Looking at NSAIDs from a historical perspective and their current status in drug repurposing for cancer treatment and prevention.

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most frequently prescribed drug classes with wide therapeutic applications over the centuries. Starting from the use of salicylate-containing willow leaves to the recent rise and fall of highly selective cyclooxygenase-2 (COX-2) inhibitors and the latest dual-acting anti-inflammatory molecules, they have displayed a rapid and ongoing evolution. Despite the enormous advances in the last twenty years, investigators are still in search of the design and development of more potent and safer therapy against inflammatory conditions. This challenge has been increasingly attractive as the emergence of inflammation as a common seed and unifying mechanism for most chronic diseases. Indeed, this fact put the NSAIDs in the spotlight for repurposing against inflammation-related disorders. This review attempts to present a historical perspective on the evolution of NSAIDs, regarding their COX-dependent/independent mode of actions, structural and mechanism-based classifications, and adverse effects. Additionally, a systematic review of previous studies was carried out to show the current situation in drug repurposing, particularly in cancers associated with the GI tract such as gastric and colorectal carcinoma. In the case of non-GI-related cancers, preclinical studies elucidating the effects and modes of action were collected and summarized.

Synthesis of new imine-/amine-bearing imidazo[1,2-a]pyrimidine derivatives and screening of their cytotoxic activity.

Imidazo[1,2-a]pyrimidine derivatives bearing imine groups (3a-e) were successfully synthesized in moderate to good yields using microwave-assisted heating. Corresponding amine derivatives (4a-e) were also obtained by the reduction reaction of the imine derivatives (3a-e). All synthesized products were characterized by FT-IR, 1H NMR, 13C NMR, and LC-MS spectroscopic techniques. In silico ADMET, Lipinski, and drug-likeness studies of the compounds were conducted and all were found to be suitable drug candidates. The cytotoxicity of the potential drug molecules was screened against the breast cancer cell lines MCF-7 and MDA-MB-231 and the healthy model HUVEC by the sulforhodamine B method. According to the antiproliferative studies, compounds 3d and 4d showed remarkable inhibition of MCF-7 cells with IC50 values of 43.4 and 39.0 µM and of MDA-MB-231 cells with IC50 values of 35.9 and 35.1 µM, respectively. In particular, compound 3d selectively inhibited the proliferation of MCF-7 1.6-fold and MDA-MB-231 2.0-fold relative to healthy cells. Moreover, the apoptotic mechanism studies indicated that compound 4d induced apoptosis by moderately increasing the ratio of Bax/Bcl-2 genes. Imidazo[1,2-a]pyrimidine derivative 3d, a promising cytotoxic agent, may be helpful in the discovery of new and more efficient anticancer agents for breast cancer treatment.

Paving Luteolin Therapeutic Potentialities and Agro-Food-Pharma Applications: Emphasis on In Vivo Pharmacological Effects and Bioavailability Traits.

Luteolin is a naturally occurring secondary metabolite belonging to the class of flavones. As many other natural flavonoids, it is often found in combination with glycosides in many fruits, vegetables, and plants, contributing to their biological and pharmacological value. Many preclinical studies report that luteolin present excellent antioxidant, anticancer, antimicrobial, neuroprotective, cardioprotective, antiviral, and anti-inflammatory effects, and as a consequence, various clinical trials have been designed to investigate the therapeutic potential of luteolin in humans. However, luteolin has a very limited bioavailability, which consequently affects its biological properties and efficacy. Several drug delivery strategies have been developed to raise its bioavailability, with nanoformulations and lipid carriers, such as liposomes, being the most intensively explored. Pharmacological potential of luteolin in various disorders has also been underlined, but to some of them, the exact mechanism is still poorly understood. Given the great potential of this natural antioxidant in health, this review is aimed at providing an extensive overview on the in vivo pharmacological action of luteolin and at stressing the main features related to its bioavailability, absorption, and metabolism, while essential steps determine its absolute health benefits and safety profiles. In addition, despite the scarcity of studies on luteolin bioavailability, the different drug delivery formulations developed to increase its bioavailability are also listed here.

