Induction of a non-apoptotic mode of cell death associated with autophagic characteristics with steroidal maleic anhydrides and 7ß-hydroxycholesterol on glioma cells.

Steroidal maleic anhydrides were prepared in one step: lithocholic, chenodeoxicholic, deoxicholic, ursocholic, and hyodeoxicholic acid derivatives. Their capability to induce cell death was studied on C6 rat glioma cells, and 7ß-hydroxycholesterol was used as positive cytotoxic control. The highest cytotoxicity was observed with lithocholic and chenodeoxicholic acid derivatives (23-(4-methylfuran-2,5-dione)-3α-hydroxy-24-nor-5ß-cholane (compound 1a), and 23-(4-methylfuran-2,5-dione)-3α,7α-dihydroxy-24-nor-5ß-cholane (compound 1b), respectively), which induce a non-apoptotic mode of cell death associated with mitochondrial membrane potential loss and reactive oxygen species overproduction. No cells with condensed and/or fragmented nuclei, no PARP degradation and no cleaved-caspase-3, which are apoptotic criteria, were observed. Similar effects were found with 7ß-hydroxycholesterol. The cell clonogenic survival assay showed that compound 1b was more cytotoxic than compound 1a and 7ß-hydroxycholesterol. Compound 1b and 7ß-hydroxycholesterol also induce cell cycle modifications. In addition, compounds 1a and 1b, and 7ß-hydroxycholesterol favour the formation of large acidic vacuoles revealed by staining with acridine orange and monodansylcadaverine evocating autophagic vacuoles; they also induce an increased ratio of [LC3-II / LC3-I], and modify the expression of mTOR, Beclin-1, Atg12, and Atg5-Atg12 which is are autophagic criteria. The ratio [LC3-II / LC3-I] is also strongly modified by bafilomycin acting on the autophagic flux. Rapamycin, an autophagic inducer, and 3-methyladenine, an autophagic inhibitor, reduce and increase 7ß-hydroxycholesterol-induced cell death, respectively, supporting that 7ß-hydroxycholesterol induces survival autophagy. Alpha-tocopherol also strongly attenuates 7ß-hydroxycholesterol-induced cell death. However, rapamycin, 3-methyladenine, and α-tocopherol have no effect on compounds 1a and 1b-induced cell death. It is concluded that these compounds trigger a non apoptotic mode of cell death, involving the mitochondria and associated with several characteristics of autophagy.

Adsorption of mercury ions from wastewater by a hyperbranched and multi-functionalized dendrimer modified mixed-oxides nanoparticles.

In this paper, a novel heterogeneous nanodendrimer with generation of G2.0 was prepared by individual grafting of diethylenetriamine, triazine and l-cysteine methyl ester on the modified aluminum-silicate mixed oxides as a potent adsorbent of Hg(II) ions from aqueous media. The prepared nanodendrimer was characterized by nuclear magnetic resonance spectrum (1H NMR and 13C NMR), Fourier transform infrared spectroscopy (FT-IR), Diffuse reflectance UV-Vis spectroscopy (DR UV-Vis), zeta potential (ζ), inductively coupled plasma atomic emission spectroscopy (ICP-AES), transmission electron microscopy (TEM), scanning electron microscopy (SEM), nitrogen adsorption experiments at -196°C and elemental analysis. Equilibrium and kinetic models for Hg(II) ions removal were used by investigating the effect of the contact time, adsorbent dosage, initial Hg(II) ions concentrations, effect of solution's temperature, interfering ions, and initial pH. The contact time to approach equilibrium for higher removal was 6min (3232mgg-1). The removal of Hg(II) ions has been assessed in terms of pseudo-first- and -second-order kinetics, and the Freundlich, Langmuir and Sips isotherms models have also been applied to the equilibrium removal data. The removal kinetics followed the mechanism of the pseudo-second order equation, where the chemical sorption is the rate-limiting step of removal process and not involving mass transfer in solution, which was further proved by several techniques such as zeta potential, FT-IR and DS UV-vis. The thermodynamic parameters (ΔG, ΔH and ΔS) implied that the removal of mercury ions was feasible, spontaneous and chemically exothermic in nature between 15 and 80°C. The nanodendrimer indicated high reusability due to its high removal ability after 15 adsorption-desorption runs. The adsorption mechanisms of Hg(II) ions onto the nanodendrimer was further studied by diverse techniques such as FTIR, EDS, zeta potential, DR UV-Vis spectroscopy and SEM. The possible mechanism of the Hg(II) ions adsorption onto the nanodendrimer could be carried out through the various paths such as electrostatic interaction, complexation, toxic metal chelation and ionic exchange, which eventually resulted in the hydrolysis and precipitation of the adsorbed Hg(II). The l-cysteine methyl ester nanodendrimer could also remove the mercury ions from the Persian Gulf water even after five times of recycling.

