Design,synthesis, and evaluation of the antiproliferative activity of hydantoin-derived antiandrogen-genistein conjugates

Androgen receptor (AR) signaling is vital to the viability of all forms of prostate cancer (PCa). With the goal of investigating the effect of simultaneous inhibition and depletion of AR on viability of PCa cells, we designed, synthesized and characterized the bioactivities of bifunctional agents which incorporate the independent cancer killing properties of an antiandrogen and genistein, and the AR downregulation effect of genistein within a single molecular template. We observed that a representative conjugate, 9b, is much more cytotoxic to both LNCaP and DU145 cells relative to the antiandrogen and genistein building blocks as single agents or their combination. Moreover, conjugate 9b more effectively down regulates cellular AR protein levels relative to genistein and induces S phase cell cycle arrest. The promising bioactivities of these conjugates warrant further investigation.     

Zinc supplementation ameliorates glycoprotein components and oxidative stress changes in the lung of streptozotocin diabetic rats

Zinc (Zn) is a component of numerous enzymes that function in a wide range of biological process, including growth, development, immunity and intermediary metabolism. Zn may play a role in chronic states such as cardiovascular disease and diabetes mellitus. Zn acts as cofactor and for many enzymes and proteins and has antioxidant, antiinflammatory and antiapoptotic effects. Taking into consideration that lung is a possible target organ for diabetic complications, the aim of this study was to investigate the protective role of zinc on the glycoprotein content and antioxidant enzyme activities of streptozotocin (STZ) induced diabetic rat tissues. Female Swiss albino rats were divided into four groups. Group I, control; Group II, control + zinc sulfate; Group III, STZ-diabetic; Group IV, diabetic + zinc sulfate. Diabetes was induced by intraperitoneal injection of STZ (65 mg/kg body weight). Zinc sulfate was given daily by gavage at a dose of 100 mg/kg body weight every day for 60 days to groups II and IV. At the last day of the experiment, rats were sacrificed, lung tissues were taken. Also, glycoprotein components, tissue factor (TF) activity, protein carbonyl (PC), advanced oxidative protein products (AOPP), hydroxyproline, and enzyme activities in lung tissues were determined. Glycoprotein components, TF activity, lipid peroxidation, non enzymatic glycation, PC, AOPP, hydroxyl proline, lactate dehydrogenase, catalase, superoxide dismutase, myeloperoxidase, xanthine oxidase, adenosine deaminase and prolidase significantly increased in lung tissues of diabetic rats. Also, glutathione levels, paraoxonase, arylesterase, carbonic anhydrase, and Na⁺/K⁺- ATPase activities were decreased. Administration of zinc significantly reversed these effects. Thus, the study indicates that zinc possesses a significantly beneficial effect on the glycoprotein components and oxidant/antioxidant enzyme activities.     

Comparative analysis of prokaryotic diversity in solar salterns in eastern Anatolia (Turkey)

The prokaryotic communities of four salterns (Bingöl, Fadlum, Kemah, and Tuzlagözü) in Turkey were examined and compared using the cultivation and cultivation-independent methods [fluorescence in situ hybridization (FISH) and 454 pyrosequencing]. FISH analysis with universal probes revealed that feeding waters carried 1.6 × 10²–1.7 × 10³ cells mL^?1, while crystallization ponds carried 3.8 × 10⁶–2.0 × 10⁷ cells mL^?1 that were mostly haloarchaea, including square cells (except for Kemah). High-throughput 16S rRNA-based gene sequencing showed that the most frequent archaeal OTUs in Bingöl, Fadlum, Tuzlagözü, and Kemah samples were affiliated with Haloquadratum (76.8 %), Haloarcula (27.8 %), Halorubrum (49.6 %), and Halonotius (59.8 %), respectively. Bacteroidetes was the dominant bacterial phylum in Bingöl and Fadlum, representing 71.5 and 79.5 % of the bacterial OTUs (respectively), while the most abundant bacterial phylum found in the Kemah saltern was Proteobacteria (79.6 %). The majority of the bacterial OTUs recovered from Tuzlagözü belonged to the Cyanobacteria (35.7 %), Bacteroidetes (35.0 %), and Proteobacteria (25.5 %) phyla. Cultivation studies revealed that the archaeal isolates were closely related to the genera Halobacterium, Haloarcula, and Halorubrum. Bacterial isolates were confined to two phyla, Proteobacteria (Alphaproteobacteria and Gammaproteobacteria classes) and Bacteroidetes. Comparative analysis showed that members of the Euryarchaeota, Bacteroidetes, Proteobacteria, and Cyanobacteria phyla were major inhabitants of the solar salterns.     

