized compounds., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Uptake of seven contaminants regularly detected in surface waters and spanning a range of hydrophobicities (log D(ow) -1 to 5) was studied for two species of freshwater bivalves, the native mussel Anodonta californiensis and the invasive clam Corbicula fluminea. Batch systems were utilized to determine compound partitioning, and flow-through systems, comparable to environmental conditions in effluent dominated surface waters, were used to determine uptake and depuration kinetics. Uptake of compounds was independent of bivalve type. Log bioconcentration factor (BCF) values were correlated with log D(ow) for nonionized compounds with the highest BCF value obtained for triclocarban (TCC). TCC concentrations were reduced in the water column due to bivalve activity. Anionic compounds with low D(ow) values, i.e., clofibric acid and ibuprofen, were not removed from water, while the organic cation propranolol showed biouptake similar to that of TCC. Batch experiments supported compound uptake patterns observed in flow-through experiments. Contaminant removal from water was observed through accumulation in tissue or settling as excreted pseudofeces or feces. The outcomes of this study indicate the potential utility of bivalve augmentation to improve water quality by removing hydrophobic trace organic compounds found in natural systems.

Khelline is naturally occurring furochromone exhibited significant Epidermal Growth Factor Receptor (EGFR) inhibitory activity. The newly synthesized compounds 2-5 displayed the most potent EGFR inhibitory activity on MCF-7 and HeLa. In vitro study against 59 different human tumour cell lines derived from nine cancer type in NCI (USA), which was presented and documented. Molecular docking simulation was performed to position compounds 1-5 into the EGFR active site to determine the probable binding mode.

A variety of 4'-aryl-3-(arylmethylidene)-1″-[(cyclic-amino)methylene]-1'-methyl-dispiro[cyclohexane-1,3'-pyrrolidine-2',3″-[3H]indole]-2,2″(1″H)-diones 4a-u were prepared via reaction of 2E,6E-bis(arylidene)-1-cyclohexanones 1a-i with azomethine ylides, generated in situ via a decarboxylative condensation of isatins 2a-c and sarcosine (3). Single crystal X-ray study of 4a, revealed structural and stereochemical features of these derivatives. While most of the synthesized compounds exhibit mild antitumor properties when tested against various human tumor cell lines (HEPG2 "liver", HELA "cervical" and PC3 "prostate" cancers), three of them, 4d and 4p (active against HEPG2), and compound 4g (active against HELA), demonstrated higher activities, that were close or even higher than that of the reference standard Doxorubicin. QSAR studies revealed good predictive and statistically significant 3 descriptor models (r2=0.903-0.812, r2adjusted=0.855-0.672, r2prediction=0.773-0.605)., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Treatment wetlands have become an attractive option for the removal of nutrients from municipal wastewater effluents due to their low energy requirements and operational costs, as well as the ancillary benefits they provide, including creating aesthetically appealing spaces and wildlife habitats. Treatment wetlands also hold promise as a means of removing other wastewater-derived contaminants, such as trace organic contaminants and pathogens. However, concerns about variations in treatment efficacy of these pollutants, coupled with an incomplete mechanistic understanding of their removal in wetlands, hinder the widespread adoption of constructed wetlands for these two classes of contaminants. A better understanding is needed so that wetlands as a unit process can be designed for their removal, with individual wetland cells optimized for the removal of specific contaminants, and connected in series or integrated with other engineered or natural treatment processes. In this article, removal mechanisms of trace organic contaminants and pathogens are reviewed, including sorption and sedimentation, biotransformation and predation, photolysis and photoinactivation, and remaining knowledge gaps are identified. In addition, suggestions are provided for how these treatment mechanisms can be enhanced in commonly employed unit process wetland cells or how they might be harnessed in novel unit process cells. It is hoped that application of the unit process concept to a wider range of contaminants will lead to more widespread application of wetland treatment trains as components of urban water infrastructure in the United States and around the globe.

