Access to cyclohexadiene and benzofuran derivatives via catalytic arene cyclopropanation of α-cyanodiazocarbonyl compounds.

The arene cyclopropanation between diazo compounds and benzene is well known to produce a tautomeric mixture of norcaradiene and cycloheptatriene in favour of the latter species. Nevertheless, previous studies have suggested that the initially formed norcaradiene can be stabilized by a C-7 cyano group with prevention of its 6π-electrocyclic ring opening. According to this feature, a synthetic route to functionalized cyclohexadienes has been designed using α-cyanodiazoacetates and α-diazo-ß-ketonitriles as the starting materials, respectively. The Rh2(esp)2-catalyzed arene cyclopropanation of α-cyanodiazoacetates in benzene afforded the expected 7-alkoxycarbonyl-7-cyanonorcaradienes as isolable compounds, which then served as templates for the second cyclopropanation with ethyl diazoacetate or α-cyanodiazocarbonyls to enable the formation of bis(cyclopropanated) adducts. Their subsequent treatment with SmI2 triggered a double ring-opening process, allowing for the generation of 1,4- and/or 1,3-cyclohexadienes as either regio- or diastereomeric mixtures. On the other hand, the norcaradienes generated from phenyl- or methyl-substituted α-diazo-ß-ketonitriles were found to undergo an in situ rearrangement to yield dihydrobenzofurans that could be converted to benzofuran derivatives by DDQ oxidation.

Expression levels of estrogen receptor α mRNA in peripheral blood cells are an independent biomarker for postmenopausal osteoporosis.

BACKGROUND: The up- and down-regulation of the osteoclastogenesis response depends on the estrogen/estrogen receptor (ER) signaling pathway. Previous reports have shown that the promoter hypermethylation and gene polymorphism of ERα are risks for menopausal osteoporosis. No previous study has evaluated the expression levels of ERα mRNA in menopausal osteoporosis using human subjects. We hypothesized that ERα mRNA expression may show less resistance to postmenopausal osteoporosis. METHODS: In this study, we enrolled 107 women older than 45 years without menstruation and classified them into control, osteopenia, and osteoporosis groups depending on their T-scores. The ERα mRNA levels in peripheral blood cells (PBCs) were analyzed via quantitative real-time reverse-transcription polymerase chain reaction (QRT-PCR), and estrogen in the serum was detected via ELISA. RESULTS: ERα mRNA levels in PBCs had a negative correlation with age and a positive correlation with estrogen and BAP in the osteopenia and osteoporosis groups, but not in the control group. Additionally, multivariate analysis showed that older age (> 55 years), and low ERα mRNA levels in PBLs (≦ 250.39 copies/µg DNA) were associated with an approximately 9.188-, and 31.25-fold risk of osteoporosis. CONCLUSION: We conclude that ERα mRNA levels in PBLs could be used as an independent risk factor for postmenopausal osteoporosis. GENERAL SIGNIFICANCE: Our findings suggested that ERα mRNA levels in PBLs may be more important than age and serum estrogen levels.

Phyllostachys edulis extract induces apoptosis signaling in osteosarcoma cells, associated with AMPK activation.

