Plasminogen activator production in a rat model of Pneumocystis carinii pneumonae

“Plasminogen activator production in a rat model of Pneumocystis carinii pneumonae” E. angelici, C. Contini, M. Spezzano, R. Romani, P. Carfagna, P. Serra, R. Canipari. Microbiol. Immunol. 45 (8) pp. 605-611, 2001

Parallel simulation of soil contamination by cellular automata

A new cellular automata model of the complex set of interacting phenomena which take place in bioremediation is described. The model allows the scaling between pilot plant situations and field operations, and - because its structure - shows interesting speed-up capabilitie

Urokinase plasminogen activator and TGF-beta production in immunosuppressed patients with and without P. Jiroveci infection.

Macrophages play a pivotal role in a host’s defence against pulmonary infections. Macrophage functions are impaired in immunosuppressed (IS) patients, regardless of whether they are HIV-positive (HIV+) or –negative (HIV). Several studies have indicated that urokinase plasminogen activator (uPA) and transforming growth factor b (TGF-b) are important factors in a host’s defence against pulmonary pathogens. We measured uPA and TGF-b activity in unstimulated peripheral blood monocytes (PBM) of both HIV-infected and non-infected IS patients with or without Pneumocystis jiroveci (formerly carinii) pneumonia (PCP). As previously found in alveolar macrophages (AMs), the majority of uPA activity was found in cell lysates. The highest values of uPA activity were found in control subjects. All the patients displayed a decreased production of uPA, irrespective of HIV infection. Similarly, active TGF-b was higher in control subjects than in HIV+ and IS patients. The presence of P. jiroveci infection further lowered uPA and TGF-b activity. Decreased TGF-b activation might be a consequence of lower uPA production, which may, in turn, influence virus replication, since it has been demonstrated that TGF-b can suppress human HIV expression in monocytes/macrophages. Further studies are warranted to elucidate whether the decrease in uPA and TGF-b activity impairs a host’s defence against P. jiroveci infection

Profiling Neuroactive Steroid Levels After Traumatic Brain Injury in Male Mice

The incidence of traumatic brain injuries (TBIs) in humans has rapidly increased in the last ten years. The most common causes are falls and car accidents. Approximately 80 000-90 000 persons per year will suffer some permanent disability as a result of the lesion, and one of the most common symptoms is the decline of hormone levels, also known as post-TBI hormonal deficiency syndrome. This issue has become more and more important, and many studies have focused on shedding some light on it. The hormonal decline affects not only gonadal steroid hormones but also neuroactive steroids, which play an important role in TBI recovery by neuroprotective and neurotrophic actions. The present work used an adolescent close-head murine model to analyze brain and plasma neurosteroid level changes after TBI and to establish correlations with edema and neurological impairments, 2 of the hallmarks of TBI. Our results showed changes in brain pregnenolone, testosterone, dihydrotestosterone (DHT), and 3α-diol levels whereas in plasma, the changes were present in progesterone, DHT, 3α-diol, and 3β-diol. Within them, pregnenolone, progesterone, DHT, and 3α-diol levels positively correlated with edema formation and neurological score, whereas testosterone inversely correlated with these 2 variables. These findings suggest that changes in the brain levels of some neuroactive steroids may contribute to the alterations in brain function caused by the lesion and that plasma levels of some neuroactive steroids could be good candidates of blood markers to predict TBI outcome

NEUROACTIVE STEROID LEVELS AND PSYCHIATRIC AND ANDROLOGICAL FEATURES IN POST-FINASTERIDE PATIENTS

Recent reports show that, in patients treated with finasteride for male pattern hair loss, persistent side effects including sexual side effects, depression, anxiety and cognitive complaints may occur. We here explored the psychiatric and andrological features of patients affected by post-finasteride syndrome (PFS) and verified whether the cerebrospinal fluid (CSF) and plasma levels of neuroactive steroids (i.e., important regulators of nervous function) are modified. We found that eight out of sixteen PFS male patients considered suffered from a DSM-IV major depressive disorder (MDD). In addition, all PFS patients showed erectile dysfunction (ED); in particular, ten patients showed a severe and six a mild-moderate ED. We also reported abnormal somatosensory evoked potentials of the pudendal nerve in PFS patients with severe ED, the first objective evidence of a neuropathy involving peripheral neurogenic control of erection. Testicular volume by ultrasonography was normal in PFS patients. Data obtained on neuroactive steroid levels also indicate interesting features. Indeed, decreased levels of pregnenolone, progesterone and its metabolite (i.e., dihydroprogesterone), dihydrotestosterone and 17beta-estradiol and increased levels of dehydroepiandrosterone, testosterone and 5alpha-androstane-3alpha,17beta-diol were observed in CSF of PFS patients. Neuroactive steroid levels were also altered in plasma of PFS patients, however these changes did not reflect exactly what occurs in CSF. Finally, finasteride did not only affect, as expected, the levels of 5alpha-reduced metabolites of progesterone and testosterone, but also the further metabolites and precursors suggesting that this drug has broad consequence on neuroactive steroid levels of PFS patients

