Determination of trace elements and electrolyte levels in kidney tissue of simvastatin-treated septic rats.

Trace elements are cofactors in various enzymes in the antioxidant defense and cell homeostasis required in the tissue during inflammation. In acute kidney injury induced by lipopolysaccharide (LPS), renal cells are affected by cytotoxicity. Renal evacuation and gastrointestinal absorption rates are important in regulating plasma levels of trace elements. Simvastatin is a widely used anti-lipidemic drug with known anti-inflammatory effects. This study aimed to examine the effect of simvastatin on trace elements and electrolyte levels in kidney tissue in rats with LPS-induced sepsis. Adult male Wistar albino rats were divided into four groups: control, LPS (20 mg/kg, i.p., single dose), simvastatin (20 mg/kg, o.p., 5 days), and LPS + Simvastatin (LPS + Sim). Sodium, potassium, calcium, magnesium, selenium, zinc, copper, and histological structural changes were examined in kidney tissue samples 4 h after LPS execution. The inductively coupled plasma optical emission spectroscopy technique (ICP-OES) was used to determine the tissue trace element levels. In rats with sepsis-induced LPS, selenium, calcium, sodium, and magnesium levels significantly decreased while copper, potassium, and zinc levels significantly increased compared to other experimental groups. In sepsis treated with the simvastatin (LPS + Simvastatin) group, trace elements and electrolyte levels are like the control groups, apart from selenium levels. Selenium levels were significantly decreased in the LPS + Simvastatin group compared to the controls. As a result of examining the kidney tissues under a light microscope, simvastatin improved tissue damage caused by LPS-induced acute kidney injury. LPS-induced renal injury and simvastatin caused significant changes in the oxidant/antioxidant system. In septic rats, simvastatin was shown to balance some trace element levels, and it may improve damage in the kidney tissue.

Synthesis and investigation of binding interactions of 1,4-benzoxazine derivatives on topoisomerase IV in Acinetobacter baumannii.

Acinetobacter baumannii has emerged as an important pathogen for nosocomial infections having high morbidity and mortality. This pathogen is notorious for antimicrobial resistance to many common antimicrobial agents including fluoroquinolones, which have both intrinsic and acquired resistance mechanisms. Fluoroquinolones targeting the bacterial topoisomerase II (DNA gyrase and Topo IV) show potent broad-spectrum antibacterial activity by the stabilization of the covalent enzyme-DNA complex. However, their efficacy is now being threatened by an increasing prevalence of resistance. Fluoroquinolones cause stepwise mutations in DNA gyrase and Topo IV, having alterations of their binding sites. Furthermore, the water-Mg+2 bridge, which provides enzyme-fluoroquinolone interactions, has a significant role in resistance. In this study, 13 compounds were synthesized as 1,4-benzoxazine derivatives which act as bacterial topoisomerase II inhibitors and their antibacterial activities were determined against multi-drug resistant Acinetobacter strains which have ciprofloxacin (CIP) resistant and GyrA mutation. Afterwards we performed docking studies with Topo IV (pdb:2XKK) of these compounds to comprehend their binding properties in Discovery Studio 3.5. The results of this study show significant conclusions to elucidate the resistance mechanism and lead to the design of new antibacterial agents as bacterial topoisomerase II inhibitors.

Synthesis and activity mechanism of some novel 2-substituted benzothiazoles as hGSTP1-1 enzyme inhibitors.

Human GSTP1-1 is one of the most important proteins, which overexpresses in a large number of human tumours and is involved in the development of resistance to several anticancer drugs. So, it has become an important target in cancer treatment. In this study, 12 benzothiazole derivatives were synthesized and screened for their in vitro inhibitory activity for hGSTP1-1. Among these compounds, two of them (compounds #2 and #5) have been found to be the leads when compared with the reference drug etoposide. In order to analyse the structure-activity relationships (SARs) and to investigate the binding side interactions of the observed lead compounds, a HipHop pharmacophore model was generated and the molecular docking studies were performed by using CDocker method. In conclusion, it is observed that the lead compounds #2 and #5 possessed inhibitory activity on the hGSTP1-1 by binding to the H-site as a substrate in which the para position of the phenyl ring of the benzamide moiety on the benzothiazole ring is important. Substitution at this position with a hydrophobic group that reduces the electron density at the phenyl ring is required for the interaction with the H side active residue Tyr108.

