Aspirin Versus Clopidogrel for Long-Term Maintenance Monotherapy After Percutaneous Coronary Intervention: The HOST-EXAM Extended Study.

BACKGROUND: Long-term outcomes of antiplatelet monotherapy in patients who receive percutaneous coronary intervention are unknown. The HOST-EXAM (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis-Extended Antiplatelet Monotherapy) Extended study reports the posttrial follow-up results of the original HOST-EXAM trial. METHODS: From March 2014 through May 2018, 5438 patients who maintained dual antiplatelet therapy without clinical events for 12±6 months after percutaneous coronary intervention with drug-eluting stents were randomly assigned in a 1:1 ratio to receive clopidogrel (75 mg once daily) or aspirin (100 mg once daily). The primary end point (a composite of all-cause death, nonfatal myocardial infarction, stroke, readmission attributable to acute coronary syndrome, and Bleeding Academic Research Consortium type 3 or greater bleeding), secondary thrombotic end point (cardiac death, nonfatal myocardial infarction, ischemic stroke, readmission attributable to acute coronary syndrome, and definite or probable stent thrombosis), and bleeding end point (Bleeding Academic Research Consortium type 2 or greater bleeding) were analyzed during the extended follow-up period. Analysis was performed on the per-protocol population (2431 patients in the clopidogrel group and 2286 patients in the aspirin group). RESULTS: During a median follow-up of 5.8 years (interquartile range, 4.8-6.2 years), the primary end point occurred in 12.8% and 16.9% in the clopidogrel and aspirin groups, respectively (hazard ratio, 0.74 [95% CI, 0.63-0.86]; P<0.001). The clopidogrel group had a lower risk for the secondary thrombotic end point (7.9% versus 11.9%; hazard ratio, 0.66 [95% CI, 0.55-0.79]; P<0.001) and secondary bleeding end point (4.5% versus 6.1%; hazard ratio, 0.74 [95% CI, 0.57-0.94]; P=0.016). There was no significant difference in the incidence of all-cause death between the 2 groups (6.2% versus 6.0%; hazard ratio, 1.04 [95% CI, 0.82-1.31]; P=0.742). Landmark analysis at 2 years showed that the beneficial effect of clopidogrel was consistent throughout the follow-up period. CONCLUSIONS: During an extended follow-up of >5 years after randomization, clopidogrel monotherapy compared with aspirin monotherapy was associated with lower rates of the composite net clinical outcome in patients without clinical events for 12±6 months after percutaneous coronary intervention with drug-eluting stents. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02044250.

Aspirin versus clopidogrel for chronic maintenance monotherapy after percutaneous coronary intervention (HOST-EXAM): an investigator-initiated, prospective, randomised, open-label, multicentre trial.

BACKGROUND: Optimal antiplatelet monotherapy during the chronic maintenance period in patients who undergo coronary stenting is unknown. We aimed to compare head to head the efficacy and safety of aspirin and clopidogrel monotherapy in this population. METHODS: We did an investigator-initiated, prospective, randomised, open-label, multicentre trial at 37 study sites in South Korea. We enrolled patients aged at least 20 years who maintained dual antiplatelet therapy without clinical events for 6-18 months after percutaneous coronary intervention with drug-eluting stents (DES). We excluded patients with any ischaemic and major bleeding complications. Patients were randomly assigned (1:1) to receive a monotherapy agent of clopidogrel 75 mg once daily or aspirin 100 mg once daily for 24 months. The primary endpoint was a composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and Bleeding Academic Research Consortium (BARC) bleeding type 3 or greater, in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02044250. FINDINGS: Between March 26, 2014, and May 29, 2018, we enrolled 5530 patients. 5438 (98·3%) patients were randomly assigned to either the clopidogrel group (2710 [49·8%]) or to the aspirin group (2728 [50·2%]). Ascertainment of the primary endpoint was completed in 5338 (98·2%) patients. During 24-month follow-up, the primary outcome occurred in 152 (5·7%) patients in the clopidogrel group and 207 (7·7%) in the aspirin group (hazard ratio 0·73 [95% CI 0·59-0·90]; p=0·0035). INTERPRETATION: Clopidogrel monotherapy, compared with aspirin monotherapy during the chronic maintenance period after percutaneous coronary intervention with DES significantly reduced the risk of the composite of all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and BARC bleeding type 3 or greater. In patients requiring indefinite antiplatelet monotherapy after percutaneous coronary intervention, clopidogrel monotherapy was superior to aspirin monotherapy in preventing future adverse clinical events. FUNDING: ChongKunDang, SamJin, HanMi, DaeWoong, and the South Korea Ministry of Health and Welfare.

