Synthesis of curcumin analogues as potential antioxidant, cancer chemopreventive agents

New series of 3, 5-bis(substituted benzylidene)-4-piperidones, 2, 7-bis(substituted benzylidene)cycloheptanones, 1, 5-bis(substituted phenyl)-1, 4-pentadien-3-ones, 1, 7-bis(substituted phenyl)-1, 6-heptadien-3, 5-diones, 1, 1-bis(substituted cinnamoyl)-cyclopentanes, and 1, 1-bis(substituted cinnamoyl)cyclohexanes have been synthesized and tested for their antioxidant activity. Among the tested compounds, compounds II(4), II(9) II(10), II(11), V(1), and V(4) exhibited higher free radical scavenger activity with % inhibition values of 90.71, 91.24, 96.91, 94.26, 99.23, and 99.85%, respectively. Moreover, compound V(1) is the safest member toward peripheral multinuclear neutrophils (PMNs) with a % viability value of 91%. Detailed synthesis, spectroscopic, and biological data are reported.     

Characterization of agonist stimulation of cAMP-dependent protein kinase and G protein-coupled receptor kinase phosphorylation of the beta2-adrenergic receptor using phosphoserine-specific antibodies

Agonist-stimulated desensitization of the beta2-adrenergic receptor (beta2AR) is caused by both a potent cAMP-dependent protein kinase (PKA)-mediated phosphorylation and a less potent, occupancy-dependent, G protein-coupled receptor kinase (GRK)-mediated phosphorylation that leads to beta-arrestin binding and internalization. In this study the kinetics of phosphorylation of the third intracellular loop PKA site Ser262 and the putative C-tail GRK sites Ser355, Ser356 of the human beta2AR overexpressed in human embryonic kidney (HEK) 293 cells were characterized using phosphoserine-specific antibodies. Specificity of the antibodies was shown by their lack of reactivity with mutant beta2ARs lacking the respective sites. In addition, overexpression of GRK2 and GRK5 increased basal levels of phosphorylation of the GRK sites Ser355, Ser356 in both COS-7 and HEK 293 cells. Epinephrine, prostaglandin E1, and forskolin at maximum concentrations stimulated phosphorylation of the beta2AR PKA site (Ser262) by 4-fold, whereas PMA stimulated it by 2-fold. Epinephrine stimulated PKA site phosphorylation with an EC50 of 20 to 40 pM. In contrast, epinephrine stimulated GRK site phosphorylation (Ser355,Ser356) with an EC50 of 200 nM (1-min treatments), which is more than 4000-fold higher relative to PKA site phosphorylation, consistent with an occupancy-driven process. After 10 to 30 min, the EC50 for epinephrine stimulation of GRK site phosphorylation was reduced to 10 to 20 nM but was still approximately 200-fold greater than for the PKA site. The EC50 for internalization correlated with GRK site phosphorylation and showed a similar shift with time of epinephrine stimulation. The kinetics of epinephrine-stimulated GRK site phosphorylation were not altered in a mutant of the beta2AR lacking the PKA consensus sites. The initial levels (2 min) of a range of agonist-stimulated GRK site phosphorylations were correlated with their efficacy for activation of adenylyl cyclase, namely epinephrine > or = formoterol = fenoterol > terbutaline = zinterol = albuterol > salmeterol > dobutamine > or = ephedrine. However, after 20 to 30 min of treatment, agonists with intermediate strengths, such as albuterol and salmeterol, stimulate GRK site phosphorylations that are approximately equal to that produced by epinephrine, and the correlation breaks down. The GRK and PKA site antibodies were also effective in detecting phosphorylation of the endogenous beta2AR expressed in A431 human epidermoid carcinoma cells. To summarize, our results show a remarkable amplification of PKA site phosphorylation relative to the putative GRK site phosphorylation, heterologous stimulation of the PKA site phosphorylation, no dependence of GRK site phosphorylation on PKA sites, and a reasonable correlation of initial levels of GRK site phosphorylation with the strength of a range of agonists.     

Neuropsychological correlates of MRI measures in the continuum of cognitive decline at old age

OBJECTIVE: To investigate the independent associations between medial temporal lobe atrophy and white matter hyperintensities (WMH) and cognitive functions in the elderly. METHODS: Cognitive functions of 41 Alzheimer's disease patients, 20 patients with mild cognitive impairment and 28 elderly subjects without memory complaints were assessed using a neuropsychological test battery. Quantitative MRI measures of medial temporal lobe volume and WMH were obtained. Multiple regression analyses were performed to assess the independent contribution of MRI measures to impairment in several cognitive functions. RESULTS: Scores on the Wechsler Memory Scale and Trails B depended selectively on medial temporal lobe volume, whereas WMH selectively contributed to performance on Trails A. Medial temporal lobe volume and WMH both contributed to scores on the Cambridge Cognitive Examination and the Boston naming task. CONCLUSIONS: MRI measures suggestive of Alzheimer-type pathology and microvascular pathology independently contribute to cognitive decline at old age. Memory impairment as measured using the Wechsler Memory Scale and performance on Trails B primarily depended on medial temporal lobe atrophy. Psychomotor slowness, as measured using Trails A, mainly depended on WMH. These results suggest that vascular pathology and Alzheimer-type pathology each have specific cognitive correlates.     

