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Hypoxia-inducible factor-1α (HIF-1α) seems central to tumor growth and progression because it up-regulates genes essential for angiogenesis and the hypoxic adaptation of cancer cells, which is why HIF-1α inhibition is viewed as a cancer therapy strategy. Paradoxically, HIF-1α also leads to cell cycle arrest or the apoptosis of cancer cells. Thus, the possibility cannot be ruled out that HIF-1α inhibitors unlock cell cycle arrest under hypoxic conditions and prevent cell death, which would limit the anticancer effect of HIF-1α inhibitors. Previously, we reported on the development of YC-1 as an anticancer agent that inhibits HIF-1α. In the present study, we evaluated the effects of YC-1 on hypoxia-induced cell cycle arrest and cell death. It was found that YC-1 does not reverse the antiproliferative effect of hypoxia, but rather that it induces S-phase arrest and apoptosis at therapeutic concentrations that inhibit HIF-1α and tumor growth; however, YC-1 did not stimulate cyclic guanosine 3′,5′-monophosphate production in this concentration range. It was also found that YC-1 activates the checkpoint kinase–mediated intra-S-phase checkpoint, independently of ataxia-telangiectasia mutated kinase or ataxia-telangiectasia mutated and Rad3-related kinase. These results imply that YC-1 does not promote the regrowth of hypoxic tumors because of its cell cycle arrest effect. Furthermore, YC-1 may induce the combined anticancer effects of HIF-1α inhibition and cell growth inhibition. (Cancer Res 2006; 66(12): 6345-52)

Supplementary Figures 1 and 2 from YC-1 Induces S Cell Cycle Arrest and Apoptosis by Activating Checkpoint Kinases

Supplementary Figure Legends from YC-1 Induces S Cell Cycle Arrest and Apoptosis by Activating Checkpoint Kinases

The tensor of the vastus intermedius (TVI) was first described by Grob et al. in 2016. It originates from the anteroinferior greater trochanter and inserts into the upper patella and receives blood and nerves independently of other muscles. It has been overlooked, but since micro-surgery and detailed rehabilitation treatments are being developed, more research on it is warranted. Here we report on the TVI in a Korean cadaveric study.A total of 58 cadavers (41 males and 17 females) were included. Thighs were examined using a standardized dissection protocol. The quadriceps femoris muscle was identified and its components were defined by blunt dissection.A total of 116 lower limbs were dissected. In 40 of them there was a separately innervated TVI muscle belly between the fasciae of the vastus lateralis (VL) and the vastus intermedius (VI) muscles. TVIs were classed as independent (ID), VI, and VL types according to the relative relationship between the TVI, VL, and VI, and subdivided into two parts: Part 1 was the proximal muscular portion of the TVI attached to the VL or VI, and part 2 was the distal aponeurotic area.TVIs were analyzed in detail via 58 Korean cadavers. We subdivided them on the basis of their location and association with related muscles. A larger study is needed to clarify the function and prevalence of the TVI.

The anterior jugular vein (AJV) is part of the superficial venous drainage system of the head and neck. Recently, interest in AJV is increasing as various surgical procedures have been developed. The authors conducted a cadaveric study to determine characteristics of AJV in Koreans.A total of 44 cadavers were dissected. Anatomical characteristics were analyzed for 34 cadavers in which AJV was well observed.In this study, 21 were males and 13 were females. There were 8 cadavers with only 1 AJV from both sides. There was no significant difference in anatomical characteristics according to gender or AJV variation except for a difference in the length of the neck according to gender. However, it was possible to find a safety zone at the main landmark of the neck that could avoid AJV damage.By using this safety zone, it is possible to prevent damage to the AJV and reduce complications during various surgical procedures on the head and neck.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with inhibitory effects on T cell-mediated immune response. MDSCs accumulate under many pathological conditions, including cancers, to avoid anticancer immunity. Unlike mouse MDSCs, common specific surface markers for human MDSCs are not clearly defined, mainly due to the complexity of MDSC subsets. In this study, we investigate specific responses of the infrared dye MHI-148 to MDSCs. Mice bearing 4T1 breast cancer cells were established, and splenocytes were isolated. Flow cytometric analyses demonstrated that MHI-148 was reactive to over 80% of MDSC-specific cells manifesting CD11b(+)/Gr-1(+) acquired from both tumor-bearing mice and naive mice. Cells sorted positive for either CD11b/Gr-1 or MHI-148 were also identical to their counterparts (99.7% and 97.7%, respectively). MHI-148, however, was not reactive to lymphocyte or monocyte populations. To determine whether MHI-148-reactive cells exert inhibitory effects on T cell proliferation, an EdU-based T cell assay was performed. MHI-148 reactive cells significantly reduced T cell proliferation with increased arginase activity and nitrite production. In an attempt to test MHI-148 as a marker for human MDSCs, MHI-148 was specifically reactive to CD11b(+)/CD33(+)/CD14(-) granulocytic MDSCs acquired from selected cancer patients. This study demonstrates that the near-infrared dye MHI-148 specifically reacts to mouse splenocytes with known MDSC-specific markers that have T cell suppressive functions. The dye also selectively binds to a subpopulation of immature myeloid cells acquired from cancer patients. While it is not clear how MHI-148 specifically stains MDSCs, this dye can be a novel tool to detect MDSCs and to predict the prognosis of human cancer patients.

