Efficient access to novel androsteno-17-(1',3',4')-oxadiazoles and 17β-(1',3',4')-thiadiazoles via N-substituted hydrazone and N,N'-disubstituted hydrazine intermediates, and their pharmacological evaluation in vitro.

A series of novel 17-exo-oxadiazoles and -thiadiazoles in the Δ(5) androstene series were efficiently synthesized from pregnenolone acetate and pregnadienolone acetate via multistep pathways. 17β-(1',3',4')-Oxadiazoles were obtained in high yields by the phenyliodonium diacetate-induced oxidative ring closure of semicarbazone and N-acylhydrazones derived from 3β-acetoxy- and 3β-hydroxyandrost-5-ene-17β-carbaldehydes. For the synthesis of analogous Δ(16)-17-oxadiazolyl derivatives, N,N'-disubstituted hydrazine intermediates were prepared from 3β-acetoxyandrosta-5,16-diene-17-carboxylic acid, which then underwent cyclodehydration in the presence of POCl3.

Acetylations of Ftz-F1 and histone H4K5 are required for the fine-tuning of ecdysone biosynthesis during Drosophila metamorphosis.

The molting during Drosophila development is tightly regulated by the ecdysone hormone. Several steps of the ecdysone biosynthesis have been already identified but the regulation of the entire process has not been clarified yet. We have previously reported that dATAC histone acetyltransferase complex is necessary for the steroid hormone biosynthesis process.

γ-Secretase modulators reduce endogenous amyloid β42 levels in human neural progenitor cells without altering neuronal differentiation.

Soluble γ-secretase modulators (SGSMs) selectively decrease toxic amyloid β (Aβ) peptides (Aβ42). However, their effect on the physiologic functions of γ-secretase has not been tested in human model systems. γ-Secretase regulates fate determination of neural progenitor cells.

Serum C-reactive protein and white blood cell level as markers of successful percutaneous drainage of acute sterile peripancreatic fluid collection.

Background: Percutaneous drainage is not a widely used therapeutic method recently for evacuating peripancreatic sterile fluid collections in patients with severe acute pancreatitis.However, many clinical studies have proved its positive effects.

Aim: We tested the changes in serum laboratory parameters:C-reactive protein (CRP), complement factor 3-4 (C 3-4),tumor necrosis factor a (TNF-a), amylase, lipase and white blood cell (WBC) count in patients treated by percutaneous drainage.

Variability in the effect of 5-HTTLPR on depression in a large European population: the role of age, symptom profile, type and intensity of life stressors.

Background: Although 5-HTTLPR has been shown to influence the risk of life stress-induced depression in the majority of studies, others have produced contradictory results, possibly due to weak effects and/or sample heterogeneity.

Methods: In the present study we investigated how age, type and intensity of life-stressors modulate the effect of 5-HTTLPR on depression and anxiety in a European population cohort of over 2300 subjects. Recent negative life events (RLE), childhood adversity (CHA), lifetime depression, Brief Symptoms Inventory (BSI) depression and anxiety scores were determined in each subject.

A rare case of a intracardiac lipoma.

Introduction: Primary tumors of the heart are exceedingly rare, accounting for less than 5% of all cardiac tumors; the remaining 95% of tumors are metastatic tumors to the heart. The most common primary cardiac tumors in adults are myxomas (usually occurring in the left atrium) followed by papillary fibroelastomas and lipomas with rhabdomyoma the most common in children.

Presentation Of Case: We are presenting a case of a 74-years-old female who initially presents with dizziness.

Meal-induced insulin sensitization is preserved after acute olanzapine administration in female Sprague-Dawley rats.

Olanzapine, an atypical antipsychotic, can acutely induce fasting insulin resistance, but we do not know whether it is able to modulate the meal-induced insulin sensitization (MIS). Two main experimental groups (control and olanzapine-treated) were created with two subgroups (fasted and re-fed) within each. After oral vehicle/olanzapine administration, the first meal size and duration and the total amount of consumed food was recorded in conscious rats.

A three-dimensional human neural cell culture model of Alzheimer's disease.

Alzheimer's disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-β plaques and neurofibrillary tangles. The amyloid hypothesis of Alzheimer's disease posits that the excessive accumulation of amyloid-β peptide leads to neurofibrillary tangles composed of aggregated hyperphosphorylated tau. However, to date, no single disease model has serially linked these two pathological events using human neuronal cells.

Three-year longitudinal clinical trial of arterial function assessed by a oscillometric non-invasive method in comparison with carotid sclerosis and transferrin kidney-transplanted patients.

Chronic kidney disease remains one of the main risk factors of cardiovascular disease. However, patients with kidney transplantation have better life expectancy and better quality of life compared with patients on dialysis. In patients with a well-functioning graft, the main cause of death is cardiovascular in origin.

Vitiligo: characterization of melanocytes in repigmented skin after punch grafting.