Removal of salicylic acid as an emerging contaminant by a polar nano-dendritic adsorbent from aqueous media.

A polar nano-dendritic adsorbent containing amine groups (SAPAMAA) was synthesized onto the nanoparticles of SiO2Al2O3 and its uptake of salicylic acid (SA) from the synthetic and real water was investigated. The synthesized nanomaterials were fully studied by nuclear magnetic resonance spectrum (1H NMR and 13C NMR), Fourier transform infrared spectroscopy (FT-IR), zeta potential (ζ), inductively coupled plasma atomic emission spectroscopy (ICP-AES), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Brunauer-Emmett-Teller (BET) and elemental analysis. Various parameters such as the effect of the contact time, adsorbent dosage, initial SA concentrations, effect of solution's temperature, interfering ions, the hydrophobicity of the nanoadsorbent and initial pH were assessed. The contact time to approach equilibrium for higher adsorption was 15min (252.8mgg-1). The isotherms could be fitted by Sips model (with the average relative error of 6.6) and the kinetic data could be characterized by pseudo-second-order rate equation (with the average relative error of 13.0), implying chemical adsorption as the ratelimiting step of uptake process which was supported by the experimental data from the effect of interfering ions, zeta potential, and altering of the adsorbent's hydrophobicity. The uptake capacities decreased with temperature increasing, and showed that the uptake of SA was chemically exothermic in nature between 15 and 80°C. In addition, the spent SAPAMAA could be regenerated by the removal of adsorbed SA with NaOH and ethanol to regain the original SAPAMAA, the regenerated SAPAMAA also exhibited the high adsorption capacity after 10 runs. Moreover, SAPAMAA could also be applied to uptake SA from a real water (Anzali lagoon water). We envisage that the prepared nano-dendritic with remarkable characteristics such as environmentally friendly, low-cost, easy preparation in large quantity, high mechanical and chemical stability will play a significant role in developing a new generation of emerging contaminants adsorbent.

Comparison of the Effect of Alemtuzumab versus Standard Immune Induction on Early Kidney Allograft Function in Shiraz Transplant Center.

BACKGROUND: Induction therapy regimens classified as conventional immunosuppressive agents and lower doses of conventional agents combined with antibodies against T-cell antigens have been purposed to prevent acute rejection after renal transplantation. Various induction agents with different doses and durations have been suggested based on the risk profile of patients. OBJECTIVE: To assess the acute rejection rate (total rate and based on the type of induction therapy regimen) during the first year after kidney transplantation, the type of acute rejection based on Banff classification and to determine the associations between rate of acute rejection, type of the rejection and induction therapy regimen. METHODS: 249 kidney transplant candidates were divided into two groups-low-risk patients (n=208) who received conventional immunosuppressive agents, and high-risk patients (n=41) who received alemtuzumab-and followed for one year to detect acute rejection first diagnosed clinically, and confirmed by percutaneous kidney biopsy based on Banff criteria. RESULTS: The total incidence of acute rejection was 19.6% (20.7% of the low-risk and 14.4% of the high-risk patients). The most prevalent types of the acute rejection in patients treated with conventional immunosuppressive agents and patients received alemtuzumab as induction therapy were grade IB and grade IA, respectively. The incidence of acute rejection among recipients received a kidney from a deceased donor was 20.6% and grade IA was the most prevalent type (6.9%) whereas the most prevalent grade of acute rejection in patients who received living donor grafts was IB (8.3%). CONCLUSION: Despite the expected greater risk for acute rejection among high-risk patients, no significant difference was observed between low- and high-risk patients, which may be justified by the greater efficacy of alemtuzumab compared with standard triple induction therapy in reducing the rate of acute rejection.

Monte Carlo sampling and multivariate adaptive regression splines as tools for QSAR modelling of HIV-1 reverse transcriptase inhibitors.

The present work focuses on the development of an interpretable quantitative structure-activity relationship (QSAR) model for predicting the anti-HIV activities of 67 thiazolylthiourea derivatives. This set of molecules has been proposed as potent HIV-1 reverse transcriptase inhibitors (RT-INs). The molecules were encoded to a diverse set of molecular descriptors, spanning different physical and chemical properties. Monte Carlo (MC) sampling and multivariate adaptive regression spline (MARS) techniques were used to select the most important descriptors and to predict the activity of the molecules. The most important descriptor was found to be the aspherisity index. The analysis of variance (ANOVA) and interpretable spline equations showed that the geometrical shape of the molecules has considerable effect on their activities. It seems that the linear molecules are more active than symmetric top compounds. The final MARS model derived displayed a good predictive ability judging from the determination coefficient corresponding to the leave multiple out (LMO) cross-validation technique, i.e. r (2 )= 0.828 (M = 12) and r (2 )= 0.813 (M = 20). The results of this work showed that the developed spline model is robust, has a good predictive power, and can then be used as a reliable tool for designing novel HIV-1 RT-INs.