Eckol Inhibits Particulate Matter 2.5-Induced Skin Keratinocyte Damage via MAPK Signaling Pathway.

Toxicity of particulate matter (PM) towards the epidermis has been well established in many epidemiological studies. It is manifested in cancer, aging, and skin damage. In this study, we aimed to show the mechanism underlying the protective effects of eckol, a phlorotannin isolated from brown seaweed, on human HaCaT keratinocytes against PM2.5-induced cell damage. First, to elucidate the underlying mechanism of toxicity of PM2.5, we checked the reactive oxygen species (ROS) level, which contributed significantly to cell damage. Experimental data indicate that excessive ROS caused damage to lipids, proteins, and DNA and induced mitochondrial dysfunction. Furthermore, eckol (30 µM) decreased ROS generation, ensuring the stability of molecules, and maintaining a steady mitochondrial state. The western blot analysis showed that PM2.5 promoted apoptosis-related protein levels and activated MAPK signaling pathway, whereas eckol protected cells from apoptosis by inhibiting MAPK signaling pathway. This was further reinforced by detailed investigations using MAPK inhibitors. Thus, our results demonstrated that inhibition of PM2.5-induced cell apoptosis by eckol was through MAPK signaling pathway. In conclusion, eckol could protect skin HaCaT cells from PM2.5-induced apoptosis via inhibiting ROS generation.

A randomized clinical trial comparing long-term clopidogrel vs aspirin monotherapy beyond dual antiplatelet therapy after drug-eluting coronary stent implantation: Design and rationale of the Harmonizing Optimal Strategy for Treatment of coronary artery stenosis-Extended Antiplatelet Monotherapy (HOST-EXAM) trial.

Percutaneous coronary intervention (PCI) has been developed by drug-eluting stent (DES), but stent implantation has brought the issue of stent thrombosis and optimal antiplatelet therapy. Guidelines recommend at least 6- to 12 months of dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor such as clopidogrel. Beyond DAPT after PCI with DES, however, there has been still a debate for antiplatelet regimen. Therefore, we report on the upcoming HOST-EXAM trial (NCT02044250), which will evaluate the efficacy and safety of aspirin and clopidogrel monotherapies beyond DAPT after DES implantation. TRIAL DESIGN: The HOST-EXAM is a prospective, randomized, open-label, multicenter, comparative effectiveness trial, to compare between clopidogrel (75 mg once daily) and aspirin (100 mg once daily) as long-term antiplatelet agents. A total of 5,530 patients with no clinical events during combined antiplatelet therapy for 12±6 months after index PCI will be screened, enrolled, and randomized to either group (1:1 ratio) receiving antiplatelet monotherapy for 2 years. The primary endpoint will be the rate of clinical events defined as a composite of all-cause death, nonfatal myocardial infarction, stroke, readmission due to acute coronary syndrome, or major bleeding at 24 months after randomization. CONCLUSIONS: The HOST-EXAM will be the first large-scale randomized controlled study to directly compare the efficacy and safety of long-term antiplatelet monotherapy beyond DAPT after DES implantation. This study will provide clinical evidence to establish optimal regimen for long-term antiplatelet therapy after DES implantation.

Pratol, an O-Methylated Flavone, Induces Melanogenesis in B16F10 Melanoma Cells via p-p38 and p-JNK Upregulation.