Trace Elements in the Soil-Plant Systems of Copper Mine Areas-A Case Study From Murgul Copper Mine From the Black Sea Region of Turkey

This study presents a case study on the heavy metal analysis of soil and plant samples around the Murgul copper mine, one of the first and most important mining areas in Turkey. An attempt has been made to investigate the status of trace elements like Al³⁺, Fe²⁺, Cu²⁺, Zn²⁺, Pb²⁺, Ni²⁺, Co²⁺ and Cd²⁺ in soils and plants. The sampling localities were taken from 500 m, 600 m, and 1000 m altitudes around the factory and at 1400 m in the forest zone. The aboveground parts and foliage ash of Silene compacta, Tussilago farfara, Smilax excelsa, Rhododendron ponticum, R. luteum, and herbal mix were analysed. The results of analysis have revealed the minimum and maximum concentrations measured in the plants as follows; aluminium (20-8985 mg kg-1), cadmium (0.0-0.5 mg kg^-1), cobalt (0.0-5.5 mg kg^-1), copper (0.0-347.5 mg kg^-1), iron (25-9320 mg kg^-1), lead (2-51 mg kg^-1), nickel (1.5-16.5 mg kg^-1), and zinc (13.0-221.0 mg kg^-1). In the soil the concentrations of aluminium, cadmium, cobalt, copper, iron, lead, nickel, and zinc vary between 33-457, 0.0-0.0, 0.0-0.4, 0.1-88.7, 14-50, 0.3-4.1, 0.2-0.8, and 4.0-20.3 mg kg^-1 respectively. These findings enlighten the fact that copper is generally toxic in the soils as well as plants. Silene compacta has been recorded as a high copper accumulator, behaving as a healthy plant on the polluted sites of the area alongside the Murgul creek (especially at 600 m). This study stresses the fact that it is imperative to assess and monitor the levels of heavy metals in the environment due to anthropogenic activities, including mining, for evaluation of human exposure and for sustainable environment.     

Reproducibility of erythrocyte polyamine measurements and correlation with plasma micronutrients in an antioxidant vitamin intervention study

Erythrocyte polyamine measurements have been previously investigated as candidate biomarkers for hyperproliferation and recently as a potential intermediate endpoint in clinical chemoprevention trials with difluoromethylornithine, an inhibitor of polyamine biosynthesis. This study was performed to determine the reproducibility of erythrocyte polyamine measurements and their possible correlation with plasma micronutrients in seven healthy adults in an antioxidant vitamin intervention study. As part of this cross-over intervention study, three subjects took β-carotene (31.4 mg/day) plus D-α-tocopherol acetate (720 IU/day) supplements during the first 3 months and four subjects took the supplements during the second 3 months. Heparinized blood samples were collected at baseline and every month over total 6 months for simultaneous determination of erythrocyte polyamines and plasma micronutrients by the high-performance liquid chromatographic method. For all the measures of erythrocyte polyamines the intraindividual variation was smaller than that between subjects, and three or four measurements required to accurately characterize long-term erythrocyte polyamines for an individual. The intra-class correlations were moderately high for all erythrocyte polyamine measurements, indicating a good reproducibility for intra-individual erythrocyte polyamine measurements. Based on monthly values, significant inverse correlations were found between erythrocyte spermidine and the plasma levels of retinol (r = -0.50) and lutein (r = -0.52). There were also significant inverse associations between erythrocyte spermine and plasma levels of α-tocopherol (r = -0.29), lutein (r = -0.44), lycopene (r = -0.29), β-cryptoxanthin (r = -0.30), and total carotenoids (r = -0.29). The effects of supplementation upon the associations between erythrocyte polyamines and plasma nutrient levels were additionally addressed. The results indicate an acceptable longitudinal reproducibility of erythrocyte polyamine measurements, support the hypothesis that erythrocyte polyamine measurements may be correlated with plasma levels of certain nutrients, and suggest a further biomarker application in cancer prevention trials involving dietary modifications or specific relevant micronutrients. © 1996 Wiley-Liss, Inc.     

