The senescence-associated secretory phenotype (SASP) from mesenchymal stromal cells impairs growth of immortalized prostate cells but has no effect on metastatic prostatic cancer cells.

Senescent cells secrete inflammatory cytokines, proteases, and other factors, which are indicated as senescence-associated secretory phenotype (SASP). There are contrasting studies on the role of the SASP in cancer. Studies suggested that cancer cells may misuse the senescent secretome for their growth. Other investigations evidenced that the SASP may induce cancer growth arrest, senescence, or apoptosis. These conflicting data can be reconciled considering that cancer cells can coax senescent cells to secrete factors for their survival, thus abrogating the SASP's anti-cancer effect. Cancer stage may also have an impact on the capacity of the SASP to block tumor proliferation and promote senescence. Indeed, senescence is associated with a permanent cell cycle arrest, which needs functional cell cycle checkpoints. We evaluated the SASP effect on the in vitro biological properties of PNT2 and PC3 cells, which are immortalized prostate cells and metastatic prostatic cancer cells, respectively. We evidenced that SASPs, coming either from mesenchymal stromal cells treated with H202 or with low X-ray doses, induced senescence of immortalized cells but not of cancer cells. Hence, the SASP released by acute senescent cells should be considered as an effective weapon against pre-tumorigenesis events rather than an anti-cancer mechanism acting on malignant cells.

Circulating factors present in the sera of naturally skinny people may influence cell commitment and adipocyte differentiation of mesenchymal stromal cells.

BACKGROUND: Research on physiopathology of obesity may receive new hints from studies on skinny people (SP). These are individuals who show a poor or null gaining of body weight, in spite of high-calorie intake, by far exceeding the body requirements. AIM: To evaluate how circulating factors present in the SP sera may affect adipogenesis of mesenchymal stromal cells (MSCs). METHODS: We isolated MSCs from bone marrow of healthy donors with both normal body mass index (BMI) and caloric consumption. MSC cultures were primed with sera collected from SP or normal people (NP). Then biomolecular assays were performed to evaluate effect on proliferation, apoptosis, senescence, cell commitment, and differentiation. RESULTS: SP priming affected adipocyte cell commitment and reduced spontaneous adipogenesis. Moreover, an in-depth analysis of exogenous-induced adipocyte differentiation showed striking differences between differentiation in SP-primed samples compared with NP ones. In adipocytes from SP cultures we observed a reduced size of lipid droplets, an increased expression of adipose triglyceride lipase, along with high mitochondria content and ability to produce ATP in starvation condition. These data and the expression of UCP1 protein, indicated that SP pretreatment produced a bias toward brown adipocyte differentiation. CONCLUSION: Our data suggest that sera from SP may promote brown adipogenesis rather that white adipocyte differentiation. This finding could explain why SP present normal body composition in spite of an excess of caloric intake. We hypothesize that some circulating components present in the blood of these individuals may favor brown adipogenesis at expense of white adipocyte production.

Late adult-onset adrenomyeloneuropathy evolving with atypical severe frontal lobe syndrome: Importance of neuroimaging.

X-linked adrenoleukodystrophy (X-ALD) is a rare inherited metabolic disease affecting the nervous system and the adrenal glands. It is caused by a mutation of the ABCD1 gene, resulting in the impaired degradation of very long-chain fatty acids and their subsequent accumulation in several organs and tissues. X-ALD is notable for its high phenotypical variability, that includes isolated adrenocortical insufficiency, slowly progressive myelopathy with paraparesis, ataxia, and peripheral neuropathy to severe childhood cerebral forms. Here, we describe the case of an X-ALD patient with a p.Gly343Val mutation in ABCD1 gene, who presented in adulthood with a spinal syndrome of mild severity, and later developed a progressive cognitive and behavioral syndrome. Our patient showed a striking correlation between clinical phenotype and neuroimaging, including a brain fluoro-2-deoxy-d-glucose positron emission tomography that displayed an atypical cerebral glucose metabolism.

Rasagiline for sleep disorders in patients with Parkinson's disease: a prospective observational study.

INTRODUCTION: Rasagiline is a selective, irreversible monoamine oxidase B inhibitor that ameliorates the symptoms of Parkinson's disease (PD) by inhibiting striatal dopamine metabolism. There is also evidence that monoamine oxidase B inhibitors increase melatonin levels in the pineal gland and may have a beneficial effect on sleep disorders, which are a common feature in patients with PD. METHODS: This single-center, prospective, observational, 12-week study compared the effect of combination therapy with levodopa 200-300 mg/d + rasagiline 1 mg/d (n=19) with levodopa 200-300 mg/d alone (n=19) in the treatment of sleep disorders in patients with idiopathic PD. RESULTS: After 12 weeks' treatment, mean sleep latency was significantly (P<0.001) lower and the improvement in sleep latency from baseline was significantly (P=0.001) greater in patients receiving levodopa + rasagiline than in patients receiving levodopa alone. Similarly, at the end of the study, the mean total sleep time was significantly (P=0.002) longer and the improvement from baseline in mean total sleep time was significantly (P=0.026) greater in patients receiving levodopa + rasagiline than levodopa alone. There were no significant differences between treatment groups for the mean number of awakenings reported at week 12 nor the change from baseline to week 12 in mean number of awakenings. CONCLUSION: Adding rasagiline to levodopa improved sleep outcomes and may be an appropriate option for patients with PD experiencing sleep disorders.