Tyrosinase is the rate-limiting enzyme critical for melanin synthesis. It controls pigmentation in the skin. Activation of tyrosinase is currently the most common approach in the development of tanning and haircare products. Pratol is a 7-hydroxy-4-methoxyflavone found in Trifoliumpratense. In this study, we investigated the effects of pratol on melanogenesis. We also studied the mechanism of action of pratol in B16F10 mouse melanoma cells. The cells were treated with various concentrations (6.25, 12.5, 25, and 50 µM) of pratol to observe its effects. The results showed that pratol significantly increased melanin content and tyrosinase activity in the cells without being cytotoxic. In addition, pratol strongly increased the expression of tyrosinase and tyrosinase-related protein-1 and 2 by enhancing the expression of microphthalmia-associated transcription factor. Furthermore, pratol stimulated melanogenesis via the phosphorylation of p38, c-Jun N-terminal kinases (JNK), and extracellular signal-regulated kinase (ERK). The findings from an assay searching for the inhibitor revealed that SB203580 (a specific p38 inhibitor) or SP600125 (a p-JNK inhibitor) attenuated pratol-induced cellular tyrosinase activity whereas PD98059 (an ERK inhibitor) did not. Additionally, pratol interfered with the phosphorylation of p-AKT. We also found that pratol-induced melanogenesis was reversed by H89, which is a specific protein kinase A inhibitor. The results suggest that, owing to its multi-functional properties, pratol may be a potential tanning agent or a therapeutic agent for hair depigmentation in the cosmetic industry.

Beetroot (Beta vulgaris) rescues mice from γ-ray irradiation by accelerating hematopoiesis and curtailing immunosuppression.

CONTEXT: Beetroot [Beta vulgaris Linné (Chenopodiaceae)], a vegetable usually consumed as a food or a medicinal plant in Europe, has been reported to have antioxidant and anti-inflammatory properties. Since the lymphohematopoietic system is the most sensitive tissue to ionizing radiation, protecting it from radiation damage is one of the best ways to decrease detrimental effects from radiation exposure. OBJECTIVE: In this study, we evaluated the radio-protective effects of beetroot in hematopoietic stem cells (HSCs) and progenitor cells. MATERIALS AND METHODS: Beetroot extract was administered at a dose of 400 mg/mouse per os (p.o.) three times into C57BL/6 mice and, at day 10 after γ-ray irradiation, diverse molecular presentations were measured and compared against non-irradiated and irradiated mice with PBS treatments. Survival of beetroot-fed and unfed irradiated animal was also compared. RESULTS: Beetroot not only stimulated cell proliferation, but also minimized DNA damage of splenocytes. Beetroot also repopulated S-phase cells and increased Ki-67 or c-Kit positive cells in bone marrow. Moreover, beetroot-treated mice showed notable boosting of differentiation of HSCs into burst-forming units-erythroid along with increased production of IL-3. Also, beetroot-treated mice displayed enhancement in the level of hematocrit and hemoglobin as well as the number of red blood cell in peripheral blood. Beetroot diet improved survival rate of lethally exposed mice with a dose reduction factor (DRF) of 1.1. DISCUSSION AND CONCLUSION: These results suggest that beetroot has the potency to preserve bone marrow integrity and stimulate the differentiation of HSCs against ionizing radiation.

3-Hydroxy-4,7-megastigmadien-9-one, isolated from Ulva pertusa, attenuates TLR9-mediated inflammatory response by down-regulating mitogen-activated protein kinase and NF-κB pathways.

CONTEXT: Seaweeds are rich in bioactive compounds in the form of vitamins, phycobilins, polyphenols, carotenoids, phycocyanins and polysaccharides; many of these are known to have advantageous applications in human health. 3-Hydroxy-4,7-megastigmadien-9-one (comp) was isolated from Ulva pertusa (U. pertusa) Kjellman (Ulvaceae), which is a familiar edible green seaweed. OBJECTIVE: This study evaluates the anti-inflammatory activity of comp in CpG DNA-stimulated bone marrow-derived dendritic cells (BMDCs). MATERIALS AND METHODS: For evaluating the effect of comp on cytokines production, BMDCs were treated with doses of comp (0, 0.5, 1, 2, 5, 10, 25 and 50 µM) for 1 h before stimulation with CpG DNA (1 µM). Cytokine production was measured by ELISA. Western blotting was conducted for evaluating effect of comp (50 µM) on MAPKs and NF-κB pathways. Luciferase reporter gene assay was conducted for effect of comp (0, 5, 10 and 25 µM) on transcriptional activity of AP-1 and NF-κB. RESULTS: Comp exhibited strong inhibition of interleukin (IL)-12 p40, IL-6 and TNF-α cytokine production with IC50 values of 6.02 ± 0.35, 27.14 ± 0.73, and 7.56 ± 0.21 µM, respectively. It blocked MAPKs and NF-κB pathways by inhibiting the phosphorylation of ERK1/2, JNK1/2, p38 and IκBα. In addition, it strongly inhibited the transcriptional activity of AP-1 and NF-κB with IC50 values of 8.74 ± 0.31 and 12.08 ± 0.24 µM, respectively. DISCUSSION AND CONCLUSION: Taken together, these data suggest that comp has a significant anti-inflammatory property and warrants further studies concerning the potential of comp for medicinal use.