Effect of cobalt-60 (γ radiation) on multidrug-resistant multiple myeloma cell lines

Emergence of resistance to chemotherapy and radiotherapy is a major obstacle for the successful treatment of MM (multiple myeloma). Prednisone, vincristine and melphalan are commonly used chemotherapeutic agents for the treatment of MM. In the current study, we examined the presence of possible cross-resistance between these drugs and gamma (γ) radiation. Prednisone, vincristine and melphalan resistant RPMI-8226 and U-266 MM cells were generated by stepwise increasing concentrations of the drugs. The sensitive and resistant cells were exposed to 200- and 800 cGy γ radiation, and proliferation was examined by XTT {2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide} assay. The results showed that Prednisone- and melphalan-resistant RPMI-8226 cells were also cross-resistant to 200 and 800 cGy γ radiation application, while vincristine-resistant cells did not show resistance. On the other hand, Prednisone-, vincristine- and melphalan-resistant U-266 cells showed cross-resistance to 200- and 800 cGy γ radiation application. These results demonstrated that MM cells resistant to anticancer agents respond to radiation in different levels. These findings may be important in the clinical applications of radiation therapy in the treatment of vincristine resistant MM.     

Protective effects of the nuclear factor kappa B inhibitor pyrrolidine dithiocarbamate in bladder ischemia–reperfusion injury in rats

The aim of the present study was to evaluate the protective effects of the NF-кB inhibition with pyrrolidine-dithiocarbamate (PDTC) in ischemia–reperfusion (I/R) injury in the rat bladder. Twenty-four Sprague-Dawley male rats were divided into three groups. Group I; (n = 8) control, group II; (n = 8) I/R group; group III (n = 8) I/R and PDTC treatment. Superoxide dismutase (SOD), catalase (CAT), and gluatathione-S-transferase (GST) enzymes was studied in bladder tissue. Lipid peroxidation (as TBARS) levels in tissue homogenate were measured with thiobarbituric acid reaction. All the slides were stained with NF-кB, p53 and HSP60 immunohistochemistry for detection genome destruction and tissue stress, respectively. Our results show that the mean TBARS levels were significantly higher in group II (p < 0.05). The TBARS levels were significantly decreased in group III compared with the group II (p < 0.05). CAT, SOD and GST activities were decreased in group II, but these enzymes levels were significantly increased in group III according to the group II (p < 0.05). Under microscopic evaluation NF-кB expression increased significantly in group II compared to the group I (p < 0.05) and then decreased in group III (p < 0.05). HSP60 and p53 expression in group II was increased significantly compared with group I. Under microscopic evaluation we detected that HSP60 and p53 expression was increased significantly in group II compared with group I. In group III PDTC administration was decreased the HSP60 and p53 expression, this difference was statistically significant (p < 0.05). The results of the present study have demonstrated that NF-кB inhibition with PDTC protects and provides beneficial effects on ischemia/reperfusion stress related bladder tissue destruction.     

