Two statins and cromolyn as possible drugs against the cytotoxicity of Aβ(31–35) and Aβ(25–35) peptides: a comparative study by advanced computer simulation methods

In this work, possible effective mechanisms of cromolyn, atorvastatin and lovastatin on the cytotoxicity of Aβ(31–35) and Aβ(25–35) peptides were investigated by classical molecular dynamics and well-tempered metadynamics simulations. The results demonstrate that all the drugs affect the behavior of the peptides, such as their ability to aggregate, and alter their secondary structures and their affinity to a particular drug. Our findings from the computed properties suggest that the best drug candidate is lovastatin. This medicine inhibits peptide aggregation, adsorbs the peptides on the surface of the drug clusters, changes the secondary structure and binds to MET₃₅, which has been seen as the reason for the toxicity of the studied peptide sequences. Moreover, lovastatin is the drug which previously has demonstrated the strongest ability to penetrate the blood–brain barrier and makes lovastatin the most promising medicine among the three investigated drugs. Atorvastatin is also seen as a potential candidate if its penetration through the blood–brain barrier could be improved. Otherwise, its properties are even better than the ones demonstrated by lovastatin. Cromolyn appears to be less interesting as an anti-aggregant from the computational data, in comparison to the two statins.

In this work, possible effective mechanisms of cromolyn, atorvastatin and lovastatin on the cytotoxicity of Aβ(31–35) and Aβ(25–35) peptides were investigated by classical molecular dynamics and well-tempered metadynamics simulations.     

The effect of the intramolecular C–H⋯O interactions on the conformational preferences of bis-arylsulfones – 5-HT6 receptor antagonists and beyond

The development of compounds with enhanced activity and selectivity by a conserved spatial orientation of the pharmacophore elements has a long history in medicinal chemistry. Rigidified compounds are an example of this concept. However, the intramolecular interactions were seldom used as a basis for conformational restraints. Here, we show the weak intramolecular interactions that contribute to the relatively well-conserved geometry of N1-arylsulfonyl indole derivatives. The structure analysis along with quantum mechanics calculations revealed a crucial impact of the sulfonyl group on the compound geometry. The weak intramolecular C–H⋯O interaction stabilizes the mutual "facing" orientation of two aromatic fragments. These findings extend the pharmacological interpretation of the sulfonyl group role from the double hydrogen bond acceptor to the conformational scaffold based on intramolecular forces. This feature has, to date, been omitted in in silico drug discovery. Our results should increase the awareness of researchers to consider the conformational preference when designing new compounds or improving computational methods.

The impact of weak intramolecular C–H⋯O interactions on the conformational stability of bis-arylsulfones is discussed, suggesting different role of sulfonyl group in the ligand – 5HT₆ receptor interaction.     

Numerical and In Vitro Investigation of a Novel Mechanical Circulatory Support Device Installed in the Descending Aorta

Traditional implantation techniques of assist devices from the apex of left ventricle to the ascending or descending aorta are highly invasive and carry substantial complications for end‐stage heart failure patients. This study has shown that the descending aorta can be a promising location to install an implantable mechanical circulatory support with minimally invasive surgery. Herein, the hemodynamic effect of an in‐house prototyped pump implanted in the descending aorta was investigated numerically as well as experimentally. The objective of the experimental study is met by using the in‐house simulator of the cardiovascular loop replicating congestive heart failure conditions. The objective of the numerical study was met by using the modified version of the concentrated lumped parameter model developed by the same team. The results show that the pump placement in the descending aorta can lead to an improvement in pulsatility. The pressure drop, generated at the upstream of the pump, facilitates the cardiac output as a result of after‐load reduction, but at the same time, it induces a slight drop in the carotid as well as the coronary perfusion. The pressure rise, generated at the downstream of the pump, improves the blood perfusion in the renal circulation.     

Association of CD36 gene polymorphisms with echo- and electrocardiographic parameters in patients with early onset coronary artery disease

Introduction

CD36 plays an important role in long-chain fatty acid homeostasis in skeletal muscle and the myocardium. CD36 deficiency may lead to reduced myocardial uptake of long-chain fatty acid. Therefore, different mutations of the CD36 gene may contribute to the clinical heterogeneity of cardiac hypertrophy.

Material and methods

The objective of the study was to investigate whether there is an association between the sequence changes in CD36 and echocardiographic and electrocardiographic parameters in Caucasian patients with early onset coronary artery disease. The study group comprised 100 patients. Electrocardiography and echocardiography were performed in all patients. Amplicons of exons 4 to 6 including fragments of introns were studied using the denaturing high-performance liquid chromatography technique.

Results

IVS3-6TC (rs3173798) heterozygotes had impaired left ventricle diastolic function. 573GA heterozygotes (rs5956) had higher frequency of pseudonormal left ventricular diastolic function and it was confirmed by the increase in wave A’ in the tissue Doppler. 591AT genotype was associated with borderline higher posterior wall end-diastolic thickness and lower E/A ratio. These results are consistent with electrocardiography parameters which could reflect left ventricular hypertrophy (higher R_V5(6) and R_V5(6) + S_V1(2) parameters, depressed ST segments and tendency to longer Qtc II interval) in 591AT heterozygotes.

Conclusions

Detected variant alleles of CD36 may be associated with features of left ventricular hypertrophy and impaired diastolic function.     

Nineteen-year single-center experience in 76 patients with penile cancer treated with high-dose-rate brachytherapy

PURPOSETo report the outcomes for 76 patients with penile cancer treated with high-dose-rate brachytherapy (HDR-BT) at a single institution.METHODSSeventy-six patients with penile cancer treated with HDR-BT in our department between October 1998 and September 2018 were analyzed. Seventy underwent interstitial HDR-BT (fractionation dose range of 3–3.5 Gy given twice a day with an interval of at least six hours between the fractions), and six underwent superficial treatment with mold applicators (fractionation dose range of 4–7 Gy given once or twice a week).RESULTSMedian follow-up was 76 months (7–204 months). In the whole group, 22/76 local failures (28.9%) were observed: 14/76 (18.4%) local recurrences and 8/76 (10.5%) cases of persistent disease. Median time to recurrence was 24 months (9–54 months). Inguinal lymph node metastases were observed in 18/76 cases (23.7%). Distant metastases occurred in 12/76 (15.8%) cases. Patients with local recurrence and persistent disease underwent salvage penectomies, except four who refused surgery and underwent a second course of interstitial HDR-BT. Five- and 10-year cause-specific survival were 85.0% and 77.8%, respectively. Local control at 5 and 10 years was 65.6%. Five- and 10-year penile preservation were 69.5% and 66.9%, respectively. There was no G3 or G4 acute toxicity. One urethral stenosis (1.3%) occurred in a patient with a T3 tumor and was treated successfully with dilatation.CONCLUSIONSHDR-BT provides good local control of penile cancer and is a good option for penis preservation therapy and in our experience achieves a penile preservation rate at 10 years of 66.9%.     

Paraneoplastic autoimmune autonomic ganglionopathy as the first symptom of bladder cancer: a case report and review of literature

Neurological Sciences - Autoimmune autonomic ganglionopathy is a rare, immune-mediated disorder associated with anti-ganglionic α3-subunit nicotinic acetylcholine receptor (anti-α3gAChR)...