Giant thrombosed intracavernous carotid artery aneurysm presenting as Tolosa-Hunt syndrome in a patient harboring a new pathogenic neurofibromatosis type 1 mutation: a case report and review of the literature.

Neurofibromatosis type 1 (NF1) is a relatively common single-gene disorder, and is caused by heterozygous mutations in the NF1 gene that result in a loss of activity or in a nonfunctional neurofibromin protein. Despite the common association of NF1 with neurocutaneous features, its pathology can extend to numerous tissues not derived from the neural crest. Among the rare cerebrovascular abnormalities in NF1, more than 85% of cases are of purely occlusive or stenotic nature, with intracranial aneurysm being uncommon. Predominantly, the aneurysms are located in the internal carotid arteries (ICAs), being very rare bilateral aneurysms. This report describes a very unusual case of fusiform aneurysms of both ICAs in a Caucasian NF1 patient, with a new pathogenic intragenic heterozygous deletion of the NF1 gene, presenting at age 22 years with Tolosa-Hunt syndrome, because of partial thrombosis of the left giant intracavernous aneurysm. Medical treatment with anticoagulant therapy allowed a good outcome for the patient. In conclusion, early identification of cerebral arteriopathy in NF1 and close follow-up of its progression by neuroimaging may lead to early medical or surgical intervention and prevention of significant neurologic complications.

Silencing of RB1 and RB2/P130 during adipogenesis of bone marrow stromal cells results in dysregulated differentiation.

Bone marrow adipose tissue (BMAT) is different from fat found elsewhere in the body, and only recently have some of its functions been investigated. BMAT may regulate bone marrow stem cell niche and plays a role in energy storage and thermogenesis. BMAT may be involved also in obesity and osteoporosis onset. Given the paramount functions of BMAT, we decided to better clarify the human bone marrow adipogenesis by analyzing the role of the retinoblastoma gene family, which are key players in cell cycle regulation. Our data provide evidence that the inactivation of RB1 or RB2/P130 in uncommitted bone marrow stromal cells (BMSC) facilitates the first steps of adipogenesis. In cultures with silenced RB1 or RB2/P130, we observed an increase of clones with adipogenic potential and a higher percentage of cells accumulating lipid droplets. Nevertheless, the absence of RB1 or RB2/P130 impaired the terminal adipocyte differentiation and gave rise to dysregulated adipose cells, with alteration in lipid uptake and release. For the first time, we evidenced that RB2/P130 plays a role in bone marrow adipogenesis. Our data suggest that while the inactivation of retinoblastoma proteins may delay the onset of last cell division and allow more BMSC to be committed to adipocyte, it did not allow a permanent cell cycle exit, which is a prerequisite for adipocyte terminal maturation.

RAGE recycles at the plasma membrane in S100B secretory vesicles and promotes Schwann cells morphological changes.

RAGE is a multiligand receptor of the immunoglobulin superfamily involved in regeneration of injured peripheral nerve and cell motility. RAGE is implicated in the development of various chronic diseases, such as neurodegenerative disorders, inflammatory responses, and diabetic complications. The correlation between RAGE endocytic trafficking and RAGE function is still uninvestigated. S100B is one of the ligands of RAGE. The molecular mechanisms responsible of S100B translocation in exocytic vesicles are still poorly investigated. In the present study we elucidate the role of RAGE endocytic trafficking in promoting S100B secretion in Schwann cells. Here we show that RAGE-induced secretion of S100B requires phosphorylated caveolin1-dependent endocytosis of RAGE. Endocytosis of RAGE in response to ligand binding promotes the fusion of endosomes with S100B-positive secretory vesicles. Src promotes the fusion of endosomes with S100B-secretory vesicles. Inhibition of src induces RAGE degradation. RAGE-mediated src activation induces cav1 phosphorylation and relocalization in the perinuclear compartment. RAGE signaling and recycling are required for S100-induced Schwann cells morphological changes and are inhibited by high-glucose, suggesting a possible link between diabetes and peripheral nerve injury. Indeed, high glucose inhibits RAGE-mediated src activation. Src inhibition blocks RAGE recycling, S100B secretion, and morphological changes. In summary, we identified a novel pathway of vesicular trafficking required for the amplification of RAGE signaling and cytoskeleton dynamics that is potentially involved in the regeneration of injured peripheral nerve.