In this study, we investigated the molecular basis for the altered signal transduction associated with soluble amyloid ␤-protein (A␤) oligomer-mediated neurotoxicity in the hippocampus, which is primarily linked to cognitive dysfunction in Alzheimer disease (AD). As measured by media lactate dehydrogenase levels, and staining with propidium iodide, acute exposure to low micromolar concentrations of the A␤1-42 oligomer significantly induced cell death. This was accompanied by activation of the ERK1/2 signal transduction pathway in rat organotypic hippocampal slices. Notably, this resulted in caspase-3 activation by a process that led to proteolytic cleavage of Tau, which was recently confirmed to occur in AD brains. Tau cleavage likely occurred in the absence of overt synaptic loss, as suggested by the preserved levels of synaptophysin, a presynaptic marker. Moreover, among the pharmacological agents tested to inhibit several kinase cascades, only the ERK inhibitor significantly attenuated A␤1-42 oligomer-induced toxicity concomitant with the reduction of activation of ERK1/2 and caspase-3 to a lesser extent. Importantly, the caspase-3 inhibitor also decreased A␤ oligomer-induced cell death, with no appreciable effect on the ERK signaling pathway, although such treatment was effective in reducing caspase-3 activation and Tau cleavage. Therefore, these results suggest that local targeting of the ERK1/2 signaling pathway to reduce Tau cleavage, as occurs with the inhibition of caspase-3 activation, may modulate the neurotoxic effects of soluble A␤ oligomer in the hippocampus and provide the rationale for symptomatic treatment of AD. Alzheimer disease (AD)2 neuropathology is characterized by key features that include fibrillar amyloid ␤-protein (A␤) deposition into dense senile plaques, the formation of neurofibrillary tangles composed of hyperphosphorylated Tau, and the loss of neurons and synapses in the affected brain region leading to the progressive loss of cognitive function (1, 2). Recent evidence suggests that soluble, prefibrillar, and oligomeric forms of A␤ are acutely toxic (3) and can interfere with synaptic plasticity in the brain, suggesting that this form of the peptide may be responsible for episodic memory deficits, an early symptom of AD, which is linked to hippocampal pathology (4). In fact, soluble A␤ oligomers, also referred as A␤-derived diffusible ligands, strikingly elevated in the AD brain (5-8) are also described in human amyloid precursor protein transgenic mice AD models (9) and can inhibit the long term potentiation (LTP) of synaptic efficiency (10, 11). The pathogenic relevance of this form of A␤ has been substantiated by a newly identified Arctic familial AD mutation, which has an increased propensity to oligomerize (12, 13), and by in vitro data demonstrating potent neurotoxicity upon exposure to soluble oligomer or protofibrils (3,14,15). Moreover, the ultrastructural localization of A␤ oligomer within neuritic processes and at synaptic terminals in AD brains (16,17) further supports...

Penta-1,2,3,4,6-O-galloyl-B-D-glucose (PGG) is a naturally occurring gallotannin from some Oriental herbs. Several cell culture studies suggested a potential for PGG as a novel agent for the chemoprevention and treatment of cancer. Here, we investigated the cell death signaling mechanisms induced by PGG in human prostate cancer cells of different p53 functional status. We observed the induction of G 1 -and S-phase arrests and caspasemediated apoptosis in the androgen-dependent human LNCaP cells, which express wild-type p53, and in the androgen-independent, p53-mutant DU145 cells. In LNCaP cells, caspase-mediated apoptosis induction by PGG was associated with and mediated in major part by activation of p53 as established through small interfering RNA knockdown and dominant-negative mutant approaches. Intracellular reactive oxygen species production by PGG was found to be crucial for these molecular and cellular actions. In DU145 cells, which harbor constitutively active signal transducer and activator of transcription 3 (STAT3), caspase-mediated apoptosis induction by PGG was associated with an inhibition of STAT3 Tyr 705 phosphorylation and the down-regulation of STAT3 transcriptional targets Bcl-XL and Mcl-1. Overexpression of Bcl-XL or knockdown of its binding partner Bak attenuated apoptosis induction. Furthermore, we provide, for the first time, in vivo data that PGG significantly inhibited DU145 xenograft growth in an athymic nude mouse model in association with an inhibition of pSTAT3. Our data support PGG as a multitargeting agent for chemoprevention and therapy of prostate cancer by activating the p53 tumor suppressor pathway and by inhibiting STAT3 oncogenic signaling.

Androgen and androgen receptor (AR)-mediated signaling are crucial for the development of prostate cancer. Identification of novel and naturally occurring phytochemicals that target androgen and AR signaling from Oriental medicinal herbs holds exciting promises for the chemoprevention of this disease. In this article, we report the discovery of strong and long-lasting antiandrogen and AR activities of the ethanol extract of a herbal formula (termed KMKKT) containing Korean Angelica gigas Nakai (AGN) root and nine other Oriental herbs in the androgen-dependent LNCaP human prostate cancer cell model. The functional biomarkers evaluated included a suppression of the expression of prostate-specific antigen (PSA) mRNA and protein (IC 50 , f7 Mg/mL, 48-hour exposure) and an inhibition of androgen-induced cell proliferation through G 1 arrest and of the ability of androgen to suppress neuroendocrine differentiation at exposure concentrations that did not cause apoptosis. Through activity-guided fractionation, we identified decursin from AGN as a novel antiandrogen and AR compound with an IC 50 of f0.4 Mg/mL (1.3 Mmol/L, 48-hour exposure) for suppressing PSA expression. Decursin also recapitulated the neuroendocrine differentiation induction and G 1 arrest actions of the AGN and KMKKT extracts. Mechanistically, decursin in its neat form or as a component of AGN or KMKKT extracts inhibited androgen-stimulated AR translocation to the nucleus and down-regulated AR protein abundance without affecting the AR mRNA level. The novel antiandrogen and AR activities of decursin and decursin-containing herbal extracts have significant implications for the chemoprevention and treatment of prostate cancer and other androgen-dependent diseases. (Cancer Res 2006; 66(1): 453-63)

T'ai chi increased knee extensor muscle endurance and bone mineral density in older women with osteoarthritis, and decreased their fear of falling during daily activities. Further study with long-term follow-up is needed to substantiate the role of t'ai chi exercise in the prevention of fall and its related fracture.

A Sun-style Tai Chi exercise was found as beneficial for women with osteoarthritis to reduce their perceived arthritic symptoms, improve their perception of health benefits to perform better health behaviors.