Iron-catalyzed diboration and carboboration of alkynes.

Issue published online: 27 FEB 2015An iron-catalyzed diboration reaction of alkynes with bis(pinacolato)diboron (B2pin2) and external borating agents (MeOB(OR)2) affords diverse symmetrical or unsymmetrical cis-1, 2-diborylalkenes. The simple protocol for the diboration reaction can be extended to the iron-catalyzed carboboration of alkynes with primary and, unprecedentedly, secondary alkyl halides, affording various tetrasubstituted monoborylalkenes in a highly stereoselective manner. DFT calculations indicate that a boryliron intermediate adds across the triple bond of an alkyne to afford an alkenyliron intermediate, which can react with the external trapping agents, borates and alkyl halides. In situ trapping experiments support the intermediacy of the alkenyl iron species using radical probe stubstrates

Sirt1 expression is associated with CD31 expression in blood cells from patients with chronic obstructive pulmonary disease

Background: Cigarette smoke induced oxidative stress has been shown to reduce silent information regulator 1 (Sirt1) levels in lung tissue from smokers and patients with COPD patients. Sirt1 is known to inhibit endothelial senescence and may play a protective role in vascular cells. Endothelial progenitor cells (EPCs) are mobilized into circulation under various pathophysiological conditions, and are thought to play an important role in tissue repair in chronic obstructive lung disease (COPD). Therefore, Sirt1 and EPC-associated mRNAs were measured in blood samples from patients with COPD and from cultured CD34+ progenitor cells to examine whether these genes are associated with COPD development. Methods: This study included 358 patients with a smoking history of more than 10 pack-years. RNA was extracted from blood samples and from CD34+ progenitor cells treated with cigarette smoke extract (CSE), followed by assessment of CD31, CD34, Sirt1 mRNA, miR-34a, and miR-126-3p expression by real-time RT-PCR. Results: The expression of CD31, CD34, Sirt1 mRNAs, and miR-126-3p decreased and that of miR-34a increased in moderate COPD compared with that in control smokers. However, no significant differences in these genes were observed in blood cells from patients with severe COPD compared with those in control smokers. CSE significantly decreased Sirt1 and increased miR-34a expression in cultured progenitor cells. Conclusion: Sirt1 expression in blood cells from patients with COPD could be a biomarker for disease stability in patients with moderate COPD. MiR-34a may participate in apoptosis and/or senescence of EPCs in smokers. Decreased expression of CD31, CD34, and miR-126-3p potentially represents decreased numbers of EPCs in blood cell from patients with COPD

Preliminary Clinical Evaluation of Toxicity and Efficacy of A New Astaxanthin-rich Haematococcus pluvialis Extract

Astaxanthin (Ax), a carotenoid ubiquitously distributed in microorganisms, fish, and crustaceans, has been known to be a potent antioxidant and hence exhibit various physiological effects. We attempted in these studies to evaluate clinical toxicity and efficacy of long-term administration of a new Ax product, by measuring biochemical and hematological blood parameters and by analyzing brain function (using CogHealth and P300 measures). Ax-rich Haematococcus pluvialis extracts equivalent to 4, 8, 20 mg of Ax dialcohol were administered to 73, 38, and 16 healthy adult volunteers, respectively, once daily for 4 weeks to evaluate safety. Ten subjects with age-related forgetfulness received an extract equivalent to 12 mg in a daily dosing regimen for 12 weeks to evaluate efficacy. As a result, no abnormality was observed and efficacy for age-related decline in cognitive and psychomotor functions was suggested

琉球列島奄美大島の絶滅危惧植物アマミヒイラギモチ（モチノキ科）の植物体サイズと葉の二型性

The tree Ilex dimorphophylla Koidz.（Aquifoliaceae）is a vulnerable species that is endemic to the summit of Mt. Yuwan on Amamioshima Island, Japan. This plant hows characteristic leaf dimorphism, which increases its horticultural value, and many individuals have been illegally removed from the natural habitat. We examined the umber of shoots, leaf morphology and plant size of the species in the natural habitat. Based on field observation for two years, we found 84 shoots, of which 32（38.1%）had entire mature leaves, whereas 52（61.9%）had only serrate juvenile leaves. Majority of the examined shoots surveyed fell into the smallest size classes : < 100 cm in eight（ca. 45%）and < 25 mm in diameter at the trunk base（ca. 60%）. Leaf dimorphism was clearly demarcated in trees at 130―210 cm in height and 15―27 mm in diameter at the trunk base.アマミヒイラギモチ（Ilex dimorphophylla Koidz.）は奄美大島の湯湾岳山頂付近に発達した風衝林内に生育するモチノキ科の樹木である。本種における樹木サイズと葉の二型性について自生地で調査した。84 シュートの生育を確認し，そのうちの32 シュートが全縁の成熟葉を，残りの52 シュートが鋭い鋸歯のある幼葉のみをもっていた。葉の二型性は樹木高で約130―210 cm，根元直径で15―27mm を境にして分かれていることが明らかになった