Binding site feature description of 2-substituted benzothiazoles as potential AcrAB-TolC efflux pump inhibitors in E. coli.

The resistance-nodulation-division (RND) family efflux pumps are important in the antibiotic resistance of Gram-negative bacteria. However, although a number of bacterial RND efflux pump inhibitors have been developed, there has been no clinically available RND efflux pump inhibitor to date. A set of BSN-coded 2-substituted benzothiazoles were tested alone and in combinations with ciprofloxacin (CIP) against the AcrAB-TolC overexpressor Escherichia coli AG102 clinical strain. The results indicated that the BSN compounds did not show intrinsic antimicrobial activity when tested alone. However, when used in combinations with CIP, a reversal in the antibacterial activity of CIP with up to 10-fold better MIC values was observed. In order to describe the binding site features of these BSN compounds with AcrB, docking studies were performed using the CDocker method. The performed docking poses and the calculated binding energy scores revealed that the tested compounds BSN-006, BSN-023, and BSN-004 showed significant binding interactions with the phenylalanine-rich region in the distal binding site of the AcrB binding monomer. Moreover, the tested compounds BSN-006 and BSN-023 possessed stronger binding energies than CIP, verifying that BSN compounds are acting as the putative substrates of AcrB.

Insight into human protease activated receptor-1 as anticancer target by molecular modelling.

Protease-activated receptor 1 (PAR1) has been established as a promising target in many diseases, including various cancers. Strong evidence also suggests its role in metastasis. It is proved experimentally that PAR1 can induce numerous cell phenotypes, i.e. proliferation and differentiation. A strong link between PAR1 gene overexpression and high levels of ß-catenin was suggested by a study of the PAR1-Gα(13)-DVL axis in ß-catenin stabilization in cancers. An in vitro study was carried out to analyze PAR1 expression by flow cytometry on CD38+138+ plasma cells obtained from patients either at diagnosis (n: 46) (newly diagnosed multiple myeloma (NDMM)) or at relapse (n: 45) (relapsed/refractory multiple myeloma (RRMM)) and compared with the controls. Our previously synthesized benzoxazole (XT2B) and benzamide (XT5) derivatives were tested with in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, which revealed significant inhibitory activity on PAR1. We provide docking studies using Autodock Vina of these newly tested compounds to compare with the known PAR1 inhibitors in order to examine the binding mechanisms. In addition, the docking results are validated using HYDE binding assessment and a neural network (NN) scoring function.

The value of placental protein 13, ß-human chorionic gonadotropin and progesterone in the prediction of miscarriages in threatened miscarriage patients.

The aim of this paper was to investigate the levels of maternal serum placental protein13 (PP13), beta human chorionic gonadotropin (ß-hCG) and progesterone in the prediction of miscarriages in threatened miscarriages. A total of 110 patients with a gestational age < 14 weeks were included in the study. A total of 42 patients were allocated as the study group (threatened miscarriage) and 68 patients were allocated as controls. A total of six miscarriages were observed in the study group. ß-hCG levels were significantly lower in the group with threatened miscarriage when compared with controls (p = 0.018). There was no statistically significant difference in regard to progesterone and PP13 levels occurred between two groups (p = 0.653 and p = 0.062, respectively). Following receiver operating characteristic (ROC) analysis, the ß-hCG parameter was found useful in differentiating miscarriages from the threatened miscarriage group (p = 0.031). PP13 and progesterone parameters in predicting miscarriages were not found as statistically significant (p = 0.084 and p = 0.914, respectively). This study suggests that ß-hCG measurements could be useful in predicting spontaneous miscarriage in women presenting with threatened miscarriage. Even though PP13 seems unfeasible to be used as a predictive marker for miscarriage, factors affecting PP13 levels should be considered along with the need for comprehensive studies including larger patient populations.

Diagnostic performance of p16 staining in atypical squamous cells 'cannot exclude high-grade squamous epithelial lesion' in predicting high-grade cervical pathology.

