In the present multicenter randomized trial, percutaneous coronary intervention of true distal LM bifurcation lesions using a planned DK crush 2-stent strategy resulted in a lower rate of TLF at 1 year than a PS strategy. (Double Kissing and Double Crush Versus Provisional T Stenting Technique for the Treatment of Unprotected Distal Left Main True Bifurcation Lesions: A Randomized, International, Multi-Center Clinical Trial [DKCRUSH-V]; ChiCTR-TRC-11001213).

Aim The present study aimed to assess the benefits of two-stent techniques for patients with DEFINITION criteria-defined complex coronary bifurcation lesions. Methods and results In total, 653 patients with complex bifurcation lesions at 49 international centres were randomly assigned to undergo the systematic two-stent technique (two-stent group) or provisional stenting (provisional group). The primary endpoint was the composite of target lesion failure (TLF) at the 1-year follow-up, including cardiac death, target vessel myocardial infarction (TVMI), and clinically driven target lesion revascularization (TLR). The safety endpoint was definite or probable stent thrombosis. At the 1-year follow-up, TLF occurred in 37 (11.4%) and 20 (6.1%) patients in the provisional and two-stent groups, respectively [77.8%: double-kissing crush; hazard ratio (HR) 0.52, 95% confidence interval (CI) 0.30–0.90; P = 0.019], largely driven by increased TVMI (7.1%, HR 0.43, 95% CI 0.20–0.90; P = 0.025) and clinically driven TLR (5.5%, HR 0.43, 95% CI 0.19–1.00; P = 0.049) in the provisional group. At the 1 year after indexed procedures, the incidence of cardiac death was 2.5% in the provisional group, non-significant to 2.1% in the two-stent group (HR 0.86, 95% CI 0.31–2.37; P = 0.772). Conclusion For DEFINITION criteria-defined complex coronary bifurcation lesions, the systematic two-stent approach was associated with a significant improvement in clinical outcomes compared with the provisional stenting approach. Further study is urgently warranted to identify the mechanisms contributing to the increased rate of TVMI after provisional stenting. Study registration http://www.clinicaltrials.com; Identifier: NCT02284750.

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Cerebral ischemia and trauma lead to rapid increases in cerebral concentrations of cyclic AMP and dehydroascorbic acid (DHAA; oxidized vitamin C), depletion of intracellular ascorbic acid (AA; reduced vitamin C), and formation of reactive astrocytes. We investigated astrocytic transport of AA and DHAA and the effects of cyclic AMP on these transport systems. Primary cultures of astrocytes accumulated millimolar concentrations of intracellular AA when incubated in medium containing either M or DHAA. AA uptake was Nat-dependent and inhibited by 4,4 '-diisothiocyanostilbene-2,2 '-disulfonic acid (DIDS), whereas DHAA uptake was Na~-independent and DIDS-insensitive. DHAA uptake was inhibited by cytochalasin B, D-glucose, and glucose analogues specific for facilitative hexose transporters. Once inside the cells, DHM was reduced to AA. DHAA reduction greatly decreased astrocytic glutathione concentration. However, experiments with astrocytes that had been previously depleted of glutathione showed that DHM reduction does not require physiological concentrations of glutathione. Astrocyte cultures were treated with a permeant analogue of cyclic AMP or forskolin, an activator of adenylyl cyclase, to induce cellular differentiation and thus provide in vitro models of reactive astrocytes. Cyclic AMP stimulated uptake of M, DHAA, and 2-deoxyglucose. The effects of cyclic AMP required at least 12 h and were inhibited by cycloheximide, consistent with a requirement for de novo protein synthesis. Uptake and reduction of DHM by astrocytes may be a recycling pathway that contributes to brain M homeostasis. These results also indicate a role for cyclic AMP in accelerating the clearance and detoxification of DHAA in the brain.