New nimesulide derivatives with amide/sulfonamide moieties: Selective COX-2 inhibition and antitumor effects.

Seventeen new amide/sulfonamide containing nimesulide derivatives were synthesized and characterized by several spectroscopic techniques and primarily investigated for their inhibitory potential on COX enzymes and other pro-inflammatory factors. Experimental analyses showed that among seventeen compounds, N8 and N10 have remarkable potency and selectivity for the COX-2 enzyme over COX-1 at very low doses as compared to nimesulide. Moreover, both N8 and N10 selectively reduced the Lipopolysaccharide (LPS)-stimulated COX-2 mRNA expression level while the COX-1 level remained stable. Both PGE2 release and nitric oxide production in macrophage cells were significantly suppressed by the N8 and N10 treatment groups. In silico ADME/Tox, molecular docking and molecular dynamics (MD) simulations were also conducted. Additionally, all compounds were also screened in a panel of cancer cell lines for their antiproliferative properties by MTT and SRB assays. Compound N17 exhibited a considerable antiproliferative effect on the colon (IC50: 9.24 µM) and breast (IC50: 11.35 µM) cancer cell lines. N17 exposure for 48 h decreased expression of anti-apoptotic protein BCL-2 and increased the expression of apoptogenic BAX. Besides, the BAX/BCL-2 ratio was increased with visible ultrastructural changes and apoptotic bodies under scanning electron microscopy. In order to investigate the structural and dynamical properties of selected hits on the target structures, multiscale molecular modeling studies are also conducted. Our combined in silico and in vitro results suggest that N8 and N10 could be further developed as potential nonsteroidal anti-inflammatory drugs (NSAIDs), while cytotoxic N17 might be studied as a potential lead compound that could be developed as an anticancer agent.

Dataset on the differentiation of THP-1 monocytes to LPS inducible adherent macrophages and their capacity for NO/iNOS signaling.

When THP-1 cells are differentiated into adherent macro-phage-like cells, they respond to inflammatory stimuli by changing their phenotypes to an activation state and altering the expression of inflammation-related genes. Nitric oxide (NO) is a diatomic molecule implicating in various pathological conditions including tissue damage, ER stress, obesity, and cancer. The sustained inflammatory microenvironment leads to increased NO release through the activation of the inducible nitric oxide synthase (iNOS) gene in macrophages. Here, we provide a dataset on the optimized conditions for the THP-1 differentiation and the induction of NO/iNOS signaling under inflammatory stimulus. The human monocytic cells were differentiated into adherent macrophage-like phenotype by phorbol-12-myristate-13-acetate (PMA) stimulation under optimized conditions. In this study, NO/iNOS signaling capacity and the regulation of other pro-inflammatory genes including TNF-α, IL-1ß, and COX-2 in the LPS-induced THP-1 were examined.

Phytochemical constituents, biological activities, and health-promoting effects of the genus Origanum.

Origanum species are mostly distributed around the Mediterranean, Euro-Siberian, and Iran-Siberian regions. Since time immemorial, the genus has popularly been used in Southern Europe, as well as on the American continent as a spice now known all over the world under the name "oregano" or "pizza-spice." Origanum plants are also employed to prepare bitter tinctures, wines, vermouths, beer, and kvass. The major components of Origanum essential oil are various terpenes, phenols, phenolic acids, and flavonoids with predominant occurrence of carvacrol and thymol (with reasonable amounts of p-cymen and -terpinene) or of terpinene-4-ol, linalool, and sabinene hydrate. Many species of Origanum genus are used to treat kidney, digestive, nervous, and respiratory disorders, spasms, sore throat, diabetes, lean menstruation, hypertension, cold, insomnia, toothache, headache, epilepsy, urinary tract infections, etc. Origanum essential oil showed potent bioactivities owing to its major constituents' carvacrol, thymol, and monoterpenes. Several preclinical studies evidenced its pharmacological potential as antiproliferative or anticancer, antidiabetic, antihyperlipidemic, anti-obesity, renoprotective, antiinflammatory, vasoprotective, cardioprotective, antinociceptive, insecticidal, and hepatoprotective properties. Its nanotechnological applications as a promising pharmaceutical in order to enhance the solubility, physicochemical stability, and the accumulation rate of its essential oils have been investigated. However, Origanum has been reported causing angioedema, perioral dermatitis, allergic reaction, inhibition of platelet aggregation, hypoglycemia, and abortion. Conclusive evidences are still required for its clinical applications against human medical conditions. Toxicity analyses and risk assessment will aid to its safe and efficacious application. In addition, elaborate structure-activity studies are needed to explore the potential use of Origanum-derived phytochemicals as promising drug candidates.