Atypical squamous cells 'cannot exclude high-grade squamous epithelial lesion' (ASC-H) cytology represents clear risk and has been a controversial issue in clinical practice. The objective of this study is to investigate the diagnostic performance of p16(INK4A) immunohistochemistry (IHC) among ASC-H Pap smears in predicting high-grade cervical intraepithelial lesions. Decolourisation and staining process with p16(INK4A) is applied to 27 ASC-H diagnosed conventional Pap smears, which were all managed with colposcopy-directed cervical biopsy priorly. Staining characteristics of ASC-H Pap smears were compared with histopathological data and sensitivity-specificity values of p16 triage to detect CIN2 + histopathology were determined. The sensitivity and specificity of positive p16(INK4A) immune staining to detect CIN2 + histopathology were as 87.5% and 68%, respectively. The positive predictive value of p16 triage is found as 53.8% and negative predictive value was as 92.8%. p16(INK4A) IHC seems applicable for conventional Pap smears and may provide an alternative triage option in ASC-H category.

Evaluation of inhibitory effects of benzothiazole and 3-amino-benzothiazolium derivatives on DNA topoisomerase II by molecular modeling studies.

There has been considerable interest in DNA topoisomerases over the last decade, as they have been shown to be one of the major cellular targets in anticancer drug development. Previously we synthesized some benzothiazole derivatives and corresponding benzothiazolium forms, and tested their DNA inhibitory activity to develop novel antitumor agents. Among the 12 prepared compounds, compound BM3 (3-aminobenzothiazole-3-ium 4-methylbenzene sulfonate) exhibited extreme topoisomerase II inhibitory activity compared with the reference drug etoposide. We also tried to determine the DNA and enzyme binding abilities of BM3 and found that BM3 acted on topoisomerase II first at low doses, while it had also showed DNA minor groove binding properties at higher doses. In this study the interactions between DNA topoisomerase II and the compounds were examined in detail by molecular modelling studies such as molecular docking and pharmacophore analysis performed using Discovery Studio 3.5. As a result, it was found that benzothiazolium compounds exhibited a totally different mechanism than benzothiazoles by binding to the different amino acids at the active site of the protein molecule. 3-Aminobenzothiazoliums are worthy of carrying onto anticancer studies; BM3 especially would be a good anticancer candidate for preclinical studies.

Pharmacophore generation of 2-substituted benzothiazoles as AdeABC efflux pump inhibitors in A. baumannii.

RND family efflux pumps are important for multidrug resistance in Gram-negative bacteria. To date no efflux pump inhibitors for clinical use have been found, so developing the specific inhibitors of this pump system will be beneficial for the treatment of infections caused by these multidrug-resistant pathogens. A set of BSN-coded 2-substituted benzothiazoles were tested alone and in combination with ciprofloxacin (CIP) against the RND family efflux pump AdeABC overexpressor Acinetobacter baumannii SbMox-2 strain. The results indicated that the BSN compounds did not have antimicrobial activity when tested alone. However, if they were applied in combination with CIP, it was observed that the antibiotic had antimicrobial activity against the tested pathogen, possessing a minimum inhibitory concentration value that could be utilized in clinical treatment. A 3D-common features pharmacophore model was applied by using the HipHop method and the generated pharmacophore hypothesis revealed that the hydrogen bond acceptor property of nitrogen in the thiazole ring and the oxygen of the amide substituted at the second position of the benzothiazole ring system were significant for binding to the target protein. Moreover, three hydrophobic aromatic features were found to be essential for inhibitory activity.

Micro-Raman, mid-IR, far-IR and DFT studies on 2-[4-(4-fluorobenzamido)phenyl]benzothiazole.

Molecular structure of 2-[4-(4-Fluorobenzamido)phenyl]benzothiazole was determined by quantum chemical calculations. MidIR and FarIR spectra were recorded at room temperature, with 4 cm(-1) resolution in the 4000-400 cm(-1) and 700-30 cm(-1) regions, respectively for the first time. Raman spectrum was recorded in the 4000-100 cm(-1) range. Optimized molecular structure and vibrational wavenumbers of the compound in its ground state have been calculated by using Density Functional Theory using B3LYP functional with 6-311++G(d,p) basis set. Vibrational wavenumbers were seen to be in good agreement with the experimental IR data. Furthermore, assignments of each vibrational mode were interpreted in terms of potential energy distributions in detail.

