Synthesis,molecular docking,acetylcholinesterase and butyrylcholinesterase inhibitory potential of thiazole analogs as new inhibitors for Alzheimer disease

A series of thirty (30) thiazole analogs were prepared, characterized by ¹H NMR, ¹³C NMR and EI-MS and evaluated for Acetylcholinesterase and butyrylcholinesterase inhibitory potential. All analogs exhibited varied butyrylcholinesterase inhibitory activity with IC₅₀ value ranging between 1.59 ± 0.01 and 389.25 ± 1.75 μM when compared with the standard eserine (IC₅₀, 0.85 ± 0.0001 μM). Analogs 15, 7, 12, 9, 14, 1, 30 with IC₅₀ values 1.59 ± 0.01, 1.77 ± 0.01, 6.21 ± 0.01, 7.56 ± 0.01, 8.46 ± 0.01, 14.81 ± 0.32 and 16.54 ± 0.21 μM respectively showed excellent inhibitory potential. Seven analogs 15, 20, 19, 24, 28, 30 and 25 exhibited good acetylcholinesterase inhibitory potential with IC50 values 21.3 ± 0.50, 35.3 ± 0.64, 36.6 ± 0.70, 44.81 ± 0.81, 46.36 ± 0.84, 48.2 ± 0.06 and 48.72 ± 0.91 μM respectively. All other analogs also exhibited well to moderate enzyme inhibition. The binding mode of these compounds was confirmed through molecular docking.     

Screening of coeliac disease in undetected adults and patients diagnosed with irritable bowel syndrome in Riyadh,Saudi Arabia

The present study is to determine the prevalence and implication of coeliac disease (CD) among adult Saudis and compared to those with diagnosed irritable bowel syndrome. This prospective study was conducted among 980 adults. Out of that, 482 subjects (staff and students of Riyadh Health Science College) were designated as control cohorts for undetected coeliac disease. Furthermore, another contingent of 498 subjects diagnosed with irritable bowel syndrome (IBS) at Prince Salman Hospital and Al-Iman General Hospital also constituted a segment of the overall initial 1020 subjects. Both cases and control were tested for serological markers of coeliac disease (tissues transglutaminase (tTGAs) and endomysial autoantibody (EMAs) and were confirmed by histopathology test. All the positive for cases of coeliac disease were screened for iron deficiency anaemia, Vitamin D deficiency, and osteoporosis and weight assessment. The percentage of coeliac disease in control subjects and patients diagnosed with irritable bowel syndrome (IBS) were found to be 1.9% and 9.6% respectively, about 38% of the total coeliac disease patients are among females of middle age (20–39-years) and 16% of the males in the same age range. Whereas, 20% and 25% of all coeliac disease cases with ages of 40–59 were remarked as females and males respectively. The identical nature and overlap of symptoms of the two conditions could possibly result in misdiagnosis of coeliac diseases or over-diagnosis of irritable bowel syndrome. The findings of the study might also give considerable implications of the disease in the nutritional level which is noticeable.     

Impact of Bacillus popilliae,Rickettsiella popilliae and entomopathogenic nematodes on a population of the scarabaeid,Cyclocephala hirta

Larvae of the scarabaeid, Cyclocephala hirta, are major pests of turfgrass in California. A field test was conducted against third instars that included the following treatments: untreated control; chemical insecticide (bendiocarb); milky disease bacterium (Bacillus popilliae); and entomopathogenic nematodes (Steinernema feltiae and Heterorhabditis bacteriophora). There were no significant differences in population reduction among the treatments, but the larval population in all plots showed a dramatic decline. The C. hirta population had a natural occurrence of milky disease and blue disease caused by Rickettsiella popilliae. The prevalence of blue disease during the course of the study averaged < 10% but that of milky disease averaged about 20%. More significantly, the soil from all treatment plots when bioassayed for B. popilliae showed that 67–90% of the larvae became infected with this bacterium. None of the larvae became infected with the blue disease organism. We conclude that B. popilliae was occurring in epizootic proportions in our field tests and was a significant mortality factor in causing the decline of the C. hirta population.     