The purpose of this study is to identify latent classes involving the health behaviors of patients with metabolic syndrome and to examine the effects of demographic characteristics and health- related lifestyles on their quality of life. The data was sourced from the database of the 2013 Korea health panel survey. Health behavior variables (smoking, drinking, body mass index, and physical activities) were dichotomously re-categorized for latent class analysis. Two latent classes of metabolic syndrome, named `low physical actor' and `low physical actor with smoking and alcohol' were identified. Both latent classes showed statistically significant differences in demographic characteristics and EQ-5D index. Additionally, there were differences in the factors affecting quality of life between latent classes. This study's findings suggest that a tailored intervention based on features of the latent classes is required to improve the lifestyle and quality of life of metabolic syndrome patients.

CD46 is a complement inhibitor membrane cofactor which also acts as a receptor for various microbes, including species B adenoviruses (Ads). While most Ad gene therapy vectors are derived from species C and infect cells through coxsackie-adenovirus receptor (CAR), CAR expression is downregulated in many cancer cells, resulting inefficient Ad-based therapeutics. Despite a limited knowledge on the expression status of many cancer cells, an increasing number of cancer gene therapy studies include fiber-modified Ad vectors redirected to the more ubiquitously expressed CD46. Since our finding from tumor microarray indicate that CD46 was overexpressed in cancers of the prostate and colon, fiber chimeric Ad5/35 vectors that have infection tropism for CD46 were employed to demonstrate its efficacy in colorectal cancers (CRC). CD46-overexpressed cells showed a significantly higher response to Ad5/35-GFP and to Ad5/35-tk/GCV. While CRC cells express variable levels of CD46, CD46 expression was positively correlated with Ad5/35-mediated GFP fluorescence and accordingly its cell killing. Injection of Ad5/35-tk/GCV caused much greater tumor-suppression in mice bearing CD46-overexpressed cancer xenograft compared to mock group. Analysis of CRC samples revealed that patients with positive CD46 expression had a higher survival rate (p=0.031), carried tumors that were well-differentiated, but less invasive and metastatic, and with a low T stage (all p

The prostate gland contains a high level of intracellular zinc, which is dramatically diminished during prostate cancer (PCa) development. Owing to the unclear role of zinc in this process, therapeutic applications using zinc are limited. This study aimed to clarify the role of zinc and its underlying mechanism in the growth of PCa. ZnCl2 suppressed the proliferation of androgen receptor (AR)-retaining PCa cells, whereas it did not affect AR-deficient PCa cells. In LNCaP and TRAMP-C2 cells, zinc downregulated the expression of AR in a dose- and time-dependent fashion. Zinc-mediated AR suppression accordingly inhibited the androgen-mediated transactivation and expression of the androgen target, prostate specific antigen (PSA). This phenomenon resulted from facilitated protein degradation, not transcriptional control. In studies using mice bearing TRAMP-C2 subcutaneous tumors, the intraperitoneal injection of zinc significantly reduced tumor size. Analyses of both xenograft tumors and normal prostates showed reduced expression of AR and increased cell death. Considering the significant loss of intracellular zinc and the dominant growth-modulating role of AR during PCa development, loss of zinc may be a critical step in the transformation of normal cells to cancer cells. This study provides the underlying mechanism by which zinc functions as a PCa suppressor, and forms the foundation for developing zinc-mediated therapeutics for PCa.

