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East Asian population has a low level of inflammation compared with Western population. The prognostic implication of residual inflammatory risk (RIR) remains uncertain in East Asians.This study sought to provide an analysis to estimate early-determined RIR and its association with clinical outcomes in East Asian patients with coronary artery disease (CAD).In an East Asian registry including patients with CAD undergoing percutaneous coronary intervention (PCI) (n = 4,562), RIR status was determined by measuring high-sensitivity C-reactive protein (hsCRP) serially at admission and at 1-month follow-up. Patients were stratified into 4 groups according to hsCRP criteria (≥2 mg/L): 1) persistent low RIR (lowIn our cohort, median levels of hsCRP were significantly decreased over time (1.3 to 0.9 mg/L;Approximately one-fifth of East Asian patients with CAD have persistent high RIR, which shows the close association with occurrence of ischemic and bleeding events. (Gyeongsang National University Hospital Registry [GNUH]; NCT04650529).

Objective Human microRNA-185 (miR-185) has been reported to act as a regulator of fibrosis and angiogenesis in cancer. However, miR-185 has not been investigated in patients with ST-segment elevation myocardial infarction (STEMI). We hypothesized that the changes in miR-185 levels in STEMI patients are related to the processes of myocardial healing and remodeling. Methods Between January 2011 and December 2013, 145 patients with STEMI (65.9±11.6 years old; 41 women) were enrolled. Initial and discharge serum samples collected from 20 patients with STEMI and mixed sera from 8 healthy controls were analyzed by a microarray. A quantitative reverse transcription polymerase chain reaction (RT-qPCR) analysis of miR-185 was performed in all 145 patients. The correlation between the miR-185 levels and the clinical, laboratory, angiographic, and echocardiographic parameters was analyzed. Results The microarray analysis revealed a biphasic pattern in miR-185 levels, with an initial decrease followed by an increase at discharge. The miR-185 levels at discharge were significantly correlated with the troponin-I, CK-MB, and area under the curve of CK-MB levels. There was a positive correlation between the transforming growth factor-β and miR-185 levels at discharge (ρ=0.242, p=0.026). A high wall motion score index and a low ejection fraction, as measured by echocardiography, and high B-type natriuretic peptide level at one month after STEMI were related to high miR-185 levels. Conclusion Our results showed that elevated miR-185 levels at the late stage of STEMI were related to a large amount of myocardial injury and adverse remodeling.

Background: Although the beneficial effects of cardiac resynchronization therapy (CRT) in heart failure (HF) are fully established in HF with left ventricular ejection fraction (LVEF) ≤ 35%, CRT strategy for HF with mildly reduced ejection fraction (HFmrEF) is controversial. Left bundle branch area pacing (LBBAP) is an emerging pacing modality and an alternative option to CRT, and the efficacy and safety are promising so far. The aim of this analysis was to perform a systematic review of the literature and meta‐analysis on impact of LBBAP strategy in HFmrEF, with LVEF between 35 % and 50%. Methods: PubMed, Embase, and Cochrane Library were searched for full-text articles on LBBAP from inception to July 17, 2022. The outcomes of interest were QRS duration, and LVEF at baseline and at follow-up in mid-range HF. Data were extracted and summarized. A random-effect model incorporating the potential heterogeneity was used to synthesize the results. Results: Out of 1065 articles, 8 met the inclusion criteria for 211 mid-range HF patients with an implant LBBAP across the 16 centers. The average implant success rate with lumenless pacing lead use was 91.3%, and 19 complications were reported among all 211 enrolled patients. During the average follow-up of 9.1 months, average LVEF were 39.8% at baseline and 50.5% at follow-up (MD: 10.90%, 95% CI: 6.56 - 15.23 PConclusion: LBBAP could significantly reduce QRS duration and improve systolic function in patient with LVEF between 35 and 50%. Application of LBBAP as a CRT strategy for heart failure with mildly reduced ejection fraction may be a viable option.

Amlodipine has a potential to reduce clopidogrel bioactivation through the cytochrome P450 3A4 enzyme in vivo, but the clinical impact of this interaction remains controversial. This randomized, open-label, two-period, crossover study was performed to evaluate the influence of amlodipine on the haemostatic profiles of high-risk patients during clopidogrel treatment. We recruited 40 Asian patients (Male/Female: n = 36/4) receiving clopidogrel (75 mg/day), aspirin (100 mg/day) and rosuvastatin for at least 6 months following percutaneous coronary intervention. Patients were randomly assigned to receive either 5 mg daily amlodipine or not for 2 weeks, and then were crossed over to the other treatment for 2 weeks. Haemostatic measurements were conducted with the VerifyNow assay and thromboelastography (TEG). Primary endpoint was P2Y12 Reaction Units (PRU) during on- versus off-amlodipine treatment. The on-amlodipine strategy showed higher level of PRU compared with the off-amlodipine strategy (176.8 ± 75.4 vs. 150.7 ± 65.5 PRU; ∆mean: 26.1 PRU; ∆95% confidence interval [CI]: 4.5–47.7 PRU; p = 0.019). Platelet-fibrin clot strength measured by TEG was lower during on- versus off-amlodipine treatment (7,712 ± 1,889 vs. 8,559 ± 2,174 dyne/cm2; ∆mean: –847 dyne/cm2; ∆95% CI: –1,632 to –62 dyne/cm2; p = 0.035). After amlodipine discontinuation, 27 patients (67.5%) showed a decrease in PRU, which was associated with ‘PRU ≥ 160 on-amlodipine’ in multivariate analysis (odds ratio: 62.014; 95% CI: 2.302–1670.328; p = 0.014). In conclusion, amlodipine increases platelet reactivity and decreases platelet-fibrin clot strength during clopidogrel treatment. In addition, the effect of amlodipine discontinuation on clopidogrel responsiveness is associated with on-amlodipine platelet reactivity.

Background/Aims To examine the prevalence and clinical characteristics of apparent treatment-resistant hypertension among ambulatory hypertensive patients. Methods We enrolled adult ambulatory hypertensive patients at 13 well-qualified general hospitals in Korea from January to June 2012. Apparent resistant hypertension was defined as an elevated blood pressure > 140/90 mmHg with the use of three antihypertensive agents, including diuretics, or ≥ 4 antihypertensives, regardless of the blood pressure. Controlled hypertension was defined as a blood pressure within the target using three antihypertensives, including diuretics. Results Among 16,915 hypertensive patients, 1,172 (6.9%) had controlled hypertension, and 1,514 (8.9%) had apparent treatment-resistant hypertension. Patients with apparent treatment-resistant hypertension had an earlier onset of hypertension (56.8 years vs. 58.8 years, p = 0.007) and higher body mass index (26.3 kg/m2 vs. 24.9 kg/m2, p < 0.001) than those with controlled hypertension. Drug compliance did not differ between groups. In the multivariable analysis, earlier onset of hypertension (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.97 to 0.99; p < 0.001) and the presence of comorbidities (OR, 2.06; 95% CI, 1.27 to 3.35; p < 0.001), such as diabetes mellitus, ischemic heart disease, heart failure, and chronic kidney disease, were independent predictors. Among the patients with apparent treatment-resistant hypertension, only 5.2% were receiving ≥ 2 antihypertensives at maximally tolerated doses. Conclusions Apparent treatment-resistant hypertension prevalence is 8.9% among ambulatory hypertensive patients in Korea. An earlier onset of hypertension and the presence of comorbidities are independent predictors. Optimization of medical treatment may reduce the rate of apparent treatment-resistant hypertension.

