Synthesis and molecular docking studies of some 4-phthalimidobenzenesulfonamide derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors

A series of 4-phthalimidobenzenesulfonamide derivatives were designed, synthesized and evaluated for the inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Structures of the title compounds were confirmed by spectral and elemental analyses. The cholinesterase (ChE) inhibitory activity studies were carried out using Ellman’s colorimetric method. The biological activity results revealed that all of the title compounds (except for compound 8) displayed high selectivity against AChE. Among the tested compounds, compound 7 was found to be the most potent against AChE (IC₅₀=?1.35?±?0.08?μM), while compound 3 exhibited the highest inhibition against BuChE (IC₅₀=?13.41?±?0.62?μM). Molecular docking studies of the most active compound 7 in AChE showed that this compound can interact with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE.     

Influences of calorie restriction and lipopolysaccharide therapy on inflammation,cytokine response,and cell proliferation in pancreatic adenocarcinoma mouse model

The study aimed to investigate the effects of lipopolysaccharide (LPS) alone and in combination with calorie restriction (CR) on the pancreatic tissues in C57BL/6 mice modeled with pancreatic ductal adenocarcinoma (PDAC). Forty male C57BL/6 mice (10-13 weeks old) were divided into five groups; LPS, LPS + CR, PDAC, PDAC + LPS, and PDAC + LPS + CR. Nuclear factor kappa B (NF-κβ), interleukin-6 (IL-6), and c-Jun N-terminal kinases (JNK) mRNA expression levels were measured in pancreatic tissues. NF-κβ, IL-6, JNK, and proliferating cell nuclear antigen (PCNA) peptide levels were determined by immunohistochemistry. Oxidative stress markers and antioxidant enzyme activities were determined spectrophotometrically. TH1/TH2 cytokine measurements were determined by a flow cytometer. It was detected that the number of PCNA immune + cells in the PDAC + LPS + CR group was significantly lower than in the PDAC and PDAC + LPS groups (p < 0.01, p < 0.05 respectively). PDAC + LPS + CR group's plasma interferon-gamma (IFN-γ), IL-6, IL-2, tumor necrosis factor-alpha, IL-3, and IL-4 levels were found to be significantly lower than the PDAC group (p < 0.01, p < 0.001, p < 0.01, p < 0.05, p < 0.01, and p < 0.05 respectively). According to our findings, the combination of low-dose LPS and 40% CR was found to be more effective in PDAC model mice.     

Apo-calmodulin binds with its C-terminal domain to the N-methyl-D-aspartate receptor NR1 C0 region

Calmodulin (CaM) is the major Ca2+ sensor in eukaryotic cells. It consists of four EF-hand Ca2+ binding motifs, two in its N-terminal domain and two in its C-terminal domain. Through a negative feedback loop, CaM inhibits Ca2+ influx through N-methyl-D-aspartate-type glutamate receptors in neurons by binding to the C0 region in the cytosolic tail of the NR1 subunit. Ca2+ -depleted (apo)CaM is pre-associated with a variety of ion channels for fast and effective regulation of channel activities upon Ca2+ influx. Using the NR1 C0 region for fluorescence and circular dichroism spectroscopy studies we found that not only Ca2+ -saturated CaM but also apoCaM bound to NR1 C0. In vitro interaction assays showed that apoCaM also binds specifically to full-length NR1 solubilized from rat brain and to the complete C terminus of the NR1 splice form that contains the C0 plus C2' domain. The Ca2+ -independent interaction of CaM was also observed with the isolated C-but not N-terminal fragment of calmodulin in the independent spectroscopic assays. Fluorescence polarization studies indicated that apoCaM associated via its C-terminal domain with NR1 C0 in an extended conformation and collapsed to adopt a more compact conformation of faster rotational mobility in its complex with NR1 C0 upon addition of Ca2+. Our results indicate that apoCaM is associated with NR1 and that the complex of CaM bound to NR1 C0 undergoes a dramatic conformational change when Ca2+ binds to CaM.     

Spread of a single clone Acinetobacter baumannii strain in an intensive care unit of a teaching hospital in Turkey

Acinetobacter baumannii is an important nosocomial pathogen, especially in immunocomprimised patients and those hospitalized in intensive care units. After the first isolation of A. baumannii strains from the bronchial aspirates of two patients in the intensive care unit (ICU) of our hospital as a pure culture, screening studies were performed to define possible source(s). A. baumannii strains isolated from bronchial aspirates and blood cultures of the patients in ICU were collected as a possible part of the outbreak. A total of 23 screening samples collected from equipment (7), hands (4) and gloves (2) of the staff, and from ten different body regions of the patients in the ICU were cultured. Antimicrobial susceptibility test of the isolates was performed by the standardized disk-diffusion method. All isolates were subtyped by antibiogram, arbitrarily primed polymerase chain reaction (AP-PCR) and pulsed-field gel electrophoresis (PFGE) typing methods. A total of 26 A. baumannii strains including eight clinical and 18 screening isolates were identified. All isolates were susceptible only to meropenem, tobramycin, and imipenem. There was at least a 96% resistance rate to the other antibiotics tested. Antibiogram typing showed that 24 of the 26 isolates were epidemiologically related, two were unique. AP-PCR yielded two types, one of which had 21 isolates, the other had five. PFGE fingerprinting revealed that all isolates were clonally related, including four closely related and 22 indistinguishable strains. Based on the results of PFGE which has been accepted as a reference method it can be concluded that A. baumannii strains isolated from our intensive care unit originated from a single type of strain.     

