Computational and experimental studies on the interaction between butyrylcholinesterase and fluoxetine: implications in health and disease

1. Butyrylcholinesterase (BChE) is a serine esterase that plays a role in the detoxification of natural as well as synthetic ester-bond-containing compounds. Alterations in BChE activity are associated with a number of diseases. Cholinergic system abnormalities in particular are correlated with the formation of senile plaques in Alzheimer’s disease (AD), and administration of cholinesterase inhibitors is a common therapeutic approach used to treat AD.

2. Here, our aim was to study the interaction between BChE and fluoxetine.

3. Molecular docking simulations revealed that fluoxetine penetrated deep into the active-site gorge of BChE and that it was engaged in stabilizing noncovalent interactions with multiple subsites. In substrate kinetic studies, the V_m, K_m, k_cat and k_cat/K_m values were found to be 20.59?±?0.36?U mg^?1 protein, 194?±?14?µM, 1.3?×?10⁸?s^?1 and 6.7?×?10⁵?µM^?1s^?1, respectively. Based on inhibitory studies, fluoxetine appeared to inhibit BChE competitively, with an IC₅₀ value of 104?µM and a K_i value of 36.3?±?4.7?µM.

4. Overall, both the low K_i value and the high number of BChE–fluoxetine interactions suggest that fluoxetine is a potent inhibitor of BChE, although in vivo mechanisms for the direct effects of BChE inhibition on various pathologies remain to be further investigated.

     

The preventive role of wheat germ oil against sertraline‐induced testicular damage in male albino rats

Sertraline is an antidepressant medication used extensively in the therapy of depression. The present investigation was intended to estimate the actual protective role of wheat germ oil on sertraline‐caused testicular injury in albino rats. Sertraline (human therapeutic dose, 15.63 mg/kg) was orally administrated to rats for 28 successive days. Sertraline‐administered rats were concurrently supplemented with wheat germ oil (human therapeutic dose, 68.75 mg/kg) for 28 successive days. Sertraline administration induced an elevation in testicular DNA damage and acute testicular damage illustrated by the histopathological alterations including marked degeneration and necrosis of germ cells lining seminiferous tubules, as well as interstitial oedema, congestion of interstitial blood vessel. Wheat germ oil administration potentially mitigated the histopathological alterations of sertraline‐administered rats. Lipid peroxidation, oxidative stress biomarker, showed a significant elevation in testicular tissue of sertraline‐administered rats. Furthermore, glutathione content and catalase activity were decreased in testicular tissue of sertraline‐administered rats. Serum testosterone level was elevated in sertraline‐administered rats. Wheat germ oil significantly reduced lipid peroxidation of testicular tissue and improved the antioxidant defences. Finally, wheat germ oil has a preventive role against testicular damage induced by sertraline in rats probably via its potential to prevent reactive oxygen species.     

The effect of topical parasympathomimetics on corneal epithelial healing in rabbits

Corneal wound healing is an important process that involves interaction between the different corneal cell layers, growth factors, and environmental conditions. More powerful therapies for the treatment of delayed epithelial wound healing are still being proposed. The objective of this study is to investigate the effects of the direct-acting parasympathomimetic agents on the healing process of corneal epithelium in rabbits. The corneal epithelial defects, 10 mm in diameter, were created in 32 eyes of 16 island rabbits by combination of chemical debridement using n-heptanol and mechanical scraping. Animals were randomly divided into four groups. Groups 1, 2 and 3 were treatment groups; each group consisted of four rabbits (8 eyes). The animals in these groups were treated with topical 1% acetylcholine (ACh), 2% pilocarpine, and 0.75% carbachol drops respectively. In group 4, four rabbits (8 eyes) were used as control group and left for spontaneous healing. The length and area of the defect were measured at days 3,6,9,12,15,18 and 22 after wounding. Areas of the photographically documented fluorescein-stained defects were measured by planimetry. All eyes in the treatment groups reepithelialized completely. The duration for reepithelialization in Groups 1 and 2 was 12 days, and 18 days for Group 3. In the control group reepithelialization occurred within 22 days. The healing rates of corneal epithelium were statistically significantly faster in all treatment groups as compared with the control group at all times (p=0.0001 to 0.0279). Although the rates of wound healing varied, all of the parasympathomimetics used in the present study were found to facilitate wound healing. Our results indicate that direct-acting cholinergic agents, especially ACh and pilocarpine, may have an important therapeutic role in the treatment of severe corneal epithelial injury.     

Peripheral seventh nerve palsy due to transorbital intracranial penetrating pontine injury

The case of a child injured by a knitting needle penetrating transorbitally and intracranially, resulting in carotid cavernous fistula and pontine injury, is reported. After receiving medical and endovascular treatment, the only remaining abnormal neurological manifestation was right peripheral facial nerve palsy. The clinical sequences of events and the demonstration of a pontine lesion leading to peripheral facial palsy are presented. Facial nuclear injury with a penetrating trauma is an extremely rare condition. It is important to identify the anatomical regions injured in penetrating traumas. The lesions must be identified by computerized tomography, magnetic resonance imaging, clinical and laboratory investigation.     