CD46 is generally overexpressed in many human cancers, representing a prime target for CD46-binding adenoviruses (Ads). This could help to overcome low anti-tumoral activity by coxsackie-adenoviral receptor (CAR)-targeting cancer gene therapy viruses. However, because of scarce side-by-side information about CAR and CD46 expression levels in cancer cells, mixed observations of cancer therapeutic efficacy have been observed. This study evaluated Ad-mediated therapeutic efficacy using either CAR-targeting Ad5 or CD46-targeting Ad5/35 fiber chimera in bladder cancer cell lines. Compared with normal urothelia, bladder cancer tissue generally overexpressed both CAR and CD46. While CAR expression was not correlated with disease progression, CD46 expression was inversely correlated with tumor grade, stage, and risk grade. In bladder cancer cell lines, expression levels of CD46 and CAR were highly correlated with Ad5/35- and Ad5-mediated gene transduction and cytotoxicity, respectively. In a human EJ bladder cancer xenograft mouse model, with either overexpressed or suppressed CD46 expression levels, Ad5/35-tk followed by ganciclovir (GCV) treatment significantly affected tumor growth, whereas Ad5-tk/GCV had only minimal effects. Overall, our findings suggest that bladder cancer cells overexpress both CAR and CD46, and that adenoviral cancer gene therapy targeting CD46 represents a more suitable therapy option than a CAR-targeting therapy, especially in patients with low risk bladder cancers.

Background The rates of stent failure after percutaneous coronary intervention have decreased since the introduction of the drug-eluting stent (DES). However, chronic kidney disease (CKD) and diabetes mellitus (DM) remain strong clinical predictors of poor prognosis despite DES implantation. Sarpogrelate, a selective serotonin (5-hydroxytryptamine (HT)2a [5-HT2A]) receptor antagonist, has antiproliferative effects, reducing neointimal hyperplasia and smooth muscle cell proliferation, as well as potent antiplatelet action, inhibiting 5-HT-induced platelet aggregation. However, efficacy and safety data for sarpogrelate in patients with CKD or DM are limited. We aim to determine whether sarpogrelate has beneficial effects in patients with CDK or DM treated with DES implantation. Methods/design The SERENADE trial is a multicenter, open-label, prospective, randomized study that will test the superiority of triple anti-platelet therapy (TAT; aspirin, clopidogrel, and sarpogrelate) to conventional dual antiplatelet therapy (DAT; aspirin and clopidogrel) in preventing late lumen loss 9 months after the index procedure in patients with CKD or DM. A total of 220 patients diagnosed with coronary artery disease with DM or CKD will be randomized to the TAT or DAT groups (1:1 ratio) after DES implantation. The primary endpoint is late lumen loss at 9 months assessed by quantitative coronary angiography. Secondary efficacy endpoints are composites of major adverse cardiovascular events including cardiac death, nonfatal myocardial infarction, and target lesion revascularization. Secondary safety endpoints are major bleeding events and hepatic or renal impairment. Discussion The SERENADE trial will provide insight on the efficacy of adjunctive therapy with sarpogrelate after DES implantation for patients with high-risk profiles such as CKD or DM. Trial registration National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov NCT02294643).

Irisin, a recently identified hormone secreted by skeletal muscle in response to exercise, exhibits anabolic effects on the skeleton primarily through the stimulation of bone formation. However, the mechanism underlying the irisin-stimulated anabolic response remains largely unknown. To uncover the underlying mechanism, we biosynthesized recombinant irisin (r-irisin) using an Escherichia coli expression system and used it to treat several osteoblast cell types. Our synthesized r-irisin could promote proliferation and differentiation of osteoblasts as evidenced by enhanced expression of osteoblast-specific transcriptional factors, including Runt-related transcription factor-2 (Runx2), Oster (Osx), as well as early osteoblastic differentiation markers such as alkaline phosphatase (Alp) and collagen type I alpha 1 (Col1a1). Furthermore, we showed that the promotion of r-irisin on the proliferation and differentiation of osteoblast lineage cells are preferentially through aerobic glycolysis, as indicated by the enhanced abundance of representative enzymes such as lactate dehydrogenase A (LDHA) and pyruvate dehydrogenase kinase 1 (PDK1), together with increased lactate levels. Suppression of r-irisin-mediated aerobic glycolysis with Dichloroacetate blunted its anabolic effects. The favorite of the aerobic glycolysis after r-irisin treatment was then confirmed in primary calvarial cells by metabolic analysis using gas chromatography-mass spectrometry. Thus, our results suggest that the anabolic actions of r-irisin on the regulation of osteoblast lineage cells are preferentially through aerobic glycolysis, which may help to develop new irisin-based bone anabolic agents.

