cytotoxic-efficacy-photodynamic-therapy-osteosarcoma-cells

Cytotoxic Efficacy of Photodynamic Therapy in Osteosarcoma Cells <em>In Vitro</em>

In recent years, there has been the difficulty in finding more effective therapies against cancer with less systemic side effects. Therefore Photodynamic ...

Balgrist University Hospital, Zurich, Switzerland

Fingolimod (FTY720) represents the first in a new class of immune-modulators whose target is sphingosine-1-phosphate (S1P) receptors. It was first identified by researchers at Kyoto University and Yoshitomi Pharmaceutical as a chemical derivative of the ascomycete metabolite ISP-1 (myriocin). Unlike its natural product parent, FTY720 does not interfere with sphingolipid biosynthesis. Instead, its best characterized mechanism of action upon in vivo phosphorylation, leading to the active principle FTY720-P, is the rapid and reversible inhibition of lymphocyte egress from peripheral lymph nodes. As a consequence of S1P1 receptor internalization, tissue-damaging T-cells can not recirculate and infiltrate sites of inflammation such as the central nervous system (CNS). Furthermore, FTY720-P modulation of S1P receptor signaling also enhances endothelial barrier function. Due to its mode of action, FTY720 effectively prevents transplant rejection and is active in various autoimmune disease models. The most striking efficacy is in the multiple sclerosis (MS) model of experimental autoimmune encephalomyelitis, which has now been confirmed in the clinic. FTY720 demonstrated promising results in Phase II trials and recently entered Phase III in patients with relapsing MS. Emerging evidence suggests that its efficacy in the CNS extends beyond immunomodulation to encompass other aspects of MS pathophysiology, including an influence on the blood-brain-barrier and glial repair mechanisms that could ultimately contribute to restoration of nerve function. FTY720 may represent a potent new therapeutic modality in MS, combined with the benefit of oral administration.

Ascomycete derivative to MS therapeutic: S1P receptor modulator FTY720.

Hypoxia has been shown to reduce energy intake and lead to weight loss, but the underlying mechanisms are unclear. The aim was therefore to assess changes in eating after rapid ascent to 4,559 m and to investigate to what extent hypoxia, acute mountain sickness (AMS), food preferences and satiation hormones influence eating behavior.

Disturbed eating at high altitude: influence of food preferences, acute mountain sickness and satiation hormones.

Reduced insulin sensitivity might increase the susceptibility to acute mountain sickness (AMS). The diabetogenic side effects of dexamethasone should therefore be considered for AMS treatment. To examine whether reduced insulin sensitivity is predictive of AMS and how it is affected by dexamethasone at high altitude, we analyzed endocrine and metabolic parameters obtained from healthy mountaineers in Zurich (LA; 490 m), and 2 and 4 days after fast ascent to the Capanna Regina Margherita (HA2, HA4; 4559 m). 14 of 25 participants developed AMS and were treated with dexamethasone starting in the evening of HA2. Before and after ingestion of an 1800 kJ meal, plasma was analyzed for erythropoietin (EPO) and cholecystokinin (CCK). Insulin sensitivity (HOMA-S) and beta cell activity were calculated. HOMA-S (p<0.01) and EPO levels (p<0.05) were lower in Zurich in the group developing AMS and given dexamethasone, i.e., before treatment and exposure to hypoxia. CCK was lower (p<0.01) and glucose and insulin were higher on HA4 in the dexamethasone group compared to the untreated group. Individuals with low baseline insulin sensitivity and low baseline EPO levels were more susceptible to AMS. Reduced CCK may contribute to the beneficial effect of dexamethasone on high altitude anorexia. However, reduced insulin sensitivity questions the widespread use of dexamethasone to prevent/treat AMS.

Reduced insulin sensitivity as a marker for acute mountain sickness?

We examined the effect of fingolimod (0.1 and 0.3 mg/kg/day orally) on blood-brain barrier (BBB) function, demyelination and leukocyte recruitment at different stages of the focal delayed-type hypersensitivity (DTH) multiple sclerosis model in Lewis rats using immunohistochemistry and gadolinium (Gd)-enhancing magnetic resonance imaging (MRI). During DTH lesion formation, fingolimod reduced BBB breakdown (52%; p = 0.05), and lymphocyte (53%; p = 0.016) and macrophage/activated microglia (49%; p = 0.002) recruitment to the DTH lesion compared with vehicle-treated controls. Following DTH lesion establishment, fingolimod reduced the area of BBB breakdown (75%; p = 0.04), lymphocyte recruitment to the DTH lesion (41%; p = 0.01) and activated microglia outside of the lesion core (p = 0.01), but did not reduce recruitment of macrophages/activated microglia within the DTH lesion. During the chronic disease phase, when the BBB was resealed, fingolimod reduced the area of demyelination by 43% (p = 0.019) compared with vehicle-treated controls, while not affecting lymphocyte recruitment within the lesion. Fingolimod had different beneficial effects during different stages of DTH, reducing BBB breakdown and lesion development/brain tissue damage whilst reducing lymphocyte recruitment when BBB breakdown was apparent, but reducing demyelination independent of lymphocyte infiltration behind an intact BBB. These results suggest a direct CNS effect of fingolimod in this model.

Article	Year
Ascomycete derivative to MS therapeutic: S1P receptor modulator FTY720. Progress in drug research. Fortschritte der Arzneimittelforschung. Progrès des recherches pharmaceutiques\| PubMed ID: 18416311	2008
Disturbed eating at high altitude: influence of food preferences, acute mountain sickness and satiation hormones. European journal of nutrition\| PubMed ID: 22573211	2012
Reduced insulin sensitivity as a marker for acute mountain sickness? High altitude medicine & biology\| PubMed ID: 24067185	2013
Investigation of immune and CNS-mediated effects of fingolimod in the focal delayed-type hypersensitivity multiple sclerosis model. Neuropharmacology\| PubMed ID: 24412675	2014

Daniela Meier

Biography

JoVE Journal Publications

Other Publications