The Role of NGF and Its Receptor TrKA in Patients With Erectile Dysfunction

The aim of our study was to investigate the plasma NGF concentration and TrkA/p75NTR receptor expression on white blood cells (WBCs), in peripheral and corpus cavernosum blood isolated from patients with erectile dysfunction and metabolic syndrome (ED/MetS). This was a pilot case–control study. Inclusion criteria were as follows: men 18–65 years with ED and MetS and healthy subjects. The first sampling was performed at the level of the cubital vein (VC). Subsequently, 20 μg of intracavernous alprostadil was administered, and a second blood draw from the corpora cavernosa (CC) was performed once erection was achieved. Subsequently, the third blood sample was repeated at the level of the VC. We enrolled 8 cases with ED/MetS and 8 controls. There was no significant difference between the case and control group in terms of mean age (49.3 ± 5.9 and 53.13 ± 8.9, respectively). The case group had a lower IIEF score compared to the control group (14 ± 3.2 versus 27.3 ± 2.1; p < 0.05). Decreased NGF and TrKA expression on WBC and thiols were found in the plasma of ED/MetS patients compared to control. The study showed that patients with ED/MetS had a decrease in plasma NGF and thiol concentration, and they had a decrease in TrKA expression on WBCs

Lipokines and oxysterols: Novel adipose-derived lipid hormones linking adipose dysfunction and insulin resistance

The expansion of adipose tissue (AT.) is, by definition, a hallmark of obesity. However, not all increases in fat mass are associated with pathophysiological cues. Indeed, whereas a "healthy" fat mass accrual, mainly in the subcutaneous depots, preserves metabolic homeostasis, explaining the occurrence of the metabolically healthy obese phenotype, "unhealthy" AT expansion is importantly associated with insulin resistance/type 2 diabetes and the metabolic syndrome. The development of a dysfunctional adipose organ may find mechanistic explanation in a reduced ability to recruit new and functional (pre)adipocytes from undifferentiated precursor cells. Such a failure of the adipogenic process underlies the "AT expandability" paradigm. The inability of AT to expand further to store excess nutrients, rather than obesity per se, induces a diabetogenic milieu by promoting the overflow and the ectopic deposition of fatty acids in insulin-dependent organs (i.e., lipotoxicity), the secretion of various metabolically detrimental adipose-derived hormones (i.e., adipoldnes and lipokines), and the occurrence of local and systemic inflammation and oxidative stress. Hitherto, fatty acids (i.e., lipokines) and the oxidation by-products of cholesterol and polyunsaturated fatty acids, such as nonenzymatic oxysterols and reactive aldehyde species, respectively, emerge as key modulators of (pre)adipocyte signaling through Wnt/beta-catenin and MAPK pathways and potential regulators of glucose homeostasis. These and other mechanistic insights linking adipose dysfunction, oxidative stress, and impairment of glucose homeostasis are discussed in this review article, which focuses on adipose peroxidation as a potential instigator of, and a putative therapeutic target for, obesity-associated metabolic dysfunctions. (C) 2013 Elsevier Inc. All rights reserved

Effects of diet-derived molecules on the tumor microenvironment

It is now widely accepted that tumors are a complex tissue composed, in addition to the cancer cells, by endothelial cells and their precursors, stromal cells, pericytes, smooth muscle cells, fibroblasts, myofibroblasts. Inflammatory and immune cells such as macrophages, neutrophils, granulocytes, mast cells, B and T cells, natural killer (NK) and dendritic cells also infiltrate the tumor to constitute the microenvironment. All these players interact with each other and with tumor cells through specific molecular pathways resulting in the production of an intricate network of molecular mediators, cytokines and growth factors providing the proper conditions for tumor maintenance, growth and propagation. Several pathways of cell-cell interactions within the microenvironment have been previously investigated and extensively studied in physiological and pathological scenarios. Some of these pathways can be targeted with therapeutic drugs during tumor progression. However, a more efficacious approach would be to halt tumor-host interactions before a cancer develops or metastasizes. Many phytochemicals and diet derivatives are able to act as chemopreventive agents, targeting the tumor microenvironment and in particular inflammatory angiogenesis, in a new discipline that we named "angioprevention". In this review we analyze some of the potential phytochemical drugs, natural or synthetic, that seem to owe part of their chemopreventive potential to their action on the tumor microenvironment. In particular, we provide an overview of the pathways regulated by chemopreventive microenvironment-active substances: oleanic acid triterpenoids (CDDOs), resveratrol, epigallocathechin gallate (EGCG), xanthohumol and curcumin

Synthetic analogs of xanthohumol for use in the prevention and​/or treatment of tumors