Multitarget Profiling of a Strigolactone Analogue for Early Events of Alzheimer's Disease: In Vitro Therapeutic Activities against Neuroinflammation.

Neuropathological changes in Alzheimer's disease (AD) are directly linked to the early inflammatory microenvironment in the brain. Therefore, disease-modifying agents targeting neuroinflammation may open up new avenues in the treatment of AD. Strigolactones (SLs), subclasses of structurally diverse and biologically active apocarotenoids, have been recently identified as novel phytohormones. In spite of the remarkable anticancer capacity shown by SLs, their effects on the brain remained unexplored. Herein, the SIM-A9 microglial cell line was used as a phenotypic screening tool to search for the representative SL, GR24, demonstrating marked potency in the suppression of lipopolysaccharide (LPS)-induced neuroinflammatory/neurotoxic mediators by regulating NF-κB, Nrf2, and PPARγ signaling. GR24 also in the brain endothelial cell line bEnd.3 mitigated the LPS-increased permeability as evidenced by reduced Evans' blue extravasation through enhancing the expression of tight junction protein, occludin. Collectively, the present work shows the anti-neuroinflammatory and glia/neuroprotective properties of GR24, making SLs promising scaffolds for the development of novel anti-AD candidates.

In vitro and in silico studies of nitrobenzamide derivatives as potential anti-neuroinflammatory agents.

Communicated by Ramaswamy H. Sarma.

Insights on the Use of α-Lipoic Acid for Therapeutic Purposes.

α-lipoic acid (ALA, thioctic acid) is an organosulfur component produced from plants, animals, and humans. It has various properties, among them great antioxidant potential and is widely used as a racemic drug for diabetic polyneuropathy-associated pain and paresthesia. Naturally, ALA is located in mitochondria, where it is used as a cofactor for pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase complexes. Despite its various potentials, ALA therapeutic efficacy is relatively low due to its pharmacokinetic profile. Data suggests that ALA has a short half-life and bioavailability (about 30%) triggered by its hepatic degradation, reduced solubility as well as instability in the stomach. However, the use of various innovative formulations has greatly improved ALA bioavailability. The R enantiomer of ALA shows better pharmacokinetic parameters, including increased bioavailability as compared to its S enantiomer. Indeed, the use of amphiphilic matrices has capability to improve ALA bioavailability and intestinal absorption. Also, ALA's liquid formulations are associated with greater plasma concentration and bioavailability as compared to its solidified dosage form. Thus, improved formulations can increase both ALA absorption and bioavailability, leading to a raise in therapeutic efficacy. Interestingly, ALA bioavailability will be dependent on age, while no difference has been found for gender. The present review aims to provide an updated on studies from preclinical to clinical trials assessing ALA's usages in diabetic patients with neuropathy, obesity, central nervous system-related diseases and abnormalities in pregnancy.

Use and outcomes of amplatz renal dilator for treatment of urethral strictures.

