Synthesis and biological evaluation of new N-(2-hydroxy-4(or 5)-nitro/aminophenyl)benzamides and phenylacetamides as antimicrobial agents

A new series of N-(2-hydroxy-4(or 5)-nitro/aminophenyl)benzamide and phenylacetamide derivatives (1a-1n, 2a-2n) were synthesized and evaluated for antibacterial and antifungal activities against Staphylococcus aureus, Bacillus subtilis, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Candida albicans, and their drug-resistant isolate. Microbiological results indicated that the compounds possessed a broad spectrum of activity against the tested microorganisms at MIC values between 500 and 1.95 microg/ml. Benzamide derivative 1d exhibited the greatest activity with MIC values of 1.95, 3.9, and 7.8 microg/ml against drug-resistant B. subtilis, B. subtilis, and S. aureus, respectively.     

Epigenetic Priming of AML Blasts for All-trans Retinoic Acid-Induced Differentiation by the HDAC Class-I Selective Inhibitor Entinostat

All-trans retinoic acid (ATRA) has only limited single agent activity in AML without the PML-RARα fusion (non-M3 AML). In search of a sensitizing strategy to overcome this relative ATRA resistance, we investigated the potency of the HDAC class-I selective inhibitor entinostat in AML cell lines Kasumi-1 and HL-60 and primary AML blasts. Entinostat alone induced robust differentiation of both cell lines, which was enhanced by the combination with ATRA. This “priming” effect on ATRA-induced differentiation was at least equivalent to that achieved with the DNA hypomethylating agent decitabine, and could overall be recapitulated in primary AML blasts treated ex vivo. Moreover, entinostat treatment established the activating chromatin marks acH3, acH3K9, acH4 and H3K4me3 at the promoter of the RARβ2 gene, an essential mediator of retinoic acid (RA) signaling in different solid tumor models. Similarly, RARβ2 promoter hypermethylation (which in primary blasts from 90 AML/MDS patients was surprisingly infrequent) could be partially reversed by decitabine in the two cell lines. Re-induction of the epigenetically silenced RARβ2 gene was achieved only when entinostat or decitabine were given prior to ATRA treatment. Thus in this model, reactivation of RARβ2 was not necessarily required for the differentiation effect, and pharmacological RARβ2 promoter demethylation may be a bystander phenomenon rather than an essential prerequisite for the cellular effects of decitabine when combined with ATRA. In conclusion, as a “priming” agent for non-M3 AML blasts to the differentiation-inducing effects of ATRA, entinostat is at least as active as decitabine, and both act in part independently from RARβ2. Further investigation of this treatment combination in non-M3 AML patients is therefore warranted, independently of RARβ2 gene silencing by DNA methylation.     

Costs and risk factors for ventilator-associated pneumonia in a Turkish University Hospital's Intensive Care Unit: A case-control study

Background

Prophylactic treatment with N-acetylcysteine (NAC) for 3 months or more is associated with a reduction in the frequency of exacerbations of chronic obstructive pulmonary disease (COPD). This raises the question of whether treatment with NAC during an acute exacerbation will hasten recovery from the exacerbation.

Methods

We have examined this in a randomised, double-blind, placebo controlled trial. Subjects, admitted to hospital with an acute exacerbation of COPD, were randomised within 24 h of admission to treatment with NAC 600 mg b.d. (n = 25) or matching placebo (n = 25). Treatment continued for 7 days or until discharge (whichever occurred first). To be eligible subjects had to be ≥ 50 years, have an FEV₁ ≤ 60% predicted, FEV₁/VC ≤ 70% and ≥ 10 pack year smoking history. Subjects with asthma, heart failure, pneumonia and other respiratory diseases were excluded. All subjects received concurrent treatment with prednisone 40 mg/day, nebulised salbutamol 5 mg q.i.d and where appropriate antibiotics. FEV₁, VC, SaO₂ and breathlessness were measured 2 hours after a dose of nebulised salbutamol, at the same time each day. Breathlessness was measured on a seven point Likert scale.

Results

At baseline FEV₁ (% predicted) was 22% in the NAC group and 24% in the control group. There was no difference between the groups in the rate of change of FEV₁, VC, SaO₂ or breathlessness. Nor did the groups differ in the median length of stay in hospital (6 days for both groups).

Conclusions

Addition of NAC to treatment with corticosteroids and bronchodilators does not modify the outcome in acute exacerbations of COPD.     

Recombinant biosynthesis of bacterial cellulose in genetically modified Escherichia coli

Bioprocess and Biosystems Engineering - Bacterial cellulose (BC) exhibits unique properties such as high purity compared to plant-based cellulose; however, commercial production of BC has remained...     