In cancer cells, aerobic glycolysis rather than oxidative phosphorylation (OxPhos) is generally preferred for the production of ATP. In many cancers, highly expressed pyruvate dehydrogenase kinase 1 (PDK1) reduces the activity of pyruvate dehydrogenase (PDH) by inducing the phosphorylation of its E1&alpha, subunit (PDHA1) and subsequently, shifts the energy metabolism from OxPhos to aerobic glycolysis. Thus, PDK1 has been regarded as a target for anticancer treatment. Here, we report that ilimaquinone (IQ), a sesquiterpene quinone isolated from the marine sponge Smenospongia cerebriformis, might be a novel PDK1 inhibitor. IQ decreased the cell viability of human and murine cancer cells, such as A549, DLD-1, RKO, and LLC cells. The phosphorylation of PDHA1, the substrate of PDK1, was reduced by IQ in the A549 cells. IQ decreased the levels of secretory lactate and increased oxygen consumption. The anticancer effect of IQ was markedly reduced in PDHA1-knockout cells. Computational simulation and biochemical assay revealed that IQ interfered with the ATP binding pocket of PDK1 without affecting the interaction of PDK1 and the E2 subunit of the PDH complex. In addition, similar to other pyruvate dehydrogenase kinase inhibitors, IQ induced the generation of mitochondrial reactive oxygen species (ROS) and depolarized the mitochondrial membrane potential in the A549 cells. The apoptotic cell death induced by IQ treatment was rescued in the presence of MitoTEMPO, a mitochondrial ROS inhibitor. In conclusion, we suggest that IQ might be a novel candidate for anticancer therapeutics that act via the inhibition of PDK1 activity.

N-glycolylneuraminic acid (NeuGc), a non-human sialic acid derivative synthesized by cytidine-5&prime, monophospho-N-acetylneuraminic acid hydroxylase (CMAH), plays a crucial role in mediating infections by certain pathogens. Although it has been postulated that NeuGc biosynthesis and CMAH expression are downregulated during microbial infection, the underlying mechanisms remain unclear. The present study showed that exposure to lipopolysaccharide (LPS), a Gram-negative bacterial endotoxin, leads to loss of NeuGc biosynthesis in pig small intestinal I2I-2I cells. This LPS-induced NeuGc loss was accompanied by decreased CMAH transcript levels, especially intestine-specific 5&prime, pcmah-1. Furthermore, LPS suppressed the activity of the Pi promoter responsible for 5&prime, pcmah-1 by inhibiting DNA binding of Est1. These findings provide insight into the regulatory mechanisms of Neu5Gc biosynthesis during pathogenic infectious events, which may represent a host defense mechanism that protects the self against pathogenic bacterial infections even in non-sanitary environments.

Patients with peripheral artery disease (PAD) have shown the increased risk of cardiovascular (CV) morbidity and mortality. This study sought to evaluate the impact of clot strength on prevalence and major adverse CV events (MACE) of PAD in high-risk patients. We enrolled patients undergoing percutaneous coronary intervention (PCI) (n = 1667) with available platelet–fibrin clot strength [thrombin-induced maximal amplitude (MAthrombin) measured by thromboelastography] and inflammation [high sensitivity C-reactive protein (hs-CRP)]. PAD was defined with abnormal ankle-brachial index (≤ 0.9 or > 1.4). MACE was defined as a composite of CV death, myocardial infarction or stroke. PAD was observed in 201 patients (12.1%). In the multivariate analysis, high clot strength [MAthrombin ≥ 68 mm: odds ratio (OR) 1.70, 95% confidence interval (CI) 1.20 to 2.41, p = 0.003] and enhanced inflammation (hs-CRP ≥ 3.0 mg/L: OR 2.30, 95% CI 1.56 to 3.41, p

Objectives The aim of this study was to evaluate the effect of ticagrelor versus clopidogrel on left ventricular (LV) remodeling after reperfusion of ST-segment elevation myocardial infarction (STEMI) in humans. Background Animal studies have demonstrated that ticagrelor compared with clopidogrel better protects myocardium against reperfusion injury and improves remodeling after myocardial infarction. Methods In this investigator-initiated, randomized, open-label, assessor-blinded trial performed at 10 centers in Korea, patients were enrolled if they had naive STEMI successfully treated with primary percutaneous coronary intervention (PCI) and at least 6-month planned duration of dual-antiplatelet treatment. The coprimary endpoints were LV remodeling index (LVRI) (a relative change of LV end-diastolic volume) measured on 3-dimensional echocardiography and N-terminal pro–B-type natriuretic peptide level at 6 months. Results Among initially enrolled patients with STEMI (n = 336), 139 in each group completed the study. LVRI at 6 months was numerically lower with ticagrelor versus clopidogrel (0.6 ± 18.6% vs. 4.5 ± 16.5%; p = 0.095). Ticagrelor significantly reduced the 6-month level of N-terminal pro–B-type natriuretic peptide (173 ± 141 pg/ml vs. 289 ± 585 pg/ml; p = 0.028). These differences were prominent in patients with pre-PCI TIMI (Thrombolysis In Myocardial Infarction) flow grade 0. By multivariate analysis, ticagrelor versus clopidogrel reduced the risk for positive LV remodeling (LVRI >0%) (odds ratio: 0.56; 95% confidence interval: 0.33 to 0.95; p = 0.030). The LV end-diastolic volume index remained unchanged during ticagrelor treatment (from 54.7 ± 12.2 to 54.2 ± 12.2 ml/m2; p = 0.629), but this value increased over time during clopidogrel treatment (from 54.6 ± 11.3 to 56.4 ± 13.9 ml/m2; p = 0.056) (difference −2.3 ml/m2; 95% confidence interval: −4.8 to 0.2 ml/m2; p = 0.073). Ticagrelor reduced LV end-systolic volume index (from 27.0 ± 8.5 to 24.7 ± 8.4 ml/m2; p Conclusions Ticagrelor was superior to clopidogrel for LV remodeling after reperfusion of STEMI with primary PCI. (High Platelet Inhibition With Ticagrelor to Improve Left Ventricular Remodeling in Patients With ST Segment Elevation Myocardial Infarction [HEALING-AMI]; NCT02224534 )