Inserting a nasogastric tube (NGT) in intubated patients may be difficult because they cannot follow swallowing instructions, resulting in a high rate of first-attempt failure. We introduce a simple technique for inserting an orogastric tube in an emergency department (ED).Fifty-six patients in the ED, who were intubated and required NGT insertion, were randomly allocated to 2 groups. We inserted the NGT using a conventional technique from the nostril (control group) and an endotracheal tube (ET)-assisted technique from the mouth (ET group). The procedures' success rate, insertion duration, and complications were compared between the groups.There was a significantly higher overall success rate in the ET group than the control group (100% vs 64%, P.001). Endotracheal tube group showed 100% first-attempt success rate, but 50% of the control group failed at first attempt. Mean duration of the first trial was not significantly different between the ET and control groups (58.0±16.9 vs 57.3±29.5 seconds, P=.903), but total time for successful insertion was longer in the control group than the ET group (58.0±16.9 vs 111.7±74.5 seconds, P.001). There was less NGT kinking and more mucosal bleeding in the ET group than in the control group (0% vs 16%, P=.019; 16% vs 7%, P=.225, respectively).Endotracheal tube-assisted orogastric tube insertion technique showed a higher rate of successful insertion and shorter total duration. With this result, ET-assisted orogastric tube insertion would be useful in ED.

Rationale: Procalcitonin (PCT) is used as a biomarker for identifying the occurrence of sepsis. Previous studies have reported high levels of PCT with acetaminophen intoxication without evidence of infection. Here, we report two patients with acetaminophen intoxication with high levels of PCT without showing any symptoms of bacterial infection. Patient concerns: This case study examined two unrelated patients with acetaminophen intoxication admitted to emergency at different times. The first patient was admitted to the emergency department after ingesting approximately 8000 mg (153.8 mg/kg) of acetaminophen. On admission, C-reactive protein (CRP), glutamic oxaloacetic transaminase (GOT), and glutamic pyruvic transaminase (GPT) were normal. PCT and acetaminophen levels were 31.89 ng/mL and below 0.5 μg/mL, respectively. The second patient was admitted to the emergency department 8 h after ingesting ∼23,600 mg (280.6 mg/kg) of acetaminophen. By the second day of admission, GOT and GPT increased to 2508 and 1473 IU/L, respectively. PCT was 45.66 ng/mL with acetaminophen level at 116.9 μg/mL. Both patients were clear of symptoms associated with bacterial infection. Diagnosis: Acetaminophen intoxication. Interventions: N-acetylcysteine was given intravenously to both patients for 20 h per protocol. Outcomes: Both patients were discharged without complications. Lessons: Observations suggests that elevated levels of PCT in patients intoxicated with acetaminophen may be associated with involvement of other organs impacted by cytokine stimuli from sterile inflammation resulting from hepatic damage rather than PCT secretion directly caused by hepatic cell damage.

Introduction The aim of this study was to ascertain if a modified carotid sinus massage (CSM) using ultrasonography is superior to the conventional CSM for vagal tone generation. Methods This was a prospective, crossover, clinical trial including 30 subjects with sinus rhythm. Participants were paired, and they performed 2 types of CSM to each other. To perform the conventional technique, pressure was exerted at the point where the maximal impulse of the carotid pulse was palpated. In the modified technique, participants localized the point of maximal diameter just above the bifurcation of the common carotid artery using ultrasonography and applied pressure to that point. Mean differences between premaneuver and postmaneuver R-R intervals and heart rates were compared. The distance from the midline of the neck (x distance) to the angle of the mandible (y distance) was measured, and the mean distance between the 2 techniques was compared. Results The baseline mean premaneuver R-R interval and heart rate did not differ significantly between the 2 techniques. The postmaneuver R-R interval and heart rate as well as the mean R-R interval and heart rate differences were significantly greater in the modified CSM. The mean location determined using the modified CSM was located 0.8 cm lateral and 0.8 cm superior to the mean location of the conventional CSM. Conclusion The modified CSM using ultrasonography might be more useful than the conventional CSM in reverting episodes of paroxysmal supraventricular tachycardia and may be a suitable alternative for treating the same in the emergency department.

