A chemo-enzymatic route to differentially protected aryl-naphthalenes

Aryl-naphthalene diacetates prepared from bispropargyl sulfones, ethers and amines via Garratt–Braverman Cyclization have been selectively hydrolysed by AK lipase to the monoacetates 12a–c in high yields. The regioisomeric mono acetates 13a–c have been prepared by acetylation of the corresponding diols using the same enzyme. In both cases, the more exposed acetoxymethyl or hydroxy methyl attached to the naphthalene ring binds to the active site of the enzyme and underwent hydrolysis/acetylation. The method provides easy access to differentially protected aryl-naphthalenes which should allow further modifications.     

The cytotoxic and apoptotic effects of beta-blockers with different selectivity on cancerous and healthy lung cell lines

Molecular Biology Reports - β-blockers having specific affinities to β-adrenergic receptors are routinely used to treat cardiovascular problems. Additionally, it has been demonstrated...     

Heavy metal risk assessment of European eels (Anguilla anguilla,Linnaeus, 1758) from the Asi (Orontes) River,Turkey

The muscle tissues of a total 154 sampled eels from the Asi (Orontes) River were analyzed between January and December 2018 to determine the content of heavy metals (Hg, Pb, Cd and As). Determination of heavy metals in muscle tissue was carried out with an Inductively Coupled Plasma Mass Spectrometer (ICP-MS). To express the risk level for human consumption of heavy metal contaminated eels we used common concepts and criteria such as Hazard Index (HI), Target Hazard Quotient (THQ) and Total THQ (TTHQ). From the human health point of view, the indices HI, THQ, TTHQ values of Hg, Cd, Pb and As indicate no risks for the consumers at assumed intake levels per unit time.     

Increased Noradrenaline Levels in the Rostral Pons can be Reversed by M1 Antagonist in a Rat Model of Post-traumatic Stress Disorder

The dysregulation of hypothalamic–pituitary–adrenal axis and noradrenergic, serotonergic and glutamatergic systems are thought to be involved in the pathophysiology of post-traumatic stress disorder. The effect of selective M1 muscarinic receptor antagonist, pirenzepine on anxiety indices was investigated by using elevated plus maze, following exposure to trauma reminder. Upon receiving the approval of ethics committee, Sprague–Dawley rats were exposed to dirty cat litter (trauma) for 10 min and 1 week later, the rats confronted to a trauma reminder (clean litter). The rats also received intraperitoneal pirenzepine (1 or 2 mg/kg/day) or saline for 8 days. Noradrenaline (NA) concentration in the rostral pons was analyzed by HPLC with electrochemical detection. The anxiety indices of the rats subjected to the trauma reminder were increased when compared to control rats (p < 0.05). Pirenzepine treatment in traumatized rats displayed similar anxiety indices of non-traumatized rats treated with physiological saline. Although freezing time was prolonged with pirenzepine in traumatized groups the change was not found statistically significant. The NA level was 1.5 ± 0.1 pg/mg in non-traumatized rats and increased to 2.4 ± 0.2 pg/mg in traumatized rats. Bonferroni post hoc test revealed that the NA content of the rostral pons of the traumatized rats treated with physiological saline was significantly higher than the content of other groups (p < 0.01). We conclude that NA content in the rostral pons increases in respect to confrontation to a trauma reminder which can be reversed by M1 antagonist pirenzepine indicating the roles of M1 receptors.     

The Effects of Levosimendan Exposure on Oxidant/Antioxidant Status and Trace Element Levels in the Pulmonary Artery of Rats

We investigated both the effect of levosimendan and the role of oxidant/antioxidant status and trace element levels in the pulmonary artery of rats. Fourteen male Wistar albino rats were randomly divided into two groups of seven animals each. Group 1 was not exposed to levosimendan and served as a control. Levosimendan (12 μg/kg) diluted in 10 ml 0.9 % NaCl was administered intraperitoneally to group 2. Animals of both groups were killed after 3 days, and their pulmonary arteries were harvested to determine changes in tissue oxidant/antioxidant status and trace element levels. The animals in both groups were killed 72 h after the levosimendan exposure treatment, and pulmonary arteries were harvested to determine levels of the lipid peroxidation product MDA and the antioxidant GSH as well as the decreased activity of antioxidant enzymes such as SOD, GSH-Px and CAT. It was found that MDA levels increased in pulmonary artery tissues of rats after levosimendan administration. The GSH level decreased in the pulmonary artery of rats after levosimendan treatment. Co, Mn, Fe, Cd and Pb levels were significantly higher (P < 0.001) and Mg, Zn and Cu levels significantly lower (P < 0.001) in the levosimendan group compared to the control group. These results suggest that levosimendan treatment caused an increase in free radical production and a decrease in antioxidant enzyme activity in the pulmonary artery of levosimendan-treated rats. It also caused a decrease or increase in the levels of many minerals in the pulmonary artery, which is an undesirable condition for normal pharmacological function.     

Evaluation of Epidemiological Cut-Off Values Indicates that Biocide Resistant Subpopulations Are Uncommon in Natural Isolates of Clinically-Relevant Microorganisms

To date there are no clear criteria to determine whether a microbe is susceptible to biocides or not. As a starting point for distinguishing between wild-type and resistant organisms, we set out to determine the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) distributions for four common biocides; triclosan, benzalkonium chloride, chlorhexidine and sodium hypochlorite for 3319 clinical isolates, with a particular focus on Staphylococcus aureus (N = 1635) and Salmonella spp. (N = 901) but also including Escherichia coli (N = 368), Candida albicans (N = 200), Klebsiella pneumoniae (N = 60), Enterobacter spp. (N = 54), Enterococcus faecium (N = 53), and Enterococcus faecalis (N = 56). From these data epidemiological cut-off values (ECOFFs) are proposed. As would be expected, MBCs were higher than MICs for all biocides. In most cases both values followed a normal distribution. Bimodal distributions, indicating the existence of biocide resistant subpopulations were observed for Enterobacter chlorhexidine susceptibility (both MICs and MBCs) and the susceptibility to triclosan of Enterobacter (MBC), E. coli (MBC and MIC) and S. aureus (MBC and MIC). There is a concern on the potential selection of antibiotic resistance by biocides. Our results indicate however that resistance to biocides and, hence any potential association with antibiotic resistance, is uncommon in natural populations of clinically relevant microorganisms.     

