Identification and characterization of potent and selective aquaporin-3 and aquaporin-7 inhibitors.

The aquaglyceroporins are a subfamily of aquaporins that conduct both water and glycerol. Aquaporin-3 (AQP3) has an important physiological function in renal water reabsorption, and AQP3-mediated hydrogen peroxide (H2O2) permeability can enhance cytokine signaling in several cell types. The related aquaglyceroporin AQP7 is required for dendritic cell chemokine responses and antigen uptake. Selective small-molecule inhibitors are desirable tools for investigating the biological and pathological roles of these and other AQP isoforms. Here, using a calcein fluorescence quenching assay, we screened a library of 7360 drug-like small molecules for inhibition of mouse AQP3 water permeability. Hit confirmation and expansion with commercially available substances identified the ortho-chloride-containing compound DFP00173, which inhibited mouse and human AQP3 with an IC50 of ∼0.1-0.4 µm but had low efficacy toward mouse AQP7 and AQP9. Surprisingly, inhibitor specificity testing revealed that the methylurea-linked compound Z433927330, a partial AQP3 inhibitor (IC50, ∼0.7-0.9 µm), is a potent and efficacious inhibitor of mouse AQP7 water permeability (IC50, ∼0.2 µm). Stopped-flow light scattering measurements confirmed that DFP00173 and Z433927330 inhibit AQP3 glycerol permeability in human erythrocytes. Moreover, DFP00173, Z433927330, and the previously identified AQP9 inhibitor RF03176 blocked aquaglyceroporin H2O2 permeability. Molecular docking to AQP3, AQP7, and AQP9 homology models suggested interactions between these inhibitors and aquaglyceroporins at similar binding sites. DFP00173 and Z433927330 constitute selective and potent AQP3 and AQP7 inhibitors, respectively, and contribute to a set of isoform-specific aquaglyceroporin inhibitors that will facilitate the evaluation of these AQP isoforms as drug targets.

Modulation of Aquaporins by Dietary Patterns and Plant Bioactive Compounds.

Healthful dietary patterns and bioactive compounds supplementation can be adopted as simple and easy intervention to prevent, attenuate or cure clinical disorders, especially when it comes to degenerative and chronic diseases. In the recent years, a growing body of evidence indicates Aquaporins (AQPs), a family of membrane channel proteins widely expressed in the human body, among the targets underlying the beneficial action played by some food nutrients and phytochemical compounds. Here, we provide an overview of what is known regarding the AQP modulation exerted by healthful dietary patterns and plant polyphenols.

The Role of Dietary Approach in Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS) is a chronic functional disorder of the gastrointestinal tract and is one of the most frequent gastrointestinal diseases. In IBS multiple pathophysiological mechanisms including alterations in intestinal motility, permeability, nutrient absorption, and intestinal microbiota have been implicated. Foods are commonly reported by patients to be a trigger of symptoms and therefore are likely involved in the generation of symptoms in IBS. Among all possible therapeutic options, a first-line approach to IBS is dietary education and identification of foods potentially responsible for the onset or worsening of symptoms. Dietary approaches include reduction of gas-producing foods (i.e. fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs)), lactose and gluten. Further studies are required to link the ultimate role of diets in different IBS subtypes.

A Stopped-Flow Light Scattering Methodology for Assessing the Osmotic Water Permeability of Whole Sertoli Cells.

Movement of water into and out of the cell is fundamental to life. In the male reproductive tract, at the level of the seminiferous epithelium, Sertoli cells are pivotal in mediating the movement of water into the luminal compartment, a process providing a means of transport of spermatozoa into the epididymal ducts. Here, we describe a stopped-flow light-scattering methodology to easily assess the Sertoli cell osmotic water permeability. The devised methodology is well suited for studying how the Sertoli cell's permeability changes following exogenous stimuli.

Hepatocyte and Sertoli Cell Aquaporins, Recent Advances and Research Trends.