INTRODUCTION: Urethral stricture disease is still a major problem in men. Many procedures are available for the treatment of urethral strictures; urethral dilatation is one of the oldest. The blind dilatation of urethral strictures may be a difficult and potentially dangerous procedure. The purpose of this study was to describe safe urethral dilatation using amplatz renal dilator and to report outcomes. MATERIALS AND METHODS: From 2010 to 2014, a total of 26 men with primary urethral strictures were managed by urethral dilatation using amplatz renal dilators. The parameters analyzed included presentation of patients, retrograde urethrography (RGU) findings, pre-and postoperative maximum flow rate (Qmax) on uroflowmetry (UF) and post-void residual urine (PVR). Patients were followed-up at 1.6 and 12 months. The technique described in this paper enables such strictures to be safely dilated after endoscopic placement of a suitable guidewire and stylet over which amplatz renal dilators are introduced. RESULTS: The mean age of the patients was 57.6 (35-72) years. The median stricture length was 0.82 (0.6-1.5)cm. Pre-operative uroflowmetry showed Qmax of 7.00 (4-12) mL/sec and ultrasonography showed PVR of 75.00 (45-195)mL. Postoperatively, Qmax improved to 18.00 (15-22)mL/sec (p<0.001) at 1 month, 17.00 (13-21)mL/sec (p<0.001) at 6 months and 15.00 (12-17)mL/sec (p<0.001) at 12 months. The post-operative PVR values were 22.50 (10-60)mL (p<0.001), 30.00 (10-70)mL (p<0.001) and 30.00 (10-70) mL (p<0.001) at 1.6 12 months, respectively. The median procedure time was 15.00 (12-22) minutes. None of the patients had a recurrence during a 12-month period of follow-up. CONCLUSION: Urethral dilatation with amplatz renal dilators avoids the risks associated with blind dilatation techniques. This tecnique is a safe, easy, well-tolerated and cost-effective alternative for treatment of urethral strictures.

Use and outcomes of amplatz renal dilator for treatment of urethral strictures

ABSTRACT Introduction Urethral stricture disease is still a major problem in men. Many procedures are available for the treatment of urethral strictures; urethral dilatation is one of the oldest. The blind dilatation of urethral strictures may be a difficult and potentially dangerous procedure. The purpose of this study was to describe safe urethral dilatation using amplatz renal dilator and to report outcomes. Materials and Methods From 2010 to 2014, a total of 26 men with primary urethral strictures were managed by urethral dilatation using amplatz renal dilators. The parameters analyzed included presentation of patients, retrograde urethrography (RGU) findings, pre-and postoperative maximum flow rate (Qmax) on uroflowmetry (UF) and post-void residual urine (PVR). Patients were followed-up at 1.6 and 12 months. The technique described in this paper enables such strictures to be safely dilated after endoscopic placement of a suitable guidewire and stylet over which amplatz renal dilators are introduced. Results The mean age of the patients was 57.6 (35–72) years. The median stricture length was 0.82 (0.6–1.5)cm. Pre-operative uroflowmetry showed Qmax of 7.00 (4–12) mL/sec and ultrasonography showed PVR of 75.00 (45–195)mL. Postoperatively, Qmax improved to 18.00 (15–22)mL/sec (p<0.001) at 1 month, 17.00 (13–21)mL/sec (p<0.001) at 6 months and 15.00 (12–17)mL/sec (p<0.001) at 12 months. The post-operative PVR values were 22.50 (10–60)mL (p<0.001), 30.00 (10–70)mL (p<0.001) and 30.00 (10–70) mL (p<0.001) at 1.6 12 months, respectively. The median procedure time was 15.00 (12–22) minutes. None of the patients had a recurrence during a 12-month period of follow-up. Conclusion Urethral dilatation with amplatz renal dilators avoids the risks associated with blind dilatation techniques. This tecnique is a safe, easy, well-tolerated and cost-effective alternative for treatment of urethral strictures.

Resting eggs as new biosorbent for preconcentration of trace elements in various samples prior to their determination by FAAS.

In this study, the resting eggs of aquatic creatures living in freshwater (Daphnia, Cladocera, Crustacean) ecosystems were used as a novel biosorbent extractant for synchronous preconcentration of trace Cd(II), Co(II), Cu(II), Mn(II), and Ni(II) previous to measurement by flame atomic absorpiton spectrometry (FAAS). Using column procedures, optimization studies were conducted to realize the effective adsorption of the analyte ions such as the solution pH, amount of the biosorbent, volume of the sample, interfering ions, etc. A high preconcentration factor of 67 and low relative standard deflection of ≤4.1% (n=8) were obtained. The invention constrains based on the 3 s/b criterion were 2.4 for Cd(II), 41.4 for Co(II), 4.2 for Cu(II), 3.0 for Mn(II), and 9.6 µg L(-1) for Ni(II). The accuracy of the method was verified by analysis of a certified standard reference material. The used procedure was applied to the definition of the analytes in diverse environmental samples with convincing results. Consequently, the resting eggs of Daphnia can be used as a biosorbent for preconcentration and biosorption studies.