Background: Punch grafting is a surgical technique mainly applied in therapy-resistant, stable and circumscribed vitiligo.

Objective: (i) To characterize in detail the features of the repigmented skin among punch grafts; and (ii) to correlate the ex vivo results with clinical data and punch grafting outcome.

Methods: We evaluated by immunohistochemistry and image analysis the expression of a panel of specific melanocyte markers including HMB45, MITF, c-kit, MART-1 and TRP1, the proliferation marker Ki67 and the cell-cell adhesion molecule E-cadherin in tissue samples collected from nine patients after punch grafting.

Antidepressant treatment response is modulated by genetic and environmental factors and their interactions.

Although there is a wide variety of antidepressants with different mechanisms of action available, the efficacy of treatment is not satisfactory. Genetic factors are presumed to play a role in differences in medication response; however, available evidence is controversial. Even genome-wide association studies failed to identify genes or regions which would consequently influence treatment response.

Leptin promotes a proinflammatory lipid profile and induces inflammatory pathways in human SZ95 sebocytes.

Background: Leptin, the adipocyte-secreted hormone that regulates weight, is known to link lipid metabolism with inflammation in various cell types. However, its role in human sebocytes has not yet been investigated.

Objectives: The purpose of this study was to investigate the effects of leptin in human sebaceous gland biology.

Regio- and stereoselective access to novel ring-condensed steroidal isoxazolines.

Novel 5α-androstanes containing an isoxazoline moiety condensed to ring A or D were efficiently synthetized by 1,3-dipolar cycloadditions of aryl nitrile oxides to steroidal α,β-unsaturated ketones. During the ring closures, regioisomers in which the O terminus of the nitrile oxide dipoles is attached to the β-carbon of the dipolarophile were formed in a stereoselective manner to furnish exclusively 1α,2α- or 15β,16β-condensed heterocycles. The cyclic enone moiety of the six-membered ring A proved to be less reactive than that of the five-membered ring D, but all the reactions were affected significantly by the substitution pattern of the nitrile oxide.

Inflammasome activation and vitiligo/nonsegmental vitiligo progression.

Background: Polymorphisms of NLR (nucleotide-binding domain and leucine rich repeat containing) family, pyrin domain containing protein 1 (NLRP1) have been found in patients with vitiligo/nonsegmental vitiligo (NSV), and increased NLRP1 expression has been detected in the leading edge of lesional skin biopsies.

Objectives: To evaluate the presence and intensity of NLRP1 immunostaining in lesional and perilesional skin of patients with vitiligo/NSV and to search for possible correlations between NLRP1 and interleukin (IL)-1β expression, lymphocytic infiltrates and disease activity.

Methods: Of 14 consecutive vitiligo/NSV patients, eight had active disease [Vitiligo European Task Force (VETF) spreading score +1 to +5], one patient had stable disease and five patients had regressive disease (VETF spreading score -1 to -3).

Synthesis of novel steroidal 16-spiroisoxazolines by 1,3-dipolar cycloaddition, and an evaluation of their antiproliferative activities in vitro.

Efficient synthesis of novel 16-spiroisoxazolines in the androst-5-ene series was carried out by 1,3-dipolar cycloadditions of different aryl nitrile oxides to 3β-acetoxy-16-methylene-androst-5-en-17-one. During the intermolecular ring closures, the attack of the O terminus of the nitrile oxide dipole from the α side on C-16 predominated for steric reasons permitting the reactions to occur in a regio- and stereoselective manner. The minor isomers in which the angular methyl group on C-13 and the O atom of the isoxazoline heteroring were in the β, β-cis orientation were obtained in a yield of only ~10 %.

A facile access to novel steroidal 17-2'-(1',3',4')-oxadiazoles, and an evaluation of their cytotoxic activities in vitro.

Novel types of 17-exo-heterocycles in the Δ(5) androstene series carrying an 1,3,4-oxadiazole moiety were efficiently synthesized via aldehyde N-acylhydrazone intermediates, obtained from the microwave-assisted condensation of 3β-hydroxy- or 3β-acetoxyandrost-5-ene-17β-carbaldehyde with different acylhydrazides. The subsequent phenyl iodonium diacetate-induced oxidative cyclization proceeded under mild conditions. The synthesized compounds were subjected to in vitro pharmacological studies to investigate their antiproliferative activities on four malignant adherent cell lines (HeLa, MCF7, A2780 and A431), and exhibited the highest potency against HeLa cells, some of them revealing action comparable to that of the reference agent cisplatin.

Rare case of "wandering artery of drummond" as a result of chronic triple mesenteric vessel occlusion treated by isolated angioplasty and stenting of the inferior mesenteric artery.

