Inhibition of the immunoproteasome modulates innate immunity to ameliorate muscle pathology of dysferlin-deficient BlAJ mice.

Muscle repair in dysferlinopathies is defective. Although macrophage (Mø)-rich infiltrates are prominent in damaged skeletal muscles of patients with dysferlinopathy, the contribution of the immune system to the disease pathology remains to be fully explored. Numbers of both pro-inflammatory M1 Mø and effector T cells are increased in muscle of dysferlin-deficient BlAJ mice. In addition, symptomatic BlAJ mice have increased muscle production of immunoproteasome. In vitro analyses using bone marrow-derived Mø of BlAJ mice show that immunoproteasome inhibition results in C3aR1 and C5aR1 downregulation and upregulation of M2-associated signaling. Administration of immunoproteasome inhibitor ONX-0914 to BlAJ mice rescues muscle function by reducing muscle infiltrates and fibro-adipogenesis. These findings reveal an important role of immunoproteasome in the progression of muscular dystrophy in BlAJ mouse and suggest that inhibition of immunoproteasome may produce therapeutic benefit in dysferlinopathy.

Leptin: pharmacological aspects in gynecology.

Hematic levels of leptin vary in relation to numerous metabolic factors and are able to interact in perfect synchrony with the hormones involved in the hypothalamus-pituitary-ovarian axis during the various phases of the reproductive cycle. In general it is maintained that the complex and multiple action mechanisms of leptin need to be clarified by further in-depth research studies. It is likely that valid pharmacological applications of leptin will be found for human use although it is too premature to talk about concrete pharmacological answers and to formulate the relative complete technical protocols. In medicine the therapeutic use of leptin for humans has been reported in only a few cases. In fact human recombinant leptin has already been administered in gynecology for hypothalamic amenorrhea with precise protocols. In addition, very recent studies have provided the basis for new strategies to be developed concerning the use of leptin to fight multiple sclerosis. At present there are considerable technical and economic problems in the production of leptin on a large scale. Most likely these problems will be overcome in the foreseeable future, and will involve new techniques related to genetics, cellular reprograming, and stem cells. In fact, new pharmacogenetic research has provided encouraging results for the production in industrial quantities of a more effective and fail-proof leptin. Even considering that norms have not yet been proposed for pharmacological interventions with leptin for use directly on humans, in our work we have studied by immunohistochemistry methods the distribution of leptin and its receptor (Ob-R) in the ovaries of the female dog as a biological model, in the pre- and postpubertal phases and in other phases of the ovarian cycle. Given the hypothesis that the information obtained from immunohistochemical localization of the hormone and its receptor in various ovarian structures is transferable to humans, it could be useful to define therapeutic protocols based on the effective role of leptin and its receptor in folliculogenesis.

Pharmacological effects of melatonin on reproductive activity: experimental bioimplants with sustained-release polymeric systems.

A vast literature documents the role of melatonin in human reproductive function including: a) the relation between melatonin and the menstrual cycle in relation to the peak time of luteinizing hormone in the middle of the cycle; b) the varying concentrations of melatonin in the control of puberty; c) the fewer conceptions in some artic populations where melatonin is connected significantly to seasonal photoperiodicity during the months of the polar nights. The aim of this paper is to report our findings on the pharmacological action of this molecule on reproduction in which gonadal activity is clearly connected to photoperiodicity. We used polymer bioimplants programmed for the sustained release of melatonin for experimental gynecologic protocols. These implants had beneficial results with respect to the use of progestinics because melatonin allowed ovarian activity to be induced for at least two to three consecutive cycles with one single bioimplant. We thought it indispensable to use pharmacological systems with a sustained release because different preliminary tests showed that the half-life of melatonin is limited at maximum to two to three hours and, consequently, any other tested modalities of administration would not provide any appreciable results for our study. As a model for our research we used goats to administer melatonin via targeted programs since these animals clearly respond (even against the rule of the light/dark relation) in contrast to humans in whom response is less evident. For controls, after inserting bioimplants in the animals, we tested their efficiency in vitro and subsequently in vivo, evaluating blood parameters and pharmacological effects of melatonin occurring during the treatment. The final results proved to be interesting in relation to reproductive activity in that regular and programmed births were achieved.

Pharmacological action and therapeutic effects of glutathione on hypokinetic spermatozoa for enzymatic-dependent pathologies and correlated genetic aspects.

In this study, the pharmacologic substance reduced glutathione (GSH) was used in men with hypofertility problems linked to varicocele, in bulls with spermatozoa hypomobility due to varicocele, and in rabbits with dispermy caused by cryptorchidism. An efficacious therapeutic effect of increased motility of the spermatozoa was seen in subjects who were submitted to appropriate doses of glutathione I.M. GSH also showed some neutralizing effect on the catabolytes produced during spontaneous or induced peroxidation processes of the unsaturated lipids contained in the membranes of male germinal cells. The genetic aspects of the involved enzymes were also evaluated and the research was extended in vitro by incubating samples of spermatozoa with arachidonic acid homogenates, L-tryptophan, hematein, and with an addition of glutathione. The results showed that polynsaturated fatty acid metabolic substances (PUFA) play an important role in the acrosomal reaction of spermatozoa and that GSH has a determining role in increasing the motility of spermatozoa with consequent improved fertilization. The spermatozoa of bulls provided us with a valid model to study for the morphostructural, biochemical and pharmacological analyses of human spermatozoa.

Early induction of labor with PGE2-intravaginal gel in premature rupture of membranes.

Results of induction of labor with PGE2-intravaginal gel in PROM, were evaluated considering the best management.

The effect of treatment on Actinobacillus actinomycetemcomitans in localized juvenile periodontitis.

Three treatment regimens including local tetracycline delivery, systemic doxycycline and surgery plus systemic doxycycline were investigated in a localized juvenile periodontitis (LJP) population. Of the investigated treatments only surgery plus systemic doxycycline for 14 days was effective in eliminating or suppressing Actinobacillus actinomycetemcomitans, an organism strongly associated with LJP lesions. While surgery plus antibiotics was the superior treatment, it appears that the possibility of reinfection or incomplete elimination of the organism exists. Careful long-term follow-up, including clinical and microbiological monitoring, is highly recommended in this periodontal population.