Background and objectives After the first acute myocardial infarction (AMI), a considerable proportion of patients are newly diagnosed with diabetes mellitus (DM). However, in AMI, controversy remains regarding the disparity in prognosis between previously diagnosed DM (known-DM) and newly diagnosed DM (new-DM). Methods The study included 10,455 patients with AMI (non-DM, 6,236; new-DM, 659; known-DM, 3,560) admitted to one of 15 participating centers in Korea between November 2011 and January 2016 (average follow-up, 523 days). We compared the characteristics and clinical course of patients with known-DM and those with new- or non-DM. Results Compared to patients with known-DM, those with new-DM or non-DM were younger, more likely to be male, and less likely to have hypertension, dyslipidemia, prior stroke, angina, or myocardial infarction. Compared to patients with new-DM or non-DM (reference), those with known-DM had higher risks of major adverse cardiac events (hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.06-1.35; p=0.004), cardiac death (HR, 1.26; 95% CI, 1.01-1.57; p=0.042), and congestive heart failure (HR, 1.58; 95% CI, 1.20-2.08). Unlike known-DM, new-DM did not increase the risk of cardiac events (including death). Conclusions Known-DM was associated with a significantly higher risk of cardiovascular events after AMI, while new-DM had a similar risk of cardiac events as that noted for non-DM. There were different cardiovascular outcomes according to diabetes status in patients with AMI.

We investigated the utility of nutrition scores in predicting mortality and prognostic importance of nutrition status using three different scoring systems in patients with acute myocardial infarction (AMI).In total, 1147 patients with AMI were enrolled in this study (72.5 % men; mean age 65.6 years). Patients were divided into three groups according to the geriatric nutritional risk index (GNRI); prognostic nutritional index (PNI); and triglycerides, total cholesterol, and body weight index(TCBI) scores as tertile: low (GNRI ≤ 103.8, n = 382), intermediate (103.8GNRI ≤ 112.3, n = 383), and high (GNRI112.3, n = 382) GNRI groups; low (PNI ≤ 50.0, n = 382), intermediate (50.0PNI ≤ 56.1, n = 383), and high (PNI56.1, n = 382) PNI groups; and low (TCBI ≤ 1086.4, n = 382), intermediate (1086.3GNRI ≤ 2139.1, n = 383), and high (TCBI2139.1, n = 382) TCBI groups.In the GNRI, TCBI, and PNI groups, the cumulative incidence of all-cause death and major adverse cardiovascular events (MACEs) was significantly higher in the low score group, followed by the intermediate and high score groups. Moreover, both intermediate and low PNI groups had a similar cumulative incidence of all-cause death and MACE. The GNRI score (AUC 0.753, 95% CI 0.608~0.745, P = 0.009) had significantly higher areas under the curve (AUCs) than the TCBI (AUC 0.659, 95% CI 0.600~0.719, reference) and PNI (AUC 0.676, 95% CI 0.608~0.745, P = 0.669) scores.Patients with low nutrition scores were at a higher risk of MACE and all-cause death than patients with high nutrition scores. Additionally, the GNRI had the greatest incremental value in predicting risks among the three different scoring systems used in this study.

Objective Brachial-ankle pulse wave velocity (baPWV) measurement is a well-established modality for assessing arterial stiffness and predicting cardiovascular events. However, to our knowledge, its usefulness has not been clarified among patients with non-ST-elevation myocardial infarction (NSTEMI). This study assessed the prognostic value of baPWV in patients with NSTEMI. Patients and methods Patients (n=411, mean age, 63.8±13.5 years, 75.2% men) with NSTEMI who underwent a percutaneous coronary intervention and baPWV measurement were recruited between January 2013 and December 2015. Cardiac mortality and major adverse cardiovascular events (MACE) including cardiac death, re-acute myocardial infarction, revascularization, heart failure, and stroke after discharge were analyzed. The mean follow-up duration was 350 days. Results MACE and cardiac mortality occurred in 26 (6.3%) patients and 13 (3.1%) patients. Kaplan-Meier survival curves showed that MACE and cardiac mortality were significantly higher in patients with high baPWV (1708.0 cm/s). In multivariable Cox regression analysis, high baPWV (hazard ratio: 2.55; 95% confidence interval: 1.03-6.30, P=0.043) was an independent predictor of MACE even after adjusting for possible confounders. Conclusion Our findings indicate that baPWV was a strong independent prognostic factor of MACE in patients with NSTEMI. This suggests that baPWV can be a useful prognostic factor in the clinical setting for easier and less invasive prediction of MACE in patients with NSTEMI.

Moyamoya disease is characterized by progressive stenosis of the distal portion of the internal carotid arteries and fragile collateral vessels in the brain. The precise pathogenesis is still not known. Although extracranial vessel involvement is very rare, coronary arterial involvement has recently been reported. Here, we report a case of diffuse, multivessel coronary spasm leading to cardiac arrest and myocardial infarction in a 47-year-old man with moyamoya disease with no underlying emotional or physical stress.

// Tae-Wook Chung 1 , Eun-Young Kim 1, 2 , Seok-Jo Kim 3 , Hee-Jung Choi 1 , Se Bok Jang 4 , Keuk-Jun Kim 5 , Sun-Hyung Ha 3 , Fukushi Abekura 3 , Choong-Hwan Kwak 3 , Cheorl-Ho Kim 3 and Ki-Tae Ha 1, 2 1 School of Korean Medicine, Healthy Aging Korean Medical Research Center, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea 2 Graduate Training Program of Korean Medicine for Healthy-Aging, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea 3 Department of Biological Science, Sungkyunkwan University, Suwon, Kyunggi-do 16419, Republic of Korea 4 Department of Molecular Biology, College of Natural Sciences, Pusan National University, Geumjeong-gu, Busan 46241, Republic of Korea 5 Department of Clinical Pathology, TaeKyeung University, Gyeongsan 38547, Republic of Korea Correspondence to: Cheorl-Ho Kim, email: chkimbio@skku.edu Ki-Tae Ha, email: hagis@pusan.ac.kr Keywords: sialyllactose, milk, oligosaccharides, angiogenesis, VEGF receptor-2 Received: May 31, 2016 Accepted: February 15, 2017 Published: March 14, 2017 ABSTRACT The oligosaccharides in human milk have various biological functions. However, the molecular mechanism(s) underlying the anti-angiogenic action of sialylated human milk oligosaccharides (HMOs) are still unclear. Here, we show that siallylactose (SL) found in human milk can inhibit the activation of vascular endothelial growth factor (VEGF)-mediated VEGF receptor-2 (VEGFR-2) by binding to its VEGF binding site (second and third IgG-like domains), thus blocking downstream signal activation. SL also inhibits growth of VEGF-stimulated endothelial cells. In endothelial cells treated with VEGF, SL diminished tube formation, migration, and the arrangement of actin filament. In addition, SL clearly suppressed VEGF-induced neovascularization in an in vivo Matrigel plug assay. Notably, SL prevented the growth of tumor cells, and angiogenesis on tumor tissues in in vivo mice models allotransplanted with Lewis lung carcinoma, melanoma, and colon carcinoma cells. Taken together, we have demonstrated that the sialylated milk oligosaccharide sialyllactose functions as an inhibitor of angiogenesis through suppression of VEGF-mediated VEGFR-2 activation in endothelial cells, Accordingly, it could be a novel candidate for the development of anti-angiogenic drugs without any side effects.