The purpose of this study was to assess the plasma neutrophil gelatinase-associated lipocalin (NGAL) for early detection of acute kidney injury (AKI) and prediction of mortality in severely burned patients. From January 2014 to September 2015, 76 consecutive patients with more than 20% of TBSA burned were enrolled. Blood samples for plasma NGAL were collected at 0, 7, 14, 21, and 28 days after admission and analyzed with injury severity, clinical outcome, and AKI development. Plasma NGAL was significantly affected by the TBSA burned, AKI, and mortality, and it was significantly increased after operation and septic shock. Plasma NGAL was significantly increased within 7 days before AKI development in total patients (P < .001) and septic shock patients (P < .001) but not significantly increased in patients without septic shock (P = .167). Though, in a receiver operating characteristic curve analysis for predicting AKI, continuous renal replacement therapy application, and mortality, plasma NGAL was statistically significant; plasma NGAL was not independently associated with mortality in a multivariate logistic regression analysis. Plasma NGAL should be interpreted carefully in the major burn patients because it can reflect both inflammatory condition and AKI.

Dried leaves of Raphanus sativus L. and Angelica keiskei L. extracts have strong antioxidant potential and in consequence profound effects on ulcerative colitis. Present study was conducted to explore the effect of diet mixtures containing dried leaves of Raphanus sativus and Angelica keiskei powder on ulcerative colitis in mice and antioxidant potential of radish green and Angelica extracts as well. Both dried leaves of Raphanus sativus and Angelica keiskei extracts exhibited higher antioxidant activity due to the presence of polyphenols, favonoids and antioxidant enzymes like superoxide dismutase (SOD). Analyzed data indicate that Angelica keiskei extract had higher polyphenol and flavonoid contents compared with radish green, while maximum SOD activity was noted in dried leaves of Raphanus sativus extract Likewise, higher antioxidant () and radical scavenging (17%) activities were noted in dried leaves of Raphanus sativus extract compared with Angelica keiskei.

The value of late gadolinium-enhanced (LGE) magnetic resonance imaging (MRI) for the prediction of functional recovery after surgical revascularization has been previously established. However, the impact of LGE-MRI on the long-term prognosis after coronary artery bypass grafting (CABG) remains incompletely understood. Therefore, we aimed to evaluate the long-term prognostic value of LGE-MRI, based on the presence or absence of left ventricular (LV) dysfunction, in patients with coronary artery disease undergoing CABG. One hundred forty-six consecutive patients underwent cine- and LGE-MRI before CABG. Adverse cardiac events included cardiac death, nonfatal myocardial infarction, heart failure, and unstable angina. A 3-year landmark analysis of the primary end point was also performed for patients surviving beyond 3 years after CABG. During a median follow-up of 9.4 years, 44 patients (30%) experienced adverse cardiac events. Although a LV ejection fraction50% was associated only with adverse cardiac events at 3 years after CABG, LGE was associated with a worse outcome both at and beyond 3 years after CABG. In the overall study population, LGE presence (adjusted hazard ratio [HR] 2.58; p = 0.027), score (adjusted HR 1.06; p0.001), and extent (adjusted HR 1.08; p0.001) were independent predictors of adverse cardiac events. Moreover, in both the LV ejection fraction50% and ≥50% groups, the LGE extent was an independent predictor of adverse cardiac events. In conclusion, our qualitative and quantitative analyses of LGE-MRI provide long-term prognostic information after surgical revascularization. The LGE extent was a strong predictor of adverse cardiac events, independent of the LV function.

