Brain-derived neurotrophic factor administration mediated oligodendrocyte differentiation and myelin formation in subcortical ischemic stroke.

BACKGROUND AND PURPOSE: Translational research is beginning to reveal the importance of trophic factors as a therapy for cellular brain repair. The purpose of this study was to analyze whether brain-derived neurotrophic factor (BDNF) administration could mediate oligodendrogenesis and remyelination after white matter injury in subcortical stroke. METHODS: Ischemia was induced in rats by injection of endothelin-1. At 24 hours, 0.4 µg/kg of BDNF or saline was intravenously administered to the treatment and control groups, respectively. Functional evaluation, MRI, and fiber tract integrity on tractography images were analyzed. Proliferation (KI-67) and white matter repair markers (A2B5, 2',3'-cyclic-nucleotide 3'-phosphodiesterase [CNPase], adenomatous polyposis coli [APC], platelet-derived growth factor receptor alpha [PDGFR-α], oligodendrocyte marker O4 [O4], oligodendrocyte transcription factor [Olig-2], and myelin basic protein [MBP]) were analyzed at 7 and 28 days. RESULTS: The BDNF-treated animals showed less functional deficit at 28 days after treatment than the controls (P<0.05). Although T2-MRI did not show differences in lesion size at 7 and 28 days between groups, diffusion tensor imaging tractography analysis revealed significantly better tract connectivity at 28 days in the BDNF group than in the controls (P<0.05). Increased proliferation of oligodendrocyte progenitors was observed in treated animals at 7 days (P<0.05). Finally, the levels of white matter repair markers (A2B5, CNPase, and O4 at 7 days; Olig-2 and MBP at 28 days) were higher in the BDNF group than in the controls (P<0.05). CONCLUSIONS: BDNF administration exerted better functional outcome, oligodendrogenesis, remyelination, and fiber connectivity than controls in rats subjected to subcortical damage in ischemic stroke.

Design and Synthesis of TASIN Analogues Specifically Targeting Colorectal Cancer Cell Lines with Mutant Adenomatous Polyposis Coli (APC).

Despite advances in targeted anticancer therapies, there are still no small-molecule-based therapies available that specifically target colorectal cancer (CRC) development and progression, the second leading cause of cancer deaths. We previously disclosed the discovery of truncating adenomatous polyposis coli (APC)-selective inhibitor 1 (TASIN-1), a small molecule that specifically targets colorectal cancer cells lines with truncating mutations in the adenomatous polyposis coli (APC) tumor suppressor gene through inhibition of cholesterol biosynthesis. Here, we report a medicinal chemistry evaluation of a collection of TASIN analogues and activity against colon cancer cell lines and an isogenic cell line pair reporting on the status of APC-dependent selectivity. A number of potent and selective analogues were identified, including compounds with good metabolic stability and pharmacokinetic properties. The compounds reported herein represent a first-in-class genotype-selective series that specifically target apc mutations present in the majority of CRC patients and serve as a translational platform toward a targeted therapy for colon cancer.

Cyclosporine A enhances gingival ß-catenin stability via Wnt signaling.

BACKGROUND: Cyclosporine A (CsA) increases ß-catenin messenger RNA (mRNA) and protein expression. The present study demonstrates that Wnt/ß-catenin signaling inhibits ß-catenin degradation in the gingiva. METHODS: Forty 5-week-old male Sprague-Dawley rats were assigned to two study groups after healing from right maxillary molar extractions. The rats in the experimental group were fed 30 mg/kg CsA daily for 4 weeks, whereas the control rats were fed mineral oil. At the end of the study, all rats were sacrificed, and the gingivae were obtained. The gingival morphology after CsA treatment was evaluated by histology, and the genes related to Wnt/ß-catenin signaling were initially screened by microarray. Polymerase chain reaction, Western blotting, and immunohistochemistry were used to examine the mRNA and protein expression of proliferating cell nuclear antigen, cyclin D1, E-cadherin, ß-catenin, Dvl-1, glycogen synthase kinase-3ß, axin-1, and adenomatous polyposis coli (APC). Phosphoserine and ubiquitinylated ß-catenin were detected after immunoprecipitation. RESULTS: In rats treated with CsA, overgrowth of gingivae was observed, and altered expression of genes related to Wnt/ß-catenin signaling was detected by the microarray. The gingival mRNA and protein expression profiles for genes associated with Wnt/ß-catenin signaling further confirmed the effect of CsA: ß-catenin and Dvl-1 expression increased, but APC and axin-1 expression decreased. Western blotting and immunohistochemistry showed decreases in ß-catenin serine phosphorylation (33/37) and ubiquitinylation in the gingivae of CsA-treated rats. CONCLUSION: CsA-enhanced gingival ß-catenin stability may be involved in gene upregulation or ß-catenin degradation via the Wnt/ß-catenin pathway.

Familial adenomatous polyposis (FAP): genotype correlation to FAP phenotype with osteomas and sebaceous cysts.

Gardner syndrome is characterized by the triad of colorectal adenomas, soft and hard tissue tumors. This disorder was regarded as a separate disease until the identification of the APC gene when it was recognized that mutations in the APC gene were the underlying cause of both Gardner syndrome and familial adenomatous polyposis (FAP). The present study aimed at examining whether a particular APC genotype could be delineated in FAP patients with benign extracolonic manifestations: sebaceous cysts and/or osteomas. A questionnaire was sent to all Danish FAP patients (N = 234) asking for occurrence of sebaceous cysts and palpable osteomas. Medical records later verified positive findings, when possible. The results for each patient were correlated to the position of his or her mutation in the APC gene. Positive participation compliance was 77% (N = 180), and in 105 of these patients the pathogenic APC mutation was known. Palpable osteomas were reported in 17 of the patients in whom a pathogenic mutation had been identified. Osteomas were only identified in patients with mutations between codon 767 and 1513, a gene area also associated with congenital hypertrophy of the retinal-pigmented epithelium (CHRPE) and hepatoblastoma. Sebaceous cysts were reported in 51% of the patients, and their APC mutations were evenly distributed in the gene with no particular hotspot. Osteomas appeared most frequently in patients with sebaceous cysts, odds ratio 6.6, P < 0.001. The study provides molecular evidence that Gardner syndrome is a variant of FAP and essentially obsolete in clinical practice.

Cyclooxygenase-2 (COX-2)-independent anticarcinogenic effects of selective COX-2 inhibitors.

Nonsteroidal antiinflammatory drugs (NSAIDs) appear to reduce the risk of developing cancer. One mechanism through which NSAIDs act to reduce carcinogenesis is to inhibit the activity of cyclooxygenase-2 (COX-2), an enzyme that is overexpressed in various cancer tissues. Overexpression of COX-2 increases cell proliferation and inhibits apoptosis. However, selective COX-2 inhibitors can also act through COX-independent mechanisms. In this review, we describe the COX-2-independent molecular targets of these COX-2 inhibitors and discuss how these targets may be involved in the anticarcinogenic activities of these selective COX-2 inhibitors. We also compare the concentrations of these inhibitors used in in vitro and in vivo experiments and discuss the implications of the in vitro studies for clinical management of cancer with these drugs.