Essential elements regulating HDAC8 inhibition: a classification based structural analysis and enzyme-inhibitor interaction study of hydroxamate based HDAC8 inhibitors
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
Authors: Banerjee, Suvankar; Amin, Sk Abdul; Adhikari, Nilanjan; Jha, Tarun
Abstract
Histone deacetylase 8 (HDAC8) expressions are correlated with a variety of cancer and tumor conditions. For the pathophysiological contributions of HDAC8, it is classified as an important target for cancer research. The hydroxamate derivatives are identified as more efficient HDAC8 inhibitors. However, strong chelating properties of hydroxamate group with the catalytic zinc ion of HDAC8 resulted in some demerits. Hence, in this current study, classification based chemoinformatic approaches including Bayesian modeling and recursive partitioning studies were conducted on a large and diverse set of 607 hydroxamates having less, very poor to high HDAC8 inhibitory properties. The main motto of this study is to identify and analyze the pivotal structural features of the cap and linker moieties required to obtain better HDAC8 inhibition. Moreover, a scrutiny of the HDAC8 crystal structure bound inhibitors was performed to correlate enzyme-inhibitor interactions with important molecular features resulted from these two classification-based models. The approach may be used to design novel HDAC8 inhibitors. Communicated by Ramaswamy Sarma
Light-sheet microscopy-based 3D single-cell tracking reveals a correlation between cell cycle and the start of endoderm cell internalization in early zebrafish development
DEVELOPMENT GROWTH & DIFFERENTIATION
Authors: Kondow, Akiko; Ohnuma, Kiyoshi; Kamei, Yasuhiro; Taniguchi, Atsushi; Bise, Ryoma; Sato, Yoichi; Yamaguchi, Hisateru; Nonaka, Shigenori; Hashimoto, Keiichiro
Abstract
Controlling the initiation of cell migration plays a fundamental role in shaping the tissue during embryonic development. During gastrulation in zebrafish, some mesendoderm cells migrate inward to form the endoderm as the innermost germ layer along the yolk syncytial layer. However, how the initiation of inward migration is regulated is poorly understood. In this study, we performed light-sheet microscopy-based 3D single-cell tracking consisting of (a) whole-embryo time-lapse imaging with light-sheet microscopy and (b) three-dimensional single cell tracking in the zebrafish gastrula in which cells are marked with histone H2A-mCherry (nuclei) and the sox17:EGFP transgene (expressed in endoderm cells). We analyzed the correlation between the timing of cell internalization and cell division. Most cells that differentiated into endoderm cells began to internalize during the first half of the cell cycle, where the length of a cell cycle was defined by the period between two successive cell divisions. By contrast, the timing of other internalized cells was not correlated with a certain phase of the cell cycle. These results suggest the possibility that cell differentiation is associated with the relationship between cell cycle progression and the start of internalization. Moreover, the 3D single-cell tracking approach is useful for further investigating how cell migration is integrated with cell proliferation to shape tissues in zebrafish embryos.