Assesment life quality of familial Mediterranean fever patients by short form-36 and its relationship with disease parameters.

BACKGROUND: Familial Mediterranean fever is an auto-inflammatory disorder. Long term complications of the disease include decreased quality of life. The measurement of quality of life in the patients with chronic disease has become an important research topic during the last years. AIM: We aimed to evaluate life quality of the FMF patients by SF-36, and examine its relationship with the disease parameters. PATIENTS AND METHODS: One hundred voluntary patients (69 female, 31 male) admitted to the rheumatology clinic were included in the study. The control group consisted of 100 healthy individuals. All subjects in the study were asked to complete SF-36 questionnaire. Age of onset of FMF, age at diagnosis, age at the beginning of colchicine therapy, number of attacks per month, family history of FMF and dialysis were inquired of patients with FMF. Disease severity was determined using the FMF severity score. RESULTS: The mean age of the patient group was 31±12 and that of the control group was 29±9. Sixty-nine patients (69%) were female, and 31 patients were male (31%) in both groups. The mean scores of the physical function, physical role function, emotional role function, mental health, and general health parameters of the patients were statistically significantly lower than those of healthy volunteers (p < 0.05). The difference in social function and vitality between two groups was found to be insignificant (p > 0.05). CONCLUSIONS: We have shown that FMF had a negative impact on SF-36. FMF reduces quality of life both in physical and mental dimensions.

Insight into eukaryotic topoisomerase II-inhibiting fused heterocyclic compounds in human cancer cell lines by molecular docking.

Etoposide is effective as an anti-tumour drug by inhibiting eukaryotic DNA topoisomerase II via establishing a covalent complex with DNA. Unfortunately, its wide therapeutic application is often hindered by multidrug resistance (MDR), low water solubility and toxicity. In our previous study, new derivatives of benzoxazoles, benzimidazoles and related fused heterocyclic compounds, which exhibited significant eukaryotic DNA topoisomerase II inhibitory activity, were synthesized and exhibited better inhibitory activity compared with the drug etoposide itself. To expose the binding interactions between the eukaryotic topoisomerase II and the active heterocyclic compounds, docking studies were performed, using the software Discovery Studio 2.1, based on the crystal structure of the Topo IIA-bound G-segment DNA (PDB ID: 2RGR). The research was conducted on a selected set of 31 fused heterocyclic compounds with variation in structure and activity. The structural analyses indicate coordinate and hydrogen bonding interactions, van der Waals interactions and hydrophobic interactions between ligands and the protein, as Topo IIA-bound G-segment DNA are responsible for the preference of inhibition and potency. Collectively, the results demonstrate that the compounds 1a, 1c, 3b, 3c, 3e and 4a are significant anti-tumour drug candidates that should be further studied.

Synthesis, antimicrobial activity and QSAR studies of 2,5-disubstituted benzoxazoles.

In this study, a new series of 2,5-disubstituted benzoxazoles was synthesized and their structures were elucidated by elemental analysis, MASS, (1)H-NMR, (13)C-NMR and IR spectral data. Newly and previously synthesized 2,5-disubstituted benzoxazole derivatives were evaluated for antibacterial and antifungal activity against standard strains and their drug-resistant isolates. Microbiological results showed that the compounds presented a large spectrum of activity having MIC values of 250-7.8 microg mL(-1) against the tested microorganisms. Among the newly synthesized derivatives 3-22, compound 11 was the most active against Candida krusei out of all; however, it was one dilution less potent than standard drug fluconazole. In addition, all the new and previous compounds were more active than standard drugs ampicillin trihydrate and rifampicin against Pseudomonas aeruginosa and its gentamicin-resistant isolate. The 2D-QSAR (Quantitative Structure-Activity Relationship) analysis of a set of newly and previously synthesized benzoxazoles tested for growth inhibitory activity against methicillin-resistant Staphylococcus aureus (MRSA) was also performed by using multivariable regression analysis. The activity contributions for substituent effects of these compounds were determined from the correlation equation for predictions of the lead optimization.