The Effect of Cisplatin Toxicity and Capsaicin on Electron Transport Chain in Liver and Kidney of Sprague Dawley Rats

Cisplatin accumulates in mitochondria, which is a potent and widely used chemotherapeutic agent. In order to clarify the potential effect of cisplatin on electron transport chain (ETC), the variation of succinate dehydrogenase (SDH) and cytochrome c oxidase (COX) enzyme activities, nucleotide levels, as well as catalase (CAT) enzyme and membrane lipid peroxidation (LPO) level with respect to liver and kidney of cisplatin-exposed rats were studied. We found that cisplatin caused significant impairment in the SDH, COX, and CAT activities, and nucleotide levels associated with membrane LPO in isolated mitochondria. It was determined whether capsaicin, as an antioxidant, has a possible protective role on all investigated parameters of liver and kidney induced by cisplatin. The results of capsaicin + cisplatin suggest that capsaicin have antioxidant capacity to scavenge ROS to prevent membrane damage.     

Chronic hypoperfusion alters the content and structure of proteins and lipids of rat brain homogenates: a Fourier transform infrared spectroscopy study

Arteriovenous malformations (AVMs), masses of abnormal blood vessels which grow in the brain, produce high flow shunts that steal blood from surrounding brain tissue, which is chronically hypoperfused. Hypoperfusion is a condition of inadequate tissue perfusion and oxygenation, resulting in abnormal tissue metabolism. Fourier transform infrared (FTIR) spectroscopy is used in this study to investigate the effect of hypoperfusion on homogenized rat brain samples at the molecular level. The results suggest that the lipid content increases, the protein content decreases, the lipid-to-protein ratio increases, and the state of order of the lipids increases in the hypoperfused brain samples. FTIR results also revealed that, owing to hypoperfusion, not only the protein synthesis but also the protein secondary structure profile is altered in favor of -sheets and random coils. These findings clearly demonstrate that, FTIR spectroscopy can be used to extract valuable information at the molecular level so as to have a better understanding of the effect of hypoperfusion on rat brain.     

Effect of enhanced red blood cell aggregation on blood flow resistance in an isolated-perfused guinea pig heart preparation

The role of red blood cell (RBC) aggregation as a determinant of in vivo blood flow is still unclear. This study was designed to investigate the influence of a well-controlled enhancement of RBC aggregation on blood flow resistance in an isolated-perfused heart preparation. Guinea pig hearts were perfused through a catheter inserted into the root of the aorta using a pressure servo-controlled pump system that maintained perfusion pressures of 30 to 100 mmHg. The hearts were beating at their intrinsic rates and pumping against the perfusion pressure. RBC aggregation was increased by Pluronic (F98) coating of RBC at a concentration 0.025 mg/ml, corresponding to about a 100% increment in RBC aggregation as measured by erythrocyte sedimentation rate. Isolated heart preparations were perfused with 0.40 l/l hematocrit unmodified guinea pig blood and with Pluronic-coated RBC suspensions in autologous plasma. At high perfusion pressures there were no significant differences between the flow resistance values for the two perfusates, with differences in flow resistance only becoming significant at lower perfusion pressures. These results can be interpreted to reflect the shear dependence of RBC aggregation: higher shear forces associated with higher perfusion pressures should have dispersed RBC aggregates resulting in blood flow resistances similar to control values. Experiments repeated in preparations in which the smooth muscle tone was inhibited by pre-treatment with papaverine indicated that significant effects of enhanced RBC aggregation could be detected at higher perfusion pressures, underlining the compensatory role of vasomotor control mechanisms.     

Targeted disruption of inducible 6-phosphofructo-2-kinase results in embryonic lethality

Inducible 6-phosphofructo-2-kinase (iPFK-2; PFKFB3) produces fructose-2,6-bisphosphate (F2,6BP), which is a potent allosteric activator of 6-phosphofructo-1-kinase (PFK-1), the rate-limiting step in glycolysis. iPFK-2 functions as an activator of anaerobic glycolysis within the hypoxic microenvironment of growing tumors. The early embryo is challenged similarly since the process of vasculogenesis does not begin until after embryonic day 7. We hypothesized that iPFK-2 expression is essential for the survival of the growing embryo. First, we cloned the mouse homolog of iPFK2 and found that it is abundantly expressed in cortical neurons, epithelial cells, and secretory cells of the choroid plexus, pancreas, and adrenal gland of the adult mouse. Using gene targeting, we then disrupted exons 3-7 of the mouse iPFK2 gene, which encode the substrate binding site. No full-term homozygous iPFK-2(-/-) progeny were produced from 11 F7 iPFK-2(+/-) crosses and no homozygous iPFK-2(-/-) embryos were detected after 8 days of embryogenesis.     

The investigation of glutamate transporter 1 (GLT-1) degradation pathway in glioblastoma cells

Molecular Biology Reports - Glioblastoma multiform is a primary brain tumor derived from glial cells. The aim of this study is to investigate how glutamate metabolism is regulated by glutamate...