Phase I Trial of Intra-arterial Administration of Autologous Bone Marrow-Derived Mesenchymal Stem Cells in Patients with Multiple System Atrophy.

BACKGROUND: This study is aimed at investigating the safety and tolerability of the intra-arterial administration of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in patients with multiple system atrophy- (MSA-) cerebellar type (MSA-C). METHODS: This was a single-center, open-label phase I clinical trial in patients with MSA-C. A three-stage dose escalation scheme (low-dose, 3.0 × 105 cells/kg; medium-dose, 6.0 × 105 cells/kg; high-dose, 9.0 × 105 cells/kg) was applied to determine the maximum tolerated dose of intra-arterial administration of BM-MSCs based on the no-observed-adverse-effect level derived from the toxicity study. The occurrence of adverse events was evaluated 1 day before and 1, 14, and 28 days after BM-MSC therapy. Additionally, we assessed changes in the Unified MSA Rating Scale (UMSARS) score 3 months after BM-MSC treatment. RESULTS: One serious adverse drug reaction (ADR) of leptomeningeal enhancement following the intra-arterial BM-MSC administration occurred in one patient in the low-dose group. The safety review of the Internal Monitoring Committee interpreted this as radiological evidence of the blood-brain barrier permeability for MSCs. No other ADRs were observed in the medium- or high-dose groups. In particular, no ischemic lesions on diffusion-weighted images were observed in any of the study participants. Additionally, the medium- and high-dose groups tended to show a slower increase in UMSARS scores than the low-dose group during the 3-month follow-up. CONCLUSION: The present study confirmed that a single intra-arterial administration of autologous BM-MSCs is a safe and promising neuroprotective strategy in patients with MSA-C.

Beneficial effect of estrogen on nigrostriatal dopaminergic neurons in drug-naïve postmenopausal Parkinson's disease.

This study aimed to investigate the potential beneficial effects of estrogen on nigrostriatal dopaminergic neuron degeneration in postmenopausal drug-naïve Parkinson's disease (PD). Based on the ratio of lifetime estrogen exposure length to the total length of the estrogen exposure and deprivation period, postmenopausal women with drug-naïve PD were divided into low (n = 31) and high (n = 31) estrogen exposure ratio groups. We performed a comparative analysis of the striatal dopamine transporter (DAT) availability between the two groups. Additionally, we evaluated the longitudinal change in the levodopa equivalent dose per month using a linear mixed model. The motor symptoms were more severe in the low estrogen exposure ratio group than in the high estrogen exposure ratio group (P = 0.016). PD patients in the two groups had significantly lower DAT availability on all striatal sub-regions except for ventral striatum than did age- and sex-matched normal controls. When comparing the two groups, PD patients in the low estrogen exposure ratio group exhibited significantly lower DAT availability in the posterior putamen (P = 0.024) and in the ventral putamen (P = 0.036) than those in the high estrogen exposure ratio group. The estimated monthly levodopa equivalent dose changes were 10.9 in the low estrogen exposure ratio group and 7.1 in the high estrogen exposure ratio group with a significant interaction between the two groups (P = 0.001). These in vivo data provide indirect evidence showing that estrogen may elicit a beneficial effect on nigrostriatal dopamine neurons in PD.

A case of isolated middle cerebral artery stenosis with hemichorea and moyamoya pattern collateralization.

Isolated middle cerebral artery (MCA) stenosis in young patients with no other medical condition may be a unique pathologic entity with a benign long-term course. Generally, moyamoya disease shows a progression of stenosis from internal cerebral artery (ICA) to other intracranial vessel. A 26-year-old woman was admitted for choreic movements of the right arm and leg. Brain magnetic resonance imaging showed no stroke. Conventional angiography revealed 48% stenosis of the left M1 without ICA stenosis. Single photon emission computed tomography revealed perfusion asymmetry after acetazolamide injection, suggesting decreased uptake in the left basal ganglia and the cerebral cortex. Her hemichorea was mildly decreased with risperidone. One year later, follow-up angiography showed complete occlusion of the left M1 with neovascularization suggestive of moyamoya disease. The patient underwent bypass surgery and her hemichorea disappeared. This may be an atypical presentation of moyamoya disease. The bypass surgery was an effective measure for restoring the vascular insufficiency and, resultantly, controlling her hemichorea.

2-hydroxycinnamaldehyde inhibits SW620 colon cancer cell growth through AP-1 inactivation.

Cinnamaldehyde derivatives isolated from Cinnamomum cassia have been widely used for treating dyspepsia, gastritis, and inflammatory disease as well as cancer. To investigate the anti-tumor activities of several cinnamaldehyde derivatives, we compared the inhibitory effect of cinnamaldehyde derivatives on cell growth and AP-1 transcriptional activity in SW620 human colon cancer cells since AP-1 is a transcriptional factor implicated to control cancer cell growth. Among the derivatives, 2'-hydroxycinnamaldehyde (HCA) most significantly inhibited cancer cell growth and AP-1 transcriptional activity in a dose-dependent manner with an IC50 value of 12.5 and 9 microg/ml, respectively. In further studies on the mechanism, we found that consistent with the inhibitory effect on cell growth, HCA dose-dependently (0-20 microg/ml) inhibited DNA binding activity of AP-1 accompanied with down regulation of c-Jun and c-Fos expressions. HCA also induced apoptotic cell death as well as expression of the apoptosis-regulating gene caspase-3, but inhibited the anti-apoptosis regulating gene bcl-2 in a dose-dependent manner. These results suggested that HCA has the most potent inhibitory effect against human colon cancer cell growth, and AP-1 may be an important target of HCA.

Inhibitory effect of green tea extract on beta-amyloid-induced PC12 cell death by inhibition of the activation of NF-kappaB and ERK/p38 MAP kinase pathway through antioxidant mechanisms.

Beta-amyloid peptide (Abeta) is considered responsible for the pathogenesis of Alzheimer's disease (AD). Several lines of evidence support that Abeta-induced cytotoxicity is mediated through the generation of reactive oxygen species (ROS). Thus, agents that scavenge ROS level may usefully impede the development or progress of AD. Green tea extract has been known to have such antioxidant properties. Our previous studies demonstrate that green tea extract protected ischemia/reperfusion-induced brain cell death by scavenging oxidative damages of macromolecules. In this study, we investigated the effects of green tea extract on Abeta-induced oxidative cell death in cultured rat pheochromocytoma (PC12) cells. PC12 cells treated with Abeta25-35 (10-50 microM) showed intracellular ROS elevation, the formation of 8-oxodG (an oxidized form of DNA), and underwent apoptotic cell death in a dose-dependent manner. Abeta(25-35) treatment upregulated pro-apoptotic p53 at the gene level, and Bax and caspase-3 at the protein level, but downregulated anti-apoptotic Bcl-2 protein. Interestingly, co-treated green tea extract (10-50 microg/ml) dose-dependently attenuated Abeta(25-35) (50 microM)-induced cell death, intracellular ROS levels, and 8-oxodG formation, in addition to p53, Bax, and caspase-3 expression, but upregulated Bcl-2. Furthermore, green tea extract prevented the Abeta(25-35)-induced activations of the NF-kappaB and ERK and p38 MAP kinase pathways. Our study suggests that green tea extract may usefully prevent or retard the development and progression of AD.