Retrospective evaluation of urological admissions to emergency service of a training and research hospital.

OBJECTIVE: Many patients consult emergency services with urological complaints. The aim of this study was to investigate the epidemiology, clinical presentation and treatments of urological emergency cases in a training and research hospital. MATERIAL AND METHODS: We retrospectively evaluated urological emergency patients referred to the emergency unit between July 2012 and July 2013 according to age, gender, affected organ, radiological imaging techniques and treatment. RESULTS: Among 141.844 emergency cases, 3.113 (2.19%) were urological emergencies and 53.2% of the patients were male (mean age: 49.1), and 46.8% of them were female (median age: 42.8). The most frequent illness was genitourinary infection constituting 41.2% of the cases followed by renal colic (36.9%). Among the urological emergencies 483 (15.5%) patients were hospitalized and 152 surgical operations were performed. The mostly performed procedure was the placement of a suprapubic catheter in 34 patients constituting (22.3%) of the cases. Totally eight patients were referred to another experienced health center due to different reasons. CONCLUSION: Most of the urological emergency patients do not require emergency surgical interventions however, timely identification and management of urological emergencies with in-depth clinical evaluation are important to prevent late complications. Therefore the doctors working in emergency services must be heedful of urological emergencies.

The diagnosis and treatment of penile fracture: our 19-year experience.

BACKGROUND: The aim of this study was to retrospectively evaluate our approach to the diagnosis and treatment of penile fracture. METHODS: We retrospectively evaluated the results of 107 patients with penile fracture treated in our clinic between January 1990 and January 2009. Patient age, etiology of each fracture, history, physical examination results, radiologic findings, type of treatment, and postoperative complications were recorded. In 5 cases cavernosography was performed and in 8 cases retrograde urethrography. RESULTS: The most common etiologies of penile fracture were coitus and manually bending the penis for detumescence. Diagnoses were made based on history and physical examination in 102 patients and cavernosography in 5 patients. In order to evaluate urethral injury in 8 cases, retrograde urethrography was performed. Rupture was repaired surgically in 101 patients, but 6 patients were treated conservatively. Among the 6 conservatively treated patients, 3 developed penile curvature 6 months post-treatment; no complications occurred in the surgically treated patients. CONCLUSION: Cavernosography should be performed only when history and physical examination are insufficient for diagnosis, and retrograde urethrography should be performed when urethral injury is suspected. In order to prevent the development of penile curvature and to ensure rapid recovery, early surgical repair is advised.

Percutaneous nephrolithotomy in pediatric patients: is computerized tomography a must?

The aim of this study was to retrospectively evaluate the results of pediatric percutaneous nephrolithotomy (PNL) cases, and discuss the results and necessity of non-contrast computerized tomography (CT) in these cases. In all, 48 pediatric patients who underwent PNL were retrospectively evaluated. Before PNL, either intravenous urography or CT was performed. In all patients, we evaluated the PNL time, scopy time with stone burden, and complications. During the PNL procedure, we switched to open surgery in two cases: in one because of renal pelvis perforation and in the other because of transcolonic access. In one patient who was scheduled to undergo PNL, we performed open surgery, primarily because we detected a retrorenal colon with CT. The stone burden in 45 patients who underwent PNL was 445 ± 225 mm(2), the PNL time was 51 ± 23 min, and the scopy time was 6.1 ± 2.7 min. We removed nephrostomy tubes 1-4 days after the procedure. In two patients, 24 h after removal of nephrostomy tubes, we inserted double J stents because of prolonged urine extravasation from the tract. In all, 34 of the 45 patients were stone-free, 5 patients had clinically insignificant stone fragments, and 6 patients had residual stones. PNL is a safe and effective method in the treatment of pediatric patients with kidney stones. Clinical experience is the most important factor in obtaining stone-free results. CT should be performed in all pediatric patients in order to prevent colon perforation.