Inhibition of PirB Activity by TAT-PEP Improves Mouse Motor Ability and Cognitive Behavior.

Paired immunoglobulin-like receptor B (PirB), a functional receptor for myelin-associated inhibitory proteins, plays an important role in axon regeneration in injured brains. However, its role in normal brain function with age has not been previously investigated. Therefore in this study, we examined the expression level of PirB in the cerebral cortex, hippocampus and cerebellum of mice at 1 month, 3 months and 18 months of age. The results showed that the expression of PirB increased with age. We further demonstrated that overexpression of PirB inhibited neurite outgrowth in PC12 cells, and this inhibitory activity of PirB could be reversed by TAT-PEP, which is a recombinant soluble PirB ectodomain fused with TAT domain for blood-brain barrier penetration. In vivo study, intraperitoneal administration of TAT-PEP was capable of enhancing motor capacity and spatial learning and memory in mice, which appeared to be mediated through regulation of brain-derived neurotrophic factor (BDNF) secretion. Our study suggests that PirB is associated with aging and TAT-PEP may be a promising therapeutic agent for modulation of age-related motor and cognitive dysfunctions.

The mitotic-arresting and apoptosis-inducing effects of diosgenyl saponins on human leukemia cell lines.

Diosgenyl saponins are the most abundant steroid saponins, and exert a large variety of biological functions. In a previous report, we showed that dioscin was able to induce cytotoxicity and apoptosis in human myeloblast leukemia HL-60 cells. This study further investigated the action mechanisms underlying this effect. The activation of caspase-9 and -3, but not caspase-8, together with the down-regulation of anti-apoptotic Bcl-2 protein, demonstrated that the apoptotic signaling triggered by dioscin was mediated through the intrinsic mitochondria-dependent pathway. We also investigated its anti-proliferative effect on human chronic myelogenous leukemia K562 cells. Flow cytometry analysis showed that dioscin treatment induced the accumulation of cells in the G(2)/M phase. Cytomorphology with DAPI and Wright-Giemsa staining demonstrated the enlargement of cell volume and multinucleation in the treated cells. Subsequent apoptosis was delineated with phosphatidylserine externalization and DNA hypodiploidy. Trillin was one of the hydrolysates of dioscin. We demonstrated that it could induce multinucleation in HL-60, K562 and human promyelocytic leukemia NB(4) cells, suggesting its extensive mitotic-arresting effects. As the diosgenyl sapogenin, diosgenin was also shown to be able to induce multinucleation and apoptosis in K562 cells in a similar manner to dioscin. These findings suggest that diosgenyl saponins have the properties to induce mitotic arrest and apoptosis, suggesting that they may be a new kind of antimitotic agent.