In vivo induction of tolerance by an Ig peptide is not affected by the deletion of FcR or a mutated IgG Fc fragment

To induce tolerance to a variety of epitopes, we have designed a gene therapy approach in which peptides or antigens are expressed in frame on a soluble IgG fusion protein scaffold and delivered via retroviral gene therapy in B cells in vivo. Initially, tolerance to the lambda repressor cI sequence p1-102 or its immunodominant epitopes (e.g. p12-26 or p73-88) was elicited in both T cells and B cells when lipopolysaccharide (LPS) blasts are transduced and injected into naive or even primed recipients. While a role of secreted Ig fusion protein in this process is not clear, we have previously demonstrated the importance of antigen presentation on MHC class II of B cell antigen-presenting cells (APC) for tolerance induction. To further examine the role of the Ig and especially of the Fc portion of the IgG in tolerogenesis, we transduced LPS blasts from FcR gamma II(-/-), Fc gamma RI(-/-), Fc gamma RIII(-/-), FcR(-/-) or naive mice with retroviral vectors expressing IgG1-102, Delta IgG1-102 (mutated construct on position 297 of the Fc portion) or IgG12-26. When these transduced LPS blasts from FcR knockout mice were injected into normal (or knockout) syngeneic recipient mice, they induced tolerance both to the immunodominant epitopes and the full-length protein in that the antibody responses to the immunodominant epitopes were reduced. In this paper, we show that this tolerance resides at both the T and B cell level. Moreover, mutation of residue 297, which affects IgG functions including FcR binding, did not alter the tolerogenicity of the construct. These results suggest that the Fc portion of the IgG molecules is not required for humoral nor for cellular tolerance induction using the IgG-antigen tolerogens.     

Bone From Blood: Characteristics and Clinical Implications of Circulating Osteogenic Progenitor (COP) Cells

Circulating osteogenic progenitor (COP) cells are a population of cells in the peripheral blood with the capacity for bone formation, as well as broader differentiation into mesoderm-like cells in vitro. Although some of their biological characteristics are documented in vitro, their role in diseases of the musculoskeletal system remains yet to be fully evaluated. In this review, we provide an overview of the role of COP cells in a number of physiological and pathological conditions, as well as identify areas for future research. In addition, we suggest possible areas for clinical utilization in the management of musculoskeletal diseases. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Comparison of subclinical left and right ventricular systolic dysfunction in non-dipper and dipper hypertensives: impact of isovolumic acceleration

Objectives: To evaluate subclinical left ventricular and right ventricular systolic impairment in dipper and non-dipper hypertensives by using isovolumic acceleration.

Methods: About 45 normotensive healthy volunteers (20 men, mean age 43?±?9 years), 45 dipper (27 men, mean age 45?±?9 years) and 45 non-dipper (25 men, 47?±?7 years) hypertensives were enrolled. Isovolumic acceleration was measured by dividing the peak myocardial isovolumic contraction velocity by isovolumic acceleration time.

Results: Non-dippers indicated lower left ventricular (2.2?±?0.4?m/s² versus 2.8?±?1.0?m/s², p?2 versus 3.5?±?1.0?m/s², p?=?0.012) compared with dippers. Left ventricular mass index (p?=?0.001), interventricular septal thickness (p?=?0.002) and myocardial performance index (p?p?=?0.002), mass index (p?=?0.001) and right ventricular myocardial performance index (p?Conclusion: The present study demonstrates that non-dipper hypertensives have increased left and right ventricular subclinical systolic dysfunction compared with dippers. Isovolumic acceleration is the only echocardiographic parameter in predicting this subtle impairment.     

Spondyloarthritis in North Africa: an update

Clinical Rheumatology - Spondyloarthritis (SpA) has been less well studied than rheumatoid arthritis in North Africa, due to a belief that it is rare and benign in certain populations. The main...     

Midterm Outcomes of Revisional Surgery for Gastric Pouch and Gastrojejunal Anastomotic Enlargement in Patients with Weight Regain After Gastric Bypass for Morbid Obesity

Reoperative surgery for the morbidly obese has become increasingly common due to postoperative weight regain. There are limited studies evaluating the effectiveness of revisional surgery. This study evaluates the weight loss outcomes of revisional surgery over a 2-year period at our University Hospital, USA. Of the 412 patients who underwent laparoscopic bariatric surgery between June 2009 and June 2011, we identified 25 patients who had Roux-en-Y gastric bypass (RYGB) originally, who underwent laparoscopic revisional surgery for weight regain. Preoperative and postoperative data were reviewed. Statistical analysis was performed using paired t test. This study includes 0 male and 25 female patients with an average age of 42 (range min to max: 28–58), mean original body mass index (BMI) of 54.6 kg/m² (r?=?37.3–80.7), average lowest BMI achieved of 32.2 (r?=?20.1–50.9), and average BMI at the time of revision of 41.0 kg/m² (r?=?29.5–60.7, standard deviation (SD)?=?8.5). All laparoscopic revisions consisted of resizing the gastric pouch by resection and recreating the gastrojejunostomy. Average hospital length of stay was 1.28 days (r?=?1–4). Perioperative morbidity was 8 %; one patient developed a trocar site hernia which required repair, and another suffered postoperative bleeding requiring transfusion. There was no mortality. Postoperative BMI averages at 3, 6, 9, 12, and 24 months were 35.0 (SD?=?7.15), 34.7 (SD?=?4.26), 36.2 (SD?=?7.63), 33.0 (SD?=?6.58), and 44.2 (SD?=?12.87), respectively. Statistically significant weight loss was achieved at 3 [t (10)?=?6.74, p?<?0.05], 6 [t (7)?=?4.69, p?<?0.05], 9 [t (9)?=?2.94, p?<?0.05], and 12 [t (6)?=?3.78, p?<?0.05] months. However, there was no statistically significant weight loss at 24 months postoperatively [t (4)?=??0.16, p?>?0.05]. Laparoscopic revisional bariatric surgery can be performed with significant weight loss up to 1 year postoperatively. However, additional studies are required to evaluate longer-term success.