Metabolic State Determines Sensitivity to Cellular Stress in Huntington Disease: Normalization by Activation of PPARγ

Impairments in mitochondria and transcription are important factors in the pathogenesis of Huntington disease (HD), a neurodegenerative disease caused by a polyglutamine expansion in the huntingtin protein. This study investigated the effect of different metabolic states and peroxisome proliferator-activated receptor γ (PPARγ) activation on sensitivity to cellular stressors such as H2O2 or thapsigargin in HD. Striatal precursor cells expressing wild type (STHdhQ7) or mutant huntingtin (STHdhQ111) were prepared in different metabolic conditions (glucose vs. pyruvate). Due to the fact that STHdhQ111 cells exhibit mitochondrial deficits, we expected that in the pyruvate condition, where ATP is generated primarily by the mitochondria, there would be greater differences in cell death between the two cell types compared to the glucose condition. Intriguingly, it was the glucose condition that gave rise to greater differences in cell death. In the glucose condition, thapsigargin treatment resulted in a more rapid loss of mitochondrial membrane potential (ΔΨm), a greater activation of caspases (3, 8, and 9), and a significant increase in superoxide/reactive oxygen species (ROS) in STHdhQ111 compared to STHdhQ7, while both cell types showed similar kinetics of ΔΨm-loss and similar levels of superoxide/ROS in the pyruvate condition. This suggests that bioenergetic deficiencies are not the primary contributor to the enhanced sensitivity of STHdhQ111 cells to stressors compared to the STHdhQ7 cells. PPARγ activation significantly attenuated thapsigargin-induced cell death, concomitant with an inhibition of caspase activation, a delay in ΔΨm loss, and a reduction of superoxide/ROS generation in STHdhQ111 cells. Expression of mutant huntingtin in primary neurons induced superoxide/ROS, an effect that was significantly reduced by constitutively active PPARγ. These results provide significant insight into the bioenergetic disturbances in HD with PPARγ being a potential therapeutic target for HD

Identification and manipulation of tumor associated macrophages in human cancers

Evading immune destruction and tumor promoting inflammation are important hallmarks in the development of cancer. Macrophages are present in most human tumors and are often associated with bad prognosis. Tumor associated macrophages come in many functional flavors ranging from what is known as classically activated macrophages (M1) associated with acute inflammation and T-cell immunity to immune suppressive macrophages (M2) associated with the promotion of tumor growth. The role of these functionally different myeloid cells is extensively studied in mice tumor models but dissimilarities in markers and receptors make the direct translation to human cancer difficult. This review focuses on recent reports discriminating the type of infiltrating macrophages in human tumors and the environmental cues present that steer their differentiation. Finally, immunotherapeutic approaches to interfere in this process are discussed

Sedimentary characteristics of relict deposits on the western South Yellow Sea

Integrated studies of vertical sedimentary sequences, grain sizes, and benthic foraminifera and ostracoda, in combination with AMS 14C dating, and 210Pb and 137Cs analysis were carried out in three vibracores taken from the area of relict deposits on the western South Yellow Sea. The relict sands, which are about 0.4 m thick, overlie on the Early Holocene coastal marsh or tidal flat deposits with an evident erosional interface in between. The middle and upper parts or sometimes the whole of the relict sands have been reworked under the modern dynamic environment. The sedimentation rate varies between 0.20-0.30 cm year-1. The relict sands show a bimodal grain-size distribution pattern in frequency curves, with a sharp peak in the coarse fraction between 3F and 4F and a secondary peak in the fine fraction of about 7F. Of the benthic foraminiferal and ostracod assemblages, the reworked relict sands are characterized by the mixing of the nearshore euryhaline shallow-water species and deeper water species. The erosional interface at the bottom of the relict sands is considered as a regional ravinement surface formed during the transgression in the Early Holocene due to shoreface retreating landwards. The relict sands were accumulated on the ravinement surface during the transgression in the deglaciation period as lag deposits after winnowing and reworking by marine dynamic processes. And the secondary peak of fine fraction in the frequency curve for the relict sands suggests the input of fine-grained sediments during the reworking process. As the conclusion, the relict sands in the study area are interpreted as a type of reworked relict sediments. © 2014 Science Press, Ocean University of China and Springer-Verlag Berlin Heidelberg