A pleiotropic chemoreceptor facilitates the functional coupling of pheromone production and perception

Optimal mating decisions depend on the robust coupling of signal production and perception because independent changes in either could carry a fitness cost. However, since the perception and production of mating signals are often mediated by different tissues and cell types, the mechanisms that drive and maintain their coupling remain unknown for most animal species. Here, we show that in Drosophila, sensory perception and production of an inhibitory mating pheromone are co-regulated by Gr8a, a member of the Gustatory receptor gene family. Specifically, we found that the pleiotropic action of Gr8a independently regulates the perception of pheromones by the chemosensory systems of males and females, as well as their production in the fat body and oenocytes of males. These findings provide a relatively simple molecular explanation for how pleiotropic receptors maintain robust mating signaling systems at the population and species levels.

Current Trends in Treatment for Acid-Dependent Diseases: Clinical Efficacy and Safety of Rabeprazole

Aim. A comparative review of the rabeprazole properties vs. other PPIs, its efficacy and safety in treatment for aciddependent diseases.Key points. Rabeprazole provides a rapid proton pump blockade in parietal cells due to its high dissociation constant (pKa). A lower rabeprazole metabolic dependence on cytochrome P-450 enzyme system renders its antisecretory effect predictable and reduces the risk of interactions with other drugs metabolised through this system. A faster antisecretory effect and higher acid-suppressive activity of rabeprazole determine its better clinical efficacy in treatment for such acid-dependent diseases as gastroesophageal reflux disease and peptic ulcer. This makes rabeprazole (Pariet) a preferred drug in course and maintenance therapies for acid-dependent diseases, as well as in H. pylori eradication.Conclusion. The rabeprazole properties of high acid suppression potential, persistent antisecretory effect from first day of therapy, non-enzymatic metabolism and pleiotropic action determine its high efficacy in treatment for a wide range of acid-dependent diseases at a minimal risk of drug interaction.

Patient with hypertension, metabolic disorder and benign prostatic hyperplasia in the primary care physician’s office – the role of doxazosin

In recent years, the therapy for patients with metabolic syndrome, which is a risk factor for cardiovascular complications, has become a challenge. Doxazosin – a selective α-adrenergic receptor antagonist, has emerged as a promising research target in the context of metabolic syndrome. It is pleiotropic action contributes to the reduction of metabolic syndrome indices. The results of clinical trials allow the construction of a promising, highly effective, and above all safe therapy in this group of patients.

In Vitro Anti-Candida Activity and Action Mode of Benzoxazole Derivatives

A newly synthetized series of N-phenacyl derivatives of 2-mercaptobenzoxazole, including analogues of 5-bromo- and 5,7-dibromobenzoxazole, were screened against Candida strains and the action mechanism was evaluated. 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(4-bromophenyl)ethanone (5d), 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(2,3,4-trichloro-phenyl)ethanone (5i), 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(2,4,6-trichlorophenyl)ethanone (5k) and 2-[(5-bromo-1,3-benzoxazol-2-yl)sulfanyl]-1-phenylethanone (6a) showed anti-C. albicans SC5314 activity, where 5d displayed MICT = 16 µg/mL (%R = 100) and a weak anti-proliferative activity against the clinical strains: C. albicans resistant to azoles (Itr and Flu) and C. glabrata. Derivatives 5k and 6a displayed MICP = 16 µg/mL and %R = 64.2 ± 10.6, %R = 88.0 ± 9.7, respectively, against the C. albicans isolate. Derivative 5i was the most active against C. glabrata (%R = 53.0 ± 3.5 at 16 µg/mL). Benzoxazoles displayed no MIC against C. glabrata. Benzoxazoles showed a pleiotropic action mode: (1) the total sterols content was perturbed; (2) 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(3,4-dichlorophenyl)ethanol and 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(2,3,4-trichlorophenyl)ethanol (8h–i) at the lowest fungistatic conc. inhibited the efflux of the Rho123 tracker during the membrane transport process; (3) mitochondrial respiration was affected/inhibited by the benzoxazoles: 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(4-chlorophenyl)ethanol and 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(4-bromophenyl)ethanol 8c–d and 8i. Benzoxazoles showed comparable activity to commercially available azoles due to (1) the interaction with exogenous ergosterol, (2) endogenous ergosterol synthesis blocking as well as (3) membrane permeabilizing properties typical of AmB. Benzoxazoles display a broad spectrum of anti-Candida activity and action mode towards the membrane without cross-resistance with AmB; furthermore, they are safe to mammals.

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) in Physiological and Pathological Processes within the Gastrointestinal Tract: A Review

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide widely distributed in the central nervous system (CNS) and many peripheral organs, such as the digestive tract, endocrine, reproductive and respiratory systems, where it plays different regulatory functions and exerts a cytoprotective effect. The multifarious physiological effects of PACAP are mediated through binding to different G protein-coupled receptors, including PAC1 (PAC1-R), VPAC1 (VPAC1-R) and VPAC2 (VPAC2-R) receptors. In the gastrointestinal (GI) tract, PACAP plays an important regulatory function. PACAP stimulates the secretion of digestive juices and hormone release, regulates smooth muscle contraction, local blood flow, cell migration and proliferation. Additionally, there are many reports confirming the involvement of PACAP in pathological processes within the GI tract, including inflammatory states, neuronal injury, diabetes, intoxication and neoplastic processes. The purpose of this review is to summarize the distribution and pleiotropic action of PACAP in the control of GI tract function and its cytoprotective effect in the course of GI tract disorders.

