Diminished Vision in Healthy Aging Is Associated With Increased Retinal L-Type Voltage Gated Calcium Channel Ion Influx.

Diminished vision in healthy aging is associated with increased retinal L-type voltage gated calcium channel ion influx.

PLoS One. 2013; 8(2): e56340
Bissig D, Goebel D, Berkowitz BA

Extensive evidence implicates an increase in hippocampal L-type voltage-gated calcium channel (L-VGCC) expression, and ion influx through these channels, in age-related cognitive declines. Here, we ask if this “calcium hypothesis” applies to the neuroretina: Is increased influx via L-VGCCs related to the well-documented but poorly-understood vision declines in healthy aging? In Long-Evans rats we find a significant age-related increase in ion flux through retinal L-VGCCs (manganese-enhanced MRI (MEMRI)) that are longitudinally linked with progressive vision declines (optokinetic tracking). Importantly, the degree of retinal Mn uptake early in adulthood significantly predicted later visual contrast sensitivity declines. Furthermore, as in the aging hippocampus, retinal expression of a drug-insensitive L-VGCC isoform (?) increased – a pattern confirmed by an age-related decline in sensitivity to L-VGCC blockade. These data highlight mechanistic similarities between retinal and hippocampal aging, and raise the possibility of new treatment targets for minimizing vision loss during healthy aging. HubMed – drug


Differential Effects of Drug Interventions and Dietary Lifestyle in Developing Type 2 Diabetes and Complications: A Systems Biology Analysis in LDLr-/- Mice.

PLoS One. 2013; 8(2): e56122
Radonjic M, Wielinga PY, Wopereis S, Kelder T, Goelela VS, Verschuren L, Toet K, van Duyvenvoorde W, van der Werff van der Vat B, Stroeve JH, Cnubben N, Kooistra T, van Ommen B, Kleemann R

Excess caloric intake leads to metabolic overload and is associated with development of type 2 diabetes (T2DM). Current disease management concentrates on risk factors of the disease such as blood glucose, however with limited success. We hypothesize that normalizing blood glucose levels by itself is insufficient to reduce the development of T2DM and complications, and that removal of the metabolic overload with dietary interventions may be more efficacious. We explored the efficacy and systems effects of pharmaceutical interventions versus dietary lifestyle intervention (DLI) in developing T2DM and complications. To mimic the situation in humans, high fat diet (HFD)-fed LDLr-/- mice with already established disease phenotype were treated with ten different drugs mixed into HFD or subjected to DLI (switch to low-fat chow), for 7 weeks. Interventions were compared to untreated reference mice kept on HFD or chow only. Although most of the drugs improved HFD-induced hyperglycemia, drugs only partially affected other risk factors and also had limited effect on disease progression towards microalbuminuria, hepatosteatosis and atherosclerosis. By contrast, DLI normalized T2DM risk factors, fully reversed hepatosteatosis and microalbuminuria, and tended to attenuate atherogenesis. The comprehensive beneficial effect of DLI was reflected by normalized metabolite profiles in plasma and liver. Analysis of disease pathways in liver confirmed reversion of the metabolic distortions with DLI. This study demonstrates that the pathogenesis of T2DM towards complications is reversible with DLI and highlights the differential effects of current pharmacotherapies and their limitation to resolve the disease. HubMed – drug


Targeting heat shock protein 90 for the treatment of malignant pheochromocytoma.

PLoS One. 2013; 8(2): e56083
Giubellino A, Sourbier C, Lee MJ, Scroggins B, Bullova P, Landau M, Ying W, Neckers L, Trepel JB, Pacak K

Metastatic pheochromocytoma represents one of the major clinical challenges in the field of neuroendocrine oncology. Recent molecular characterization of pheochromocytoma suggests new treatment options with targeted therapies. In this study we investigated the 90 kDa heat shock protein (Hsp90) as a potential therapeutic target for advanced pheochromocytoma. Both the first generation, natural product Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin), and the second-generation synthetic Hsp90 inhibitor STA-9090 (ganetespib) demonstrated potent inhibition of proliferation and migration of pheochromocytoma cell lines and induced degradation of key Hsp90 clients. Furthermore, ganetespib induced dose-dependent cytotoxicity in primary pheochromocytoma cells. Using metastatic models of pheochromocytoma, we demonstrate the efficacy of 17-AAG and ganetespib in reducing metastatic burden and increasing survival. Levels of Hsp70 in plasma from the xenograft studies served as a proximal biomarker of drug treatment. Our study suggests that targeting Hsp90 may benefit patients with advanced pheochromocytoma. HubMed – drug