Design, synthesis and biological evaluation of novel naturally-inspired multifunctional molecules for the management of Alzheimer's disease.

In our overall goal to overcome the limitations associated with natural products for the management of Alzheimer's disease and to develop in-vivo active multifunctional cholinergic inhibitors, we embarked on the development of ferulic acid analogs. A systematic SAR study to improve upon the cholinesterase inhibition of ferulic acid with analogs that also had lower logP was carried out. Enzyme inhibition and kinetic studies identified compound 7a as a lead molecule with preferential acetylcholinesterase inhibition (AChE IC50 = 5.74 ± 0.13 µM; BChE IC50 = 14.05 ± 0.10 µM) compared to the parent molecule ferulic acid (% inhibition of AChE and BChE at 20 µM, 15.19 ± 0.59 and 19.73 ± 0.91, respectively). Molecular docking and dynamics studies revealed that 7a fits well into the active sites of AChE and BChE, forming stable and strong interactions with key residues Asp74, Trp286, and Tyr337 in AChE and with Tyr128, Trp231, Leu286, Ala328, Phe329, and Tyr341 in BChE. Compound 7a was found to be an efficacious antioxidant in a DPPH assay (IC50 = 57.35 ± 0.27 µM), and it also was able to chelate iron. Data from atomic force microscopy images demonstrated that 7a was able to modulate aggregation of amyloid ß1-42. Upon oral administration, 7a exhibited promising in-vivo activity in the scopolamine-induced AD animal model and was able to improve spatial memory in cognitive deficit mice in the Y-maze model. Analog 7a could effectively reverse the increased levels of AChE and BChE in scopolamine-treated animals and exhibited potent ex-vivo antioxidant properties. These findings suggest that 7a can act as a lead molecule for the development of naturally-inspired multifunctional molecules for the management of Alzheimer's and other neurodegenerative disorders.

Assessment of Correlation between Craniofacial Proportions and Genetic Indicators.

AIM AND OBJECTIVE: To assess correlation among craniofacial proportions and genetic indicators using estrogen receptors (ESR1 and ESR2). MATERIALS AND METHODS: A total of 128 patients undergoing orthodontic treatment with age range 12-18 years of both genders were included. Lateral cephalogram of all subjects were taken. Vertical and sagittal parameters were studied on these cephalogram. Saliva was used for DNA extraction. Real-time polymerase chain reaction was performed for assessment of genetic indicators in ESR1 (rs9340799 and rs2234693) and in ESR2 (rs4986938 and rs1256049). RESULTS: The mean SN cranial base was 68.4 mm, ANB (sagittal jaw relationship) was 2.8°, Ptm-A maxillary length was 46.2 mm, Go-Pg (mandibular body length) was 68.2 mm, Co-Gn (total mandibular length) was 112.8 mm, lower anterior facial height (ANS-Me) was 58.4 mm, N-Me (total anterior facial height) was 108.4 mm, lower posterior facial height (Co-Go) was 58.7 mm, and S-Go (total posterior facial height) was 72.4 mm. It was found that rs4986938 in ESR2 was linked with S-N dimension, with patients having CC genotype possessing negative correlation values (p value 0.05). Similarly, CC genotype possessed minimum mandibular body dimension, and it was found that rs4986938 in ESR2 was also linked with Go-Pg dimension (p value = 0.02). We found reduction in the ANS-Me values in patients with CC genotype in ESR1 rs2234693 (p value = 0.02), whereas there was no correlation of rest genotype with other craniofacial measurements (p value > 0.05). CONCLUSION: Evaluation of ESR1 and ESR2 may show role of genetic markers in disparity of craniofacial dimensions in individuals. CLINICAL SIGNIFICANCE: This study provides an outlay and supports the concept of possible correlation between genetic markers and craniofacial measurements.

A review on iron chelators as potential therapeutic agents for the treatment of Alzheimer's and Parkinson's diseases.

Iron plays a vital role in several cellular functions due to its unique physiochemical properties. Iron concentration increases in the brain with age due to multiple factors. Excessive amount of iron can lead to formation of reactive oxygen species. Neurodegenerative disorders are characterized by iron supplemented increase in oxidative stress and cellular damage. There is an urgent need of novel therapies which should not only provide symptomatic relief but also be able to modulate iron accumulation in the brain. Therefore, the development of novel iron chelators as neuroprotective agents for the treatment of neurodegeneration is an emerging trend. Several iron chelators including 8-hydroxyquinoline derivatives, dopaminergic agonists and natural products are under preclinical and clinical investigations for the treatment of neurodegenerative disorders.