Pleiotropic effects of vitamin D3

Introduction: Vitamin D belongs to the group of fat-soluble vitamins. cholecalciferol (D3) and ergocalciferol (D2) are the most important forms. Vitamin D is associated with a regulatory role in calcium and phosphate metabolism. In recent years, there has been attention to its pleiotropic action. Aim: The aim of the study was to present the general characteristics of vitamin D and explore its relation with polycystic ovary syndrome (PCOS), endometriosis, pain management, insulin resistance, influenza and chronic kidney disease (CKD).Description: VDR receptor has been detected in the cells of the intestines, bones, kidneys, heart, brain, prostate, breast, ovaries, skin. In the ovaries, vit. D3 affects the production of progesterone, estradiol or estrone which suggest its important role in the folliculogenesis and ovulation. Women with PCOS have significantly lower levels of vitamin D3 compared to healthy women. It has been suggested that the deficiency of this vitamin may be related to infertility. Research show that vit. D3 may affect the mechanisms of the inflammatory and nocyceptive pain perception. A significant connection has also been found between vit. D3 and the metabolism of the adipose tissue and insulin secretion. Vitamin D3 deficiency may increase the risk of development of obesity and insulin resistance as well as CKD.Summary: The observation of statistically significant correlation between the reduced level of vit. D3 and occurrence of numerous diseases indicates the need for further research to explain the mechanisms in which D3 deficiency may contribute to development of these diseases. This knowledge is important for the development of new prevention and treatment methods of the diseases mentioned in this article.

Novel Insights into the Molecular Mechanisms of Ischemia/Reperfusion Injury in Kidney Transplantation

Ischemia reperfusion injury (IRI) is one of the most important mechanisms involved in delayed or reduced graft function after kidney transplantation. It is a complex pathophysiological process, followed by a pro-inflammatory response that enhances the immunogenicity of the graft and the risk of acute rejection. Many biologic processes are involved in its development, such as transcriptional reprogramming, the activation of apoptosis and cell death, endothelial dysfunction and the activation of the innate and adaptive immune response. Recent evidence has highlighted the importance of complement activation in IRI cascade, which expresses a pleiotropic action on tubular cells, on vascular cells (pericytes and endothelial cells) and on immune system cells. The effects of IRI in the long term lead to interstitial fibrosis and tubular atrophy, which contribute to chronic graft dysfunction and subsequently graft failure. Furthermore, several metabolic alterations occur upon IRI. Metabolomic analyses of IRI detected a “metabolic profile” of this process, in order to identify novel biomarkers that may potentially be useful for both early diagnosis and monitoring the therapeutic response. The aim of this review is to update the most relevant molecular mechanisms underlying IRI, and also to discuss potential therapeutic targets in future clinical practice.

Detection of loci exhibiting pleiotropic effects on body weight and egg number in female broilers

The objective of the present study was to discover the genetic variants, functional candidate genes, biological processes and molecular functions underlying the negative genetic correlation observed between body weight (BW) and egg number (EN) traits in female broilers. To this end, first a bivariate genome-wide association and second stepwise conditional-joint analyses were performed using 2586 female broilers and 240 k autosomal SNPs. The aforementioned analyses resulted in a total number of 49 independent cross-phenotype (CP) significant SNPs with 35 independent markers showing antagonistic action i.e., positive effects on one trait and negative effects on the other trait. A number of 33 independent CP SNPs were located within 26 and 14 protein coding and long non-coding RNA genes, respectively. Furthermore, 26 independent markers were situated within 44 reported QTLs, most of them related to growth traits. Investigation of the functional role of protein coding genes via pathway and gene ontology analyses highlighted four candidates (CPEB3, ACVR1, MAST2 and CACNA1H) as most plausible pleiotropic genes for the traits under study. Three candidates (CPEB3, MAST2 and CACNA1H) were associated with antagonistic pleiotropy, while ACVR1 with synergistic pleiotropic action. Current results provide a novel insight into the biological mechanism of the genetic trade-off between growth and reproduction, in broilers.

The microRNA let-7b-5p Is Negatively Associated with Inflammation and Disease Severity in Multiple Sclerosis

The identification of microRNAs in biological fluids for diagnosis and prognosis is receiving great attention in the field of multiple sclerosis (MS) research but it is still in its infancy. In the present study, we observed in a large sample of MS patients that let-7b-5p levels in the cerebrospinal fluid (CSF) were highly correlated with a number of microRNAs implicated in MS, as well as with a variety of inflammation-related protein factors, showing specific expression patterns coherent with let-7b-5p-mediated regulation. Additionally, we found that the CSF let-7b-5p levels were significantly reduced in patients with the progressive MS compared to patients with relapsing-remitting MS and were negatively correlated with characteristic hallmark processes of the two phases of the disease. Indeed, in the non-progressive phase, let-7b-5p inversely associated with both central and peripheral inflammation; whereas, in progressive MS, the CSF levels of let-7b-5p negatively correlated with clinical disability at disease onset and after a follow-up period. Overall, our results uncovered, by the means of a multidisciplinary approach and multiple statistical analyses, a new possible pleiotropic action of let-7b-5p in MS, with potential utility as a biomarker of MS course.