Objective The purpose of this study was to determine how the energies supplied from a cosmetic vibrator are deeply or far transferred into organs and tissues, and how these depths or distances are influenced by tissue elasticity. Methods External vibration energy was applied to model skin surfaces through a facial cleansing vibrator, and we measured a distance- and depth-dependent energy that was transferred to model skin matrices. As model skin matrices, we synthesized hard and soft poly(dimethylsiloxane) (PDMS) gels, as well as hydrogels with a modulus of 2.63 MPa, 0.33 MPa and 21 kPa, respectively, mostly representing those of skin and other organs. The transfer of vibration energy was measured either by increasing the separation distances or by increasing the depth from the vibrator. Results The energies were transmitted deeper into the hard PDMS than into the soft PDMS and hydrogel matrices. This finding implies that the vibration forces influence a larger area of the gel matrices when the gels are more elastic (or rigid). There were no appreciable differences between the soft PDMS and hydrogel matrices. However, the absorbed energies were more concentrated in the area closest to the vibrator with decreasing elasticity of the matrix. Softer materials absorbed most of the supplied energy around the point of the vibrator. In contrast, harder materials scattered the external energy over a broad area. Conclusions The current results are the first report in estimating how the external energy is deeply or distantly transferred into a model skins depending on the elastic moduli of the models skins. In doing so, the results would be potentially useful in predicting the health of cells, tissues and organs exposed to various stimuli.

In this study, the effects of the use of a starter on radish soaked at for 28 days using two kinds of domestic sun-dried salt (white and gray salt) were determined. As a result, the moisture contents of the radish soaked with white and gray salt were 7.93 and 4.50%, respectively. The salinity levels were found to be equal (90%). No significant difference was found between the two groups in terms of the mineral contents of the salts therein ( and mg/100 g, respectively). However, iron and zinc contents of gray salt were higher than those of white salt while the calcium, potassium, and magnesium contents were lower than those of white salt. After the addition of the starter, the sugar content increased, the pH decreased, and the total acidity rapidly decreased compared with the non-starter group during fermentation. The total microorganism count of the two groups increased during the fermentation period of 28 days. From the initial fermentation for 7 days, the lactic acid bacteria in the non-starter group increased while those in the leuconostoc starter group steadily increased within the whole fermentation period. The Leuconostoc spp. in non-starter group increased, but that in the starter group decreased to pH 4.0 on day 14.

The aims of this research were to determine the proximate composition of various salts and to compare two digestion methods (direct digestion without heating, and microwave digestion) for the determination of the main mineral contents of various salts. Twelve salt samples were divided into three groups of four samples each (imported, Korean gray, and Korean white salts). As a result, the NaCl contents of the Korean white, Korean gray, and imported salts were 85.1, 89.3, and 91.3%, respectively. The salts in the three groups were analyzed for their main mineral contents via AAS. The sodium (Na) content of the Korean white salt was found to be slightly lower than that of the imported salt while the magnesium (Mg) and potassium (K) contents of the Korean white salt were found to be higher than those of the imported salt. The mineral composition (% Na:Mg) obtained using microwave-assisted digestion procedures, and the other dissolutions for the subsequent sample analysis, were 89:1 (for both the imported and Korean gray salts) and 82:3 vs. 81:3 (Korean white salt), respectively. The data regarding the mineral contents and composition of the sun-dried salts obtained through the analysis method of wet digestion and the dissolution procedure were compared, and no significant difference was found between the two datasets. Consequently, in this paper, a direct dissolution procedure is suggested for the analysis of the mineral composition of salt.

Benign prostatic hyperplasia (BPH) is a disease that impairs the well-being of many aged men. To alleviate BPH symptoms or to find a cure for this disease, key molecules should be identified that control prostate cell proliferation. Recently, HIF-1alpha has attracted attention in this context, because it is highly expressed in hyperplasic prostates and prevents prostate cell death. Thus, given that vitamin C inhibits HIF-1alpha expression in several malignant tumors, we examined its therapeutic potential in BPH. HIF-1alpha was noticeably induced by testosterone in prostate cells, and this HIF-1alpha induction was abolished by vitamin C. Vascular endothelial growth factor (VEGF) promoter activity reporter assays and semi-quantitative RT-PCR revealed that vitamin C inhibited HIF-1-dependent VEGF expression. Furthermore, HIF-1alpha suppression by vitamin C was rescued by knocking down HIF-prolyl hydroxylase-2, suggesting that vitamin C destabilizes HIF-1alpha via prolyl hydroxylation. Moreover, vitamin C treatment abolished cell proliferation induced by testosterone treatment to the control level. These results suggest that vitamin C inhibits testosterone-induced HIF-1alpha expression and by so doing effectively prevents prostate hyperplasia. In male rats, testosterone treatment for 4 weeks induced prostate hyperplasia. Furthermore, HIF-1alpha and VEGF levels were significantly elevated in hyperplasic prostates. In vitamin C-treated rats, however, most prostate hyperplasia parameters and prostrate HIF-1alpha/VEGF levels were markedly reduced. Accordingly, our findings indicate that vitamin C could be further developed clinically for use as an anti-BPH agent.