Effects of ascorbic acid on cadmium-induced oxidative stress and performance of broilers

The effects of cadmium on performance, antioxidant defense system, liver and kidney functions, and cadmium accumulation in selected tissues of broiler chickens were studied. Whether the possible adverse effects of cadmium would reverse with the antioxidant ascorbic acid was also investigated. Hence, 4 treatment groups (3 replicates of 10 chicks each) were designed in the study: control, ascorbic acid, cadmium, and cadmium plus ascorbic acid. Cadmium was given via the drinking water at a concentration of 25 mg/L for 6 wk. Ascorbic acid was added to the basal diet at 200 mg/kg either alone or with cadmium. Cadmium decreased the body weight (BW), body weight gain (BWG), and feed efficiency (FE) significantly at the end of the experiment, wheras its effect on feed consumption (FC) was not significant. Cadmium increased the plasma malondialdehyde (MDA) level as an indicator of lipid peroxidation and lowered the activity of blood superoxide dismutase (SOD). Liver function enzymes, aspartate amino transferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), and gamma glutamyl transferase (GGT) activities were not changed by cadmium. Cadmium ingestion did not alter serum creatinine levels. Although the serum cadmium level was not elevated, cadmium mainly accumulated in the kidneys, liver, pancreas, and muscle. Ascorbic acid supplementation resulted in a reduction of MDA level previously increased by cadmium and a restoration in SOD activity. However, ascorbic acid did not ameliorate the growth inhibitory effect of cadmium nor did it prevent accumulation of cadmium in analyzed tissues. These data indicate that oxidative stress, induced by cadmium, plays a role in decreasing the performance of broilers and that dietary supplementation by ascorbic acid might be useful in reversing the lipid peroxidation induced by cadmium and partly alleviating the adverse effect of cadmium on performance of broilers.     

A Simulation Study to Examine the Effect of Common Motoneuron Inputs on Correlated Patterns of Motor Unit Discharge

The influence of common oscillatory inputs to the motoneuron pool on correlated patterns of motor unit discharge was examined using model simulations. Motor unit synchronization, in-phase fluctuations in mean firing rates known as ‘common drive’, and the coefficient of variation of the muscle force were examined as the frequency and amplitude of common oscillatory inputs to the motoneuron pool were varied. The amount of synchronization, the peak correlation between mean firing rates and the coefficient of variation of the force varied with both the frequency and amplitude of the common input signal. Values for ‘common drive’ and the force coefficient of variation were highest for oscillatory inputs at frequencies less than 5 Hz, while synchronization reached a maximum when the frequency of the common input was close to the average motor unit firing rate. The frequency of the common input signal for which the highest levels of synchronization were observed increased as motoneuron firing rates increased in response to higher target force levels. The simulation results suggest that common low-frequency oscillations in motor unit firing rates and short-term synchronization result from oscillatory activity in different bands of the frequency spectrum of shared motoneuron inputs. The results also indicate that the amount of synchronization between motor unit discharges depends not only on the amplitude of the shared input signal, but also on its frequency in relation to the present firing rates of the individual motor units.     

Cytokine polymorphisms in silicosis and other pneumoconioses

Silicosis and coal workers' pneumoconiosis are complex multifactorial lung diseases whose etiopathogenesis are not well defined. It is generally accepted that fibrotic lung disorders are mediated by macrophage-derived cytokines and growth factors. There is evidence showing a crucial role for tumor necrosis factor-a (TNF-alpha) and interleukin-1 (IL-1) in inflammation caused by silica dust and in the transition from simple to progressive massive fibrosis. In this review we discuss genetic polymorphisms responsible for regulating the production of these proinflammatory cytokines and their role in modifying silicosis severity.     

Assessment of DNA base oxidation and glutathione level in patients with type 2 diabetes

Genetic instability resulting from the disturbances in various mechanisms of DNA-repair is the characteristic feature of cancer cells. One of the possibilities to evaluate the effectiveness of DNA-repair system is the adaptive response (AR) analysis. The AR is a phenomenon by which cells exposed to low, non-genotoxic doses of a mutagen become significantly resistant to a subsequent higher dose of the same or another genotoxic agent. Generally, it is postulated that AR is related to a reduction of damage by the induction of free radical detoxification and/or DNA-repair systems.The existence of various DNA-repair mechanisms poses the question whether there are differences in AR induced by chemicals causing DNA-damage that requires different pathways for its repair. In this paper we present the study on the AR induced by two chemical mutagens, bleomycin (BLM) and mitomycin C (MMC), which differ in their action on DNA. BLM is a radiomimetic agent causing mainly single-strand breaks (SSB) and double-strand breaks (DSB) and, thus, inducing chromosomal aberrations (CA). MMC is a potent bifunctional mutagen acting as an alkylating agent, causing DNA cross-links and inducing sister chromatid exchanges (SCEs).The protective effect induced by low doses of tested chemicals was analysed in whole blood human lymphocytes using cytogenetic endpoints (CA for BLM and SCE for MMC, respectively) as a measure of chromosomal instability. There was a significant difference between the protective effects induced by BLM and MMC in the lymphocytes of the same group of donors. The pre-treatment with a low dose of BLM-induced almost 50% decrease in the frequency of CA induced by challenging dose (CD), while the protective effect of MMC was below 20%. The higher AR induced by BLM may be related to the repair processing of BLM-induced DNA-damages. There was also a variability in ARs among individuals, which may reflect the differences in individual DNA-repair capacity.