저나트륨혈증은 심부전 환자에서 흔하게 관찰되며 이환율 및 사망률의 증가와 관련되어 있다. Tolvaptan은 V2-수용체 항길항제로서 심부전 환자에서 저나트륨혈증의 새로운 치료 약제로 이용되고 있다. 그러나 tolvaptan에 의한 삼투성 탈수초 증후군의 보고는 거의 없었다. 78세 여자가 심부전, 심방세동 및 저나트륨혈증으로 내원하여 tolvaptan을 투여받았다. 약제 처방 후 3일째 갑작스런 소변량 증가 및 혈청 나트륨 증가가 발생하였으며 의식저하가 동반되었다. 고령, 저체중 등의 위험 인자를 가진 심부전 환자에서 tolvaptan의 비정상적인 지연 반응이 나타나 탈수초 증후군이 발생한 증례를 보고하는 바이다.

Background/Aims: Although a low triiodothyronine (T3) state is closely associated with heart failure (HF), it is uncertain whether total T3 levels on admission is cor related with the clinical outcomes of acute myocardial infarction (AMI). The aim of this study is to investigate the prognostic value of total T3 levels for major ad verse cardiovascular and cerebrovascular events (MACCEs) in patients with AMI undergone percutaneous coronary intervention (PCI). Methods: A total of 765 PCI-treated AMI patients (65.4 ± 12.6 years old, 215 women) between January 2012 and July 2014 were included and 1-year MACCEs were ana lyzed. We assessed the correlation of total T3 and free thyroxine (fT4) with preva lence of 1-year MACCEs and the predictive values of total T3, fT4, and the ratio of total T3 to fT4 (T3/fT4), especially for HF requiring re-hospitalization. Results: Thirty patients (3.9%) were re-hospitalized within 12 months to control HF symptoms. Total T3 levels were lower in the HF group than in the non-HF group (84.32 ± 21.04 ng/dL vs. 101.20 ± 20.30 ng/dL, p < 0.001). Receiver operating characteristic curve analysis showed the cut-offs of total T3 levels (≤ 85 ng/dL) and T3/fT4 (≤ 60) for HF (area under curve [AUC] = 0.734, p < 0.001; AUC = 0.774, p < 0.001, respectively). In multivariate analysis, lower T3/fT4 was an independent predictor for 1-year HF in PCI-treated AMI patients (odds ratio, 1.035; 95% confidential in terval, 1.007 to 1.064; p = 0.015). Conclusions: Lower levels of total T3 were well correlated with 1-year HF in PCI-treated AMI patients. The T3/fT4 levels can be an additional marker to pre dict HF.

The disialoganglioside GD3 has been considered to be involved in tumor progression or suppression in various tumor cells. However, the significance of the biological functions of GD3 in breast cancer cells is still controversial. This prompted us to study the possible relationship(s) between GD3 expression and the metastatic potential of a breast cancer MDA-MB231 cells as an estrogen receptor negative (ER-) type. The human GD3 synthase cDNA was transfected into MDA-MB231 cells, and G-418 bulk selection was used to select cells stably overexpressing the GD3 synthase. In vitro invasion potentials of the GD3 synthase over-expressing cells (pc3-GD3s) were significantly suppressed when compared with control cells. Expression of intercellular adhesion molecule-1 (ICAM-1; CD54) was down-regulated in the pc3-GD3s cells and the decrease in ICAM-I expression is directly related to the decrease in invasiveness of the pc3-GD3s cells. Another type of ER negative SK-BR3 cells exhibited the similar level of ICAM-1 expression as MDA-MB231 cells, while the ER positive MCF-7 cells (ER+) showed the increased expression level of ICAM-1. Then, we investigated signaling pathways known to control ICAM-1 expression. No difference was observed in the phosphorylation of ERK and p38 between the pc3-GD3s and control cells (pc3), but the activation of AKT was inhibited in pc3-GD3s, and not in the control (pc3). In addition, the composition of total gangliosides was changed between control (pc3) and pc3-GD3s cells, as confirmed by HPTLC. The pc3-GD3s cells had an accumulation of the GD2 instead of the GD3. RT-PCR results showed that not only GD3 synthase, but also GM2/GD2 synthase (β4-GalNc T) expression was increased in pc3-GD3s cells. Overexpression of GD3 synthase suppresses the invasive potential of human breast cancer MDA-MB-231 cells through down-regulation of ICAM-1 and the crucial pathway to allow the apoptotic effect has been attributed to accumulation of the GD2 ganglioside. ER has been linked to the ICAM-1 expression with GD3 to GD2 conversion in human breast cancer cells. This is the first finding of the endogenous sialyltransferase functions in tumor cells.

SummaryThe role of platelet-leukocyte interaction in the infarct myocardium still remains unveiled. We aimed to determine the linkage of platelet activation to post-infarct left ventricular remodelling (LVR) process. REMODELING was a prospective, observational, cohort trial including patients (n = 150) with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. Patients were given aspirin plus clopidogrel therapy (600 mg loading and 75 mg daily). Platelet reactivity (PRU: P2Y12 Reaction Units) was assessed with VerifyNow P2Y12 assay on admission. Transthoracic echocardiography was performed on admission and at one-month follow-up. The primary endpoint was the incidence of LVR according to PRU-based quartile distribution. LVR was defined as a relative ≥ 20 % increase in LV end-diastolic volume (LVEDV) between measurements. Adverse LVR was observed in 36 patients (24.0 %). According to PRU quartile, LVR rate was 10.8 % in the first, 23.1 % in the second, 27.0 % in the third, and 35.1 % in the fourth (p = 0.015): the optimal cut-off of PRU was ≥ 248 (area under curve: 0.643; 95 % confidence interval: 0.543 to 0.744; p = 0.010). LVR rate also increased proportionally according to the level of high sensitivity-C reactive protein (hs-CRP) (p = 0.012). In multivariate analysis, the combination of PRU (≥ 248) and hs-CRP (≥ 1.4 mg/l) significantly increased the predictive value for LVR occurrence by about 21-fold. In conclusion, enhanced levels of platelet activation and inflammation determined the incidence of adverse LVR after STEMI. Combining the measurements of these risk factors increased risk discrimination of LVR. The role of intensified antiplatelet or anti-inflammatory therapy in post-infarct LVR process deserves further study.