QSAR and pharmacophore analysis on amides against drug-resistant S. aureus.

Considering the worth of developing new antibacterial agents against drug-resistant Stapylococcus aureus, the present study explores the structure-activity relationships analysis of N-(2-hydroxy-4(or 5)-nitro/aminophenyl)benzamide and phenylacetamide derivatives using classical QSAR and 3D-common-feature pharmacophore hypothese approaches. QSAR analysis revealed that the compounds possessing a methylene group between the phenyl and the carboxyamido moiety played a role for decreasing the activity. On the other side, substituent effects on position R1 was found important for the activity and holding a substituent possessing a minimum width property on this position like as alkyl groups enhanced the activity. Moreover, substituting position R3 with a group enhancing the electron-donor capability of the phenolic ring system increased the potency. 3D-common-feature pharmacophore approach considered that the conformational properties of the compounds were important for the activity against drug-resistant S. aureus and compounds possessing a benzamide moiety rather than phenylacetamide structure increased the activity. Furthermore, holding NO2 and OH groups on the phenyl ring attached to the benzamide moiety was important for improving the potency against drug-resistant S. aureus.

QSAR of genotoxic active benzazoles.

Previously synthesized 2,5-disubstituted benzoxazole and benzimidazole derivatives, were tested for their genotoxic activity in the Bacillus subtilis rec- assay. The results revealed that 5-methyl-2-(p-aminobenzyl)benzoxazole exhibited the highest genotoxic response, which was comparable to 4-nitroquinoline 1-oxide (4-NQO), the reference agent of classical positive mutagen. Among the other tested compounds, four showed a genotoxic activity. A QSAR study revealed that structural parameters IY(C(2)H(4)) and IY(CH(2)O), indicating the bridge elements between the phenyl moiety and the fused ring system at position 2 and the quantum chemical parameter (DeltaE ), showing the difference between HOMO and LUMO energies, were found significant for enhancing the genotoxic activity in these compounds. In addition, the substituent effects on positions R and R(1) were found important for the activity as well as holding a substituent possessing a maximum length with a minimum width property on position R(1) like alkyl groups. On the other hand, substituting position R with an electron donating group instead of electron withdrawing group increased the genotoxic activity.

Synthesis, antimicrobial activity and QSARs of new benzoxazine-3-ones.

New ethyl 3,4-dihydro-3-oxo-4,6,7-trisubstituted-2H-1,4-benzoxazine-2-acetate derivatives were synthesized and their structures were elucidated by IR, (1)H NMR and mass spectral data. Antimicrobial activity of the compounds was investigated by using the method of twofold serial dilution technique against different Gram-positive, Gram-negative bacteria and some Candida species in comparison to standard drugs. Microbiological results indicated that the synthesized compounds possessed a broad spectrum of activity having MIC values of 6.25-100 micro g/ml against the tested microorganisms. The QSAR analysis of a set of these compounds tested for growth inhibitory activity against Candida krusei was performed by using the computer-assisted multiple regression procedure. The activity contributions for substituent effects of these compounds were determined from the correlation equation for predictions of the lead optimization.

A study on the antioxidant activities of some new benzazole derivatives.

The in vitro antioxidant properties of some new benzazole derivatives (1-10) such as benzoxazoles, benzimidazoles, and benzothiazoles were determined by their effects on the rat liver microsomal NADPH-dependent lipid peroxidation (LP) level, the scavenging of superoxide anion and the stable radical 2,2-diphenyl-1-picrylhydrazyl (DPPH). Compounds 1, 2, 4 and 6, showed potent scavenging effect on superoxide radical at 10(-3) M. Compound 8, 5-nitro-2-(phenoxymethyl)benzimidazole, strongly inhibited lipid peroxidation at 10(-3) M concentration.

Neuropeptides in psychiatric diseases: an overview with a particular focus on depression and anxiety disorders.