Aquaporins (AQPs) are proteinaceous channels widespread in nature where they allow facilitated permeation of water and uncharged through cellular membranes. AQPs play a number of important roles in both health and disease. This review focuses on the most recent advances and research trends regarding the expression and modulation, as well as physiological and pathophysiological functions of AQPs in hepatocytes and Sertoli cells (SCs). Besides their involvement in bile formation, hepatocyte AQPs are involved in maintaining energy balance acting in hepatic gluconeogenesis and lipid metabolism, and in critical processes such as ammonia detoxification and mitochondrial output of hydrogen peroxide. Roles are played in clinical disorders including fatty liver disease, diabetes, obesity, cholestasis, hepatic cirrhosis and hepatocarcinoma. In the seminiferous tubules, particularly in SCs, AQPs are also widely expressed and seem to be implicated in the various stages of spermatogenesis. Like in hepatocytes, AQPs may be involved in maintaining energy homeostasis in these cells and have a major role in the metabolic cooperation established in the testicular tissue. Altogether, this information represents the mainstay of current and future investigation in an expanding field.

[Chronicity practices - The integrated management for chronic conditions in the health district of Campi Salentina (Lecce ASL)]. / Ambulatori per la cronicità - La gestione integrata delle malattie croniche nel Distretto Sanitario di Campi Salentina (ASL Lecce).

A program concerning the care management of chronic conditions has been carried out in the primary care setting, starting from previous projects based on delivering integrated care and on promoting patient empowerment. The chronicity practice, which is based on common facilities and time of work, is aimed to improve communication about individual care plan of patients, to improve adherence to the treatment and to the follow-up. The expected outcome are: the increasing adherence to healthy lifestyle and doctor's recommendations, improved clinical outcome, satisfaction of patients and health professionals.

[Indicators of communication and degree of professional integration in healthcare]. / Gli indicatori della comunicazione e dell'integrazione professionale in sanità

According to the chronic care model, improving the management of chronic illness requires efficient communication between health care professionals and the creation of a web of integrated healthcare The aim of this study was to identify an efficient methodology for evaluating the degree of professional integration through indicators related to communication between healthcare professionals. The following types of indicators were identified:-structure indicators to evaluate the presence of prerequisites necessary for implementing the procedures -functional indicators to quantitatively evaluate the use of communications instruments-performance indicators Defining specific indicators may be an appropriate methodology for evaluating the degree of integration and communication between health professionals, available for a bargaining system of incentives.

Medicines informal market in Congo, Burundi and Angola: counterfeit and sub-standard antimalarials.

BACKGROUND: The presence of counterfeits and sub-standards in African medicines market is a dramatic problem that causes many deaths each year. The increase of the phenomenon of pharmaceutical counterfeiting is due to the rise of the illegal market and to the impossibility to purchase branded high cost medicines. METHODS: In this paper the results of a quality control on antimalarial tablet samples purchased in the informal market in Congo, Burundi and Angola are reported. The quality control consisted in the assay of active substance by means of validated liquid chromatographic methods, uniformity of mass determination, disintegration and dissolution tests. Moreover, a general evaluation on label and packaging characteristics was performed. RESULTS: The results obtained on thirty antimalarial tablet samples containing chloroquine, quinine, mefloquine, sulphadoxine and pyrimethamine showed the presence of different kinds of problems: a general problem concerning the packaging (loose tablets, packaging without Producer name, Producer Country and sometimes without expiration date); low content of active substance (in one sample); different, non-declared, active substance (in one sample); sub-standard technological properties and very low dissolution profiles (in about 50% of samples). This last property could affect the bioavailability and bioequivalence in comparison with branded products and could be related to the use of different excipients in formulation or bad storage conditions. CONCLUSION: This paper evidences that the most common quality problem in the analysed samples appears to be the low dissolution profile. Here it is remarked that the presence of the right active substance in the right quantity is not a sufficient condition for a good quality drug. Dissolution test is not less important in a quality control and often evidences in vitro possible differences in therapeutic efficacy among drugs with the same active content. Dissolution profile can be dramatically affected by the choice of excipients in the oral solid formulation and, in many cases, is out of specifications due to the absence of formulation studies by producers of developing countries.