Dobutamine stress echocardiography (DSE) and coronary computed tomography angiography (CTA) can provide perioperative prognostic information in risk stratification of patients undergoing noncardiac surgery. This study directly compared the prognostic value of DSE and CTA in patients undergoing noncardiac surgery.Between 2014 and 2016, 215 patients with more than one clinical risk factor for perioperative cardiovascular (CV) events were enrolled prospectively. They received both DSE and CTA before noncardiac surgery. Perioperative clinical risk was classified according to the revised cardiac risk index (RCRI), DSE results were categorized as abnormal (inducible ischemia and/or nonviable infarction) or not. CTA results were assessed using the severity of stenosis, with significant stenosis being ≥50% of the luminal diameter). After the exclusion, a total of 206 patients remained. Perioperative CV events were defined as CV death, non-fatal myocardial infarction (MI), myocardial injury, pulmonary edema, non-fatal stroke, and systemic embolism within 30 days after surgery.Twenty-four patients (12%) had perioperative cardiac events (1 cardiac death, 10 non-fatal MI, 8 myocardial injury, 11 pulmonary edema, 1 non-fatal stroke, and 1 pulmonary embolism). Following adjustment for baseline RCRI score, abnormal result on DSE (OR, 6.08, 95% CI, 2.41 to 15.31, P 0.001), significant CAD on CTA (OR, 18.79; 95% CI, 5.24 to 67.42, P 0.001), and high CACS (OR, 4.19; 95% CI, 1.39 to 12.60, P = 0.011) remained significant predictors of perioperative CV events.DSE and CTA are independent predictive factors of events in patients undergoing noncardiac surgery. Among them, assessment of significant CAD using CTA might show a higher prognostic value compared with DSE before noncardiac surgery.URL: http://www.clinicaltrials.gov. Unique identifier: NCT02250963.

Although acid suppressants are needed to attenuate gastrointestinal bleeding (GIB) after percutaneous coronary intervention (PCI), pharmacodynamic interaction between clopidogrel and proton pump inhibitor (PPI) can increase the risk of high platelet reactivity (HPR). We sought to evaluate serial changes of platelet measures and influence of rabeprazole on platelet measures. After 600-mg clopidogrel loading for elective PCI, clopidogrel-sensitive patients were recruited and randomly assigned to add rabeprazole of daily 20 mg (n = 40) or famotidine of daily 40 mg (n = 40). Platelet measures were performed with light transmittance aggregometry and VASP-P assay. Primary endpoint was 5 μM ADP-induced platelet aggregation (PA) at 30-day follow-up. HPR was defined as 5 μM ADP-induced PA > 46%. Baseline platelet measures did not differ significantly between the groups. The 30-day level of 5 μM ADP-induced PA was similar between the famotidine vs. rabeprazole group (30.0 ± 16.4% vs. 30.2 ± 13.9%, P= .956). In addition, other platelet measures were comparable between the groups. At 30-day follow-up, the incidence of HPR was similar between the famotidine and rabeprazole groups (20.5% vs. 15.4%; P= .555). In conclusion, adjunctive use of rabeprazole showed the similar antiplatelet effect even in clopidogrel-sensitive patients compared with adjunctive famotidine, which may support the similar effect of rabeprazole and famotidine on the antiplatelet effect of dual antiplatelet therapy with clopidogrel plus aspirin.

3′-sialyllactose is one of the abundant components in human milk oligosaccharides (HMOs) that protect infants from various viral infections in early stages of immune system development. 3SL is a combination of lactose and sialic acid. Most sialic acids are widely expressed in animal cells and they bind to siglec proteins. In this study, we demonstrate that 3SL specifically binds to CD33. It induces megakaryocyte differentiation and subsequent apoptosis by targeting cell surface protein siglec-3 (CD33) in human chronic myeloid leukemia K562 cells. The 3SL-bound CD33 was internalized to the cytosol via caveolae-dependent endocytosis. At the molecular level, 3SL-bound CD33 recruits the suppressor of cytokine signaling 3 (SOCS3) and SH2 domain-containing protein tyrosine phosphatase 1 (SHP1). SOCS3 is degraded with CD33 by proteasome degradation, while SHP-1 activates extracellular signal–regulated kinase (ERK) to induce megakaryocytic differentiation and subsequent apoptosis. The present study, therefore, suggests that 3SL is a potential anti-leukemia agent affecting differentiation and apoptosis.

Background: High-flow oxygen therapy through nasal cannula (HFNC) could reduce intubation rate and mortality rate among patients with acute respiratory failure. We evaluated the physiological responses and clinical outcomes of HFNC in patients with acute heart failure (AHF). Methods: A retrospective cohort analysis was performed in single medical tertiary center. Patients with AHF who had a progressive hypoxemia after oxygenation via facemask were divided into intubation group and HFNC group. We analyzed the physiological responses and in-hospital clinical outcomes between two groups. Results: Seventy-three patients of intubation group and 76 patients of HFNC group were included. Baseline characteristics were well-balanced between two groups. There were no differences in changes of mean arterial pressure, heart rate, and pulse oxygen saturation during the first 6 hours. Among HFNC group, 66 of 76 patients (86.8%) were successfully recovered from progressive hypoxemia without endotracheal intubation, and there were no differences in in-hospital clinical outcomes between two groups. Conclusions: This study showed HFNC group had a similar result of improvement of oxygen saturation and in-hospital clinical outcomes compared with intubation group in AHF. Present study supported HFNC could be considered as initial choice of oxygen therapy in selected patients of AHF.

Appropriate risk stratification and timely revascularization of acute myocardial infarction (AMI) are available in percutaneous coronary intervention (PCI) - capable hospitals (PCHs). This study evaluated whether direct admission vs inter-hospital transfer influences cardiac mortality in patients with AMI. This study was conducted in the PCH where the patients were able to arrive within an hour. The inclusion criteria were AMI with a symptom onset time within 24 hours and having undergone PCI within 24 hours after admission. The cumulative incidence of cardiac death after percutaneous coronary intervention was evaluated in the direct admission versus inter-hospital transfer groups. Among the 3178 patients, 2165 (68.1%) were admitted via inter-hospital transfer. Patients with ST-segment elevation myocardial infarction (STEMI) in the direct admission group had a reduced symptom onset-to-balloon time (121 minutes, P