Two series of peptidomimetics were designed, prepared and evaluated for their anti-HCV activity. One series possesses a C-terminal carboxylate functionality. In the other series, the electrophilic vinyl sulfonate moiety was introduced as a novel class of HCV NS3/4A protease inhibitors. In vitro based studies were then performed to evaluate the efficacies of the inhibitors using Human hepatoma cells, with the vinyl sulfonate ester (10) in particular, found to have highly potent anti-HCV activity with an EC(50) = 0.296 μM. Finally, molecular modeling studies were performed through docking of the synthesized compounds in the HCV NS3/4A protease active site to assess their binding modes with the enzyme and gain further insight into their structure-activity relationships., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Hepatitis C virus inhibitors based on benzoxazole scaffold were designed based on molecular modeling simulation study including docking into the NS5B polymerase active site. Several compounds showed significant high simulation docking scores relative to the assigned benzimidazole lead compound. The designed compounds were synthesized, structurally elucidated and their antiviral activity was evaluated through cell-based replicon in cultured Huh 5-2 cells. A number of the synthesized compounds showed significant inhibitory activity ranging from (52.2% inhibition up to 98% at<50 µg/mL). N-Benzyl-2-phenylbenzo[1,3]oxazole-5-carboxamide (8b) and N-Phenethyl-2-phenylbenzo[1,3] oxazole-5-carboxamide (8c) demonstrated genuine HCV inhibitory activity with EC50 values of 41.6 and 24.5 µg/mL respectively., (© Georg Thieme Verlag KG Stuttgart · New York.)

Antiangiogenesis therapy has become a vital part of the armamentarium against cancer. Hypertension is a dose-limiting toxicity for VEGF inhibitors. Thus, there is a pressing need to address the associated adverse events so these agents can be better used. The hypertension may be mediated by reduced NO bioavailability resulting from VEGF inhibition. We proposed that the hypertension may be prevented by coadministration with endostatin (ES), an endogenous angiogenesis inhibitor with antitumor effects shown to increase endothelial NO production in vitro. We determined that Fc-conjugated ES promoted NO production in endothelial and smooth muscle cells. ES also lowered blood pressure in normotensive mice and prevented hypertension induced by anti-VEGF antibodies. This effect was associated with higher circulating nitrate levels and was absent in eNOS-knockout mice, implicating a NO-mediated mechanism. Retrospective study of patients treated with ES in a clinical trial revealed a small but significant reduction in blood pressure, suggesting that the findings may translate to the clinic. Coadministration of ES with VEGF inhibitors may offer a unique strategy to prevent drug-related hypertension and enhance antiangiogenic tumor suppression.

This review article deals with the structure activity relationship (SAR) for a variety of palladacycles in biomedical applications. Moreover, the types of antibacterial, antifungal, antimycobacterial and antiprotozoal (antiamoebic and antitrypanosomal) activities will vary considerably from one country to another. Therefore, all efforts will be required to face such a vast diversity of problems. This study gives an up to date overview of the antibacterial, antifungal, antimycobacterial and antiprotozoal chemistry of the palladium group elements with an emphasis on the new strategies used in the development of new antibacterial agents. Methodologies for application of bulky aromatic or aliphatic nitrogen ligands, chiral organic moieties, chelates containing other donor atoms than nitrogen, and biologically active ligands in the design of agents analogous to palladacycles are presented. Therefore, the use of palladacycles in medicinal chemistry is interesting as potential application in the biological properties with less toxic drugs compounds..

1,3-Dipolar cycloaddition reaction of 1-aryl-1H-pyrrole-2,5-diones 1a-e with non-stabilized azomethine ylides, generated in situ via decarboxylative condensation of isatins 2a-c and sarcosine (3) in refluxing ethanol, afforded 4'-aryl-5'a,6'-dihydro-1'-methyl-spiro[3H-indole-3,2'(1'H)-pyrrolo[3,4-c]pyrrole]-2,3',5'(1H,2'aH,4'H)-triones 4a-o in good yields. Compound 4l exhibited high anti-tumor activity against HEPG2 (liver cancer) cell line (IC(50) = 12.16 μM) compared to that of Doxorubicin (IC(50) = 7.36 μM), and the other synthesized compounds revealed moderate anti-tumor properties against HCT116 (colon), MCF7 (breast) and HEPG2 (liver) human tumor cell lines. 3D-Pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis were combined to explore the structural requirements controlling the observed anti-tumor properties. It was found that the major structural factors affecting potency of these compounds were related to their basic skeleton., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

