Cyclodidepsipeptides with a promising scaffold in medicinal chemistry

Among the large family of cyclodepsipeptides, the simplest members are the cyclodidepsipeptides which have an ester group and an amide group in the same six-membered ring. To point out the pharmacological potential of this class of compounds, the present article reviews structure, isolation, synthesis and biological properties of the known cyclodidepsipeptides. Synthesis of cyclodidepsipeptides is achieved by two general approaches—by initial formation of the amide bond, or initial formation of the ester bond; and subsequent intermolecular cyclization to cyclodidepsipeptide structure. It is closely related to the condensation and ring-closure strategies applied in the preparation of the larger members of the cyclodepsipeptide family. However, due to synthesis of the smaller heretocycles it allows for the use of more versatile building blocks. There are data on antimicrobial, antioxidant and immunomodulatory activities of cyclodidepsipeptides as well as their inhibitory activities toward α-glucosidase, acyl-CoA:cholesterol acyltransferase, xanthine oxidase and platelet aggregation. Because we have recently found that two 6-(propan-2-yl)-4-methyl-morpholine-2,5-diones, as novel non-purine xanthine oxidase inhibitors, may give promise to be used in the treatment of gout, in this review we have included a study of molecular interactions of the selected cyclodidepsipeptides with xanthine oxidase using idTarget web server. Cyclodidepsipeptides showed promising pharmacological activities and meet all criteria for good solubility and permeability. However, further research of their medical application is necessary. In addition to this, the diversity of natural cyclodidepsipeptides, simplicity for synthesis and convenience for rational drug design indicate the cyclodidepsipeptide as promising scaffold in medicinal chemistry.     

The possibilities and limitations of direct digital radiography, ultrasound and computed tomography in diagnosing pleural mesotelioma

The goal of this study was to compare the possibilities and limitations of direct digital radiography of the chest (DDR), the use of ultrasound of the chest (US) and single slice computed tomography of the chest (CT) in diagnosing pleural mesothelioma. The study was conducted during the course of one year, on 80 patients who were successively referred to a specialized institution, under clinical suspicion of mesothelioma. The method of investigation was the comparison of findings, obtained by the reviewed methods of examination, with the pathohistologic results of a biopsy performed on each patient. The findings that were obtained by the enumerated methods were classified according to the radiologic signs that were found in each individual patient. We evaluated following radiological findings (signs), on each of the investigated methods: plaques, localized and generalized pleural thickenings, calcifications of the pleura, pleural effusions, parapneumonic effusions, pleural empyema, (round) atelectasis, pneumothorax, tumor mass or node, inflammatory infiltrate, elevation of the hemidiaphragm and osteolysis. The results of these were compared with pathohistologic findings and analyzed by means of standard statistical methods. The highest sensitivity was found for CT (94.4%), followed by US (92.6%), and by DDR (90.7%). The highest specificity was obtained with DDR (46.2%), followed by CT (35.5%) and US (23.8%). The comparison of these methods showed 90% diagnostic accuracy for DDR in relation to CT CT as an individual method best satisfied most of the criteria for diagnosing mesothelioma. No pathognomonic radiologic sign for mesothelioma was found.     

Hsp110 Is a Bona Fide Chaperone Using ATP to Unfold Stable Misfolded Polypeptides and Reciprocally Collaborate with Hsp70 to Solubilize Protein Aggregates

Structurally and sequence-wise, the Hsp110s belong to a subfamily of the Hsp70 chaperones. Like the classical Hsp70s, members of the Hsp110 subfamily can bind misfolding polypeptides and hydrolyze ATP. However, they apparently act as a mere subordinate nucleotide exchange factors, regulating the ability of Hsp70 to hydrolyze ATP and convert stable protein aggregates into native proteins. Using stably misfolded and aggregated polypeptides as substrates in optimized in vitro chaperone assays, we show that the human cytosolic Hsp110s (HSPH1 and HSPH2) are bona fide chaperones on their own that collaborate with Hsp40 (DNAJA1 and DNAJB1) to hydrolyze ATP and unfold and thus convert stable misfolded polypeptides into natively refolded proteins. Moreover, equimolar Hsp70 (HSPA1A) and Hsp110 (HSPH1) formed a powerful molecular machinery that optimally reactivated stable luciferase aggregates in an ATP- and DNAJA1-dependent manner, in a disaggregation mechanism whereby the two paralogous chaperones alternatively activate the release of bound unfolded polypeptide substrates from one another, leading to native protein refolding.     

Analysis of bone tissue mechanical properties

This paper deals with the torsional moment depending on the angle of torsion of the compact bone in laboratory animals and humans. Based on the data from laboratory animals, obtained by measurement, the data on dependence of the torsional moment and the angle of torsion were assumed for humans. Measurements were carried out on four groups of compact bone in laboratory animals. One was the control group, and three other groups were treated by various vitamin D3 metabolites. Equal measurements were performed in only one group of compact bone in humans, due to the impossibility to treat humans with vitamin D3 metabolites. Functional relations between the angle of torsion and the torsional moment for all groups of animal body tissue were determined by measurements, and the results were used to assume the reaction of human compact bone tissue if treated by vitamin D3 metabolites.     