SummaryAim We aimed to compare the effects of fixed-dose combinations of ezetimibe plus rosuvastatin to rosuvastatin alone in patients with primary hypercholesterolemia, including a subgroup analysis of patients with diabetes mellitus (DM) or metabolic syndrome (MetS). Method This multicenter eight-week randomized double-blind phase III study evaluated the safety and efficacy of fixed-dose combinations of ezetimibe 10 mg plus rosuvastatin, compared with rosuvastatin alone in patients with primary hypercholesterolemia. Four hundred and seven patients with primary hypercholesterolemia who required lipid-lowering treatment according to the ATP III guideline were randomized to one of the following six treatments for 8 weeks: fixed-dose combinations with ezetimibe 10 mg daily plus rosuvastatin (5, 10, or 20 mg daily) or rosuvastatin alone (5, 10, or 20 mg daily). Results Fixed-dose combination of ezetimibe plus rosuvastatin significantly reduced LDL cholesterol, total cholesterol, and triglyceride levels compared with rosuvastatin alone. Depending on the rosuvastatin dose, these fixed-dose combinations of ezetimibe plus rosuvastatin provided LDL cholesterol, total cholesterol, and triglyceride reductions of 56%–63%, 37%–43%, and 19%–24%, respectively. Moreover, the effect of combination treatment on cholesterol levels was more pronounced in patients with DM or MetS than in non-DM or non-MetS patients, respectively, whereas the effect of rosuvastatin alone did not differ between DM vs non-DM or MetS vs non-MetS patients. Conclusion Fixed-dose combinations of ezetimibe and rosuvastatin provided significantly superior efficacy to rosuvastatin alone in lowering LDL cholesterol, total cholesterol, and triglyceride levels. Moreover, the reduction rate was greater in patients with DM or MetS.

Background/Aims: This study is a head-to-head comparison of predictive values for long-term cardiovascular outcomes between exercise electrocardiography (ex-ECG) and computed tomography coronary angiography (CTCA) in patients with chest pain. Methods: Four hundred and forty-two patients (mean age, 56.1 years; men, 61.3%) who underwent both ex-ECG and CTCA for evaluation of chest pain were included. For ex-ECG parameters, the patients were classified according to negative or positive results, and Duke treadmill score (DTS). Coronary artery calcium score (CACS), presence of plaque, and coronary artery stenosis were evaluated as CTCA parameters. Cardiovascular events for prognostic evaluation were defined as unstable angina, acute myocardial infarction, revascularization, heart failure, and cardiac death. Results: The mean follow-up duration was 2.8 ± 1.1 years. Fifteen patients experienced cardiovascular events. Based on pretest probability, the low- and intermediate-risks of coronary artery disease were 94.6%. Odds ratio of CACS > 40, presence of plaque, coronary stenosis ≥ 50% and DTS ≤ 4 were significant (3.79, p = 0.012; 9.54, p = 0.030; 6.99, p < 0.001; and 4.58, p = 0.008, respectively). In the Cox regression model, coronary stenosis ≥ 50% (hazard ratio, 7.426; 95% confidence interval, 2.685 to 20.525) was only significant. After adding DTS ≤ 4 to coronary stenosis ≥ 50%, the integrated discrimination improvement and net reclassification improvement analyses did not show significant. Conclusions: CTCA was better than ex-ECG in terms of predicting long-term outcomes in low- to intermediate-risk populations. The predictive value of the combination of CTCA and ex-ECG was not superior to that of CTCA alone.

In the present study, we isolated pCMAH house-keeping promoter regions (Ph), which are responsible for transcriptional regulation and which are located upstream of the alternative transcript pcmah-2. Luciferase reporter assays using serial construction of each deleted promoter demonstrated that the Ph promoter was highly active in pig-derived kidney PK15. Ph promoter of pcmah lacked a TATA box, but contained three putative Sp1 binding sites. Mutations of these Sp1 binding sites always resulted in the reduction of luciferase activities in Ph-334. In addition, treatment with mithramycin A (25-100 nM) decreased the luciferase activities of the Ph promoters and NeuGc expression in a dose-dependent manner. Electrophoretic mobility shift assay analysis revealed that the probes containing each Sp1 binding site bound to Sp1. Taken together, the results indicate that Sp1 bind to their putative binding sites on the Ph promoter regions of pcmah and positively regulate the promoter activity in pig kidney cells. Interspecies comparison of 5'UTRs and 5'flanking regions shows high homology between pig and cattle, and Sp1 binding sites existing in genomic regions corresponding Ph region are evolutionally conserved.

A natural compound C23 H32 O4 Cl, ascochlorin (ASC) isolated from an incomplete fungus, Ascochyta viciae has been known to have several biological activities as an antibiotic, antifungal, anti-cancer, anti-hypolipidemic, and anti-hypertension agent. In this study, anti-inflammatory activity has been investigated in lipopolysaccharide (LPS)-induced murine macrophage RAW 264.7 cells, since ASC has not been observed on the inflammatory events. The present study has clearly shown that ASC (1-50 μM) significantly suppressed the production of nitric oxide (NO) and prostaglandin E2 (PGE2 ) and decreased the gene expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) in a dose-dependent manner. Moreover, ASC inhibited the mRNA expression and the protein secretion of interleukin (IL)-1β and IL-6 but not tumor necrosis factor (TNF)-α in LPS-stimulated RAW 264.7 macrophage cells. In addition, ASC suppressed nuclear translocation and DNA binding affinity of nuclear factor-κB (NF-κB). Furthermore, ASC down-regulated phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2) and p-p38. These results demonstrate that ASC exhibits anti-inflammatory effects in RAW 264.7 macrophage cells.

The recent studies have shown that adjunctive use of anticoagulant can reduce the risk of atherothrombotic event occurrence in patients with coronary artery disease (CAD). We performed this analysis to evaluate the level of hypercoagulability and its impact on clinical events according to the

Ethnopharmacological relevance Plant-specific fungus of natural compound of Ascochyta viciae has traditionally been used in the treatment of sleeping sickness and tumors. The anti-tumor activities of the compounds obtained from Pisum sativum L were evaluated in this study. Aim of the study In this study, during the prolonged incubation, treatment of the LPS-stimulated tumor-like macrophage RAW 264.7 cells with ASC exhibited the shift of anti-inflammatory behavior to a type of necroptotic cell death named necroptosis. Materials and methods Ascochlorin (ASC) purified from plant-specific fungus Ascochyta viciae is a natural compound with the trimethyl oxocyclohexyl structure and an anti-cancer and antibiotic agent. The fungus contributes to the Ascochyta blight disease complex of pea (Pisum sativum L). RAW 264.7 cells have been stimulated with LPS and treated with ASC. Cell viability of the LPS-treated RAW 264.7 cells and bone marrow-derived macrophage (BMDM) cells were examined. Flow cytometry analysis with 7AAD and Annexin V was examined for the apoptotic or necroptosis/late-apoptosis. Cleaved caspase-3, -7 and -8 as well as cleaved PARP were assessed with a caspase inhibitor, z-VAD-fmk. LPS-responsible human leukemic U937 and colon cancer SW480 and HT-29 cells were also examined for the cell viabilities. Results Flow cytometry analysis after Annexin V and 7AAD double staining showed that ASC alone induces apoptosis in RAW 264.7 cells, while it induces necroptosis/late-apoptosis in LPS-treated RAW 264.7 cells. 7AAD and Annexin V positive populations were increased in the LPS-treated cells with ASC. Although viability of LPS-treated cells with ASC was decreased, the amounts of cleaved caspase-3, -7 and -8 as well as cleaved PARP were reduced when compared with ASC-treated cells. Upon ASC treatment, the cleaved caspase-8 level was not changed, however, cleaved caspase-3, -7, and PARP were reduced in LPS-stimulated RAW 264.7 cells treated with ASC, claiming a caspase-8 independent necroptosis of ASC. Furthermore, ASC and LPS-cotreated cells which a caspase inhibitor, z-VAD-fmk, was pretreated, showed the decreased cell viability compared with control cells without the inhibitor. Cell viability of RAW 264.7 cells co-treated with ASC and LPS when treated with z-VAD was decreased. In the LPS-responsible human leukemic U937 and colon cancer SW480 and HT-29 cells, cell viabilities were decreased by 10 μM ASC. Conclusion Prolonged stimulation of ASC with LPS induces the necroptosis in RAW cells. Activated immune cells may share the susceptibility of antitumor agents with the cancer cells.