The design and synthesis of a small library of 4-aminopyrido[2,3-d]pyrimidine derivatives is reported. The potential activity of these compounds as CDK2/Cyclin A, CDK4/Cyclin D, EGFR and anti-tumor was evaluated by cytotoxicity studies in A431a, SNU638b, HCT116 and inhibition of CDK2-Cyclin A, CDK4/Cyclin D and EGFR enzyme activity in vitro. The anti-proliferative and CDK2-Cyclin A inhibitory activity of compounds 4c and 11a was significantly more active than roscovotine with IC(50) 0.3 and 0.09 μM respectively. Molecular modeling study, including fitting to a 3D-pharmacophore model, docking into cyclin dependant kinase2 (CDK2) active site and binding energy calculations were carried out and these studies suggested the same binding orientation inside the CDK2 binding pocket for these analogs compared to ATP., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

1,3-Dipolar cycloaddition reaction of nitrilimines with 5-arylidene-1,3-dimethyl-2,4,6-pyrimidinetriones 1a-i afforded 7,9-dimethyl-1,3,4-triaryl-1,2,7,9-tetraaza-spiro[4.5]dec-2-ene-6,8,10-triones 3a-k in a high regioselective manner. Single crystal X-ray study of 3d added a conclusive support for the assigned structure. Potentiating effects of the synthesized compounds 3a-k (at a dose of 25 mg/kg body weight) on hypnotic action of sodium thiopental (at a dose of 75 mg/kg body weight i.p.) were investigated in vivo using Albino mice according to the standard method. Most of the tested compounds revealed promising hypnotic potentiating effects especially compounds 3k and 3e that could be nominated as short-acting hypnotics. A hypothesis of molecular modeling study, including fitting of the synthesized compounds into 3D-pharmacophore using Discovery Studio 2.5 software and their docking into optimized homology model of GABA(A)-α(1) showed good results consistent with the observed pharmacological properties., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Vascular endothelial growth factor regulates neoplastic angiogenesis through production of endothelium-derived NO. We performed a prospective evaluation of vascular function during treatment with vandetanib, a vascular endothelial growth receptor 2 and 3 receptor tyrosine kinase inhibitor, to determine the effects of vascular endothelial growth receptor signal interruption on endothelial function in humans. Seventeen patients with stage IV breast cancer received dose-escalated vandetanib in combination with low-dose oral chemotherapy. We measured blood pressure, systemic nitrate/nitrite levels, and brachial artery vascular function. In vitro analyses of cultured endothelial cells were performed to determine the effect of vandetanib on NO production, akt(473) phosphorylation, and endothelial NO synthase protein content and membrane localization. Vandetanib treatment for 6 weeks significantly increased blood pressure, decreased resting brachial artery diameter, and decreased plasma systemic nitrate/nitrite levels compared with baseline. Flow-mediated vasodilation was preserved, and no change was noted in nitroglycerin-mediated vasodilation. In vitro, endothelial cell nitrite levels and akt(473) phosphorylation were reduced and vascular endothelial growth receptor 2 levels did not change, but endothelial NO synthase membrane concentration doubled. Vandetanib reduces constitutive NO production and increases blood pressure, yet flow-stimulated NO bioavailability was preserved. Changes in vascular function with tyrosine kinase inhibition are complex and require further study in humans.

A facile synthetic approach towards 6-alkyl-2-amino-4-aryl-4a,5,6,7,8,8a-hexahydro-8a-methoxy-4H-pyrano[3,2-c]pyridine-3-carbonitriles 3a-n was reported via reaction of 1-alkyl-4-piperidones 1a,b with ylidenemalononitriles 2a-h in methanol in the presence of sufficient amount of sodium. The structure of 3 was established through different spectroscopic techniques and confirmed by single crystal X-ray studies. Vasodilation activities of the synthesized compounds were investigated in vitro using isolated thoracic aortic rings of Wister rats pre-contracted with norepinephrine hydrochloride standard method. All the prepared analogues exhibited considerable vasodilation properties especially, 3g and 3c which revealed the best vasodilation potency (IC50=0.30, 0.37 mM, respectively) among all the tested compounds. Molecular modeling studies, including fitting of the synthesized compounds to a 3D-pharmacophore and their docking into optimized homology model as α1-AR antagonists showed high docking score and fit values. The experimental vasodilation activities of compounds 3a-n are consistent with their molecular modeling results., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