Carbon composite-PVC based membrane coated platinum electrode for chromium determination.

A new synthesized 1-(2-(1H-imidazole-1-yl)-1-(4-methoxyphenyl)ethylidene)-2-phenyl hydrazine has been used as an ionophore in carbon composite-PVC coated platinum electrode for fabrication of chromium(III)-selective sensor. The homogenization procedure of membrane mixture was performed by applying of the ultrasound in this respect. The sensor shows a good Nernstian slope of 19.62 ± 0.45 mV decade(-1) in a wide linear range concentration of 8.4 × 10(-8)-1.0 × 10(-2)M and a detection limit of 6.8 × 10(-8)M for Cr(NO(3))(3). The proposed electrode has a short response time of about 10s and is reproducible and stable for a period of at least 2 months. The performance of the sensor is pH independent in the pH range of 3.3-5.9 and it also works well in partially non-aqueous medium. The electrode has good selectivity relative to variety of metal ions. The practical analytical utility of the electrode is demonstrated by measurement of Cr(III) quantitatively in multivitamin, mineral water and also as an indicator electrode in the potentiometric titration of chromium (III) against EDTA.

Kinetic and conformational studies of adenosine deaminase upon interaction with oxazepam and lorazepam.

Oxazepam and lorazepam inhibit the adenosine deaminase (ADA) differently. In the case of lorazepam temperature increment causes an increase in the inhibition potency whereas higher temperature reduces the inhibitory effect of oxazepam; which proposes the overall profounder structural changes in the case of lorazepam relative to those caused by oxazepam.

A selective and sensitive carbon composite coated platinum electrode for aluminium determination in pharmaceutical and mineral water samples.

A novel coated wire electrode (CWE) for Al(III) ions is described based on 2-(1H-benzo[d]imidazole-1-yl)-1-phenylethanoneoxime as a new ionophore in carbon-PVC composite. The sensor exhibits significantly enhanced selectivity toward Al(3+) ions over the concentration range 4.3 x 10(-7) to 5.0 x 10(-2)M with a lower detection limit of 2.5 x 10(-7) M and a Nernstian slope of 19.41+/-0.52 mV decade(-1) of aluminium activity. This sensor has a short response time of about 10s and is reproducible and stable for at least forty-five days. This proposed CWE which is designed for the first time revealed good selectivity for Al(III) over a wide variety of other cations. The performance of the sensor is best in the pH range of 3.1-5.5 and it also works well in partially non-aqueous medium. Moreover, the assembly has been successfully used as an indicator electrode in the potentiometric titration of aluminium (III) against EDTA and also in determining Al(III) quantitatively in pharmaceutical and mineral water samples.

Effects of 4-chloro-2,6-bis-(2-hydroxyl-benzyl)-phenol on healing of skin wounds and growth of bacteria.

In this investigation, the effects of synthesized 4-chloro-2,6-bis-(2-hydroxyl-benzyl)-phenol (CBHBP) on cutaneous wound healing and growth of some of the wound contaminating microorganisms were studied. The antibacterial effects of this compound were then evaluated on Staphylococcus aureus (S. aureus), Pseudomonas aeruginosa (P. aeruginosa), Escherichia coli (E. coli) and Klebsiella spp., using solid dilution method. It was demonstrated that CBHBP has a significant antimicrobial activity against S. aureus but it is not effective in the case of other microorganisms studied in this experiment. The effect of local administration of CBHBP on healing of a standard full-thickness 2 cm skin incision of skeletally mature rats was evaluated. Histological changes together with mechanical properties and dry weight content of the healing tissues at the site of the lesions were assessed in treated and untreated animals. It was observed that the injured area of the treated animals was more organized and showed more fibroblasts and less inflammatory cells. Much better maturation criteria in treated tissues were observed in comparison with those of the untreated ones which contained numerous polymorphonuclear inflammatory cells after 14 days post-injury. Many infiltrated macrophages and lymphocytes were present even 28 days after injury induction in the haphazardly organized dermis and also in subcutaneous tissues of the untreated animals. The percentage dry weight content of the treated lesions at 14 days post-injury was remarkably higher than those of the untreated animals. The results of biomechanical tensile testing showed that the ultimate tensile strength and stress of the injured skin of the treated animals were higher than those of the untreated ones. From these results, it could be concluded that CBHBP can be effective on wound healing and may be considered as a treatment regimen after evaluating its mechanism of action as well as testing its contraindications.