The Effect of Two Soft Drinks on Bracket Bond Strength and on Intact and Sealed Enamel: An In Vitro Study.

BACKGROUND AND OBJECTIVES: This study was conducted to evaluate the effect of two soft drinks, Coca-Cola and Mirinda orange on bracket bond strength, on adhesive remnant on teeth after debonding the bracket, and to observe by means of scanning electron microscope (SEM) the effect of these drinks on intact and sealed enamel. METHODS: 120 non-carious maxillary premolar teeth already extracted for Orthodontic purposes were taken and divided into three groups, i.e., Coca-Cola drink, Mirinda orange, and control (artificial saliva) group. Brackets were bonded using conventional methods. Teeth were kept in soft drinks for 15 days, for 15 min, 3 times a day, separated by intervals of 2 h. At other times, they were kept in artificial saliva. The samples, thus obtained were evaluated for shear bond strength using the universal testing machine and subsequently subjected for adhesive remnant index (ARI) scores. SEM study on all the three groups was done for evaluating enamel surface of the intact and sealed enamel. RESULTS: The lowest mean resistance to shearing forces was shown by Mirinda orange group (5.30 ± 2.74 Mpa) followed by Coca-Cola group (6.24 ± 1.59 Mpa) and highest resistance to shearing forces by control group (7.33 ± 1.72 Mpa). The ARI scores revealed a cohesive failure in control samples and an adhesive failure in Mirinda and cola samples. SEM results showed areas of defect due to erosion caused by acidic soft drinks on intact and sealed enamel surface. CONCLUSION: Mirinda group showed the lowest resistance to shearing forces, followed by Coca-Cola group and with the highest resistance to shearing forces by the control group. There were significant differences between the control group and the study groups. Areas of defects, which were caused by erosion related to acidic soft drinks on the enamel surface around the adhesive, were seen. Areas of defects caused by Coca-Cola were more extensive when compared to Mirinda orange drink.

Comparison of Frictional Forces Generated by a New Ceramic Bracket with the Conventional Brackets using Unconventional and Conventional Ligation System and the Self-ligating Brackets: An In Vitro Study.

BACKGROUND: Fixed orthodontic mechanotherapy is associated with friction between the bracket - wire - ligature interfaces during the sliding mechanics. A sound knowledge of the various factors affecting the magnitude of friction is of paramount importance. The present study was done to analyze and compare the frictional forces generated by a new ceramic (Clarity Advanced) bracket with the conventional, (metal and ceramic) brackets using unconventional and conventional ligation system, and the self-ligating (metal and ceramic) brackets in the dry condition. MATERIALS AND METHODS: The various bracket wire ligation combinations were tested in dry condition. The brackets used were of 0.022″ × 0.028″ nominal slot dimension of MBT prescription: Stainless steel (SS) self-ligating bracket (SLB) of (SmartClip), SS Conventional bracket (CB) (Victory series), Ceramic SLB (Clarity SL), Conventional Ceramic bracket with metal slot (Clarity Bracket), Clarity Advanced Ceramic Brackets (Clarity(™) ADVANCED, 3M Unitek). These brackets were used with two types of elastomeric ligatures: Conventional Elastomeric Ligatures (CEL) (Clear medium mini modules) and Unconventional Elastomeric Ligatures (UEL) (Clear medium slide ligatures, Leone orthodontic products). The aligning and the retraction wires were used, i.e., 0.014″ nickel titanium (NiTi) wires and 0.019″ × 0.025″ SS wires, respectively. A universal strength testing machine was used to measure the friction produced between the different bracket, archwires, and ligation combination. This was done with the use of a custom-made jig being in position. RESULTS: Mean, standard deviation, and range were computed for the frictional values obtained. Results were subjected to statistical analysis through ANOVA. The frictional resistance observed in the new Clarity Advanced bracket with a conventional elastomeric ligature was almost similar with the Clarity metal slot bracket with a conventional elastomeric ligature. When using the UEL, the Clarity Advanced bracket produced lesser friction than the conventional metal bracket; but not less than the ceramic metal slot bracket. Ceramic SLB produced lesser friction when compared with the Clarity Advanced bracket with UEL, but the metal SLB produced the least friction among all the groups and subgroups. CONCLUSION: The present study concluded that the SS SLB produced least friction among all groups. Using the archwire and ligation method, frictional forces observed in the Clarity Advanced bracket and the conventional ceramic with metal slot bracket were almost similar; but the least resistance was determined in SS CB using both the ligation (CEL and UEL) system.