Promotion Effect of Apo-9'-fucoxanthinone from Sargassum muticum on Hair Growth via the Activation of Wnt/ß-Catenin and VEGF-R2.

This study was conducted to evaluate the effects of Sargassum muticum extract and apo-9'-fucoxanthinone, a principal component of S. muticum, on hair growth. When rat vibrissa follicles were treated with S. muticum extract for 21 d, the hair-fiber lengths for the vibrissa follicles increased significantly. Treatment with the S. muticum extract and the EtOAc fraction of the S. muticum extract markedly increased the proliferation of dermal papilla cells (DPCs) and decreased the 5α-reductase activity. In addition, the EtOAc fraction of the S. muticum extract significantly promoted anagen initiation in C57BL/6 mice. Especially, apo-9'-fucoxanthinone, an active constituent from the S. muticum extract, caused an increase in DPC proliferation and a decrease in 5α-reductase activity. To elucidate the molecular mechanisms of apo-9'-fucoxanthinone on the proliferation of DPCs, we examined the level of various signaling proteins. Apo-9'-fucoxanthinone increased the level of vascular endothelial growth factor receptor-2 (VEGF-R2), Wnt/ß-catenin signaling proteins such as phospho(ser9)-glycogen synthase kinase-3ß (GSK-3ß) and phospho(ser552)-ß-catenin, whereas apo-9'-fucoxanthinone did not affect the transforming growth factor-ß (TGF-ß) signaling proteins such as Smad2/3. These results suggest that apo-9'-fucoxanthinone from S. muticum could have the potential for hair growth with DPC proliferation via the activation of Wnt/ß-catenin signaling and the VEGF-R2 pathway.

4-Hydroxy-2,3-Dimethyl-2-Nonen-4-Olide Has an Inhibitory Effect on Pro-Inflammatory Cytokine Production in CpG-Stimulated Bone Marrow-Derived Dendritic Cells.

This study was intended to assess the anti-inflammatory properties of 4-hydroxy-2,3-dimethyl-2-nonen-4-olide (Comp) isolated from Ulva pertusa Kjellman on production of pro-inflammatory cytokines. Comp revealed remarkable inhibitory effects on production of pro-inflammatory cytokines in bone marrow-derived dendritic cells (BMDCs). Comp pre-treatment in the CpG DNA-stimulated BMDCs exhibited strong inhibition of interleukin (IL)-12 p40 and IL-6 production with IC50 values ranging from 7.57 ± 0.2 to 10.83 ± 0.3, respectively. It revealed an inhibitory effect on the phosphorylation of ERK1/2, JNK1/2, and p38, and on activator protein (AP)-1 reporter activity. Comp displayed noteworthy inhibitory effects on phosphorylation and degradation of IκBα, and on NF-κB reporter activity. In summary, these data propose that Comp has substantial anti-inflammatory properties and warrants further study concerning its potential use as a therapeutic agent for inflammation-associated maladies.

Protective Effect of Diphlorethohydroxycarmalol against Ultraviolet B Radiation-Induced DNA Damage by Inducing the Nucleotide Excision Repair System in HaCaT Human Keratinocytes.

