We hypothesized that Nandrolone (ND)-abuse induces cardiac hypertrophy, increases myocardial susceptibility to ischemia/reperfusion (I/R) injury, and reduces responsiveness to postconditioning (PostC) cardioprotection. Wistar-rats were ND-treated for 2-weeks (short_ND) or 10-weeks (long_ND). Vehicle-treated rats served as controls. Hearts were retrogradely perfused and left ventricular pressure (LVP) was measured before and after 30-min global ischemia. In subgroups of hearts, to induce cardioprotection a PostC protocol (five cycles of 10-s reperfusion and 10-s ischemia) was performed. β-adrenoreceptors, kinases (Akt and GSk-3β) and phosphatases (PP2A sub A and PP2A sub B) were examined by Western blot before and after ischemia. After 120-min reperfusion infarct-size was measured. Short_ND slightly increased cardiac/body weight ratio, but did not affect cardiac baseline nor post-ischemic contractile function or infarct-size when compared to vehicle hearts. However, PostC limited cardiac dysfunction much more in short_ND hearts than other groups. Although cardiac/body weight ratio markedly increased after long_ND, baseline LVP was not affected. Yet, post-ischemic contracture and infarct-size were exacerbated and PostC was unable to reduce infarct-size and ventricular dysfunction. While short_ND increased phosphatases, non-phosphorylated and phosphorylated Akt, long_ND reduced phosphatase-expression and Akt-phosphorylation. Both short_ND and long_ND had no effect on the GSK-3β-phosphorylation but increased the expression of β 2 -adrenoreceptors. In reperfusion, PostC increased Akt-phosphorylation regardless of protective effects, but reduced phosphataseexpression in protected hearts only. In conclusion: short_ND improves post-ischemic myocardial performance in postconditioned hearts. However, long_ND increases myocardial susceptibility to I/R injury and abolishes cardioprotection by PostC. This increased susceptibility might be related to steroid-induced hypertrophy and/or to altered enzyme expression/phosphorylation.

Evaluation of the CYP2B6 polymorphism enabled prediction of the individual response to adjuvant mitotane treatment.

In vitro studies on the effects of dexamethasone on human synovial cells have shown that with high concentrations of the steroid in the culture medium cellular activity was completely blocked whereas with low concentrations (10(-6)M), cellular density decreased but there was an increase in the synthesis of RNA, DNA, protein and hyaluronic acid. These data, coupled with clinical experience of using intra-articular hyaluronic acid to treat patients with osteoarthritis of the knee, prompted the investigators to carry out an open, randomized study of the use of very small doses of dexamethasone in association with hyaluronic acid in 40 osteoarthritic patients. Twenty patients received a weekly intra-articular injection of 20 mg sodium hyaluronate in 2 ml phosphate buffer for 5 weeks; the other 20 patients followed a similar treatment regimen, the only difference being the addition of 0.4 mg dexamethasone phosphate to the first injection. Clinical examination of the knee was made before each injection, 7 days after the fifth injection and 60 days after the start of the trial. Rating scale assessments were made at each visit of spontaneous pain, pain during the day, at night, weight bearing and whilst walking. The results showed that whilst a progressive decrease in all pain parameters was evident and persisted after the end of treatment in both patient groups, pain intensity decreased more rapidly and to lower levels in all but weight-bearing pain, as did improvement in joint mobility, in the combined treatment group. Local tolerance was good with both treatment regimens, with no untoward signs or symptoms at any time.(ABSTRACT TRUNCATED AT 250 WORDS)

PurposeTransient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel belonging to the transient receptor potential family, and it is expressed in different neoplastic tissues. Its activation is associated with regulation of cancer growth and progression. The aim of this research was to study the expression and pharmacological characteristics of TRPV1 in cells derived from human breast cancer MCF-7 cells.MethodsTRPV1 presence was assessed by binding studies and Western blotting. Receptor binding characteristics were evaluated through competition assays, while 3-(4,5-dimethylthiazol-2-yl)-2,5,-dipheyltetrazolium bromide reduction assays were performed to confirm an early hypothesis regarding the modulation of cancer cell proliferation. The functionality of TRPV1 was evaluated by measuring Ca2+ uptake in the presence of increasing concentrations of TRPV1 agonists and antagonists.ResultsBinding studies identified a single class of TRPV1 (Bmax 1,492±192 fmol/mg protein), and Western blot showed a signal at 100 kDa corresponding to the molecular weight of human TRPV1. Among the different tested agonists and antagonists, anandamide (Ki: 2.8×10-11 M) and 5-iodoresiniferatoxin (5-I-RTX) (Ki: 5.6×10-11 M) showed the highest degrees of affinity for TRPV1, respectively. All tested TRPV1 agonists and antagonists caused a significant (p<0.05) decrease in cell growth rate in MCF-7 cells. For agonists and antagonists, the efficacy of tested compounds displayed the following rank order: resiniferatoxin>anandamide>capsaicin and 5-I-RTX=capsazepine, respectively.ConclusionThese data indicate that both TRPV1 agonists and antagonists induce significant inhibition of MCF-7 cell growth. Even though the mechanisms involved in the antiproliferative effects of TRPV1 agonists and antagonists should be further investigated, it has been suggested that agonists cause desensitization of the receptor, leading to alteration in Ca2+-influx regulation. By contrast, antagonists cause a functional block of the receptor with consequent fatal dysregulation of cell homeostasis.