In an attempt to identify potential HCV NS3 protease inhibitors lead compounds, a series of novel indoles (10a-g) was designed. Molecular modeling study, including fitting to a 3D-pharmacophore model of the designed molecules (10a-g), with HCV NS3 protease hypothesis using catalyst program was fulfilled. Also, the molecular docking into the NS3 active site was examined using Discovery Studio 2.5 software. Several compounds showed significant high simulation docking score and fit values. The designed compounds with high docking score and fit values were synthesized and biologically evaluated in vitro using an NS3 protease binding assay. It appears that most of the tested compounds reveal promising inhibitory activity against NS3 protease. Of these, compounds 10a and 10b demonstrated potent HCV NS3 protease inhibitors with IC(50) values of 9 and 12μg/mL, respectively. The experimental serine protease inhibitor activities of compounds 10a-g were consistent with their molecular modeling results. Inhibitors from this class have promising characteristics for further development as anti-HCV agents., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

A series of novel purine and pyrimidine derivatives were prepared and biologically evaluated for their in vitro anti-CDK2/cyclin A3 and antitumor activities in Ehrlich ascites carcinoma (EAC) cell based assay. The novel purine derivatives 13a,b demonstrated potent inhibitor activities with IC(50) values of 14±9 and 13±9 μM, respectively. Additionally, compound 15a showed the highest potency (IC(50)=10±6 μM) in EAC cell based assay. Molecular modeling study, including fitting to a 3D-pharmacophore model and their docking into cyclin dependant kinase2 (CDK2) active site showed high fit values and docking scores., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Dysregulated fibroblast growth factor (FGF) signaling has been implicated in the pathogenesis of human cancers. Aberrant activation of FGF receptor 2 (FGFR2) signaling, through overexpression of FGFR2 and/or its ligands, mutations, and receptor amplification, has been found in a variety of human tumors. We generated monoclonal antibodies against the extracellular ligand-binding domain of FGFR2 to address the role of FGFR2 in tumorigenesis and to explore the potential of FGFR2 as a novel therapeutic target. We surveyed a broad panel of human cancer cell lines for the dysregulation of FGFR2 signaling and discovered that breast and gastric cancer cell lines harboring FGFR2 amplification predominantly express the IIIb isoform of the receptor. Therefore, we used an FGFR2-IIIb-specific antibody, GP369, to investigate the importance of FGFR2 signaling in vitro and in vivo. GP369 specifically and potently suppressed ligand-induced phosphorylation of FGFR2-IIIb and downstream signaling, as well as FGFR2-driven proliferation in vitro. The administration of GP369 in mice significantly inhibited the growth of human cancer xenografts harboring activated FGFR2 signaling. Our findings support the hypothesis that dysregulated FGFR2 signaling is one of the critical oncogenic pathways involved in the initiation and/or maintenance of tumors. Cancer patients with aberrantly activated/amplified FGFR2 signaling could potentially benefit from therapeutic intervention with FGFR2-targeting antibodies., (© 2010 AACR.)

Myocardial infarction (MI) results in the death of cardiomyocytes (CM), which causes scar formation and pathological remodeling of the heart. The delivery of healthy myocytes or bone marrow cells reduces pathological remodeling after MI, however, current cell injection methods have low cell survival rates and high cell loss. The main objective of this work was to develop a novel hydrogel that can promote survival of CMs. Photocrosslinkable azidobenzoic acid modified chitosan (Az-chitosan) was conjugated with the angiopoietin-1-derived peptide, QHREDGS. This novel peptide is thought to mediate attachment and survival responses of CM to angiopoietin-1 via integrin binding. Thin layers of Az-chitosan, Az-chitosan-QHREDGS, and Az-chitosan-DGQESHR (scrambled peptide control) were spin coated on glass slides and photocrosslinked with application of UV light (365 nm). Neonatal rat heart cells cultured up to 5 days, demonstrated significantly higher attachment and viability on Az-chitosan-QHREDGS compared to cells on other hydrogel controls. Surfaces were also stained for the CM-specific marker troponin I, demonstrating significantly higher percentage of CMs on Az-chitosan-QHREDGS compared to Az-chitosan. The cells cultivated on Az-chitosan-QHREDGS demonstrated significantly lower levels of caspase 3/7 activation after taxol treatment in comparison to cells cultivated on the control hydrogels, glass substrate, or Az-chitosan linked to RGD, an established integrin binding peptide that did not protect against apoptosis. Thus, Az-chitosan-QHREDGS supports attachment and survival of neonatal rat heart cells., (Copyright 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2010.)