Nasopharyngeal carcinoma (NPC) is a malignant tumor associated with a genetic predisposition, Epstein-Barr virus infection and chromosomal abnormalities. Recently, several miRNAs have been shown to target specific mRNAs to regulate NPC development and progression. However, the involvement of miRNAs in processes leading to NPC migration and invasion remains to be elucidated. We predicted that miR-29a/b are associated with dysregulated genes controlling NPC through an integrated interaction network of miRNAs and genes. miR-29a/b over-expression in NPC cell lines had no significant effect on proliferation, whereas miR-29b mildly increased the percentage of cells in the G1 phase with a concomitant decrease in the percentage of cells in S phase. Furthermore, we demonstrated that miR-29a/b might be responsible for increasing S18 cell migration and invasion, and only COL3A1 was identified as a direct target of miR-29b despite the fact that both SPARC and COL3A1 were inhibited by miR-29a/b over-expression. Meanwhile, SPARC proteins were increased in metastatic NPC tissue and are involved in NPC progression. Unexpectedly, we identified that miRNA-29b expression was elevated in the serum of NPC patients with a high risk of metastasis. The 5-year actuarial overall survival rates in NPC patients with high serum miR-29b expression was significantly shorter than those with low serum miR-29b expression; therefore, serum miR-29b expression could be a promising prognostic marker.

Aim: Aconiti Lateralis Radix Preparata is a traditional Chinese medicine used to treat chronic arthritis and is highly effective against rheumatoid arthritis. However, the effects of aconine, a derivative of aconitum alkaloids, on osteoclasts, which can absorb bone, remain unknown. Here, we investigated the effects of aconine on osteoclast differentiation and bone resorption in vitro. Methods: The viability of mouse leukemic monocyte/macrophage cell line RaW264.7 was measured using CCK-8 assays. osteoclast differentiation was induced by incubation of RaW264.7 cells in the presence of RanKL, and assessed with TRaP staining assay. Bone resorption was examined with bone resorption pits assay. The expression of relevant genes and proteins was analyzed using RT-PCR and Western blots. The activation of NF-κB and nuclear factor of activated T-cells (NFAT) was examined using stable NF-κB and NFATc1 luciferase reporter gene systems, RT-PCR and Western blot analysis. Results: Aconine (0.125, 0.25 μmol/L) did not affect the viability of RAW264.7 cells, but dose-dependently inhibited RANKL-induced osteoclast formation and bone resorptive activity. Furthermore, aconine dose-dependently inhibited the RanKL-induced activation of NF-κB and NFATc1 in RAW264.7 cells, and subsequently reduced the expression of osteoclast-specific genes (c-Src, β3-Integrin, cathepsin K and MMP-9) and the expression of dendritic cell-specific transmembrane protein (DC-STAMP), which played an important role in cell-cell fusion. Conclusion: These findings suggest that aconine inhibits RANKL-induced osteoclast differentiation in RAW264.7 cells by suppressing the activation of NF-κB and NFATc1 and the expression of the cell-cell fusion molecule DC-STAMP.

An increasing body of evidence indicates that inflammation and apoptosis are involved in the development of acute myocardial infarction (AMI). In this study, we sought to investigate the specific role and the underlying regulatory mechanism of miR-145-5p in myocardial ischemic injury. H9c2 cardiac cells were exposed to hypoxia to establish a model of myocardial hypoxic/ischemic injury. We found that miR-145-5p was notably down-regulated, while CD40 expression was highly elevated in H9c2 cells following exposure to acute hypoxia. Additionally, hypoxia markedly enhanced the inflammatory response, as reflected by an increase in the secretion of the cytokines IL-1β, TNF-α, and IL-6, whereas the introduction of miR-145-5p effectively suppressed inflammatory factor production triggered by hypoxia. Furthermore, we observed hypoxia stimulation significantly augmented apoptosis accompanied by a decrease in the expression of Bcl-2 and an increase in the expression of Bax, Caspase-3, and Caspase-9. However, augmentation of miR-145-5p led to a dramatic prevention of hypoxia-induced apoptosis. Importantly, we identified CD40 as a direct target of miR-145-5p. Interestingly, the depletion of CD40 with small interfering RNAs (siRNAs) apparently repressed the production of inflammatory cytokines and apoptosis in the setting of acute hypoxic treated. Taken together, these data demonstrated that miR-145-5p may function as a cardiac-protective molecule in myocardial ischemic injury by ameliorating inflammation and apoptosis via negative regulation of CD40. The study gives evidence that miR-145-5p provides an interesting strategy for protecting cardiomyocytes from hypoxia-induced inflammatory response and apoptosis.

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