Physiological mechanisms and movement analysis in Parkinson's disease

We present new ideas about motor control in the human central nervous system and about pathophysiological mechanisms of Parkinson's disease, and we describe the Posturo-Locomotion-Manual (PLM) method, which is a new technique utilizing optoelectronic camera recording for objective, fully quantitative, and standardized assessment of human motor performance. In the PLM test, recordings of body movements are made during a simple motor task, where the subject repeatedly moves a small object from its starting position on the floor to a shelf located at chin height a few steps forward. The duration of the postural (raising up), locomotor and the goal-directed manual phase of the forward directed body movement is automatically calculated by a small computer as well as the degree of coordination (simultaneity) of these phases. The technique has high resolution and has been used for clinical assessment of motor performance, drug testing, and so on, in neurological and geriatric practice.     

Coumarin-dithiocarbamate hybrids as novel multitarget AChE and MAO-B inhibitors against Alzheimer’s disease: Design,synthesis and biological evaluation

A series of new coumarin-dithiocarbamate hybrids were designed and synthesized as multitarget agents for the treatment of Alzheimer’s disease. Most of them showed potent and clearly selective inhibition towards AChE and MAO-B. Among these compounds, compound 8f demonstrated the most potent inhibition to AChE with IC₅₀ values of 0.0068 μM and 0.0089 μM for eeAChE and hAChE, respectively. Compound 8g was identified as the most potent inhibitor to hMAO-B, and it is also a good and balanced inhibitor to both hAChE and hMAO-B (0.114 µM for hAChE; 0.101 µM for hMAO-B). Kinetic and molecular modeling studies revealed that 8g was a dual binding site inhibitor for AChE and a competitive inhibitor for MAO-B. Further studies indicated that 8g could penetrate the BBB and exhibit no toxicity on SH-SY5Y neuroblastoma cells. More importantly, 8g did not display any acute toxicity in mice at doses up to 2500 mg/kg and could reverse the cognitive dysfunction of scopolamine-induced AD mice. Overall, these results highlighted 8g as a potential multitarget agent for AD treatment and offered a starting point for design of new multitarget AChE/MAO-B inhibitors based on dithiocarbamate scaffold.     

Neurologic Abnormalities in Two Dogs Suspected Lyme Disease

A 2-year-old mongrel dog developed neurological signs following tick bite. These included astasia, persistent tonic convulsions and hyper-reflexia. Both serum IgG and IgM antibody titers against Borrelia burgdorferi were positive in enzyme-linked immunosorbent assay (ELISA). The neurological signs subsided after high-dose penicillin and streptomycin treatment. A strain of spirochetes (P427a) was isolated from the midgut of Ixodes persulcatus feeding on the dog. Morphological characteristic, immunological property and protein profile revealed that the isolate was B. burgdorferi. Similarly, a 2-year-old Labrador retriever dog developed neurological signs after tick bite and showed a positive IgG antibody titer against B. burgdorferi. Antibiotic treatment was effective also in this case. These findings suggest that neurological symptoms shown in both dogs were caused by infection with B. burgdorferi.     

Indoleacetic acid enhancement of 14C methionine uptake by tomato cell cultures aids assay of pathogen extracts

Incorporation of one micromolar IAA in the assay system increased the rate of ¹⁴C methionine uptake by tomato cells in suspension and effectively differentiated the rates of uptake such that cells treated with pathogenic and non-pathogenic Fusarium extracts could be easily distinguished in a rapid 3 h assay.     

D-Cycloserine: Agonist turned antagonist

Summary D-Cycloserine can enhance activation of the NMDA receptor complex and could enhance the induction of long-term potentiation (LTP). In animals and humans, D-cycloserine can enhance performance in learning and memory tasks. This enhancing effect can disappear during repeated administration. The enhancing effects are also lost when higher doses are used, and replaced by behavioral and biochemical effects like those produced by NMDA antagonists. It has been reported that NMDA agonists, applied before or after tetanic stimulation, can block the induction of LTP. This may be the result of feedback inhibition of second messenger pathways stimulated by receptor activation. This may explain the antagonist-like effects of glycine partial agonists like D-cycloserine. In clinical trials of D-cycloserine in age-associated memory impairment (AAMI) and Alzheimer's disease, chronic treatment provided few positive effects on learning and memory. This may be due to inhibition of second messenger pathways following chronic stimulation of the receptor complex.