Synthesis,molecular modeling studies,ADME prediction of arachidonic acid carbamate derivatives,and evaluation of their acetylcholinesterase activity

In this work, a series of novel anandamide units containing carbamate were designed and synthesized. All the derivatives were evaluated in vitro for their inhibitory potential against the electric eel acetylcholinesterase enzyme (AChE) and showed reversible inhibitions. The compounds 7a , 7d , 7e , and 7f are mixed inhibitors of AChE, while the compounds 7b , 7c , and 7g are uncompetitive (K_i in the range 0.93–8.86 μM). The kinetic studies revealed that compounds 7b , 7c , 7f , and 7g inhibit considerably AChE activity. Molecular docking analyses were made to evaluate the binding type and interactions of the synthesized compounds to the ligand-binding site of hAChE. It was observed that the docking results were in parallel with the in vitro results. The adsorption, distribution, metabolism, and excretion properties were computed for the compounds, and were found within the acceptable range. This study suggests the compounds 7b , 7c , 7f , and 7g identified as novel reversible AChE inhibitors may be useful lead compounds for the treatment of Alzheimer's disease.     

Eficácia de bupivacaína e associação com dexmedetomidina em bloqueio do plano transverso abdominal guiado por ultrassom na dor após cirurgia abdominal

Background and objectives

We aimed to evaluate the effect of bupivacaine and dexmedetomidine added to bupivacaine used in tranversus abdominis plane (TAP) block on postoperative pain and patient satisfaction in patients undergoing lower abdominal surgery.

The ΔF508 mutation causes CFTR misprocessing and cystic fibrosis-like disease in pigs

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. The most common CF-associated mutation is ΔF508, which deletes a phenylalanine in position 508. In vitro studies indicate that the resultant protein, CFTR-ΔF508, is misprocessed, although the in vivo consequences of this mutation remain uncertain. To better understand the effects of the ΔF508 mutation in vivo, we produced CFTR(ΔF508/ΔF508) pigs. Our biochemical, immunocytochemical, and electrophysiological data on CFTR-ΔF508 in newborn pigs paralleled in vitro predictions. They also indicated that CFTR(ΔF508/ΔF508) airway epithelia retain a small residual CFTR conductance, with maximal stimulation producing ~6% of wild-type function. Cyclic adenosine 3',5'-monophosphate (cAMP) agonists were less potent at stimulating current in CFTR(Δ)(F508/)(Δ)(F508) epithelia, suggesting that quantitative tests of maximal anion current may overestimate transport under physiological conditions. Despite residual CFTR function, four older CFTR(ΔF508/ΔF508) pigs developed lung disease similar to human CF. These results suggest that this limited CFTR activity is insufficient to prevent lung or gastrointestinal disease in CF pigs. These data also suggest that studies of recombinant CFTR-ΔF508 misprocessing predict in vivo behavior, which validates its use in biochemical and drug discovery experiments. These findings help elucidate the molecular pathogenesis of the common CF mutation and will guide strategies for developing new therapeutics.     

A partial epithelial-mesenchymal transition signature for highly aggressive colorectal cancer cells that survive under nutrient restriction

Partial epithelial-mesenchymal transition (p-EMT) has recently been identified as a hybrid state consisting of cells with both epithelial and mesenchymal characteristics and is associated with the migration, metastasis, and chemoresistance of cancer cells. Here, we describe the induction of p-EMT in starved colorectal cancer (CRC) cells and identify a p-EMT gene signature that can predict prognosis. Functional characterisation of starvation-induced p-EMT in HCT116, DLD1, and HT29 cells showed changes in proliferation, morphology, and drug sensitivity, supported by in vivo studies using the chorioallantoic membrane model. An EMT-specific quantitative polymerase chain reaction (qPCR) array was used to screen for deregulated genes, leading to the establishment of an in silico gene signature that was correlated with poor disease-free survival in CRC patients along with the CRC consensus molecular subtype CMS4. Among the significantly deregulated p-EMT genes, a triple-gene signature consisting of SERPINE1, SOX10, and epidermal growth factor receptor (EGFR) was identified. Starvation-induced p-EMT was characterised by increased migratory potential and chemoresistance, as well as E-cadherin processing and internalisation. Both gene signature and E-cadherin alterations could be reversed by the proteasomal inhibitor MG132. Spatially resolving EGFR expression with high-resolution immunofluorescence imaging identified a proliferation stop in starved CRC cells caused by EGFR internalisation. In conclusion, we have gained insight into a previously undiscovered EMT mechanism that may become relevant when tumour cells are under nutrient stress, as seen in early stages of metastasis. Targeting this process of tumour cell dissemination might help to prevent EMT and overcome drug resistance. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.     

Evaluation of the Protective Effect of Beta Glucan on Amikacin Ototoxicity Using Distortion Product Otoacoustic Emission Measurements in Rats

Objectives

This experimental study investigated the possible protective effect of beta glucans on amikacin ototoxicity.

Methods

Thirty-eight rats with normal distortion product otoacoustic emissions (DPOAEs) were divided into four groups. Group K was the control group. Group A was injected intramuscularly (i.m.) with amikacin 600 mg/kg/day between days 1-15. Group AB was given beta glucan gavage 1 mg/kg/day on days 0-15 and given amikacin 600 mg/kg/day i.m. on days 1-15. Group B was administered only beta glucan gavage, 1 mg/kg/day, on days 0-15. The DPOAEs were elicited in different frequency regions between 2,003 and 9,515 Hz, as distortion product diagrams (DPgrams), before and after the medication was administered, in all groups, on days 1, 5, 10, and 15.