Natural compound esculentoside B (EsB), (2S,4aR,6aR,6aS,6bR,8aR,9R,10R,11S,12aR,14bS)-11-hydroxy-9-(hydroxymethyl)-2 methoxycarbonyl-2,6a,6b,9,12a-pentamethyl-10-[(2S,3R,4S,5R)-3,4,5-trihydroxyoxan-2-yl]oxy-1,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydropicene-4a-carboxylic acid with molecular weight of 664.833, isolated from roots of Phytolacca acinosa Roxb has been widely used as a constituent of traditional Chinese medicine (TCM). However, the anti-inflammatory capacity of EsB has not been reported yet. Therefore, the objective of this study was to investigate anti-inflammatory activities of EsB in LPS-treated macrophage RAW 264.7 cells. EsB could inhibit nitric oxide (NO) production. EsB also suppressed gene and protein expression levels of inducible isoform of NO synthase (NOS) and cyclooxygenase-2 in a dose-dependent manner. In addition, EsB decreased gene expression and protein secretion levels of pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6. EsB remarkably suppressed nuclear translocation of nuclear factor kappa-B (NF-κB) from cytosolic space. Phosphorylation of IκB was also inhibited by EsB. Moreover, EsB specifically down-regulated phospho-c-Jun N-terminal kinase (p-JNK), but not p-p38 or phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2). Taken together, these results suggest that EsB has inhibitory effect on inflammatory response by inactivating NF-κB and p-JNK. It could be used as a new modulatory drug for effective treatment of inflammation-related diseases.

BACKGROUND This study aimed to evaluate whether the coronary artery calcium score (CACS) measured with computed tomography coronary angiography (CTCA) predicts periprocedural myocardial infarction (PMI) in patients undergoing an elective percutaneous coronary intervention (PCI). PATIENTS AND METHODS A total of 197 patients with stable angina underwent elective PCI after CTCA. We evaluated CACS using CTCA and assessed the clinical risk factors for PMI. PMI was defined as an elevation of troponin I levels exceeding five times the upper limit of normal within 24 h after PCI. Patients were followed up for major adverse cardiovascular events for a median of 4.6 years. RESULTS The prevalence of PMI was 18.7% (37 patients) and patients with PMI showed a trend toward a higher CACS (721±779 vs. 498±842, P=0.142). The prevalence of PMI showed a positive correlation with the CACS distribution [8.0%, first interquartile range (IQR); 14.3%, second IQR; 22.4%, third IQR; 30.6%, fourth IQR; P=0.002]. The CACS cut-off value for PMI was greater than 113 (area under the curve: 0.670; 95% confidence interval: 0.600-0.736; P

BACKGROUND Acute myocardial infarction (AMI) caused by total occlusion of the left circumflex artery (LCX) can present as non-ST-segment elevation myocardial infarction (NSTEMI). We evaluate whether door-to-balloon time (DBT) is associated with cardiac mortality in patients with total occlusion of the LCX. PATIENTS AND METHODS From the Korea Acute Myocardial Infarction Registry, patients with AMI who had total occlusion with a Thrombolysis In Myocardial Infarction flow grade of 0 were included. We determined the factors for delay in primary percutaneous coronary intervention (DBT>90 min) and evaluated cardiac mortality for a median period of 14 months. RESULTS Mean DBT was 68 min (interquartile range=50-156 min), and the achievement rate of DBT less than or equal to 90 min was 66.9% in the entire study population. More than half of patients with total occlusion of LCX were presented as NSTEMI (57.7%). Among patients with total occlusion of the LCX, the mean DBT was 136 min (interquartile range=60-484 min), and the achievement rate of DBT less than or equal to 90 min was 42.8%. On multivariate analysis, LCX occlusion was an important factor for DBT more than 90 min (odds ratio: 1.766, P

The mechanisms by which hypoglycemia increases cardiovascular mortality remain unclear. The aim of the study is to investigate changes in serum electrolytes, norepinephrine concentrations, electrocardiography, and baroreflex sensitivity (BRS) and associations between corrected QT (QTc) intervals and the changes in serum electrolytes during combined pituitary stimulation test (CPST). We recruited the subjects who were admitted to the Gyeongsang National University Hospital to undergo CPST between September 2013 and December 2014. Participants were 12 patients suspected of having hypopituitarism. Among 12 patients, cardiac arrhythmia in two patients occurred during hypoglycemia. There were significant differences in serum levels of potassium (P<0.001), sodium (P=0.003), chloride (P=0.002), and calcium (P=0.017) at baseline, hypoglycemia, and 30 and 120 minutes after hypoglycemia. Also, there was a significant increase in heart rate (P=0.004), corrected QT (QTc) interval (P=0.008), QRS duration (P=0.021), and BRS (P=0.005) at hypoglycemia, compared to other time points during CPST. There was a positive association between QTc intervals and serum sodium levels (P<0.001) in 10 patients who did not develop arrhythmia during CPST. This study showed that there were significant changes in serum levels of potassium, sodium, chloride, and calcium, as well as heart rate, QTc interval, QRSd, and BRS during CPST. It was revealed that QTc intervals had a significant association with concentrations of sodium.