Stenotic occlusive lesions of internal carotid artery in diabetic patients

Diabetes deteriorates atherosclerotic changes in the arteries. The aim of the study was to assess the prevalence and localization of stenotic atherosclerotic lesions of the internal carotid artery (ICA) in patients with diabetes. A prospective analysis of angiography findings was carried out in 150 diabetic and 150 non-diabetic patients with symptoms of cerebral ischemia using double-blind angiogram readings by two independent investigators. The degree of stenosis was determined using the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria. Stenoses of the proximal arterial segment accounted for the majority of extracranial ICA stenoses, being more frequent in diabetic (left ICA 50.7%, right ICA 58.0%) than in the non-diabetic patients (left ICA 29.3%, right ICA 32.7%). Diabetic patients revealed a more significant rate of unilateral tandem ICA stenoses (14.0-21.3%), as well as a statistically significantly higher prevalence of intracranial ICA stenoses (left ICA 24.0% and right ICA 17.3%) than did non-diabetic patients (left and right ICA 3.3% each). Our results confirm that there is a morphological basis in ICA for increased incidence of ICA lesions in patients with diabetes as compared to those without it. Data on the incidence of stenotic ICA lesions in diabetes suggest the importance of assessing overall ICA status using digital subtraction angiography. Such an assessment is a precondition for an optimal therapeutic approach, especially in diabetic patients who are at an increased risk of cerebrovascular disease.     

Essential oil composition of Hypericum L. species from Southeastern Serbia and their chemotaxonomy

The essential oils of the aerial parts of nine species of Hypericum (Hypericum barbatum, Hypericum hirsutum, Hypericum linarioides, Hypericum maculatum, Hypericum olympicum, Hypericum perforatum, Hypericum richeri, Hypericum rumeliacum and Hypericum tetrapterum), collected from different locations in Southeast Serbia, were obtained by steam distillation and analyzed by GC and GC–MS. The essential oils investigated were characterized by a high content of non-terpene compounds and a low content of monoterpenes. The contents of non-terpenes, monoterpenes and sesquiterpenes in oils of the species H. barbatum, H. richeri and H. rumeliacum (section Drosocaprium) were similar and these oils were characterized by high contents of fatty acids. The oils of H. hirsutum and H. linarioides (section Taeniocarpium) contained a high percentage of n-nonane. There were similarities in contents of non-terpenes and sesquiterpenes in oils of species that belong to the section Hypericum (H. maculatum, H. perforatum and H. tetrapterum). The oil of H. olympicum differed from others by higher terpene content. A comparison was also carried out of the chemical composition of the essential oils from flower, leaf and stem of H. perforatum and it revealed that the highest concentration of non-terpene compounds was found in the flower and stem oil, while a high concentration of sesquiterpenes was characteristic for leaf oil. There were significant differences in the concentrations of the same compounds in the essential oils of H. maculatum, H. olympicum and H. perforatum, collected in different years from the same location which could be explained by seasonal differences. All data were statistically processed with principal component analysis and cluster analysis. The main conclusion from the above data is that genetic and environmental factors both play a role in determining the composition of essential oils of the Hypericum species studied.     

Parkinson Patients’ Initial Trust in Avatars: Theory and Evidence

Parkinson’s disease (PD) is a neurodegenerative disease that affects the motor system and cognitive and behavioral functions. Due to these impairments, PD patients also have problems in using the computer. However, using computers and the Internet could help these patients to overcome social isolation and enhance information search. Specifically, avatars (defined as virtual representations of humans) are increasingly used in online environments to enhance human-computer interaction by simulating face-to-face interaction. Our laboratory experiment investigated how PD patients behave in a trust game played with human and avatar counterparts, and we compared this behavior to the behavior of age, income, education and gender matched healthy controls. The results of our study show that PD patients trust avatar faces significantly more than human faces. Moreover, there was no significant difference between initial trust of PD patients and healthy controls in avatar faces, while PD patients trusted human faces significantly less than healthy controls. Our data suggests that PD patients’ interaction with avatars may constitute an effective way of communication in situations in which trust is required (e.g., a physician recommends intake of medication). We discuss the implications of these results for several areas of human-computer interaction and neurological research.     

A 10-year experience in the treatment of intraabdominal cerebrospinal fluid pseudocysts

The aim of this retrospective study was to assess a ten-year experience in the treatment of rare complications of ventriculoperitoneal shunting--intraabdominal cerebrospinal fluid pseudocysts. At this time there are no data about incidence, clinical course and treatment of these complications in Croatia. Cerebrospinal fluid (CSF) abdominal pseudocyst is an uncommon but important complication of ventriculoperitoneal shunts. Retrospective data were obtained from 5 children with abdominal CSF pseudocysts, treated between 1996 and 2007. The incidence of intraabdominal CSF pseudocysts in our study is 2.9%. All patients were girls ranged in age from 4 to 12 years old (mean 8.8 years). In most cases etiology of hydrocephalus was congenital, idiopathic. Abdominal pain and distension were the most frequent clinical finding (4/5). Although infection has been reported as responsible for pseudocyst formation, we did not found it in our series. Laparotomy with cyst wall excision and catheter replacement was performed in 2/5 cases, and only cyst fluid aspiration with catheter replacement in 3/5 cases. Recurrence of the abdominal cyst was observed in one girl who was in terminal stadium of anaplastic ependymoma. It is our opinion that only catheter replacement and cyst fluid evacuation, as one of the treatment modalities, may be successful, even in large CSF intraperitoneal pseudocysts.