Design,synthesis, and evaluation of novel cinnamic acid-tryptamine hybrid for inhibition of acetylcholinesterase and butyrylcholinesterase

BackgroundAcetylcholine deficiencies in hippocampus and cortex, aggregation of β-amyloid, and β-secretase over activity have been introduced as main reasons in pathogenesis of Alzheimer’s disease.MethodsColorimetric Ellman’s method was used for determination of IC₅₀ value in AChE and BChE inhibitory activity. The kinetic studies, neuroprotective and β-secretase inhibitory activities, evaluation of inhibitory potency on β-amyloid (Aβ) aggregations induced by AChE, and docking study were performed for prediction of the mechanism of action.Result and discussionA new series of cinnamic acids-tryptamine hybrid was designed, synthesized, and evaluated as dual cholinesterase inhibitors. These compounds demonstrated in-vitro inhibitory activities against acetyl cholinesterase (AChE) and butyryl cholinesterase (BChE). Among of these synthesized compounds, (E)-N-(2-(1H-indol-3-yl)ethyl)-3-(3,4-dimethoxyphenyl)acrylamide (5q) demonstrated the most potent AChE inhibitory activity (IC₅₀ = 11.51 μM) and (E)-N-(2-(1H-indol-3-yl)ethyl)-3-(2-chlorophenyl)acrylamide (5b) were the best anti-BChE (IC₅₀ = 1.95 μM) compounds. In addition, the molecular modeling and kinetic studies depicted 5q and 5b were mixed type inhibitor and bound with both the peripheral anionic site (PAS) and catalytic sites (CAS) of AChE and BChE. Moreover, compound 5q showed mild neuroprotective in PC12 cell line and weak β-secretase inhibitory activities. This compound also inhibited aggregation of β-amyloid (Aβ) in self-induced peptide aggregation test at concentration of 10 μM.ConclusionIt is worth noting that both the kinetic study and the molecular modeling of 5q and 5b depicted that these compounds simultaneously interacted with both the catalytic active site and the peripheral anionic site of AChE and BChE. These findings match with those resulted data from the enzyme inhibition assay. Graphical abstractOpen in a separate windowA new series of cinnamic-derived acids-tryptamine hybrid derivatives were designed, synthesized and evaluated as butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) inhibitors and neuroprotective agents. Compound 5b and 5q, as the more potent compounds, interacted with both the peripheral site and the choline binding site having mixed type inhibition. Results suggested that derivatives have a therapeutic potential for the treatment of AD.Electronic supplementary materialThe online version of this article (10.1007/s40199-020-00346-9) contains supplementary material, which is available to authorized users.     

Evaluation of corneal biomechanical properties in mustard gas keratopathy

Background

Degenerative biomechanical factors and immunologic processes with effect on collagen and corneal reparative process are known as the main cause of ocular surface dysfunction in mustard gas keratopathy (MGK) and may cause changes in the corneal biomechanical values. Therefore, we evaluate corneal biomechanical properties of these patients.

Malignant Adenomyoepithelioma of the Breast: A Review

Malignant adenomyoepithelioma (MAME) of the breast is a rare lesion characterized by dual population of epithelial and myoepithelial cells which one or both components show malignant features. We report a case of MAME of the breast in a 46‐year‐old woman diagnosed by fine‐needle aspiration with extensive review of the literature. Classification, clinical presentation, cyto‐pathologic, and immunohistochemical features are described. This lesion showed both malignant components of epithelial and myoepithelial cells in cytology and histology. The malignancy was convincingly supported by high mitotic figures, pleomorphism, and invasion in tissue sections. This review of MAMEs showed that cyto‐histologic diagnosis is difficult and should be supported by immunohistochemical study.     

Heated humidified high-flow nasal cannula versus low-flow nasal cannula as weaning mode from nasal CPAP in infants ≤28 weeks of gestation

Despite the paucity of evidence, the practice of weaning nasal continuous positive airway pressure (NCPAP) is widespread. However, the most clinically effective non-invasive ventilatory support strategy remains to be determined. We compared the outcome of very premature infants with respiratory distress syndrome treated with a combination of NCPAP and heated humidified high-flow nasal cannula (HHFNC) versus NCPAP and low-flow nasal cannula (LFNC). Between 2004 and 2008, patients ≤28 weeks of gestation and <1,250 g of birth weight were treated with NCPAP + HHFNC or NCPAP + LFNC. Their respiratory and non-respiratory outcome including cost-effectiveness was compared after matching for antenatal steroid doses, mode of delivery, birth plurality, gestational age, birth weight, gender, surfactant doses, length of mechanical ventilation and clinical risk index for babies-II (CRIB-II) score. Thirty-nine infants received HHFNC + NCPAP, and 40 received NCPAP + LFNC. Median gestational age and birth weight were 27 weeks and 930 g and 27 weeks and 980 g, respectively. The total number of NCPAP days was significantly reduced by 50 % in the HHFNC group. Thirteen percent of the patients on NCPAP suffered from nasal bridge lesions compared to none on HHFNC. Respiratory and non-respiratory outcome was not significantly different otherwise. Combination of NCPAP and HHFNC reduced costs by 33 %. Conclusions: HHFNC shortens NCPAP time without increasing overall length of non-invasive respiratory support in very preterm infants. Unlike NCPAP, HHFNC does not seem to increase the risk of nasal trauma and appears to improve cost-effectiveness whilst producing otherwise equal respiratory and non-respiratory outcomes.     

Mandibular setback by sagittal split ramus osteotomy: a 12-year follow-up

Short- and long-term skeletal changes after mandibular setback were analyzed using bilateral sagittal split ramus osteotomy. Twelve patients who had undergone mandibular setback surgery between 1986 and 1990 were available for long-term cephalography on average 12 years after primary surgery. The mean amount of surgical setback had been 6.4 mm. After the first postoperative year, there was skeletal relapse of 1 mm at the B-point and pogonion (Pg), amounting to 14% of the initial skeletal setback. In contrast to condylar displacement and proximal segment rotation, osteotomy slippage was associated with positional changes at the B-point and Pg. From 1 to 12 years postoperatively, the B-point and Pg remained stable. Mandibular ramus and corpus length decreased 2.1 mm and 1.3 mm, respectively, indicating remodeling at the osteotomy sites and probably condylar resorption.     

Alteration of cyclic nucleotides levels and oxidative stress in saliva of human subjects with periodontitis

Experimental findings suggest a protective role for cyclic nucleotides against induction of oxidative stress in saliva. Oxidative stress is a major contributor to the pathogenesis of inflammatory diseases. This study was conducted to evaluate salivary oxidative stress along with cGMP and cAMP levels in periodontitis subjects. cAMP and cGMP are second messengers that have important roles in salivary gland functions. Unstimulated whole saliva samples were obtained from periodontitis patients and age- and sex-matched healthy individuals. Saliva samples were analyzed for thiobarbituric reactive substances (TBARS) as a marker of lipid peroxidation, ferric reducing ability (total antioxidant power, TAP), and levels of cAMP and cGMP. Concentrations of cAMP and cGMP were reduced in the saliva of patients with moderate and severe periodontitis. Saliva of patients with severe periodontitis had higher TBARS and lower TAP than control subjects. The presence of oxidative stress and lower levels of salivary cGMP and cAMP in periodontitis are in association with disease severity.