Integration-Free iPS Cells Engineered Using Human Artificial Chromosome Vectors

Human artificial chromosomes (HACs) have unique characteristics as gene-delivery vectors, including episomal transmission and transfer of multiple, large transgenes. Here, we demonstrate the advantages of HAC vectors for reprogramming mouse embryonic fibroblasts (MEFs) into induced pluripotent stem (iPS) cells. Two HAC vectors (iHAC1 and iHAC2) were constructed. Both carried four reprogramming factors, and iHAC2 also encoded a p53-knockdown cassette. iHAC1 partially reprogrammed MEFs, and iHAC2 efficiently reprogrammed MEFs. Global gene expression patterns showed that the iHACs, unlike other vectors, generated relatively uniform iPS cells. Under non-selecting conditions, we established iHAC-free iPS cells by isolating cells that spontaneously lost iHAC2. Analyses of pluripotent markers, teratomas and chimeras confirmed that these iHAC-free iPS cells were pluripotent. Moreover, iHAC-free iPS cells with a re-introduced HAC encoding Herpes Simplex virus thymidine kinase were eliminated by ganciclovir treatment, indicating that the HAC safeguard system functioned in iPS cells. Thus, the HAC vector could generate uniform, integration-free iPS cells with a built-in safeguard system

Clopidogrel Monotherapy After 1-Month DAPT in Patients With High Bleeding Risk or Complex PCI

BACKGROUND: High bleeding risk (HBR) and complex percutaneous coronary intervention (PCI) are major determinants for dual antiplatelet therapy (DAPT) duration. OBJECTIVES: The aim of this study was to evaluate the effects of HBR and complex PCI on short vs standard DAPT. METHODS: Subgroup analyses were conducted on the basis of Academic Research Consortium-defined HBR and complex PCI in the STOPDAPT-2 (Short and Optimal Duration of Dual Antiplatelet Therapy After Verulam's-Eluting Cobalt-Chromium Stent-2) Total Cohort, which randomly compared clopidogrel monotherapy after 1-month DAPT with 12-month DAPT with aspirin and clopidogrel after PCI. The primary endpoint was the composite of cardiovascular (cardiovascular death, myocardial infarction, definite stent thrombosis, or stroke) or bleeding (Thrombolysis In Myocardial Infarction [TIMI] major or minor) endpoints at 1 year. RESULTS: Regardless of HBR (n = 1, 893 [31.6%]) and complex PCI (n = 999 [16.7%]), the risk of 1-month DAPT relative to 12-month DAPT was not significant for the primary endpoint (HBR, 5.01% vs 5.14%; non-HBR, 1.90% vs 2.02%; P interaction = 0.95) (complex PCI, 3.15% vs 4.07%; noncomplex PCI, 2.78% vs 2.82%; P interaction = 0.48) and for the cardiovascular endpoint (HBR, 4.35% vs 3.52%; and non-HBR, 1.56% vs 1.22%; P interaction = 0.90) (complex PCI, 2.53% vs 2.52%; noncomplex PCI, 2.38% vs 1.86%; P interaction = 0.53), while it was lower for the bleeding endpoint (HBR, 0.66% vs 2.27%; non-HBR, 0.43% vs 0.85%; P interaction = 0.36) (complex PCI, 0.63% vs 1.75%; noncomplex PCI, 0.48% vs 1.22%; P interaction = 0.90). The absolute difference in the bleeding between 1- and 12-month DAPT was numerically greater in patients with HBR than in those without HBR (-1.61% vs -0.42%). CONCLUSIONS: The effects of 1-month DAPT relative to 12-month DAPT were consistent regardless of HBR and complex PCI. The absolute benefit of 1-month DAPT over 12-month DAPT in reducing major bleeding was numerically greater in patients with HBR than in those without HBR. Complex PCI might not be an appropriate determinant for DAPT durations after PCI. (Short and Optimal Duration of Dual Antiplatelet Therapy After Everolimus-Eluting Cobalt-Chromium Stent-2 [STOPDAPT-2], NCT02619760; Short and Optimal Duration of Dual Antiplatelet Therapy After Everolimus-Eluting Cobalt-Chromium Stent-2 for the Patients With ACS [STOPDAPT-2 ACS], NCT03462498)