We investigated the protective properties of diphlorethohydroxycarmalol (DPHC), a phlorotannin, against ultraviolet B (UVB) radiation-induced cyclobutane pyrimidine dimers (CPDs) in HaCaT human keratinocytes. The nucleotide excision repair (NER) system is the pathway by which cells identify and repair bulky, helix-distorting DNA lesions such as ultraviolet (UV) radiation-induced CPDs and 6-4 photoproducts. CPDs levels were elevated in UVB-exposed cells; however, this increase was reduced by DPHC. Expression levels of xeroderma pigmentosum complementation group C (XPC) and excision repair cross-complementing 1 (ERCC1), which are essential components of the NER pathway, were induced in DPHC-treated cells. Expression of XPC and ERCC1 were reduced following UVB exposure, whereas DPHC treatment partially restored the levels of both proteins. DPHC also increased expression of transcription factor specificity protein 1 (SP1) and sirtuin 1, an up-regulator of XPC, in UVB-exposed cells. DPHC restored binding of the SP1 to the XPC promoter, which is reduced in UVB-exposed cells. These results indicate that DPHC can protect cells against UVB-induced DNA damage by inducing the NER system.

Diphlorethohydroxycarmalol inhibits interleukin-6 production by regulating NF-κB, STAT5 and SOCS1 in lipopolysaccharide-stimulated RAW264.7 cells.

Diphlorethohydroxycarmalol (DPHC) is a phlorotannin compound isolated from Ishige okamuarae, a brown alga. This study was conducted to investigate the anti-inflammatory effect and action mechanism of DPHC in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. We found that DPHC strongly reduces the production of interleukin 6 (IL-6), but not that of tumor necrosis factor-alpha (TNF-α) induced by LPS. DPHC (12.5 and 100 µM) suppressed the phosphorylation and the nuclear translocation of NF-kappaB (NF-κB), a central signaling molecule in the inflammation process induced by LPS. The suppressor of cytokine signaling 1 (SOCS1) is a negative feedback regulator of Janus kinase (Jak)-signal transducer and activator of transcription (STAT) signaling. In this study, DPHC inhibited STAT5 expression and upregulated that of SOCS1 at a concentration of 100 µM. Furthermore, N-tosyl-l-phenylalanine chloromethyl ketone (TPCK) (a specific NF-κB inhibitor) and JI (a specific Jak2 inhibitor) reduced the production of IL-6, but not that of tumor necrosis factor-alpha (TNF-α) in LPS-stimulated RAW 264.7 macrophages. These findings demonstrate that DPHC inhibits IL-6 production via the downregulation of NF-κB and Jak2-STAT5 pathway and upregulation of SOCS1.

Cytoprotective effect of eckol against oxidative stress-induced mitochondrial dysfunction: involvement of the FoxO3a/AMPK pathway.

This study investigated the cytoprotective effect of Ecklonia cava-derived eckol against H2O2-induced mitochondrial dysfunction in Chang liver cells. While H2O2 augmented levels of mitochondrial reactive oxygen species (ROS), eckol decreased it. Eckol also attenuated high intracellular Ca(2+) levels stimulated by H2O2 and recovered H2O2-diminished ATP levels and succinate dehydrogenase activity. Eckol time-dependently increased the expression of manganese superoxide dismutase (Mn SOD), a mitochondrial antioxidant enzyme with cytoprotective effect against oxidative stress. Eckol recovered Mn SOD expression and activity that were decreased by H2O2. Finally, eckol induced Mn SOD through phosphorylated AMP-activated protein kinase (AMPK) and forkhead box O3a (FoxO3a). Specific silencing RNAs (siRNAs) against FoxO3a and AMPK reduced eckol-stimulated Mn SOD expression, and diethyldithiocarbamate (Mn SOD inhibitor) and siRNA against Mn SOD reduced the cytoprotective effect of eckol against H2O2-provoked cell death. These results demonstrate that eckol protects cells from mitochondrial oxidative stress by activating AMPK/FoxO3a-mediated induction of Mn SOD.

Triphlorethol-A from Ecklonia cava up-regulates the oxidant sensitive 8-oxoguanine DNA glycosylase 1.