The behaviors of charge carriers were investigated to understand the reversible bistability in the polymer device with an embedded thin metal layer between the metal electrodes. The reversible bistability was sensitive to the condition of the embedded thin metal layer that was prepared by depositing 5 nm Al by 0.8 A/sec. The device was controlled by the charge and the discharge in the effective trap sites of the embedded Al layer. Poly(N-vinylcarbazole) as an organic active material merely conducted the charge transport function. The effective trap sites were contributed by the change of the reversible conductance and also preferred to be in a high conduction state. They took relatively low energy states easily as the device was affected by thermal stimulation at 150°C. The modification of the embedded Al layer improved its performances. Copyright © 2009 John Wiley & Sons, Ltd.

Bistability is often observed in thin organic materials, but it is not a typical property of the bulk state. The origin of that bistability was investigated in a 30-nm Polyvinylcarbazole(PVK) device. This device was a reproducible write-once-read-many memory, which changed from the OFF to the ON state at around 2 V in the rst forward bias. Its conductivity in the ON state was similar to that of a poor metal, but some of the devices shifted their electric properties into reversible bistability with a small ON/OFF ratio or an open circuit with a low leakage current during repeated bias scans. The initial change in the conductance was caused by the eld-induced metal lament, which originated from the deposition of the top electrode. Because the repeating bias scan led to the oxidation of the lament by joule heating, the device changed into a reversible bistability due to non-stoichiometric aluminum oxide or into an open circuit due to alumina.

Spermidine/spermine N-1-acetyl-transferase (SSAT) is a catabolic enzyme that participates in polyamine metabolism. SSAT has been reported to be induced in some organs subjected to ischemia-reperfusion, but its induction mechanism has not been clarified, and little is known about SSAT regulation by ischemia per se. We induced regional ischemia of rat heart by coronary ligation and found that SSAT expression increased in ischemic myocardium. In neonatal rat cardiomyocytes and HEK293 cells, SSAT was up-regulated at the transcriptional step primarily by ATP depletion rather than oxygen deprivation. Moreover, an AMPK inhibitor compound C and AMPKalpha1-silencing RNAs attenuated the SSAT induction by ATP depletion, and an AMPK activator AICAR induced SSAT expression even without ATP depletion. When SSAT was suppressed using siRNA, the caspase activities and Bax/Bcl-2 ratios further increased in ATP depletion. These results suggest that myocardial SSAT is induced by AMPK signaling and function as a cardioprotectant under ATP-depleted conditions.

Circulating erythropoietin (EPO) is mainly produced by the kidneys and mediates erythrogenesis in bone marrow and nonhematopoietic cell survival. EPO is also produced in other tissues where it functions as a paracrine. Moreover, the hypoxic induction of EPO is known to be mediated by HIF-1alpha and HIF-2alpha, but it remains obscure as to which of these two mediators mainly contributes to EPO expression. Thus, we designed in vivo experiments to evaluate the contributions made by HIF-1alpha and HIF-2alpha to EPO expression. In mice exposed to mild whole body hypoxia, HIF-1alpha and HIF-2alpha were both induced in all tissues examined. However, EPO mRNA was expressed in kidney and brain, but not in liver and lung. Likewise, chromatin immunoprecipitation (CHIP) analyses demonstrated that HIF-1alpha or HIF-2alpha binding to the EPO gene increased under hypoxic conditions only in kidney and brain. A comparison of CHIP data and EPO mRNA levels suggested that, during mild hypoxia, renal EPO transcription is induced equally by HIF-1alpha and HIF-2alpha, but that brain EPO is mainly induced during hypoxia by HIF-2alpha. Thus, HIF-1alpha and HIF-2alpha appear to contribute to EPO expression tissue specifically.

This study shows to blend ethylene vinyl acetate(EVA) and a flame retardant agent, , and synergists, zinc borate for improving flame retardancy of low density polyethylene(LDPE). And it studied the property of flame retardancy of LDPE/EVA blend by the amount of addition through LOI and TGA, estimated the electrical characteristics such as volume resistivity and breakdown strength. The flame retardancy of LDPE/EVA blend was much improved in case of adding zinc borate with 6phr degree, and the electrical characteristics were more or less decreased depending on increasing the amount of addition. Zinc borate used for improving the flame retardancy of LDPE/EVA blend let the added amount of a flame retardant agent, limited, and the electrical characteristics decreased extremely by adding a good deal of .