The present invention relates to novel synthetic analogs I [wherein: R1 and R2 are independently selected from the group consisting of H, Me, straight or branched C2-​10-​alkyl, straight or branched C2-​10-​alkenyl or -​alkadienyl, C4-​6-​cycloalkyl, C4-​6-​cycloalkenyl or -​alkadienyl, alkoxyalkyl, (un)​substituted benzyl; n is an integer ranging from I to 5;]​. [A is a mono- or bicyclic aryl, or an (non)​arom. heterocycle ring selected from the group consisting of pyrrole, pyrrolidine, 3-​pyrroline, 2H-​pyrrole, 2-​pyrroline, indole, isoindole, 3H-​indole, indolizine, indoline, carbazole, furan, benzofuran, isobenzofuran, 2H-​pyran, 4H-​pyran, benzo[b]​thiophene, thiophene, pyridine, piperidine, 4H-​quinolizine, isoquinoline, quinoline, tetrahydroquinoline, 1,​8-​naphthyridine, acridine, oxazole, isoxazole, benzoxazole, benzothiazole, isothiazole, thiazole, imidazole, 2-​imidazole, imidazolidine, tetrazole, 1,​2,​3-​triazole, 1,​2,​4-​triazole, 1,​2,​3-​oxadiazole, benzimidazole, purine, 1,​4-​dioxane, 1,​3-​dioxolane, 1,​3-​dithiane, 1,​4-​dithiane, 1,​3,​5-​trithiane, morpholine, thiomorpholine, phenothiazine, pyrazole, 2-​pyrazoline, pyrazolidine, quinazoline, cinnoline, pyrimidine, pyrazine, pteridine, phthalazine, 1,​2,​4-​triazine, 1,​3,​5-​triazine, pyridazine, piperazine, quinoxaline, phenazine, lH-​indazole;]​. [Wherein the substituents on ring A, independently from each other, are selected from the group consisting of H, O-​alkyl, OCH3, Cl, F, Br, iodo, NO2, NH2, NHCH3, NH-​alkyl, NHCOCH3, NHCO-​alkyl, NHSO2CH3, NHSO2-​alkyl, SO2CH3, SO2-​alkyl, SO2NH2, SO2NHCH2, SO2NH-​alkyl, SO2NHCOCH3, SO2NHCO-​alkyl, CO2H, CONHCH3, CONH-​alkyl, CO2CH3, CO2-​alkyl, CONHSO2CH3, CONHSO2-​alkyl, alkyl being as defined above for R1 and R2; wherein at least one of the substituents on the A ring is H;]​. [Provided that the compd. of general formula I is not: (E)​-​3-​phenyl-​1-​(2,​4,​6-​trimethoxy-​3-​(3-​methylbut-​2-​enyl)​phenyl)​prop-​2-​en-​1-​one or (E)​-​3-​phenyl-​1-​(2-​hydroxy-​4,​6-​dimethoxy-​3-​(3-​methylbut-​2-​enyl)​phenyl)​prop-​2-​en-​1-​one;] and tautomers, pharmaceutically acceptable salts and pro-​drugs thereof, of xanthohumol (II) and the use thereof. Thus, (E)​-​1-​[2,​4-​dihydroxy-​6-​methoxy-​3-​(3-​methylbut-​2-​enyl)​prenyl]​-​3-​(4-​fluorophenyl)​prop-​2-​en-​1-​one (III) was prepd. from 2',​4',​6'-​trihydroxyacetophenone monohydrate (IV·H2O) via regioselective O-​protection with MOM-​Cl in CH2Cl2 contg. DIPEA; O-​etherification with 3-​methyl-​2-​buten-​1-​ol in THF contg. PPh3 and DEAD;. Claisen rearrangement of the prenyl ether in N,​N-​dimethylaniline; O-​methylation with Me2SO4 in acetone contg. K2CO3; aldol condensation with 4-​FC6H4CHO in MeOH contg. aq. NaOH; and, demethoxymethylation with HCl in MeOH. The antitumor activity of III was detd. [significant inhibition of HUVEC cell growth at concn. of 20 μM after only 24 h; at the concn. of 10 μM it was proved able to reduce cell proliferation after 72 and 96 h treatment]​

A Dynamic Model for Estimating the Interaction of ROS–PUFA–Antioxidants in Rabbit

International audienceDefining optimal nutrition in animals and humans remains a main scientific challenge. The objective of the work was to develop a dynamic model of reactive oxygen species (ROS)–polyunsaturated fatty acid (PUFA)–antioxidant homeostasis using the rabbit as a model. The problem entity was to evaluate the main metabolites generated from interactions between traits included in the conceptual model and identified by three main sub–models: (i) ROS generation, (ii) PUFA oxidation and (iii) antioxidant defence. A mathematical model (VENSIM software) that consisted of molecular stocks (INPUTs, OUTPUTs), exchange flows (intermediate OUTPUTs) and process rates was developed. The calibration was performed by using standard experimental data (Experiment 1), whereas the validation was carried out in Experiments 2 and 3 by using supra–nutritional dietary inputs (VIT E+ and PUFA+). The accuracy of the models was measured using 95% confidence intervals. Analytical OUTPUTs (ROS, PUFA, Vit E, Ascorbic acid, Iso–/NeuroProstanes, Aldehydes) were well described by the standard model. There was also good accuracy for the VIT E+ scenario, whereas some compensatory rates (Kc1–Kc4) were added to assess body compensation when high levels of dietary PUFA were administered (Experiment 3). In conclusion, the model can be very useful for predicting the effects of dietary treatments on the redox homeostasis of rabbits