This study investigated the protective mechanisms of triphlorethol-A, isolated from Ecklonia cava, against oxidative stress-induced DNA base damage, especially 8-oxoguanine (8-oxoG), in Chinese hamster lung fibroblast V79-4 cells. 8-Oxoguanine DNA glycosylase-1 (OGG1) plays an important role in the removal of 8-oxoG during the cellular response to DNA base damage. Triphlorethol-A significantly decreased the levels of 8-oxoG induced by H2O2, and this correlated with increases in OGG1 mRNA and OGG1 protein levels. Furthermore, siOGG1-transfected cell attenuated the protective effect of triphlorethol-A against H2O2 treatment. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor for OGG1, and Nrf2 combines with small Maf proteins in the nucleus to bind to antioxidant response elements (ARE) in the upstream promoter region of the OGG1 gene. Triphlorethol-A restored the expression of nuclear Nrf2, small Maf protein, and the Nrf2-Maf complex, all of which were reduced by oxidative stress. Furthermore, triphlorethol-A increased Nrf2 binding to ARE sequences and the resulting OGG1 promoter activity, both of which were also reduced by oxidative stress. The levels of the phosphorylated forms of Akt kinase, downstream of phosphatidylinositol 3-kinase (PI3K), and Erk, which are regulators of OGG1, were sharply decreased by oxidative stress, but these decreases were prevented by triphlorethol-A. Specific PI3K, Akt, and Erk inhibitors abolished the cytoprotective effects of triphlorethol-A, suggesting that OGG1 induction by triphlorethol-A involves the PI3K/Akt and Erk pathways. Taken together, these data indicate that by activating the DNA repair system, triphlorethol-A exerts protective effects against DNA base damage induced by oxidative stress.

The ethyl acetate fraction of Sargassum muticum attenuates ultraviolet B radiation-induced apoptotic cell death via regulation of MAPK- and caspase-dependent signaling pathways in human HaCaT keratinocytes.

CONTEXT: Our previous work demonstrated that an ethyl acetate extract derived from Sargassum muticum (Yendo) Fenshol (SME) protected human HaCaT keratinocytes against ultraviolet B (UVB)-induced oxidative stress by increasing antioxidant activity in the cells, thereby inhibiting apoptosis. OBJECTIVE: The aim of the current study was to further elucidate the anti-apoptotic mechanism of SME against UVB-induced cell damage. MATERIALS AND METHODS: The expression levels of several apoptotic-associated and mitogen-activated kinase (MAPK) signaling proteins were determined by western blot analysis of UVB-irradiated HaCaT cells with or without prior SME treatment. In addition, the loss of mitochondrial membrane potential (Δψm) was detected using flow cytometry or confocal microscopy and the mitochondria membrane-permeate dye, JC-1. Apoptosis was assessed by quantifying DNA fragmentation and apoptotic body formation. Furthermore, cell viability was evaluated using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. RESULTS: SME absorbed electromagnetic radiation in the UVB range (280-320 nm) of the UV/visible light spectrum. SME also increased Bcl-2 and Mcl-1 expression in UVB-irradiated cells and decreased the Bax expression. Moreover, SME inhibited the UVB-induced disruption of mitochondrial membrane potential and prevented UVB-mediated increases in activated caspase-9 and caspase-3 (an apoptotic initiator and executor, respectively) levels. Notably, treatment with a pan-caspase inhibitor enhanced the anti-apoptotic effects of SME in UVB-irradiated cells. Finally, SME reduced the UVB-mediated phosphorylation of p38 MAPK and JNK, and prevented the UVB-mediated dephosphorylation of Erk1/2 and Akt. DISCUSSION AND CONCLUSION: The present results indicate that SME safeguards HaCaT keratinocytes from UVB-mediated apoptosis by inhibiting a caspase-dependent signaling pathway.

Six-month versus 12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) randomized, multicenter study.