OBJECTIVE: Bamboo is distributed worldwide, and its different parts are used as foods or as a traditional herb. Recently, antitumoral effects of bamboo extracts on several tumors have been increasingly reported; however, antitumoral activity of bamboo extracts on osteosarcoma remains unclear. In the present study, we investigated effects of an aqueous Phyllostachys edulis leaf extract (PEE) on osteosarcoma cells and the underlying mechanism of inhibition. METHODS: The growth of human osteosarcoma cell lines 143 B and MG-63 and lung fibroblast MRC-5 cells was determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Apoptosis was demonstrated using TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assay and flow cytometric analysis. Phosphorylation and protein levels were determined by immunoblotting. RESULTS: After treatment with PEE, viability of 143 B and MG-63 cells was dose-dependently reduced to 36.3% ± 1.6% of control values, which were similar to AICAR (5-aminoimidazole-4-carboxamide 1-ß-D-ribofuranoside) treatments. In parallel, ratios of apoptotic cells and cells in the sub-G1 phase were significantly increased. Further investigation showed that PEE treatments led to activation of caspase cascades and changes of apoptotic mediators Bcl2, Bax, and p53. Consistently, our results revealed that PEE activated adenosine monophosphate-activated protein kinase (AMPK) signaling, and the AMPK activation was associated with the induction of apoptotic signaling. CONCLUSION: Our results indicated that PEE suppressed the growth of 143 B and MG-63 cells but moderately affected MRC-5 cells. PEE-induced apoptosis may attribute to AMPK activation and the following activation of apoptotic signaling cascades. These findings revealed that PEE possesses antitumoral activity on human osteosarcoma cells by manipulating AMPK signaling, suggesting that PEE alone or combined with regular antitumor drugs may be beneficial as osteosarcoma treatments.

Clinical practice guidelines in severe traumatic brain injury in Taiwan.

BACKGROUND: Severe TBIs are major causes of disability and death in accidents. The Brain Trauma Foundation supported the first edition of the Guidelines for the Management of Severe Traumatic Brain Injury in 1995 and revised it in 2000. The recommendations in these guidelines are well accepted in the world. There are still some different views on trauma mechanisms, pathogenesis, and managements in different areas. Individualized guidelines for different countries would be necessary, and Taiwan is no exception. METHODS: In November 2005, we organized the severe TBI guidelines committee and selected 9 topics, including ER treatment, ICP monitoring, CPP, fluid therapy, use of sedatives, nutrition, intracranial hypertension, seizure prophylaxis, and second-tier therapy. We have since searched key questions in these topics on Medline. References are classified into 8 levels of evidence: 1++, 1+, 1-, 2++, 2+, 2-, 3, and 4 based on the criteria of the SIGN. RESULTS: Recommendations are formed and graded as A, B, C, and D. Grade A means that at least one piece of evidence is rated as 1++, whereas grade B means inclusion of studies rated as 2++. Grade C means inclusion of references rated as 2+, and grade D means levels of evidence rated as 3 or 4. Overall, 42 recommendations are formed. Three of these are rated as grade A, 13 as grade B, 21 as grade C, and 5 as grade D. CONCLUSIONS: We have completed the first evidence-based, clinical practice guidelines for severe TBIs. It is hoped that the guidelines will provide concepts and recommendations to promote the quality of care for severe TBIs in Taiwan.

Hylan G-F 20 has better pain relief and cost-effectiveness than sodium hyaluronate in treating early osteoarthritic knees in Taiwan.

BACKGROUND/PURPOSE: Intra-articular injection of hyaluronan (hyaluronic acid; HA) products is available to treat early osteoarthritis (OA) of the knee in Taiwan. We tested whether HA products with different molecular weights have significantly different effects on clinical efficacy and cost-effectiveness. METHODS: Thirty-seven patients with mild to moderate OA of both knees underwent five weekly intra-articular injections of sodium hyaluronate (Artz) in one knee and three weekly intra-articular injections of chemically cross-linked Hylan G-F 20 (Synvisc) in the other. Visual analog scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Lequesne's index, and Hospital for Special Surgery (HSS) knee scores were compared initially and at the last injection, and at 8, 12, 16, 20, and 26 weeks after the first injection. RESULTS: VAS, WOMAC, WOMAC-A1 (pain when walking on a flat surface) scores before week 16, HSS scores before week 12, and Lequesne's index scores except at week 26 all showed that HA significantly improved the scores time-dependently. In VAS scores, Synvisc showed better improvement before week 20, while this effect appeared at week 12 for the WOMAC-A1 scores. The incremental cost-effectiveness ratio of the Taiwan National Health Insurance Program, of the patient, and both of these was lower for Synvisc, which also reduced the number of additional hospital visits for injections by two. CONCLUSION: Synvisc possesses better symptom-modifying ability and cost-utility in treating early OA of the knee in Taiwan.