Bazedoxifene, a Selective Estrogen Receptor Modulator, Promotes Functional Recovery in a Spinal Cord Injury Rat Model.

In research on various central nervous system injuries, bazedoxifene acetate (BZA) has shown two main effects: neuroprotection by suppressing the inflammatory response and remyelination by enhancing oligodendrocyte precursor cell differentiation and oligodendrocyte proliferation. We examined the effects of BZA in a rat spinal cord injury (SCI) model. Anti-inflammatory and anti-apoptotic effects were investigated in RAW 264.7 cells, and blood-spinal cord barrier (BSCB) permeability and angiogenesis were evaluated in a human brain endothelial cell line (hCMEC/D3). In vivo experiments were carried out on female Sprague Dawley rats subjected to moderate static compression SCI. The rats were intraperitoneally injected with either vehicle or BZA (1mg/kg pre-SCI and 3 mg/kg for 7 days post-SCI) daily. BZA decreased the lipopolysaccharide-induced production of proinflammatory cytokines and nitric oxide in RAW 264.7 cells and preserved BSCB disruption in hCMEC/D3 cells. In the rats, BZA reduced caspase-3 activity at 1 day post-injury (dpi) and suppressed phosphorylation of MAPK (p38 and ERK) at dpi 2, hence reducing the expression of IL-6, a proinflammatory cytokine. BZA also led to remyelination at dpi 20. BZA contributed to improvements in locomotor recovery after compressive SCI. This evidence suggests that BZA may have therapeutic potential to promote neuroprotection, remyelination, and functional outcomes following SCI.

Alcohol-induced suppression of KDM6B dysregulates the mineralization potential in dental pulp stem cells.

Epigenetic changes, such as alteration of DNA methylation patterns, have been proposed as a molecular mechanism underlying the effect of alcohol on the maintenance of adult stem cells. We have performed genome-wide gene expression microarray and DNA methylome analysis to identify molecular alterations via DNA methylation changes associated with exposure of human dental pulp stem cells (DPSCs) to ethanol (EtOH). By combined analysis of the gene expression and DNA methylation, we have found a significant number of genes that are potentially regulated by EtOH-induced DNA methylation. As a focused approach, we have also performed a pathway-focused RT-PCR array analysis to examine potential molecular effects of EtOH on genes involved in epigenetic chromatin modification enzymes, fibroblastic markers, and stress and toxicity pathways in DPSCs. We have identified and verified that lysine specific demethylase 6B (KDM6B) was significantly dysregulated in DPSCs upon EtOH exposure. EtOH treatment during odontogenic/osteogenic differentiation of DPSCs suppressed the induction of KDM6B with alterations in the expression of differentiation markers. Knockdown of KDM6B resulted in a marked decrease in mineralization from implanted DPSCs in vivo. Furthermore, an ectopic expression of KDM6B in EtOH-treated DPSCs restored the expression of differentiation-related genes. Our study has demonstrated that EtOH-induced inhibition of KDM6B plays a role in the dysregulation of odontogenic/osteogenic differentiation in the DPSC model. This suggests a potential molecular mechanism for cellular insults of heavy alcohol consumption that can lead to decreased mineral deposition potentially associated with abnormalities in dental development and also osteopenia/osteoporosis, hallmark features of fetal alcohol spectrum disorders.

Internal thoracic artery malperfusion: fast decision for an additional vein graft has impact on patient outcome.

BACKGROUND: Internal thoracic artery (ITA) malperfusion has been described as a potentially devastating and lethal complication of coronary artery bypass grafting (CABG). It is our practice to perform an additional vein graft to the distal left anterior descending (LAD) artery in such cases. METHODS: From August 1999 to July 2002, 2877 CABG procedures were performed at our institution. In 65 patients (2.3%) ITA malperfusion was observed. All of them were treated with an additional vein graft to the distal LAD. All patient data were screened for the time interval between the occurrence of ITA malperfusion and the decision to perform an additional vein graft. RESULTS: Of 65 patients with ITA malperfusion, 54 patients (83%) survived (group 1), 11 patients (17%) died (group 2). There was no difference in preoperative risk status between the groups. Cross clamp time was 88 +/- 4 minutes in group 1 and 104 +/- 11 minutes in group 2 (p = 0.04). Intraoperative ITA flow to LAD was 6 +/- 1 mL/min in group 1 and 10 +/- 5 mL/min in group 2 (p = 0.2). Time between release of cross clamp and second period of cross clamping was 50 +/- 5 minutes in group 1 and 75 +/- 11 minute group 2 (p = 0.02). Time between termination of cardiopulmonary bypass (CPB) and second period of cross clamping was 23 +/- 3 minutes in group 1 and 46 +/- 7 minutes in group 2 (p = 0.003). Vein graft flow to distal LAD was 54 +/- 4 mL/min in group 1 and 52 +/- 12 mL/min in group 2 (p = 0.5). Maximum postoperative troponin I was 35 +/- 11 ng/mL in group 1 and 136 +/- 32 in group 2 (p = 0.003). CONCLUSIONS: Survivors of ITA malperfusion had shorter cross clamp times and less myocardial damage as evidenced by lower postoperative troponin I levels. Time intervals between first and second cross clamp and between termination of CPB and second cross clamp were lower in survivors, thus indicating that a fast decision for an additional vein graft may influence postoperative patient outcome.

Molecular effect of ethanol during neural differentiation of human embryonic stem cells in vitro.

Potential teratogenic effects of alcohol on fetal development have been documented. Especially studies have demonstrated deleterious effect of ethanol exposure on neuronal development in animal models and on the maintenance and differentiation of neuronal precursor cells derived from stem cells. To better understand molecular effect of alcohol on the process of neural differentiation, we have performed gene expression microarray analysis on human embryonic stem cells being directed to neural rosettes and neural precursor cells in the presence of ethanol treatment. Here we provide detailed experimental methods, analysis and information associated with our data deposited into Gene Expression Omnibus (GEO) under GSE56906. Our data provide scientific insight on potential molecular effects of fetal alcohol exposure on neural differentiation of early embryo development.