Introduction Diabetic men with erectile dysfunction (ED) are less responsive to therapy with type 5 phosphodiesterase (PDE5) inhibitors. Although an impairment of the nitric oxide (NO)/cyclic guanosin-monophosphate (cGMP) pathway has been shown in diabetic ED vs. non-diabetic ED, the functionality of NO/cGMP pathway in non-diabetic and diabetic ED patients with respect to non-ED patients has not been established. Aim The aim of this study is to evaluate the function of NO/cGMP signalling in human erectile tissues from ED patients exploring the added impact of diabetes. Methods Corpus cavernosum strips (human corpus cavernosum [HCC]) and penile resistance arteries (HPRA) were collected from penile specimens from organ donors (OD) and from diabetic and non-diabetic men with ED undergoing penile prosthesis implantation. Main Outcome Measures Relaxations to acetylcholine, electrical field stimulation, sodium nitroprusside, and sildenafil were evaluated in phenylephrine-contracted HCC and norepinephrine-contracted HPRA. cGMP content in HCC was also determined. Results The impairment of endothelium-dependent relaxation in HCC and HPRA from ED patients was exacerbated by diabetes (Emax 76.1, 62.9, and 49.3% in HCC and 73.1, 59.8, and 46.0% in HPRA from OD, non-diabetic and diabetic ED, respectively). Hypertension, hypercholesterolemia, or aging did not exert a further impairment of endothelial relaxation among ED patients. Diabetes also causes a further impairment of neurogenic relaxation in HCC and HPRA. The basal and stimulated content of cGMP in HCC was significantly decreased in patients with ED, but specially reduced in diabetic patients. Diabetes clearly impaired PDE5 inhibitor-induced vasodilation of HPRA from ED patients. Conclusions ED is related to impaired vasodilation, reduced relaxant capacity, and diminished cGMP content in penile tissue. These alterations are more severe in diabetes and accompany reduced relaxant efficacy of PDE5 inhibition. Thus, an exacerbated reduction of nitric oxide/cGMP signaling could be responsible for ED in diabetic men and would explain their reduced response to treatment.

Fibroblast growth factors are key proteins in many intercellular signaling networks. They normally remain attached to the extracellular matrix, which confers on them a considerable stability. The unrestrained accumulation of fibroblast growth factors in the extracellular milieu, either due to uncontrolled synthesis or enzymatic release, contributes to the pathology of many diseases. Consequently, the neutralization of improperly mobilized fibroblast growth factors is of clear therapeutic interest. In pursuing described rules to identify potential inhibitors of these proteins, gentisic acid, a plant pest-controlling compound, an aspirin and vegetarian diet common catabolite, and a component of many traditional liquors and herbal remedies, was singled out as a powerful inhibitor of fibroblast growth factors. Gentisic acid was used as a lead to identify additional compounds with better inhibitory characteristics generating a new chemical class of fibroblast growth factor inhibitors that includes the agent responsible for alkaptonuria. Through low and high resolution approaches, using representative members of the fibroblast growth factor family and their cell receptors, it was shown that this class of inhibitors may employ two different mechanisms to interfere with the assembly of the signaling complexes that trigger fibroblast growth factor-driven mitogenesis. In addition, we obtained evidence from in vivo disease models that this group of inhibitors may be of interest to treat cancer and angiogenesis-dependent diseases.The fibroblast growth factors (FGFs) 4 constitute one of the largest families of polypeptide growth factors. There are 22FGFs in humans and mice that differ significantly in both size (17-20 kDa) and sequence, although each contains a core homology region encompassing 120 -130 residues. Phylogenetic analyses suggest that the FGF genes can be arranged into seven subfamilies. All FGFs bind to heparin with high affinity (K d between 1-2 nM), except for the members of the FGF-19 subfamily (i.e.: FGF-15, -19, -21, and -23) that have little or no affinity for these glycosaminoglycans (1). Apart from the family comprising FGF-11 to FGF-14, FGFs exert their diverse biological actions by binding to a series of membrane tyrosine kinase receptors (FGFRs) that are encoded by four genes (2-4). For this reason the FGF family is currently considered to be constituted by 18 members.FGFs were first isolated in the 1980s from bovine brain extracts due to their mitogenic and angiogenic activities (5). The affinity of FGFs for heparin was recognized very soon after their discovery (6), although the physiological substrate for FGF in normal conditions is heparan sulfate, a proteoglycan whose glycoside moiety is a glycosaminoglycan like heparin. Although initially conceived as FGF traps and protectors, it was later shown that these proteoglycans also participate in FGF signaling, although they are not absolutely required (4,7,8).In addition to the effects on cell replication and angiogenesis observed initially, FGFs r...

Adult bone marrow contains stem cells that have attracted interest through their possible use for cell therapy in neurological diseases. Bone marrow stromal cells (MSCs) were harvested from donor adult rats, cultured and pre-labeled with bromodeoxyuridine (BrdU) previously to be injected in the distal stump of transected sciatic nerve of the rats. Distal nerve stump of control rats received culture medium solution. MSCs-treated rats exhibit significant improvement on walking track test at days 18 and 33 compared to controls. Dual immunofluorescence labeling shows that BrdU reactive cells survive in the injected area of transected sciatic nerve at least 33 days after implantation, and almost 5% of BrdU cells express Schwann cell-like phenotype (S100 immunoreactivity). Because MSCs injected in a lesioned peripheral nerve can survive, migrate, differentiate in Schwann cells, and promote functional recovery, they may be an important source for cellular therapy in several neurological diseases.