The discovery of potential acetylcholinesterase inhibitors: A combination of pharmacophore modeling, virtual screening, and molecular docking studies

<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease (AD) is the most common cause of dementia characterized by progressive cognitive impairment in the elderly people. The most dramatic abnormalities are those of the cholinergic system. Acetylcholinesterase (AChE) plays a key role in the regulation of the cholinergic system, and hence, inhibition of AChE has emerged as one of the most promising strategies for the treatment of AD.</p> <p>Methods</p> <p>In this study, we suggest a workflow for the identification and prioritization of potential compounds targeted against AChE. In order to elucidate the essential structural features for AChE, three-dimensional pharmacophore models were constructed using Discovery Studio 2.5.5 (DS 2.5.5) program based on a set of known AChE inhibitors.</p> <p>Results</p> <p>The best five-features pharmacophore model, which includes one hydrogen bond donor and four hydrophobic features, was generated from a training set of 62 compounds that yielded a correlation coefficient of R = 0.851 and a high prediction of fit values for a set of 26 test molecules with a correlation of R²= 0.830. Our pharmacophore model also has a high Güner-Henry score and enrichment factor. Virtual screening performed on the NCI database obtained new inhibitors which have the potential to inhibit AChE and to protect neurons from Aβ toxicity. The hit compounds were subsequently subjected to molecular docking and evaluated by consensus scoring function, which resulted in 9 compounds with high pharmacophore fit values and predicted biological activity scores. These compounds showed interactions with important residues at the active site.</p> <p>Conclusions</p> <p>The information gained from this study may assist in the discovery of potential AChE inhibitors that are highly selective for its dual binding sites.</p

Effectiveness and response differences of a multidisciplinary workplace health promotion program for healthcare workers

BackgroundWorkplace health promotion (WHP) in the healthcare industry is an important yet challenging issue to address, given the high workload, heterogeneity of work activities, and long work hours of healthcare workers (HCWs). This study aimed to investigate the effectiveness and response differences of a multidisciplinary WHP program conducted in HCWs.MethodsThis retrospective cohort study included HCWs participating in a multidisciplinary WHP program in five healthcare facilities. The 20-week intervention included multiple easy-to-access 90-min exercise classes, one 15-min nutrition consultation, and behavioral education. Pre- and post-interventional anthropometrics, body composition, and physical fitness (PF) were compared with paired sample t-tests. Response differences across sex, age, weight status, and shiftwork status were analyzed with a generalized estimating equation.ResultsA total of 302 HCWs were analyzed. The intervention effectively improved all anthropometric (body mass index, waist circumference, waist-hip ratio, and waist-to-height ratio), body composition (body fat percentage, muscle weight, visceral fat area), and PF (grip strength, high jump, sit-up, sit-and-reach, step test) parameters in all participants (all p &lt; 0.05). Subgroup analyses revealed shift workers had a more significant mean reduction in body mass index than non-shift workers (adjusted p = 0.045). However, there was no significant response difference across sex, age, and weight subgroups.ConclusionThis study suggested that a multidisciplinary WHP program can improve anthropometric and PF profiles regardless of sex, age, and weight status for HCWs, and shifter workers might benefit more from the intervention

Effects of Growth Hormone Treatment on Height, Weight, and Obesity in Taiwanese Patients with Prader-Willi Syndrome