This paper aimed at reviewing the involvement of neuropeptides in various psychiatric diseases, particularly in depression, and anxiety disorders. General features of neuropeptides are first described, including the history of their discovery, their definition, classification, biosynthesis, transport, release, inactivation, as well as their interaction with specific neuronal receptors. The differences with classical neurotransmitters are mentioned, as well as the different patterns of co-transmission. Finally, different mechanisms, both at the cellular and at the systemic level, are proposed that may explain the involvement of these molecules in various psychiatric diseases. Indeed, at the cellular level, a neuropeptide can be involved in a psychiatric disease, either because it is co-localized with a classical neurotransmitter involved in a disease, or because the neuropeptide-containing neuron projects on a target neuron involved in the disease. At the systemic level, a neuropeptide can play a direct role in the expression of a symptom of the disease. This is illustrated by different examples.

3D-QSAR study on heterocyclic topoisomerase II inhibitors using CoMSIA.

Selective topoisomerase II (Topo II) inhibitors have interested to a great extent for the design of new antitumoral compounds in recent years. Comparative molecular similarity indices analysis (CoMSIA) was performed on a series of previously synthesized benzoxazole, benzimidazole, and oxazolo(4,5-b)pyridine derivatives as eukaryotic Topo II inhibitors. A training set of 16 heterocyclic compounds was used to establish the CoMSIA model. They were constructed and geometrically optimized using SYBYL v7.0. The predictive ability of the model was assessed using a test set of 7 compounds. The best model has demonstrated a good fit having r2 value of 0.968 and cross-validated coefficient q2 value as 0.562 including steric and hydrophobic fields. The hydrophobic interactions showed a dominant role for increasing Topo II inhibitor activity and hydrophilic substituent was found more important than hydrophobic one on the 5 or 6 position of benzazole moiety. The model obtained from the present study can be useful for the modification and/or evaluation of the development of new Topo II inhibitors as potential antitumor compounds.

Duloxetine vs placebo in the treatment of stress urinary incontinence: a four-continent randomized clinical trial.

OBJECTIVES: To further assess, in a phase 3 study, treatment with duloxetine for women with stress urinary incontinence (SUI) in other geographical regions, including Argentina, Australia, Brazil, Finland, Poland, South Africa and Spain, as previous trials in North America and Europe provided evidence for the safety and efficacy of duloxetine as a pharmacological treatment for SUI in women. PATIENTS AND METHODS: The study included 458 women aged 27-79 years enrolled in a double-blind, placebo-controlled trial. The patients with predominantly SUI were identified using a validated clinical algorithm. They were randomly assigned to receive placebo (231) or duloxetine 40 mg twice daily (227) for 12 weeks. The primary outcome variables included the incontinence episode frequency (IEF) and the Incontinence Quality of Life (I-QOL) questionnaire. Van Elteren's test was used to analyse the percentage changes in IEF where the stratification variable was weekly baseline IEF (IEF < 14 and > or = 14). Analysis of covariance was used to analyse I-QOL scores. RESULTS: The mean baseline IEF was 18.4/week; 55% of patients had a baseline IEF of > or = 14. There was a significantly greater median decrease in IEF with duloxetine with placebo (54% vs 40%, P = 0.05), with comparable significant improvements in quality of life (I-QOL score increases of 10.3 vs 6.4, P = 0.007). The improvements with duloxetine were associated with significantly greater increases in voiding intervals than with placebo (20.4 vs 8.5 min, P < 0.001). The placebo response was 10.7% and 12.5% higher than those reported in two European and North American phase 3 trials. This may have been related to more patients being naïve for incontinence management in the current trial. Discontinuation rates for adverse events were 1.7% for placebo and 17.2% for duloxetine (P < 0.001), with nausea being the most common reason for discontinuation (3.1%); it was the most common adverse event with duloxetine, but was mild or moderate in most (81%), did not worsen in any patient and resolved within 7 days in 60% and within 1 month in 86% of continuing patients; 88% of women who experienced nausea while taking duloxetine completed the trial. CONCLUSIONS: These results show improvements in incontinence and quality of life with duloxetine 40 mg twice daily for 12 weeks that are in keeping with those reported in two other recently completed phase 3 trials in Europe and North America.