Bacterial Cyanuric Acid Hydrolase for Water Treatment

Di- and trichloroisocyanuric acids are widely used as water disinfection agents, but cyanuric acid accumulates with repeated additions and must be removed to maintain free hypochlorite for disinfection. This study describes the development of methods for using a cyanuric acid-degrading enzyme contained within nonliving cells that were encapsulated within a porous silica matrix. Initially, three different bacterial cyanuric acid hydrolases were compared: TrzD from Acidovorax citrulli strain 12227, AtzD from Pseudomonas sp. strain ADP, and CAH from Moorella thermoacetica ATCC 39073. Each enzyme was expressed recombinantly in Escherichia coli and tested for cyanuric acid hydrolase activity using freely suspended or encapsulated cell formats. Cyanuric acid hydrolase activities differed by only a 2-fold range when comparing across the different enzymes with a given format. A practical water filtration system is most likely to be used with nonviable cells, and all cells were rendered nonviable by heat treatment at 70°C for 1 h. Only the CAH enzyme from the thermophile M. thermoacetica retained significant activity under those conditions, and so it was tested in a flowthrough system simulating a bioreactive pool filter. Starting with a cyanuric acid concentration of 10,000 μM, more than 70% of the cyanuric acid was degraded in 24 h, it was completely removed in 72 h, and a respike of 10,000 μM cyanuric acid a week later showed identical biodegradation kinetics. An experiment conducted with water obtained from municipal swimming pools showed the efficacy of the process, although cyanuric acid degradation rates decreased by 50% in the presence of 4.5 ppm hypochlorite. In total, these experiments demonstrated significant robustness of cyanuric acid hydrolase and the silica bead materials in remediation.     

Dosimetric and physical comparison of IMRT and CyberKnife plans in the treatment of localized prostate cancer

Aim

The aim of our study was the dosimetric and physical evaluation of the CK and IMRT treatment plans for 16 patients with localized prostate cancer.

Background

Intensity modulated radiation therapy (IMRT) is one of the recent technical advances in radiotherapy. The prostate is a well suited site to be treated with IMRT. The challenge of accurately delivering the IMRT needs to be supported by new advances such as image-guidance and four-dimensional computed conformal radiation therapy (4DCRT) tomography. CyberKnife (CK) provides real time orthogonal X-ray imaging of the patient during treatment course to follow gold fiducials installed into the prostate and to achieve motion correlation between online acquired X-ray imaging and digital reconstructed radiographs (DRRs) which are obtained from planning computed tomography images by translating and rotating the treatment table in five directions.

Methods and materials

Sixteen IMRT and CK plans were performed to be compared in terms of conformity (CI), heterogeneity indices (HI), percentage doses of 100% (V100), 66% (V66), 50% (V50), 33% (V33) and 10% (V10) volumes of the bladder and rectum. Dose-volume histograms for target and critical organs, (CI) and indices (HI) and isodose lines were analyzed to evaluate the treatment plans.

Results

Statistically significant differences in the percentage rectal doses delivered to V10, V33, and V50 of the rectum were detected in favor of the CK plans (p values; <0.001, <0.001 and 0.019, respectively). The percentage doses for V66 and V100 of the rectum were larger in CK plans (13%, 2% in IMRT and 21%, 3% in CK plans, respectively). Percentage bladder doses for V10 and V33 were significantly lower in CK plans [96% in IMRT vs 48% in CK (p < 0.001) and 34% in IMRT vs 24% in CK (p = 0.047)]. Lower percentage doses were observed for V50, V66 of the bladder for the IMRT. They were 5.4% and 3.45% for IMRT and 13.4% and 8.05% for CK, respectively. Median CI of planning target volume (PTV) for IMRT and CK plans were 0.94 and 1.23, respectively (p < 0.001).

Conclusion

Both systems have a very good ability to create highly conformal volumetric dose distributions. Median HI of PTV for IMRT and CK plans were 1.08 and 1.33, respectively (p < 0.001).