Carbonic anhydrase inhibitors: Benzenesulfonamides incorporating cyanoacrylamide moieties are low nanomolar/subnanomolar inhibitors of the tumor-associated isoforms IX and XII

A series of benzenesulfonamides incorporating cyanoacrylamide moieties (tyrphostine analogues) have been obtained by reaction of sulfanilamide with ethylcyanoacetate followed by condensation with aromatic/heterocyclic aldehydes, isothiocyanates or diazonium salts. The new compounds have been investigated as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4. 2.1.1), and more specifically against the cytosolic human (h) isoforms hCA I and II, as well as the transmembrane, tumor-associated ones CA IX and XII, which are validated antitumor targets. Most of the new benzenesulfonamides were low nanomolar or subnanomolar CA IX/XII inhibitors whereas they were less effective as inhibitors of CA I and II. The structure–activity relationship for this class of effective CA inhibitors is also discussed. Generally, electron donating groups in the starting aldehyde reagent favored CA IX and XII inhibition, whereas halogeno, methoxy and dimethylamino moieties led to very potent CA XII inhibitors.     

Carbonic anhydrase inhibitors: Inhibition of the β-class enzyme from the yeast Saccharomyces cerevisiae with sulfonamides and sulfamates

The protein encoded by the Nce103 gene of Saccharomyces cerevisiae, a β-carbonic anhydrase (CA, EC 4.2.1.1) designated as scCA, has been cloned, purified, characterized kinetically and investigated for its inhibition with a series of sulfonamides and one sulfamate. The enzyme showed high CO₂ hydrase activity, with a k_cat of 9.4 × 10⁵ s^?1, and k_cat/K_M of 9.8 × 10⁷ M^?1 s^?1. Simple benzenesulfonamides substituted in 2-, 4- and 3,4-positions of the benzene ring with amino, alkyl, halogeno and hydroxyalkyl moieties were weak scCA inhibitors with K_Is in the range of 0.976–18.45 μM. Better inhibition (K_Is in the range of 154–654 nM) was observed for benzenesulfonamides incorporating aminoalkyl/carboxyalkyl moieties or halogenosulfanilamides; benzene-1,3-disulfonamides; simple heterocyclic sulfonamides and sulfanilyl-sulfonamides. The clinically used sulfonamides/sulfamate (acetazolamide, ethoxzolamide, methazolamide, dorzolamide, topiramate, celecoxib, etc.) generally showed effective scCA inhibitory activity, with K_Is in the range of 82.6–133 nM. The best inhibitor (K_I of 15.1 nM) was 4-(2-amino-pyrimidin-4-yl)-benzenesulfonamide. These inhibitors may be useful to better understand the physiological role of β-CAs in yeast and some pathogenic fungi which encode orthologues of the yeast enzyme and eventually for designing novel antifungal therapies.     

The effect of vaginal candidiasis on the levels of the oxidative biomarkers in plasma and tissue samples of diabetic rats

The aim of this study is to determine the relation between diabetes and vaginal candidiasis in terms of oxidative biomarker levels in a vaginal candidiasis model of the diabetic rats by evaluating malondialdehyde (MDA), sulphydrile groups or glutathione (RSH), and ascorbic acid (C vit) levels. All rats were randomly divided into five groups. All of the groups were observed for 21 days. In the treated diabetes groups, MDA (0.90, 0.68 nmol/ml and 3.78, 3.79 nmol/g tissue, plasma and vaginal tissue, respectively) and RSH (227, 171 nmol/100 ml 0.38, 0.37 μmol/g tissue, plasma and vaginal tissue, respectively) levels were found to be decreased while the levels of C vit were found to be increased (0.49, 0.37 μmol/l 2.39, 2.01 nmol/g tissue plasma, and vaginal tissue, respectively) (P < 0.05). In the groups of untreated diabetes, vaginal candidiasis were found to be more serious and oxidative biomarkers were found to be increased (MDA 1.30, 1.26 nmol/ml and 7.82, 2.37 nmol/g tissue and RSH 258, 145 nmol/100 ml and 0.31, 0.46 μmol/g tissue) while the antioxidant C vit levels were found to be decreased (0.24, 0.17 μmol/l 1.33, 2.66 nmol/g tissue) (P < 0.05). RSH, plasma MDA, blood glucose, and tissue MDA levels of vaginal candidiasis embedeled diabetic rats, were found to be higher than those in untreated diabetic and untreated vaginitis enbedeled rats ‹P < 0.05’. Vaginal candidiasis caused oxidative stress in diabetic rats working together. Systemic oxidative stress biomarkers were found to be affected from vaginal candidiasis although it was a local mucosal infection. This study was presented as a poster in the conference of ‹2nd Trends in Medical Mycology, 23–26 October 2005, Berlin, Germany’.     

Polymorphisms of DNA base‐excision repair genes APE/Ref‐1 and XRCC1 are not associated with the risk for Graves' disease

Oxidative stress has been implicated in etiopathogenesis of Graves' disease (GD). Increased lipid peroxidation and oxidative DNA damage have been found in GD patients. Oxidative DNA damage is mainly repaired by the base‐excision repair (BER) pathway. Polymorphisms in DNA‐repair genes have been associated with the increased risk of various diseases and could also be related to the etiology of GD. Therefore, we conducted a study including 197 patients with GD and age‐ and sex‐matched 303 healthy subjects to examine the role of single‐nucleotide polymorphisms of BER genes, APE/Ref‐1 (codon 148) and XRCC1 (codons 194 and 399) as a risk factor for GD. These polymorphisms were determined by quantitative real‐time PCR and melting curve analysis using LightCycler. No significant association was observed between the variant alleles of APE/Ref‐1 codon 148 [odds ratio (OR) = 0.89, 95% confidence interval (CI) = 0.69–1.17], XRCC1 codon 194 (OR = 1.24, 95% CI = 0.79–1.94), and XRCC1 codon 399 (OR = 1.12, 95% CI = 0.86–1.46) and GD. These preliminary results suggest that APE/Ref‐1 (codon 148) and XRCC1 (codons 194 and 399) polymorphisms are not significant risk factors for developing GD. Copyright © 2009 John Wiley & Sons, Ltd.     