Structure–activity relationships and the cytotoxic effects of novel diterpenoid alkaloid derivatives against A549 human lung carcinoma cells

The cytotoxicity of three alkaloids from the roots of Aconitum yesoense var. macroyesoense as well as 36 semi-synthetic C20-diterpenoid atisine-type alkaloid derivatives against A549 human lung carcinoma cells was examined. Ten acylated alkaloid derivatives, pseudokobusine 11-veratroate (9), 11-anisoate (12), 6,11-dianisoate (14), 11-p-nitrobenzoate (18), 11,15-di-p-nitrobenzoate (22), 11-cinnamate (25) and 11-m-trifluoromethylbenzoate (27), and kobusine 11-p-trifluoromethylbenzoate (35), 11-m-trifluoromethylbenzoate (36) and 11,15-di-p-nitrobenzoate (39), exhibited cytotoxic activity, and 11,15-dianisoylpseudokobusine (16) was found to be the most potent cytotoxic agent. Their IC50 values against A549 cells ranged from 1.72 to 5.44 μM. In the occurrence of cytotoxic effects of atisine-type alkaloids, replacement by an acyl group at both C-11 and C-15 resulted in the enhancement of activity of the parent alkaloids compared to that from having hydroxy groups at this position, and the presence of a hydroxy group at the C-6 position was required for the cytotoxic effects. These acylated alkaloid derivatives inhibit cell growth through G1 arrest

Clopidogrel Monotherapy After 1-Month Dual Antiplatelet Therapy in Percutaneous Coronary Intervention: From the STOPDAPT-2 Total Cohort

[Background:] The benefit of clopidogrel monotherapy after 1-month dual antiplatelet therapy (DAPT) compared with 12-month DAPT with aspirin and clopidogrel was demonstrated in the STOPDAPT-2 (Short and Optimal Duration of Dual Antiplatelet Therapy After Everolimus-Eluting Cobalt-Chromium Stent-2), but not in the STOPDAPT-2 acute coronary syndrome (ACS); however, both trials were underpowered based on the actual event rates. [Methods:] We obtained the prespecified pooled population of 5997 patients as the STOPDAPT-2 total cohort (STOPDAPT-2: N=3009/STOPDAPT-2 ACS: N=2988; ACS: N=4136/chronic coronary syndrome [CCS]: N=1861), comprising 2993 patients assigned to 1-month DAPT followed by clopidogrel monotherapy, and 3004 patients assigned to 12-month DAPT with aspirin and clopidogrel after percutaneous coronary intervention. The primary end point was the composite of cardiovascular (cardiovascular death, myocardial infarction, definite stent thrombosis, or any stroke) or bleeding (Thrombolysis in Myocardial Infarction major/minor) end points at 1 year. [Results:] One-month DAPT was noninferior to 12-month DAPT for the primary end point (2.84% versus 3.04%; hazard ratio [HR], 0.94 [95% CI, 0.70–1.27]; Pnoninferiority=0.001; Psuperiority=0.68). There was no significant risk-difference for the cardiovascular end point between the 1- and 12-month DAPT groups (2.40% versus 1.97%; HR, 1.24 [95% CI, 0.88–1.75]; Pnoninferiority=0.14; Psuperiority=0.23). There was a lower risk of the bleeding end point with 1-month DAPT relative to 12-month DAPT (0.50% versus 1.31%; HR, 0.38 [95% CI, 0.21–0.70]; Psuperiority=0.002). One-month DAPT relative to 12-month DAPT was associated with a lower risk for major bleeding regardless of ACS or CCS (ACS: HR, 0.46 [95% CI, 0.23–0.94]; P=0.03, and CCS: HR, 0.26 [95% CI, 0.09–0.79]; P=0.02; Pinteraction=0.40), while it was associated with a numerical increase in cardiovascular events in ACS patients, but not in CCS patients, although not statistically significant and without interaction (ACS: HR, 1.50 [95% CI, 0.99–2.27]; P=0.053, and CCS: HR, 0.74 [95% CI, 0.38–1.45]; P=0.39; Pinteraction=0.08). [Conclusions:] Clopidogrel monotherapy after 1-month DAPT compared with 12-month DAPT with aspirin and clopidogrel had a benefit in reducing major bleeding events without being associated with increase in cardiovascular events