Design, synthesis, antibacterial and QSAR studies of benzimidazole and imidazole chloroaryloxyalkyl derivatives.

In view of obtaining some potential antibacterial compounds, we have described synthesis of some chloroaryloxyalkyl imidazole and benzimidazole derivatives. The relevant step in the synthetic sequence was the initial condensation of 4-chloro or 2,4-dichlorophenol with 1, n-dibromoalkanes (n=2, 4, 5) to provide compounds 3a-f in sufficient yields. The subsequent condensation of 3a-f with some imidazole derivatives and benzimidazole afforded products 4a-l and 5a-e in good yields. Some of compounds 4a-l as well as 5a-e were tested in vitro against Salmonella typhi O-901 and Staphylococcus aureus A 15091. Compounds 4a and 4c showed considerable bactericidal activities against tested bacteria. Compound 4b showed significant activity against S. aureus A 15091 but was inactive against S. typhi O-901. Other compounds showed intermediate activities against S. aureus A 15091 but most of them were inactive against S. typhi O-901. Semiempirical AM1 calculations showed that negative electrostatic potentials around oxygen of the phenoxy and nitrogen of the imidazole moieties have direct effect on the antibacterial activity towards S. aureus A 15091. In QSAR analysis, different electronic, topologic, functional groups and physicochemical descriptors were calculated for each molecule and a three parametric equation was found between the logMIC and HOMO energy, hydration energy and number of primary carbon atoms of the molecules.

QSAR analysis for ADA upon interaction with a series of adenine derivatives as inhibitors.

The kinetic parameters of adenosine deaminase such as Km and Ki were determined in the absence and presence of adenine derivatives (R1-R24) in sodium phosphate buffer (50 mM; pH 7.5) solution at 27 degrees C. These kinetic parameters were used for QSAR analysis. As such, we found some theoretical descriptors to which the binding affinity of adenosine deaminase (ADA) towards several adenine nucleosides as inhibitors is correlated. QSAR analysis has revealed that binding affinity of the adenine nucleosides upon interaction with ADA depends on the molecular volume, dipole moment of the molecule, electric charge around the N1 atom, and the highest of positive charge for the related molecules.

Synthesis of N-alkylated derivatives of imidazole as antibacterial agents.

N-Alkylation of imidazole, 2-methylimidazole and 2-methyl-4-nitroimidazole have been carried out to achieve effective antibacterial agents. The products were then investigated for antibacterial activity against Escherichia coil, Staphylococcus aureus and Pseudomonas aeruginosa. Antibacterial effects of 1-alkylimidazole derivatives increase as the number of carbons in alkyl chain increases up to nine carbons. Also substitution of 2-methyl and 2-methyl-4-nitro groups on imidazole ring increases the antibacterial activity.

Design and synthesis of a cephalosporin-retinoic acid prodrug activated by a monoclonal antibody-beta-lactamase conjugate.

Two novel series of all-trans-beta-retinoic acid derivatives were synthesized and found to possess anticancer activity. The first series, cephalosporin 3'-retinoic esters 6 and 7 were, respectively, obtained by the condensation of all-trans-beta-retinoic acid (2) with cephalosporins 4 and 5. The second series, 7-(retinamido)cephalosporins 11 and 12, were synthesized, respectively, by the condensation of 2 with cephalosporins 9 and 10. These four heretofore undescribed compounds 6, 7, 11, and 12 showed inhibitory activity against murine leukemias (L1210 and P388), sarcoma 180, breast carcinoma (MCF7), and human T-lymphocytes (Molt4/C8 and CEM/0). They also inhibited squamous metaplasia and keratinization in tracheal organ cultures derived from vitamin-A-deficient hamsters. Moreover, cephalosporin 3'-retinoic ester 7 exhibited enhanced activity against keratinization with ED(50)=3.91 x 10(-11) M in the presence of a beta-lactamase from Staphylococcus aureus 95. A tumor targeting fusion protein (dsFv3-beta-lactamase) was also used in conjunction with cephem-based retinoid 7 and the potency of 7 toward L1210, P388, and MCF7 was found to approach that of the free retinoic acid (2). In the presence of dsFv3-beta-lactamase, tumor cells were found to be much more susceptible to retinoid 7 than normal human embryonic lung cells. These notions provide a new approach to the use of beta-retinoic acid for antitumor therapy.