The effect of corticosteroid medication on quantitative MR parameters of the brain

BACKGROUND AND PURPOSE: Quantitative MR imaging techniques such as magnetization transfer imaging (MTI), diffusion-weighted imaging (DWI), and MR spectroscopy are promising diagnostic tools for use with patients with diffuse brain diseases such as neuropsychiatric systemic lupus erythematosus (NPSLE). Such patients are often on corticosteroid (CS) treatment. Presently, it is unknown whether CSs per se influence quantitative MR imaging measurements. The aim of this study was to evaluate the effect of low-dose oral CSs on MTI, DWI, and MR spectroscopy parameters of the brain. METHODS: Twenty-seven rheumatoid arthritis (RA) patients with and without CS medication and 15 healthy controls were subjected to conventional MR imaging, whole-brain MTI and DWI, and single-voxel MR spectroscopy. Oral CSs were used by 13 of the RA patients. Univariate analyses with age as a covariate were performed on MTI, DWI, and MR spectroscopy parameters between RA patients with and without CSs and healthy controls. Pearson correlations were calculated between all imaging parameters and duration of disease, duration of CS use, and CS dosage. RESULTS: No significant differences between the groups of subjects or significant correlations with clinical parameters were found for MTI, DWI and MR spectroscopy parameters. CONCLUSION: In this study, we found no evidence for an effect of low-dose oral CSs on whole-brain MTI and DWI histogram parameters and single-voxel MR spectroscopy measurements of the brain. The results of this study demonstrate that it is unlikely that MTI, DWI, and MR spectroscopy parameters reported in NPSLE studies are confounded by low-dose oral CS.     

Cysticercosis: imported and autochthonous infections in Kuwait

Intracerebral and non-central nervous system (non-CNS) cysticercosis caused by the larval pork tapeworm Taenia solium was diagnosed in patients in an Islamic state. The mode of transmission and challenges in diagnosis are highlighted. Sixteen patients with neurocysticercosis and six with non-CNS lesions were diagnosed by imaging studies (computerized tomography [CT]/magnetic resonance imaging [MRI]) and serology (ELISA and/or enzyme-linked immunoelectrotransfer blot assay [EITB]). Four of 55 family members, including servants, tested for antibodies were positive by the EITB and ELISA. Only one of these sera tested for antibodies to adult T. solium was positive: that of the cook, the probable source of the infection. We postulate a similar mode of transmission in the other Kuwaitis. Evaluation of several commercially available ELISA kits showed they were of poor specificity. Even in countries where pork consumption is proscribed by religious laws, physicians should include cysticercosis in their differential diagnosis in patients with neurological symptoms or non-CNS lesions, especially in non-endemic countries with a large expatriate population such as Kuwait. In children particularly, and in this region, suspected tuberculous lesions on CT must be investigated to rule out cysticerci by a more diligent use of the sensitive and specific EITB assay. Failure to understand the local epidemiology leads to empirical, inappropriate and prolonged therapy for chronic disease.     

The spectrum of tuberculosis among patients of the King Abdul Aziz Unveristy Hospital,Jeddah, Saudi Arabia

A retrospective study, reviewing the medical records of 157 patients with a final diagnosis of tuberculosis on discharge, was conducted at King Abdul Aziz University Hospital during the period July 1999 to July 2001. The data included demographic characteristics, the spectrum of clinical presentations, diagnostic methods, and the outcome of treatment. A total of 157 patients were admitted with tuberculosis; their median age was 33(+/- 15.33) years. Fifty-seven (36%) were Saudis and 100 (64%) were non-Saudis. Pulmonary tuberculosis and pleural effusion were the commonest presentations (37.6%). Diagnosis was confirmed in most cases by either a positive sputum smear for AFB or by pleural biopsy; in five patients the diagnosis was made on clinical grounds and pleural fluid analysis. There was a wide spectrum of extra-pulmonary tuberculosis, diagnosed histologically except in five cases, in which treatment was started empirically based on high clinical suspicion and a strongly positive tuberculin test.     

Functional characterization of the novel L108W and P186L mutations detected in the type II 3{beta}-hydroxysteroid dehydrogenase gene of a male pseudohermaphrodite with congenital adrenal hyperplasia

Two Isoenzymes are responsible for 3ß-hydroxysterolddehydrogenase/     

Unique endemicity of cryptosporidiosis in children in Kuwait

To understand the transmission of Cryptosporidium infection in children, fecal specimens from 62 Kuwaiti children with gastrointestinal symptoms found to be positive by microscopy were genotyped and subtyped with a small subunit rRNA-based PCR-restriction fragment length polymorphism analysis and a 60-kDa glycoprotein-based DNA sequencing tool. The median age of infected children was 4.5 years, and 77% of infections occurred during the cool season of November to April. Fifty-eight of the children (94%) had Cryptosporidium parvum, three (5%) had Cryptosporidium hominis, and one (1%) had both C. parvum and C. hominis. Altogether, 13 subtypes of C. parvum (belonging to four subtype allele families) and C. hominis (belonging to three subtype allele families) were observed, with 92% of specimens belonging to the common allele family IIa and the unusual allele family IId. Thus, the transmission of cryptosporidiosis in Kuwaiti children differed significantly from other tropical countries.