Results

No significant changes in the DPgrams were observed in group K. In group A, significant deterioration was observed at the 8,003 and 9,515 Hz frequencies on day 10, and at the 3,991, 4,557, 5,660, 6,726, 8,003, and 9,515 Hz frequencies on day 15. For group AB, statistically significant deterioration was observed at the 2,824, 8,003, and 9,515 Hz frequencies on day 15. The results for group B showed a significant improvement of hearing at the 2,378, 2,824, 3,363, and 3,991 Hz frequencies on day 1, at the 3,363, 3,991, and 8,003 Hz frequencies on day 10, and at the 8,003 Hz frequency on day 15.

Conclusion

This study suggests that amikacin-induced hearing loss in rats may be limited to some extent by concomitant use of beta glucan.     

Is the Addition of Dexmedetomidine to a Ketamine–Propofol Combination in Pediatric Cardiac Catheterization Sedation Useful?

Pediatric patients undergoing cardiac catheterization usually need deep sedation. In this study, 60 children were randomly allocated to receive sedation with either a ketamine-propofol combination (KP group, n = 30) or a ketamine-propofol-dexmedetomidine combination (KPD group, n = 30). Both groups received 1 mg/kg of ketamine and 1 mg/kg of propofol for induction of sedation, and the KPD group received an additional 1 μg/kg of dexmedetomidine infusion during 5 min for induction of sedation and a maintenance infusion of 0.5 μg/kg/h. In both groups, 0.2 mg/kg of propofol was administered as a bolus to maintain a Ramsey sedation score (RSS) greater than 4 throughout the procedure. None of the patients in either group required intubation. In the KP group, one patient required mask ventilation. The chin-lift maneuver needed to be performed for eight patients in the KP group and one patient in the KPD group (p < 0.05). Adding dexmedetomidine to the ketamine-propofol combination decreased movement during the procedures. The heart rate in the KPD group was significantly lower after induction of sedation and throughout the procedure (p < 0.05). No significant differences in systolic blood pressure, diastolic blood pressure, or respiration rates were found between the two groups (p > 0.05). The mean recovery time was longer in the KP group (5.86 vs 3.13 min; p < 0.05). Adding dexmedetomidine to a ketamine-propofol combination led to a reduced need for airway intervention and to decreased movement during local anesthetic infiltration and throughout the procedure. The recovery time was shorter and hemodynamic stability good in the KPD group.     

Comparison between dexmedetomidine and midazolam for sedation of eclampsia patients in the intensive care unit

Purpose

This study compares the effectiveness of midazolam and dexmedetomidine for the sedation of eclampsia patients admitted to our intensive care unit (ICU).

Patients and Methods

Forty women with eclampsia requiring termination of pregnancy by caesarean delivery were randomized in to 2 groups of 20 to receive either midazolam or dexmedetomidine. The midazolam group received a loading dose of 0.05 mg/kg followed by an infusion of 0.1 mg kg⁻¹ h⁻¹. The dexmedetomidine group loading dose was 1 μg/kg per 20 minutes, followed by continuous infusion at 0.7 μg kg⁻¹ h⁻¹. Heart rate, blood pressure, Ramsey sedation score, antihypertensive need, convulsion fits, and duration in ICU were monitored and recorded all through the ICU stay.

Results

Dexmedetomidine markedly reduced heart rates for the first 24 hours (P < .05) compared with midazolam, but there were no differences at 48 and 72 hours. Mean arterial blood pressures were similar in the 2 groups (P > .05), although in the dexmedetomidine group, it was lower at 5, 6, 12, and 24 hours compared with the first 4 hours (P < .05). Moreover, fewer patients given dexmedetomidine required nitroglycerine and nitroprusside (P < .05). The duration of ICU stay was less in the dexmedetomidine group, 45.5 hours (range, 15-118 hours), than in the midazolam group, 83 hours (minimum-maximum, 15-312 hours).

Conclusion

Dexmedetomidine sedation in eclampsia patients is effective in reducing the demand for antihypertensive medicine and duration of ICU stay.     

Strain sonoelastographic evaluation of biceps muscle intrinsic stiffness after botulinum toxin-A injection

Background: The most commonly used clinical tools for measuring spasticity are modified Ashworth scale (MAS) and Tardieu scale but both yield subjective rather than objective results. Ultrasound elastography (EUS) provides information on tissue stiffness and allows the qualitative or quantitative measurements of the mechanical properties of tissues.

Objective: To assess the stiffness of biceps brachialis muscles in stroke patients by strain EUS and to investigate the sonoelastographic changes and its correlations with clinical evaluation parameters after botulinum toxin-A (BTA) injections.

Methods: This is a prospective study. A total of 48 chronic stroke patients requiring BTA injections to biceps brachialis muscles were included in the study. All patients received injections with BTA to biceps brachialis muscles under ultrasound guidance. MAS, goniometric measurements, and strain EUS assessments were performed at preintervention and at 4-week postintervention.

Results: Strain index values of biceps muscle on the affected side were significantly increased compared with those on the unaffected side (p < 0.01). At 4 weeks after BTA injection, significant improvements were observed in MAS grades and goniometric measurements (p < 0.05). Statistically significant differences were also found between the MAS grades and strain index values in both pre-/postintervention period (p < 0.01). No significant correlations were observed between clinical parameters and strain EUS findings.

Conclusions: Strain EUS is a promising diagnostic tool for assessing stiffness in spastic muscles, in establishing the treatment plan and monitoring the effectiveness of the therapeutic modality.