BACKGROUND: The optimal duration of dual antiplatelet therapy (DAPT) after implantation of drug-eluting coronary stents remains undetermined. We aimed to test whether 6-month DAPT would be noninferior to 12-month DAPT after implantation of drug-eluting stents. METHODS AND RESULTS: We randomly assigned 1443 patients undergoing implantation of drug-eluting stents to receive 6- or 12-month DAPT (in a 1:1 ratio). The primary end point was a target vessel failure, defined as the composite of cardiac death, myocardial infarction, or ischemia-driven target vessel revascularization at 12 months. Rates of target vessel failure at 12 months were 4.8% in the 6-month DAPT group and 4.3% in the 12-month DAPT group (the upper limit of 1-sided 95% confidence interval, 2.4%; P=0.001 for noninferiority with a predefined noninferiority margin of 4.0%). Although stent thrombosis tended to occur more frequently in the 6-month DAPT group than in the 12-month group (0.9% versus 0.1%; hazard ratio, 6.02; 95% confidence interval, 0.72-49.96; P=0.10), the risk of death or myocardial infarction did not differ in the 2 groups (2.4% versus 1.9%; hazard ratio, 1.21; 95% confidence interval, 0.60-2.47; P=0.58). In the prespecified subgroup analysis, target vessel failure occurred more frequently in the 6-month DAPT group than in the 12-month group (hazard ratio, 3.16; 95% confidence interval, 1.42-7.03; P=0.005) among diabetic patients. CONCLUSIONS: Six-month DAPT did not increase the risk of target vessel failure at 12 months after implantation of drug-eluting stents compared with 12-month DAPT. However, the noninferiority margin was wide, and the study was underpowered for death or myocardial infarction. Our results need to be confirmed in larger trials. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00698607.

Nine-month angiographic and intravascular ultrasound outcomes after resolute zotarolimus-eluting stent implantation for the treatment of in-stent restenosis.

OBJECTIVES: We aimed to evaluate the mid-term outcomes of resolute zotarolimus-eluting stent (R-ZES) implantation for in-stent restenosis (ISR). BACKGROUND: There has been a paucity of data regarding the effects of new-generation drug-eluting stent to treat ISR. METHODS: From 2009 to 2010, a total of 98 patients with 98 ISR lesions were prospectively enrolled after R-ZES implantation for the treatment of ISR. Among 98 patients, 73 patients underwent follow-up angiography at 9 months. Serial intravascular ultrasound (IVUS) at both postprocedure and 9 months was evaluated in 55 patients. The overlapped segment of R-ZES was defined as the portion of R-ZES superimposed on previous stent. RESULTS: Late loss and binary restenosis rate were 0.3 ± 0.5 mm and 5.5% at 9 months. On IVUS, the percentage of neointimal volume and maximum percentage of neointimal area were 3.9 ± 6.3% and 17.3 ± 15.5%, respectively. There was no significant change of vessel volume index between postprocedure and 9 months (16.9 ± 4.7 mm³ /mm vs. 17.1 ± 4.6 mm³ /mm, P = 0.251). Late-acquired incomplete stent apposition was observed in 5 (5/55, 9.1%) cases. Compared with nonoverlapped segments of R-ZES, the overlapped did not show larger neointimal volume index (0.3 ± 0.5 mm³ /mm vs. 0.2 ± 0.3 mm³ /mm, P = 0.187) on 9-month IVUS. During follow-up (median, 353 days), repeat target-lesion revascularization was performed in four cases, but there were no death or stent thrombosis. CONCLUSIONS: This study suggested that R-ZES implantation for the treatment of ISR was effective up to 9 months and showed favorable vascular responses on serial IVUS assessment.

Tyrosinase inhibitory activities of the compounds isolated from Neolitsea aciculata (Blume) Koidz.

This study was designed to investigate the mushroom tyrosinase inhibitory activity for the constituents isolated from Neolitsea aciculata. The stems of N. aciculata was extracted with aqueous ethanol and subjected to chromatographic separation, which led to the isolation of 11 compounds: methyl linoleate (1), catechin (2), epicatechin (3), afzelin-7-O-glucopyranoside (4), 2',3'-di-(p-coumaroyl)afzelin (5), 2'-p-coumaroylafzelin (6), feruloyl tyramine (7), ß-sitosterol (8), daucosterol (9), oleic acid (10), and trilaurin (11). Their structures were elucidated on the basis of spectroscopic studies as well as by comparison with the data available in the literature. Among these isolates, compounds 5 and 6 were identified as potent mushroom tyrosinase inhibitors with IC50 values of 0.067 and 0.080 mM, respectively. The inhibition kinetics, analysed by Lineweaver-Burk plots, indicated that compounds 5 and 6 are competitive tyrosinase inhibitors when using l-tyrosine as a substrate. Notably, compounds 1-11 were isolated for the first time from this plant. These results provide evidence that this plant might be a potential source of anti-melanogenesis agents.