Hypoxia-inducible factor-1α (HIF-1α) seems central to tumor growth and progression because it up-regulates genes essential for angiogenesis and the hypoxic adaptation of cancer cells, which is why HIF-1α inhibition is viewed as a cancer therapy strategy. Paradoxically, HIF-1α also leads to cell cycle arrest or the apoptosis of cancer cells. Thus, the possibility cannot be ruled out that HIF-1α inhibitors unlock cell cycle arrest under hypoxic conditions and prevent cell death, which would limit the anticancer effect of HIF-1α inhibitors. Previously, we reported on the development of YC-1 as an anticancer agent that inhibits HIF-1α. In the present study, we evaluated the effects of YC-1 on hypoxia-induced cell cycle arrest and cell death. It was found that YC-1 does not reverse the antiproliferative effect of hypoxia, but rather that it induces S-phase arrest and apoptosis at therapeutic concentrations that inhibit HIF-1α and tumor growth; however, YC-1 did not stimulate cyclic guanosine 3′,5′-monophosphate production in this concentration range. It was also found that YC-1 activates the checkpoint kinase–mediated intra-S-phase checkpoint, independently of ataxia-telangiectasia mutated kinase or ataxia-telangiectasia mutated and Rad3-related kinase. These results imply that YC-1 does not promote the regrowth of hypoxic tumors because of its cell cycle arrest effect. Furthermore, YC-1 may induce the combined anticancer effects of HIF-1α inhibition and cell growth inhibition. (Cancer Res 2006; 66(12): 6345-52)

Preconditioning with oxidative stress has been demonstrated in vitro to stimulate the cellular adaptation to subsequent severe oxidative stress. However, it is uncertain whether this preconditioning works in vivo. In the present study, we examined in vivo the beneficial effect of oxidative preconditioning. After rats were pretreated with whole-body hyperoxygenation (100% 02 at 3 atmosphere for 20 mins, four cycles with 20-min intermission), isolated hearts were subjected to 45-min ischemia followed by 90-min reperfusion. This hyperoxic preconditioning significantly reduced infarct size, cytochrome-c release, DNA fragmentation, and terminal deoxynucleotidyl transferase-mediated dUTD nick-end labeling-positive cell frequency in the left ventricle, biphasically with an early (30-min) and a delayed (48-hr) effect after the hyperoxygenation. Mechanistically, the NF-κB activity and Bcl-2 expression were enhanced in the hearts, and a NF-κB inhibitor, pyrrolidine dithiocarbamate, abolished the Bcl-2 induction as well as the infarct-limiting effect. An antioxidant, N-acetylcysteine, and protein kinase C (PKC) inhibitors chelerythrine and Gö 6983 also blocked the preconditioning effects. These results indicate that hyperoxia induces myocardial tolerance against ischemia-reperfusion injury in association with Bcl-2 induction by NF-κB activation through reactive oxygen species and PKC-dependent signaling pathway.

Amphotericin B (AmB) is widely used for treating severe systemic fungal infections. However, long-term AmB treatment is invariably associated with adverse effects such as anemia. The erythropoietin (EPO) suppression by AmB has been proposed to contribute to the development of anemia. However, the mechanism whereby EPO is suppressed remains obscure. In this study, we investigated the possibility that AmB inhibits the transcription of the EPO gene by inactivating HIF-1, which is a known key transcription factor and regulator of EPO expression. EPO mRNA levels were markedly attenuated by AmB treatment both in rat kidneys and in Hep3B cells. AmB inactivated the transcriptional activity of HIF-1α, but did not affect the expression or localization of HIF-1 subunits. Moreover, AmB was found to specifically repress the C-terminal transactivation domain (CAD) of HIF-1α, and this repression by AmB required Asn803, a target site of the factor-inhibiting HIF-1 (FIH); moreover, this repressive effect was reversed by FIH inhibitors. Furthermore, AmB stimulated CAD-FIH interaction and inhibited the p300 recruitment by CAD. We propose that this mechanism underlies the unexplained anemia associated with AmB therapy.