Gossypin induces G2/M arrest in human malignant glioma U251 cells by the activation of Chk1/Cdc25C pathway.

Gossypin is a flavone that was originally isolated from Hibiscus vitifolius and has traditionally been used for the treatment of diabetes, jaundice, and inflammation. Recently, gossypin was found to have potent anticancer properties; however, its effect on human gliomas still remain unknown. To investigate the potential anticancer effects of gossypin on malignant gliomas and analyze the associated molecular mechanisms, we treated human glioma U251 cells with gossypin. Our study showed that the treatment of U251 cells with gossypin inhibited cell proliferation in a dose- and time-dependent manner and was observed to be minimally toxic to normal human astrocytes. Gossypin's effect on cell cycle distribution was observed, and we found that it induced G2/M-phase arrest in U251 cells. An analysis of cell-cycle regulatory proteins indicated that the arresting effect of gossypin on the cell cycle at G2/M phase was involved in the phosphorylation of cell division cycle 25C (Cdc25C) tyrosine phosphatase via the activation of checkpoint kinase 1 (Chk1). These findings indicate that gossypin is a potential treatment of gliomas because of gossypin's potential to regulate the proliferation of U251 cells via the cell-cycle regulatory proteins Chk1 and Cdc25C.

Defects in mesenchymal stem cell self-renewal and cell fate determination lead to an osteopenic phenotype in Bmi-1 null mice.

In parathyroid hormone-related protein 1-84 [PTHrP(1-84)] knockin mice, expression of the polycomb protein Bmi-1 is reduced and potentially can mediate the phenotypic alterations observed. We have therefore now examined the skeletal phenotype of Bmi-1(-/-) mice in vivo and also assessed the function of bone marrow mesenchymal stem cells (BM-MSCs) from Bmi-1(-/-) mice ex vivo in culture. Neonatal Bmi-1(-/-) mice exhibited skeletal growth retardation, with reduced chondrocyte proliferation and increased apoptosis. Osteoblast numbers; gene expression of alkaline phosphatase, type I collagen, and osteocalcin; the mineral apposition rate; trabecular bone volume; and bone mineral density all were reduced significantly; however, the number of bone marrow adipocytes and Ppar-gamma expression were increased. These changes were consistent with the skeletal phenotype observed in the PTHrP(1-84) knockin mouse. The efficiency of colony-forming unit fibroblast (CFU-F) formation in bone marrow cultures was decreased, and the percentage of alkaline phosphatase-positive CFU-F and Runx2 expression were reduced. In contrast, adipocyte formation and Ppar-gamma expression in cultures were increased, and expression of the polycomb protein sirtuin (Sirt1) was reduced. Reduced proliferation and increased apoptosis of BM-MSCs were associated with upregulation of senescence-associated tumor-suppressor genes, including p16, p19, and p27. Analysis of the skeletal phenotype in Bmi-1(-/-) mice suggests that Bmi-1 functions downstream of PTHrP. Furthermore, our studies indicate that Bmi-1 maintains self-renewal of BM-MSCs by inhibiting the expression of p27, p16, and p19 and alters the cell fate of BM-MSCs by enhancing osteoblast differentiation and inhibiting adipocyte differentiation at least in part by stimulating Sirt1 expression. Bmi-1 therefore plays a critical role in promoting osteogenesis.

3,7-Dihydr-oxy-3,7-diphenyl-2H,6H-pyrrolo[3,4-f]isoindole-1,5(3H,7H)-dione methanol disolvate.

The asymmetric unit of the title compound, C(22)H(16)N(2)O(4)·2CH(4)O, contains one half-mol-ecule and a methanol solvent mol-ecule. The aromatic ring is oriented at a dihedral angle of 82.91 (3)° with respect to the planar indole ring systems. In the crystal structure, inter-molecular O-H⋯O and N-H⋯O hydrogen bonds link the mol-ecules into chains along the b axis.