Occupational exposure to magnetic fields from transformer stations and electric enclosures in Turkey

We aimed to provide a systematic evaluation of magnetic field (MF) exposure of staff working in the offices located above or close to transformer stations (TS) and electric enclosures (EE). Occupational short-term "spot" measurements with Narda EFA-300 and isotropic magnetic field probe were carried out in two National Banks and one Industrial Company having more than 500 employees. Extremely low-frequency (ELF) MFs up to several tens of μT were measured in the mentioned working environments. 25% of the measured MFs were found less than 0.3?μT, the background exposure level that staff receive at home, 75% were above 0.3?μT with the highest value of 6.8?μT. The mean and median personal exposures were calculated to be 1.19?μT and 0.56?μT, respectively. Most of the staff (83%) is under risk based on epidemiological studies that reported a statistically significant association between risk of leukemia and averaged magnetic fields of 0.2?μT or over. Results showed that risk evaluation should be considered to minimize the possibility of the workers being harmed due to exposure to work-related electromagnetic sources.     

Cytotoxicity and DNA interactions of some platinum(II) complexes with substituted benzimidazole ligands

In the present study, four Pt(II) complexes with 2-ethyl (1)/or benzyl (2)/or p-chlorobenzyl (3)/or 2-phenoxymethyl (4) benzimidazole carrier ligands were evaluated for their in vitro cytotoxic activities against the human HeLa cervix, oestrogen receptor-positive MCF-7 breast, and oestrogen receptor-negative MDA-MB 231 breast cancer cell lines. The plasmid DNA interactions and inhibition of the BamHI restriction enzyme activities of the complexes were also studied. Complex 3 was found to be more active than carboplatin for all examined cell lines and comparable with cisplatin, except for the HeLa cell line.     

Bioaccumulation of Heavy Metals in Various Tissues of Some Fish Species and Green Tiger Shrimp (<Emphasis Type="Italic">Penaeus semisulcatus</Emphasis>) from İskenderun Bay,Turkey, and Risk Assessment for Human Health

In this study, concentrations of heavy metals were determined by ICP-MS in the edible tissues of common sole (Solea solea Linnaeus, 1758), whiting (Merlangius merlangus Linnaeus, 1758), silver sillago (Sillago sihama Forsskål, 1775) and muscle-exoskeleton of green tiger shrimp (Penaeus semisulcatus De Haan, 1844), from the seas of ?skenderun Bay, Eastern Mediterranean, Turkey, in January–February, 2016. The lowest and highest mean concentrations of Mn, Cr, Cd, Ni, Hg, As, Pb, and Co in fish and shrimp’ muscles were found, respectively, as follows: 0.166–0.382, 0.134–0.336, 0.005–0.008, 0.091–0.140, 0.026–0.228, 1.741–29.254, 0.087–0.110, and <0.0005–0.027 mg kg^?1; in the skin and exoskeleton, the values were found, respectively, as 0.103–15.819, 0.301–0.778, 0.007–0.026, 0.115–0.513, 0.021–0.243, 1.548–17.930, 0.148–0.295, and <0.0005–0.140 mg kg^?1. According to the results, mean concentrations of all metals in the muscles of fish, except for arsenic and chromium, were found to be below certain legal limit values, especially arsenic levels in shrimp that were found to be above all the legal limit values. Also, the hazard quotients (HQ) of individual heavy metals in fish and shrimp, except for As, revealed safe levels for human consumption. However, the HQ values of estimated inorganic As exceeded 1 in the muscles of shrimp (P. semisulcatus), which may constitute a risk to public health.     

Vth International Conference on Environmental Mutagens in Human Populations: introduction

The Vth International Conference on Environmental Mutagens in Human Populations (VthICEMHP), 20-24 May 2007 was successfully completed in Antalya, Turkey. With approximately 200 participants from 35 countries, the conference participants enjoyed extensive exchange of scientific and cultural expertise. Like the previous conferences in this series, collaborative and sustainable projects were developed among the participants. Publications in this monograph represent outstanding reviews and experimental data from invited speakers.     

Assessment of DNA strand breakage by comet assay in diabetic patients and the role of antioxidant supplementation

Diabetes patients often show increased production of reactive oxidative species (ROS) together with vascular complications. The presence of these ROS may lead to increased DNA damage in peripheral blood lymphocytes that may be revealed by the comet assay. To test whether DNA is damaged in diabetes, peripheral blood samples were taken from 30 control individuals and 63 diabetic patients (15 insulin dependent (IDDM) and 48 non-insulin dependent (NIDDM)) and the alkaline comet assay was used to evaluate background levels of DNA damage. Significant differences were detected between control and diabetic patients in terms of frequencies of damaged cells. The extend of DNA migration was greater in NIDDM patients by comparison with IDDM patients which might indicate that IDDM patients are handling more oxidative damage on a regular basis. Smoker individuals had higher frequencies of cells with migration by comparison with the non-smokers in both groups. Also, clear differences between patients on placebo and on Vitamin E supplementation for 12 weeks were observed on the basis of the extend of DNA migration during single cell gel electrophoresis.     

Global gene expression profiling in congenital diaphragmatic hernia (CDH) patients

Functional & Integrative Genomics - Congenital diaphragmatic hernia (CDH) is an anomaly characterized by a defect in the diaphragm, leading to the passage of intra-abdominal organs into the...