Apo-9'-fucoxanthinone, isolated from Sargassum muticum, inhibits CpG-induced inflammatory response by attenuating the mitogen-activated protein kinase pathway.

Sargassum muticum (S. muticum) is a brown edible alga and widely distributed in Korea. This report was designed to evaluate the anti-inflammatory properties of apo-9'-fucoxanthinone (APO-9') isolated from S. muticum on pro-inflammatory cytokine production. S. muticum extract (SME) exhibited significant inhibitory effects on pro-inflammatory cytokine production in bone marrow-derived macrophages (BMDMs) and dendritic cells (BMDCs). APO-9' pre-treatment in the CpG DNA-stimulated BMDMs and BMDCs showed a strong dose-dependent inhibitory effect on interleukin (IL)-12 p40, IL-6 and tumor necrosis factor (TNF)-α production with IC50 values ranging from 5.31 to 13.79. It exhibited a strong inhibitory effect on the phosphorylation of ERK1/2 and on activator protein (AP)-1 reporter activity. APO-9' pre-treatment exhibited significant inhibition of CpG DNA-induced production of inducible nitric oxide synthase. Taken together, these data suggest that SME and APO-9' have a significant anti-inflammatory property and warrant further studies concerning the potentials of SME and APO-9' for medicinal use.

Sargachromenol from Sargassum micracanthum inhibits the lipopolysaccharide-induced production of inflammatory mediators in RAW 264.7 macrophages.

During our ongoing screening program designed to determine the anti-inflammatory potential of natural compounds, we isolated sargachromenol from Sargassum micracanthum. In the present study, we investigated the anti-inflammatory effects of sargachromenol on lipopolysaccharide (LPS)-induced inflammation in murine RAW 264.7 macrophage cells and the underlying mechanisms. Sargachromenol significantly inhibited the LPS-induced production of nitric oxide (NO) and prostaglandin E2 (PGE2) in a dose-dependent manner. It also significantly inhibited the protein expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in a dose-dependent manner in LPS-stimulated macrophage cells. Further analyses showed that sargachromenol decreased the cytoplasmic loss of inhibitor κBα (IκBα) protein. These results suggest that sargachromenol may exert its anti-inflammatory effects on LPS-stimulated macrophage cells by inhibiting the activation of the NF-κB signaling pathway. In conclusion, to our knowledge, this is the first study to show that sargachromenol isolated from S. micracanthum has an effective anti-inflammatory activity. Therefore, sargachromenol might be useful for cosmetic, food, or medical applications requiring anti-inflammatory properties.

Anti-inflammatory effects of apo-9'-fucoxanthinone from the brown alga, Sargassum muticum.

BACKGROUND: The marine environment is a unique source of bioactive natural products, of which Sargassum muticum (Yendo) Fensholt is an important brown algae distributed in Jeju Island, Korea. S. muticum is a traditional Korean food stuff and has pharmacological functions including anti-inflammatory effects. However, the active ingredients from S. muticum have not been characterized. METHODS: Bioguided fractionation of the ethanolic extract of S. muticum, collected from Jeju island, led to the isolation of a norisoprenoid. Its structure was determined by analysis of the spectroscopic data. In vitro anti-inflammatory activity and mechanisms of action of this compound were examined using lipopolysaccharide (LPS)-stimulated RAW 264.7 cells through ELISA assays and Western blot analysis. RESULTS: Apo-9'-fucoxanthinone, belonging to the norisoprenoid family were identified. Apo-9'-fucoxanthinone effectively suppressed LPS-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production. This compound also exerted their anti-inflammatory actions by down-regulating of NF-κB activation via suppression of IκB-α in macrophages. CONCLUSIONS: This is the first report describing effective anti-inflammatory activity for apo-9'-fucoxanthinone'-fucoxanthnone isolated from S. muticum. Apo-9'-fucoxanthinone may be a good candidate for delaying the progression of human inflammatory diseases and warrants further studies.