Nitrilimines (PhC(-):N(+):NR') generated in situ from hydrazonoyl chlorides 2a,b reacted regioselectively with 5-arylidene-2,2-dimethyl[1,3]dioxane-4,6-diones 1a-f to afford 1,3,4-triaryl-8,8-dimethyl-7,9-dioxa-1,2-diaza-spiro[4.5]dec-2-ene-6,10-diones 3a-l. In vitro vasodilation activity screening of the synthesized compounds using isolated thoracic aortic rings of male Wister rats pre-contracted with norepinephrine hydrochloride revealed considerable vasodilation activity; compounds 3f and 3j had IC(50) (concentration necessary for 50% reduction of maximal norepinephrine hydrochloride induced contracture) of 0.325, 0.321 mM, respectively. Molecular modeling, including fitting to a 3D-pharmacophore model using Discovery studio 2.1 programs and their docking into optimized alpha(1)-AR homology models as alpha(1)-AR antagonist showed high-docking score and fit values. The experimental in vitro vasodilation activity of compounds 3a-l was consistent with the molecular modeling., (2010 Elsevier Masson SAS. All rights reserved.)

Malaria is a serious infectious disease caused by protozoan parasites in tropical and subtropical regions. Even inhabitants of temperate zones are exposed to the danger of malaria infection because of travel and global warming. Novel, effective, safe, and inexpensive drugs are required to treat malaria and contribute to the global goal of eradication. A search for new antimalarial agents has been performed by the synthesis of new benzo[a]phenoxazines, followed by biological evaluations. The derivative SSJ-183 (5), having a 4-aminopyridine group, showed an IC50 value against Plasmodium falciparum of 7.6 nM and a selectivity index of >7300. Cure was achieved by three oral doses of 5 at 100 mg/kg to mice infected with the Plasmodium berghei ANKA strain. The safety of 5 was supported by acute toxicity testing in mice with single doses up to 2000 mg/kg po, chromosome aberration test, in vitro as well as in vivo micronucleus tests, and phototoxicity studies in mice. Thus, 5 is a promising candidate as a new antimalarial agent.

UV light-based damage to skin cells can cause photoaging and skin cancer. A major cause of UV light-induced damage to skin is increased free radicals, such as superoxides. Increased superoxides can cause oxidative and nitrative damage to cell components. Thus, agents that counteract these damages may have therapeutic value. Herein, we show that angiopoietin-1 (ang1) prevented and blocked H(2)O(2)-induced increases in superoxides in human spontaneously immortalized keratinocyte line, HaCaT, and primary melanocytes (HeMn). Ang1 prevented H(2)O(2)-induced increases in damage to DNA (8-hydroxy-2'-deoxyguanosine) and proteins (nitrotyrosinylation). Ang1 promoted skin cell metabolism/viability, adhesion, and akt and MAPK(p42/44) activations. Using multi-gene transcriptional profiling, we found that skin cells express integrin subunits {(beta(1), beta(4-6), beta(8), alpha(v), alpha(2), alpha(3), alpha(6) (HaCaT)), (beta(1), beta(3), beta(5), beta(8), alpha(v), alpha(3) (HeMn))} and lack tie2 receptor mRNA. Integrin antibodies (alpha(v), beta(1)) disrupted skin cell adhesion to ang1 and ang1-induced decreases in superoxides. Our findings show that ang1 blocks free radical damage to skin cells and may be clinically useful to prevent and/or reduce photoaging and skin cancer.

Magnetically separable photocatalyst beads containing nano-sized iron oxide in alginate polymer were prepared. This magnetic photocatalyst beads are used in slurry-type reactors. The magnetism of the catalyst arises from the nanostructured particles gamma-Fe(2)O(3), by which the catalyst can be easily recovered by the application of an external magnetic field. These synthesized beads are sunlight-driven photocatalyst. In the system without magnetic photocatalyst beads, no chromium reduction was observed under sunlight irradiation due to the stability of the chromium (VI). Upon the addition of magnetic photocatalyst beads, the photo-reduction of Cr(VI) was completed in just after only 50min under sunlight irradiation due to the photocatalytic activity of the beads. However when placed away from sunlight, the reduction rate of the chromium is just about 10%. These observations were explained in terms of absorption occurrence of chromium (VI) onto the catalyst surface which took place in this reaction. In addition, photo-reduction rate of chromium (VI) was more significant at lower pH. The results suggest that the use of magnetic separable photocatalyst beads is a feasible strategy for eliminating Cr(VI)., (Copyright 2009 Elsevier Ltd. All rights reserved.)