Huntingtin-interacting protein 1-mediated neuronal cell death occurs through intrinsic apoptotic pathways and mitochondrial alterations.

Huntingtin interacting protein-1 (Hip1) is known to be associated with the N-terminal domain of huntingtin. Although Hip1 can induce apoptosis, the exact upstream signal transduction pathways have not been clarified yet. In the present study, we examined whether activation of intrinsic and/or extrinsic apoptotic pathways occurs during Hip1-mediated neuronal cell death. Overexpression of Hip1 induced cell death through caspase-3 activation in immortalized hippocampal neuroprogenitor cells. Interestingly, proteolytic processing of Hip1 into partial fragments was observed in response to Hip1 transfection and apoptosis-inducing drugs. Moreover, Hip1 was found to directly bind to and activate caspase-9. This promoted cytosolic release of cytochrome c and apoptosis-inducing factor via mitochondrial membrane perturbation. Furthermore, Hip1 could directly bind to Apaf-1, suggesting that the neurotoxic signals of Hip1 transmit through the intrinsic mitochondrial apoptotic pathways and the formation of apoptosome complex.

Impact of Orthodontic Brackets on the Intraoral Scan Data Accuracy.

This study aims to compare the impact of buccal and lingual brackets on the accuracy of dental arch data acquired by 4 different digital intraoral scanners. Two pairs of dental casts, one with buccal brackets and the other with lingual brackets, were used. Digital measurements of the 3D images were compared to the actual measurements of the dental models, which were considered standard values. The horizontal measurements included intercanine widths and intermolar widths. The Mann-Whitney U test was performed for comparisons. iTero® and Trios® both showed high accuracy with relatively small maximum deviation of measurements. iTero showed a significantly higher accuracy in most of the arch width measurements on the buccal bracket model than on the lingual model (P < 0.05). Zfx IntraScan® and E4D Dentist® produced maximum deviations of more than 2 mm from both the buccal and the lingual bracket models. After comparing the degree of distortion of the arch on the digital scans with actual measurements of the same models, iTero and Trios proved to be excellent in terms of trueness and precision. Nevertheless, digital intraoral scanners should be used more cautiously in arches with lingual brackets than in those with buccal brackets.

Modulation of ionizing radiation-induced G2 arrest by cyclooxygenase-2 and its inhibitor celecoxib.

PURPOSE: Prolongation or attenuation of ionizing radiation (IR)-induced G(2)-M arrest in cyclooxygenase-2 (COX-2) overexpressing or celecoxib-treated cells, respectively, has been previously observed. To better understand the molecular mechanisms involved, we investigated the molecules involved in G(2) checkpoint pathways after treatment with IR +/- celecoxib. METHODS AND MATERIALS: Various molecules in the G(2) checkpoint pathways were investigated in HCT-116-Mock and -COX-2 cells. Western blot, reverse transcriptase polymerase chain reaction, confocal microscopy, and fluorescence activated cell sorter (FACS) analyses were performed to investigate whether expression and activity of the ataxia telangiectasia and rad3-related (ATR) could be modulated by COX-2 and its selective inhibitors. RESULTS: COX-2 overexpression increased expression and activity of ATR after IR exposure. Celecoxib downregulated ATR in all tested cell lines independent of COX-2 expression, but downregulation was greater in COX-2 overexpressing cells after cells were irradiated. Celecoxib pretreatment before radiation caused strongly inhibited G(2) arrest. CONCLUSIONS: COX-2 appears to prolong IR-induced G(2) arrest by upregulating ATR. Celecoxib downregulated ATR preferentially in irradiated COX-2 overexpressing cells. Celecoxib may radiosensitize cancer cells by inhibiting G(2) arrest through ATR downregulation.

Regulation of the proapoptotic activity of huntingtin interacting protein 1 by Dyrk1 and caspase-3 in hippocampal neuroprogenitor cells.

Dual specific protein kinase Dyrks are thought to play a key role in the regulation of cell growth in a variety of cellular systems. Interestingly, human Dyrk1 is mapped to the Down's syndrome (DS) critical region on chromosome 21, and thought to be a candidate gene responsible for the mental retardation of DS patients. Huntingtin-interacting protein 1 (Hip-1), a proapoptotic mediator, is implicated as a molecular accomplice in the pathogenesis of Huntington's disease. In the present study we found that Dyrk1 selectively binds to and phosphorylates Hip-1 during the neuronal differentiation of embryonic hippocampal neuroprogenitor (H19-7) cells. The Dyrk1-mediated phosphorylation of Hip-1, in response to bFGF, resulted in the blockade of Hip-1-mediated neuronal cell death as well as the enhancement of neurite outgrowth. Furthermore, the addition of etoposide to proliferating H19-7 cells caused the diminished binding of Hip-1 to Dyrk1 and the levels of phosphorylated Hip-1 remarkably decreased. Simultaneously, the dissociated Hip-1 from Dyrk1 bound to caspase-3 in response to etoposide, which led to its activation and consequently cell death in H19-7 cells. These data suggest that the phosphorylation of Hip-1 by Dyrk1 has a dual role in regulating neuronal differentiation and cell death. The interaction between Dyrk1 and Hip-1 appeared to be differentially modulated by different kinds of stimuli, such as bFGF and etoposide in H19-7 cells.