Exosomal Plasminogen Activator Inhibitor-1 Induces Ionizing Radiation-Adaptive Glioblastoma Cachexia.

Cancer cachexia is a muscle-wasting syndrome that leads to a severely compromised quality of life and increased mortality. A strong association between cachexia and poor prognosis has been demonstrated in intractable cancers, including glioblastoma (GBM). In the present study, it was demonstrated that ionizing radiation (IR), the first-line treatment for GBM, causes cancer cachexia by increasing the exosomal release of plasminogen activator inhibitor-1 (PAI-1) from glioblastoma cells. Exosomal PAI-1 delivered to the skeletal muscle is directly penetrated in the muscles and phosphorylates STAT3 to intensify muscle atrophy by activating muscle RING-finger protein-1 (MuRF1) and muscle atrophy F-box (Atrogin1); furthermore, it hampers muscle protein synthesis by inhibiting mTOR signaling. Additionally, pharmacological inhibition of PAI-1 by TM5441 inhibited muscle atrophy and rescued muscle protein synthesis, thereby providing survival benefits in a GBM orthotopic xenograft mouse model. In summary, our data delineated the role of PAI-1 in the induction of GBM cachexia associated with radiotherapy-treated GBM. Our data also indicated that targeting PAI-1 could serve as an attractive strategy for the management of GBM following radiotherapy, which would lead to a considerable improvement in the quality of life of GBM patients undergoing radiotherapy.

Curcumin extends life span, improves health span, and modulates the expression of age-associated aging genes in Drosophila melanogaster.

BACKGROUND: Curcumin, an extract from the rhizome of the plant Curcuma longa (turmeric), has been widely used as a spice and herbal medicine in Asia. It has been suggested to have many biological activities, such as antioxidative, antiinflammatory, anticancer, chemopreventive, and antineurodegenerative properties. We evaluated the impact of curcumin on life span, fecundity, feeding rate, oxidative stress, locomotion, and gene expression in two different wild-type Drosophila melanogaster strains, Canton-S and Ives, under two different experimental conditions. RESULTS: We report that curcumin extended the life span of two different strains of D. melanogaster, an effect that was accompanied by protection against oxidative stress, improvement in locomotion, and chemopreventive effects. Life span extension was gender and genotype specific. Curcumin also modulated the expression of several aging-related genes, including mth, thor, InR, and JNK. CONCLUSIONS: The observed positive effects of curcumin on life span and health span in two different D. melanogaster strains demonstrate a potential applicability of curcumin treatment in mammals. The ability of curcumin to mitigate the expression levels of age-associated genes in young flies suggests that the action of curcumin on these genes is a cause, rather than an effect, of its life span-extending effects.