BackgroundInformation regarding the efficacy of growth hormone (GH) therapy in Asian Prader-Willi syndrome (PWS) patients is lacking. We report our experience with GH treatment in children with PWS in Taiwan.MethodsForty-six PWS patients (27 males, 19 females; age range, 1 year 4 months to 13 years 7 months) who received and/or who are currently receiving GH treatment (0.1 IU/kg/day subcutaneously) for a period from 1 year to 3 years were retro-spectively analyzed. We evaluated height, weight, body mass index (BMI) and Rohrer index, before and after GH treatment.ResultsAfter patients had received GH for 1, 2 and 3 years, a significant improvement in mean height standard deviation score (SDS) was noted from −1.24 to −0.31 (p <0.01), 0.00 (p <0.001) and −0.26 (p <0.001), respectively. Mean BMI SDS decreased significantly from 1.93 to 1.13 (p <0.05) after 1 year of treatment; however, no significant changes were observed afterward. Mean Rohrer index decreased significantly, from 224.2 to 186.6 (p <0.001), 178.9 (p <0.001) and 169.3 (p <0.001). No significant gender or genotype pattern differences were noted among the 4 parameters examined.ConclusionThis 3-year, retrospective study indicates that PWS patients benefit from GH therapy in height increase and improved body composition

Overexpression of Akt1 Enhances Adipogenesis and Leads to Lipoma Formation in Zebrafish

<div><h3>Background</h3><p>Obesity is a complex, multifactorial disorder influenced by the interaction of genetic, epigenetic, and environmental factors. Obesity increases the risk of contracting many chronic diseases or metabolic syndrome. Researchers have established several mammalian models of obesity to study its underlying mechanism. However, a lower vertebrate model for conveniently performing drug screening against obesity remains elusive. The specific aim of this study was to create a zebrafish obesity model by over expressing the insulin signaling hub of the <em>Akt1</em> gene.</p> <h3>Methodology/Principal Findings</h3><p><em>Skin oncogenic transformation screening shows that a stable zebrafish transgenic of Tg(krt4Hsa.myrAkt1</em>)^cy18 displays severely obese phenotypes at the adult stage. In Tg(<em>krt4:Hsa.myrAkt1</em>)^cy18, the expression of exogenous human constitutively active Akt1 (myrAkt1) can activate endogenous downstream targets of mTOR, GSK-3α/β, and 70S6K. During the embryonic to larval transitory phase, the specific over expression of myrAkt1 in skin can promote hypertrophic and hyperplastic growth. From 21 hour post-fertilization (hpf) onwards, myrAkt1 transgene was ectopically expressed in several mesenchymal derived tissues. This may be the result of the integration position effect. Tg(<em>krt4:Hsa.myrAkt1</em>)^cy18 caused a rapid increase of body weight, hyperplastic growth of adipocytes, abnormal accumulation of fat tissues, and blood glucose intolerance at the adult stage. Real-time RT-PCR analysis showed the majority of key genes on regulating adipogenesis, adipocytokine, and inflammation are highly upregulated in Tg(<em>krt4:Hsa.myrAkt1</em>)^cy18. In contrast, the myogenesis- and skeletogenesis-related gene transcripts are significantly downregulated in Tg(<em>krt4:Hsa.myrAkt1</em>)^cy18, suggesting that excess adipocyte differentiation occurs at the expense of other mesenchymal derived tissues.</p> <h3>Conclusion/Significance</h3><p>Collectively, the findings of this study provide direct evidence that Akt1 signaling plays an important role in balancing normal levels of fat tissue in vivo. The obese zebrafish examined in this study could be a new powerful model to screen novel drugs for the treatment of human obesity.</p> </div

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Enzyme Replacement Therapy with Imiglucerase in a Taiwanese Child with Type 1 Gaucher Disease

The treatment of type 1 Gaucher disease has dramatically improved with the development of enzyme replacement therapy (ERT). To date, however, imiglucerase treatment of this disease in Taiwanese pediatric patients has not been reported. A Taiwanese child with type 1 Gaucher disease was regularly treated with imiglucerase beginning October 1998. This 12-year 10-month-old boy had undergone splenectomy when he was 4 years old. He received intravenous imiglucerase 60 U/kg every 2 weeks for 78 months. No signs of pubertal development were documented at the commencement of ERT. There were no serious adverse effects. The patient had significant improvement in skeletal deformity, a dramatic decrease in liver size, markedly increased linear growth, alleviation of bone pain and bone crises, correction of anemia, and improved bone mineral density. ERT with imiglucerase improved the quality of life in this child with type 1 Gaucher disease