295 Copyright c 2015 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Received: 2015. 4. 6 Revised: 2015. 5. 15 Accepted: 2015. 6. 18

For innate immune defense, lower animals such as fish and amphibian are covered with skin mucus, which acts as both a mechanical and biochemical barrier. Although several mucus sources have been isolated and studied for their biochemical and immunological functions, the precise mechanism(s) of action remains unknown. In the present study, we additionally found the eel skin mucus (ESM) to be a promising candidate for use in anti-tumor therapy. Our results showed that the viability of K562 cells was decreased in a dose-dependent manner by treatment with the isolated ESM. The cleaved forms of caspase-9, caspase-3 and poly adenosine diphosphate-ribose polymerase were increased by ESM. The levels of Bax expression and released cytochrome C were also increased after treatment with ESM. Furthermore, during the ESM mediated-apoptosis, phosphorylation levels of ERK1/2 and p38 but not JNK were increased and cell viabilities of the co-treated cells with ESM and inhibitors of ERK 1/2 or p38 were also increased. In addition, treatment with lactose rescued the ESM-mediated decrease in cell viability, indicating lactose-containing glycans in the leukemia cells acted as a counterpart of the ESM for interaction. Taken together, these results suggest that ESM could induce mitochondria-mediated apoptosis through membrane interaction of the K562 human leukemia cells. To the best of our knowledge, this is the first observation that ESM has anti-tumor activity in human cells.

Gangliosides are known to specifically inhibit vascular leukocyte recruitment and consequent interaction with the injured endothelium, the basic inflammatory process. In this study, we have found that the production of nitric oxide (NO), a main regulator of inflammation, is suppressed by GM3 on murine macrophage RAW 264.7 cells, when induced by LPS. In addition, GM3 attenuated the increase in cyclooxyenase-2 (COX-2) protein and mRNA levels in lipopolysaccharide (LPS)-activated RAW 264.7 cells in a dose-dependent manner. Moreover, GM3 inhibited the expression and release of pro-inflammatory cytokines of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) in RAW 264.7 macrophages. At the intracellular level, GM3 inhibited LPS-induced nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein (AP)-1 in RAW 264.7 macrophages. We, therefore, investigated whether GM3 affects mitogen-activated protein kinase (MAPK) phosphorylation, a process known as the upstream signaling regulator. GM3 dramatically reduced the expression levels of the phosphorylated forms of ERK, JNK, and p38 in LPS-activated RAW 264.7 cells. These results indicate that GM3 is a promising suppressor of the vascular inflammatory responses and ganglioside GM3 suppresses the LPS-induced inflammatory response in RAW 264.7 macrophages by suppression of NF-κB, AP-1, and MAPKs signaling. Accordingly, GM3 is suggested as a beneficial agent for the treatment of diseases that are associated with inflammation.

Jellyfish species are widely distributed in the world’s oceans, and their population is rapidly increasing. Jellyfish extracts have several biological functions, such as cytotoxic, anti-microbial, and antioxidant activities in cells and organisms. However, the anti-cancer effect of Jellyfish extract has not yet been examined. We used chronic myelogenous leukemia K562 cells to evaluate the mechanisms of anti-cancer activity of hexane extracts from Nomura’s jellyfish in vitro. In this study, jellyfish are subjected to hexane extraction, and the extract is shown to have an anticancer effect on chronic myelogenous leukemia K562 cells. Interestingly, the present results show that jellyfish hexane extract (Jellyfish-HE) induces apoptosis in a dose- and time-dependent manner. To identify the mechanism(s) underlying Jellyfish-HE-induced apoptosis in K562 cells, we examined the effects of Jellyfish-HE on activation of caspase and mitogen-activated protein kinases (MAPKs), which are responsible for cell cycle progression. Induction of apoptosis by Jellyfish-HE occurred through the activation of caspases-3,-8 and -9 and phosphorylation of p38. Jellyfish-HE-induced apoptosis was blocked by a caspase inhibitor, Z-VAD. Moreover, during apoptosis in K562 cells, p38 MAPK was inhibited by pretreatment with SB203580, an inhibitor of p38. SB203580 blocked jellyfish-HE-induced apoptosis. Additionally, Jellyfish-HE markedly arrests the cell cycle in the G0/G1 phase. Therefore, taken together, the results imply that the anti-cancer activity of Jellyfish-HE may be mediated apoptosis by induction of caspases and activation of MAPK, especially phosphorylation of p38, and cell cycle arrest at the Go/G1 phase in K562 cells.

The human chronic myelogenous cell line K562 has been used extensively as a model for the study of leukemia differentiation. We show here that treatment of K562 cells with caffeic acid phenethyl ester (CAPE) induced a majority of cells to differentiate towards the megakaryocytic lineage. Microscopy analysis showed that K562 cells treated with CAPE exhibited characteristic features of physiological megakaryocytic differentiation, including the presence of vacuoles and demarcation membranes. Differentiation of K562 cells treated with CAPE was also accompanied by a net increase in megakaryocytic markers. The transcriptional activity of lactosylceramide α-2,3-sialyltransferase (GM3 synthase) and synthesis of ganglioside GM3 were increased by CAPE treatment. The promoter analysis of GM3 synthase demonstrated that CAPE induced the expression of GM3 synthase mRNA via activation of the cAMP response element-binding protein (CREB), transcription factor in nucleus. Interestingly, the inhibition of ganglioside GM3 synthesis by D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propranol (D-PDMP) and GM3 synthase-siRNA blocked the CAPE-induced expression of the megakaryocytic markers and differentiation of K562 cells. Taken together, these results suggest that CAPE induces ganglioside GM3-mediated megakaryocytic differentiation of human chronic myelogenous cells.

Aim Proton pump inhibitor (PPI) therapy has been shown to attenuate the antiplatelet effects of clopidogrel. The aim of this study was to compare the antiplatelet effects of cilostazol versus clopidogrel in patients co-administered a PPI. Methods We enrolled PPI-naive stented patients treated with standard clopidogrel and aspirin therapy for at least six months (n=100). The patients were randomly assigned to receive either cilostazol at a dose of 100mg twice daily (CILO group) or clopidogrel at a dose of 75mg daily (CLPD group) in addition to lansoprazole (30mg daily). The platelet aggregation (PA) determined using light transmittance aggregometry and the platelet reactivity index (PRI) obtained using a vasodilator-stimulated phosphoprotein phosphorylation assay were measured before randomization and at the 14-day follow-up visit. The primary endpoint was the PRI value at follow-up. Results At follow-up, the CLPD group showed similar values of PRI as the CILO group (66.9±14.0% vs. 63.1±14.1%; mean difference: 3.9%; 95% confidence interval of difference: -1.7% to 9.4%; p=0.174). However, the 6μg/mL collagen- and 0.5mg/mL arachidonic acid-induced PA values in the CLPD group were higher than those observed in the CILO group (mean differences: 9.8% to 11.1%; all p values ＜0.001). CYP2C19 loss-of-function allele carriage was the major contributing factor associated with the PRI level in the absence of lansoprazole treatment (with a gene-dose effect); this association was not observed in the subjects receiving lansoprazole co-administration in the CLPD group. Conclusions During lansoprazole co-administration, cilostazol treatment achieves a more favorable platelet function profile than clopidogrel therapy. The use of combination treatment with cilostazol and aspirin deserves further attention with respect to the management of stable stented patients requiring PPI co-administration.