We report a rare clinical scenario of chronic mesenteric ischemia (CMI) patient with obstruction of all the three major gut vessels including celiac, superior mesenteric artery (SMA), and inferior mesenteric artery (IMA) with a sole artery supplying the collaterals through marginal artery of left colon (the "wandering artery of Drummond"). A 70-year-old man was presented to hospital with acute onset of dyspnea, diaphoresis, severe epigastric pain, nausea, and vomiting that started after lunch. Initially, patient was diagnosed and treated for non-ST elevation myocardial infarction (NSTEMI).

BACE1 activity regulates cell surface contactin-2 levels.

Background: Although BACE1 is a major therapeutic target for Alzheimer's disease (AD), potential side effects of BACE1 inhibition are not well characterized. BACE1 cleaves over 60 putative substrates, however the majority of these cleavages have not been characterized. Here we investigated BACE1-mediated cleavage of human contactin-2, a GPI-anchored cell adhesion molecule.

Relationship between serum paraoxonase and homocysteine thiolactonase activity, adipokines, and asymmetric dimethyl arginine concentrations in renal transplant patients.

Paraoxonase lactonase activity protects against homocysteinylation; therefore, it can be a potential contributing factor to prevent atherosclerosis. We aimed to determine paraoxonase and HTLase activities and to clarify the relationship between HTLase activity and some cardiovascular risk factors, such as homocysteine, cystatin C asymmetric dimethylarginine (ADMA), and adipokines both in hemo dialyzed and transplanted patients. Among 114 hemodialyzed, 80 transplanted and 64 healthy control subjects, we investigated body mass index (BMI) as well as fasting serum contents of urea, uric acid, creatinine, cystatin C, homocysteine, glucose, lipids, total protein and albumin.

Noninvasive perioperative monitoring of arterial function in patients with kidney transplantation.

Development of atherosclerosis is accelerated in kidney transplant recipients. Impaired metabolic pathways have a complex effect on the arterial wall, which can be measured by noninvasive techniques. Few data are available on the change of stiffness parameters in the postoperative course, so in this study we analyzed the stiffness parameters of kidney transplant recipients during the perioperative period.

The E280A presenilin mutation reduces voltage-gated sodium channel levels in neuronal cells.

Background: Familial Alzheimer's disease (FAD) mutations in presenilin (PS) modulate PS/γ-secretase activity and therefore contribute to AD pathogenesis. Previously, we found that PS/γ-secretase cleaves voltage-gated sodium channel β2-subunits (Navβ2), releases the intracellular domain of Navβ2 (β2-ICD), and thereby, increases intracellular sodium channel α-subunit Nav1.1 levels.

An efficient approach to novel 17-5'-(1',2',4')-oxadiazolyl androstenes via the cyclodehydration of cytotoxic O-steroidacylamidoximes, and an evaluation of their inhibitory action on 17α-hydroxylase/C₁₇,₂₀-lyase.

Novel 17-exo-oxadiazoles in the androst-5-ene series were efficiently synthesized in a two-step sequence via the corresponding O-acylamidoxime intermediates (obtained from steroidal 17-carboxylic acids and amidoximes in the presence of coupling reagent), which then underwent tetrabutylammonium fluoride-induced cyclocondensation under mild reaction conditions. The synthesized compounds were subjected to in vitro pharmacological studies to investigate their inhibitory effect on rat testicular C₁₇,₂₀-lyase and their antiproliferative action on four malignant human adherent cell lines (HeLa, MCF7, A2780 and A431). One of the oxadiazolyl derivatives proved to exert significant enzyme-inhibitory action (IC₅₀ = 0.

Preclinical studies of a specific PPARγ modulator in the control of skin inflammation.

Peroxisome proliferator-activated receptor γ (PPARγ) antagonizes inflammatory signals by interfering with NF-κB nuclear translocation. Consistently, PPARγ agonists have been proposed in various inflammatory skin disorders, but their wide use has been limited by severe side effects. Classes of compounds with specific PPARγ agonism have been designed to selectively target inflammatory pathways.

Identification of PPARγ ligands with One-dimensional Drug Profile Matching.

Introduction: Computational molecular database screening helps to decrease the time and resources needed for drug development. Reintroduction of generic drugs by second medical use patents also contributes to cheaper and faster drug development processes. We screened, in silico, the Food and Drug Administration-approved generic drug database by means of the One-dimensional Drug Profile Matching (oDPM) method in order to find potential peroxisome proliferator-activated receptor gamma (PPARγ) agonists.

Investigation of the metabolic effects of chronic clozapine treatment on CCK-1 receptor deficient Otsuka Long Evans Tokushima Fatty (OLETF) rats.

Clozapine increases meal size and meal duration, effects similar to the pharmacological blockade or congenital deficiency of CCK-1 receptor. We aimed to investigate the role of CCK-1 receptor in clozapine-induced weight gain and insulin sensitivity in CCK-1 receptor deficient, male Otsuka Long Evans Tokushima Fatty rats (OLETF). Long Evans Tokushima Otsuka (LETO) rats served as healthy control.