IL-10 protects mouse intestinal epithelial cells from Fas-induced apoptosis via modulating Fas expression and altering caspase-8 and FLIP expression

We have previously shown that the absence of Fas/Fas ligand significantly reduced tissue damage and intestinal epithelial cell (IEC) apoptosis in an in vivo model of T cell-mediated enteropathy. This enteropathy was more severe in IL-10-deficient mice, and this was associated with increased serum levels of IFN-gamma and TNF-alpha and an increase in Fas expression on IECs. In this study, we investigated the potential of IL-10 to directly influence Fas expression and Fas-induced IEC apoptosis. Mouse intestinal epithelial cell lines MODE-K and IEC4.1 were cultured with IFN-gamma, TNF-alpha, or anti-Fas monoclonal antibody (mAb) in the presence or absence of IL-10. Fas expression and apoptosis were determined by FACScan analysis of phycoerythrin-anti-Fas mAb staining and annexin V staining, respectively. Treatment with a combination of IFN-gamma and TNF-alpha induced significant apoptosis. Anti-Fas mAb alone did not induce much apoptosis unless cells were pretreated with IFN-gamma and TNF-alpha. These IECs constitutively expressed low levels of Fas, which significantly increased by preincubation of the cells with IFN-gamma and TNF-alpha. Treatment with cytokine or cytokine plus anti-Fas mAb increased apoptosis, which correlated with a decreased Fas-associated death domain IL-1-converting enzyme-like inhibitory protein (FLIP) level, increased caspase-8 activity, and subsequently increased caspase-3 activity. IL-10 diminished both cytokine- and anti-Fas mAb-induced apoptosis, and this was correlated with decreased cytokine-induced Fas expression, increased FLIP, and decreased caspase-8 and caspase-3 activity. In conclusion, IL-10 modulated cytokine induction of Fas expression on IEC cell lines and regulated IEC susceptibility to TNF-alpha, IFN-gamma, and Fas-mediated apoptosis. These findings suggest that IL-10 directly modulates IEC responses to T cell-mediated apoptotic signals.     

Carbonic anhydrase inhibitors. Aromatic/heterocyclic sulfonamides incorporating phenacetyl,pyridylacetyl and thienylacetyl tails act as potent inhibitors of human mitochondrial isoforms VA and VB

A series of aromatic/heterocyclic sulfonamides incorporating phenyl(alkyl), halogenosubstituted-phenyl- or 1,3,4-thiadiazole-sulfonamide moieties and thienylacetamido; phenacetamido and pyridinylacetamido tails were prepared and assayed as inhibitors of four physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic human (h) hCA I and hCA II, and the mitochondrial hCA VA and hCA VB. The new compounds showed moderate inhibition of the two cytosolic isoforms (K_Is of 50–390 nM) and excellent inhibitory activity against the two mitochondrial enzymes, with many low nanomolar inhibitors detected (K_Is in the range of 5.9–10.2 nM). All substitution patterns explored here lead to effective hCA VA/VB inhibitors. Some hCA VA/VB selective inhibitors were also detected, with selectivity ratios for inhibiting the mitochondrial over the cytosolic isozymes of around 55.5–56.9. As hCA VA/VB are involved in several biosynthetic processes catalyzed by pyruvate carboxylase, acetyl CoA carboxylase, and carbamoyl phosphate synthetases I and II, providing the bicarbonate substrate to these carboxylating enzymes involved in fatty acid biosynthesis, their selective inhibition may lead to the development of antiobesity agents possessing a new mechanism of action.     

Neurocognitive correlates of adult attention-deficit/hyperactivity disorder in a Turkish sample

We established a neuropsychological testing profile among Turkish adults presenting with ADHD controlling for general intelligence and comorbid psychiatric conditions. Adults with ADHD frequently present with comorbid conditions (e.g., mood and substance use/abuse disorders) that may have a detrimental impact on neurocognitive function. Hence, we excluded patients with ADHD meeting criteria for comorbid psychiatric syndromes. A comprehensive neuropsychological test battery was administered to adults with ADHD attending a general psychiatry clinic in Istanbul, Turkey, and healthy control participants. Adults with ADHD demonstrated performance deficits on tests of attention, information processing speed, and general and working memory. Patients with ADHD also reported a significantly greater number of symptoms associated with frontal lobe syndromes (i.e., dysexecutive symptoms and disinhibition). Patients with ADHD demonstrated rather striking deficits on tests of verbal and nonverbal memory. Once information was encoded, however, patients with ADHD do not demonstrate significant information loss. Patients with ADHD and healthy controls did not differ on tests of alternation learning, inhibitory control (error rates), and ToM skills. Findings support the contention that dorsal-prefrontal (rather than ventral-prefrontal) dysfunction is associated with adult ADHD. Unexpectedly, groups did not differ on executive control and fluency tasks. Yet patients with ADHD obtained substantially higher scores on a self-report measure of executive dysfunction. This suggests that dysexecutive symptoms among patients with ADHD in the current study do not reflect set-shifting or organizational deficits. Rather, symptoms may reflect attentional and working memory deficits as well as diminished information processing speed.