Axonal transport in a peripheral diabetic neuropathy model: sex-dimorphic features

Abstract Background Disruption of axonal transport plays a pivotal role in diabetic neuropathy. A sex-dimorphism exists in the incidence and symptomatology of diabetic neuropathy; however, no studies so far have addressed sex differences in axonal motor proteins expression in early diabetes as well as the possible involvement of neuroactive steroids. Interestingly, recent data point to a role for mitochondria in the sexual dimorphism of neurodegenerative diseases. Mitochondria have a fundamental role in axonal transport by producing the motors’ energy source, ATP. Moreover, neuroactive steroids can also regulate mitochondrial function. Methods Here, we investigated the impact of short-term diabetes in the peripheral nervous system of male and female rats on key motor proteins important for axonal transport, mitochondrial function, and neuroactive steroids levels. Results We show that short-term diabetes alters mRNA levels and axoplasm protein contents of kinesin family member KIF1A, KIF5B, KIF5A and Myosin Va in male but not in female rats. Similarly, the expression of peroxisome proliferator-activated receptor γ co-activator-1α, a subunit of the respiratory chain complex IV, ATP levels and the key regulators of mitochondrial dynamics were affected in males but not in females. Concomitant analysis of neuroactive steroid levels in sciatic nerve showed an alteration of testosterone, dihydrotestosterone, and allopregnanolone in diabetic males, whereas no changes were observed in female rats. Conclusions These findings suggest that sex-specific decrease in neuroactive steroid levels in male diabetic animals may cause an alteration in their mitochondrial function that in turn might impact in axonal transport, contributing to the sex difference observed in diabetic neuropathy.The financial support of Fondazione CARIPLO (Rif. 2012-0547) to R. C. Melcangi is gratefully acknowledged

Role of androgens in dhea-induced rack1 expression and cytokine modulation in monocytes

BACKGROUND: Over the past fifteen years, we have demonstrated that cortisol and dehydroepiandrosterone (DHEA) have opposite effects on the regulation of protein kinase C (PKC) activity in the context of the immune system. The anti-glucocorticoid effect of DHEA is also related to the regulation of splicing of the glucocorticoid receptor (GR), promoting the expression of GRβ isoform, which acts as a negative dominant form on GRα activity. Moreover, it is very well known that DHEA can be metabolized to androgens like testosterone, dihydrotestosterone (DHT), and its metabolites 3α-diol and 3β-diol, which exert their function through the binding of the androgen receptor (AR). Based on this knowledge, and on early observation that castrated animals show results similar to those observed in old animals, the purpose of this study is to investigate the role of androgens and the androgen receptor (AR) in DHEA-induced expression of the PKC signaling molecule RACK1 (Receptor for Activated C Kinase 1) and cytokine production in monocytes. RESULTS: Here we demonstrated the ability of the anti-androgen molecule, flutamide, to counteract the stimulatory effects of DHEA on RACK1 and GRβ expression, and cytokine production. In both THP-1 cells and human peripheral blood mononuclear cells (PBMC), flutamide blocked the effects of DHEA, suggesting a role of the AR in these effects. As DHEA is not considered a direct AR agonist, we investigated the metabolism of DHEA in THP-1 cells. We evaluated the ability of testosterone, DHT, and androstenedione to induce RACK1 expression and cytokine production. In analogy to DHEA, an increase in RACK1 expression and in LPS-induced IL–8 and TNF–α production was observed after treatment with these selected androgens. Finally, the silencing of AR with siRNA completely prevented DHEA-induced RACK1 mRNA expression, supporting the idea that AR is involved in DHEA effects. CONCLUSIONS: We demonstrated that the conversion of DHEA to active androgens, which act via AR, is a key mechanism in the effect of DHEA on RACK1 expression and monocyte activation. This data supports the existence of a complex hormonal balance in the control of immune modulation, which can be further studied in the context of immunosenescence and endocrinosenescence

Oral Metronomic Vinorelbine (OMV) in elderly or pretreated patients with advanced non small cell lung cancer: outcome and pharmacokinetics in the real world

Background Oral metronomic therapy (OMV) is particularly suitable for palliative care, and schedules adapted for unfit patients are advisable. This study investigated the effects of oral vinorelbine given every other day without interruption and its pharmacokinetic profile in patients with advanced lung cancer. Materials and Methods Ninety-two patients received OMV at doses of 20, 30 or 50 mg. Toxic events, clinical benefit and overall survival were analysed. Blood pharmacokinetics were evaluated in 82 patients. Results Median treatment duration and overall survival were 15 (range 1.3-144) and 32.3 weeks, respectively; fourty-eight (60%) patients experienced clinical benefit. Outcomes were unrelated to previous therapies, age, histology or comorbidities. Toxicity was associated with higher blood concentrations of the drug. Pharmacokinetics were stable for up to two years, and were not influenced by treatment line or age. Conclusions OMV produced non-negligible survival in patients and also showed stable long-term blood concentrations. The schedule of 20-30 mg every other day without interruption gave good tolerability and clinical benefit