Mild Ischemic Mitral Regurgitation: Is Revascularization Enough for Every Patient?

BACKGROUND: The progress of mild ischemic mitral regurgitation (MR) after isolated coronary artery bypass is not clear. We aimed to determine the proportion of patients with mild ischemic MR undergoing isolated coronary artery bypass grafting (CABG) presenting with regression of or persistent MR one year after CABG and to identify the significantly different echocardiographic variables between regressing and persistent MR. METHODS: Sixty-three patients with preoperative mild ischemic MR were categorized into an MR- regression or an MR-persistence group one year after isolated CABG. The echocardiographic indices, indicating mitral leaflet configuration and remodeling of the left ventricle (LV), were measured before and one year after the surgery. RESULTS: One year after CABG, MR regressed in 60% (38/63) and persisted in 40% (25/63) of the patients. The left ventricular diameter, volume, and sphericity and anteroposterior diameter of the mitral annulus improved only in the MR-regression group, while the ejection fraction improved in both groups (47.7% ± 12.4% from 40.1% ± 11.3%, P < .001 in the regression group and 43.2% ± 14.0% from 39.3% ± 11.6%, P = .035 in the persistence group). A >15% decrease in the LV end-systolic volume was noted more frequently in the MR-regression group (60.5% versus 30%, P = .027). The leaflet angle did not show asymmetry or significant changes in both groups. CONCLUSIONS: Isolated CABG improved mild MR in most patients with mild ischemic MR. These patients showed greater reverse remodeling after revascularization than the patients with persistent MR after isolated CABG. Additional tests, which can predict LV reverse remodeling, are needed to predict persistent MR.

All-trans-retinoic acid ameliorates hepatic steatosis in mice by a novel transcriptional cascade.

UNLABELLED: Mice deficient in small heterodimer partner (SHP) are protected from diet-induced hepatic steatosis resulting from increased fatty acid oxidation and decreased lipogenesis. The decreased lipogenesis appears to be a direct consequence of very low expression of peroxisome proliferator-activated receptor gamma 2 (PPAR-γ2), a potent lipogenic transcription factor, in the SHP(-/-) liver. The current study focused on the identification of a SHP-dependent regulatory cascade that controls PPAR-γ2 gene expression, thereby regulating hepatic fat accumulation. Illumina BeadChip array (Illumina, Inc., San Diego, CA) and real-time polymerase chain reaction were used to identify genes responsible for the linkage between SHP and PPAR-γ2 using hepatic RNAs isolated from SHP(-/-) and SHP-overexpressing mice. The initial efforts identify that hairy and enhancer of split 6 (Hes6), a novel transcriptional repressor, is an important mediator of the regulation of PPAR-γ2 transcription by SHP. The Hes6 promoter is specifically activated by the retinoic acid receptor (RAR) in response to its natural agonist ligand, all-trans retinoic acid (atRA), and is repressed by SHP. Hes6 subsequently represses hepatocyte nuclear factor 4 alpha (HNF-4α)-activated PPAR-γ2 gene expression by direct inhibition of HNF-4α transcriptional activity. Furthermore, we provide evidences that atRA treatment or adenovirus-mediated RAR-α overexpression significantly reduced hepatic fat accumulation in obese mouse models, as observed in earlier studies, and the beneficial effect is achieved by the proposed transcriptional cascade. CONCLUSIONS: Our study describes a novel transcriptional regulatory cascade controlling hepatic lipid metabolism that identifies retinoic acid signaling as a new therapeutic approach to nonalcoholic fatty liver diseases.

Ginseng Berry Extract Prevents Atherogenesis via Anti-Inflammatory Action by Upregulating Phase II Gene Expression.

Ginseng berry possesses higher ginsenoside content than its root, which has been traditionally used in herbal medicine for many human diseases, including atherosclerosis. We here examined the antiatherogenic effects of the Korean ginseng berry extract (KGBE) and investigated its underlying mechanism of action in vitro and in vivo. Administration of KGBE decreased atherosclerotic lesions, which was inversely correlated with the expression levels of phase II genes to include heme oxygenase-1 (HO-1) and glutamine-cysteine ligase (GCL). Furthermore, KGBE administration suppressed NF-κB-mediated expression of atherogenic inflammatory genes (TNF-α, IL-1ß, iNOS, COX-2, ICAM-1, and VCAM-1), without altering serum cholesterol levels, in ApoE(-/-) mice fed a high fat-diet. Treatment with KGBE increased phase II gene expression and suppressed lipopolysaccharide-induced reactive oxygen species production, NF-κB activation, and inflammatory gene expression in primary macrophages. Importantly, these cellular events were blocked by selective inhibitors of HO-1 and GCL. In addition, these inhibitors reversed the suppressive effect of KGBE on TNF-α-mediated induction of ICAM-1 and VCAM-1, resulting in decreased interaction between endothelial cells and monocytes. These results suggest that KGBE ameliorates atherosclerosis by inhibiting NF-κB-mediated expression of atherogenic genes via upregulation of phase II enzymes and thus has therapeutic or preventive potential for atherosclerosis.

Association between Age of Onset of Hypertension and Incident Atrial Fibrillation.

We investigated whether age at hypertension (HTN) onset was associated with the risk of atrial fibrillation (AF) in the general population. This prospective longitudinal community-based cohort study included 9892 participants without AF at baseline, who underwent biennial electrocardiography for a median duration of 11.5 years. The participants were divided into five groups, consisting of a normotensive group (Group-N) and four HTN groups based on HTN onset age: <45 years (Group-H1); 45−54 years (Group-H2); 55−64 years (Group-H3); and ≥65 years (Group-H4). A multivariate Cox proportional hazards model showed that the presence of HTN at baseline was associated with higher AF risk (hazard ratio [HR], 1.93; 95% confidence interval [CI] 1.32−2.80). The participants in Group-H1 had the highest risk of AF (HR 3.18; CI 1.74−5.82), and the risk of AF decreased as HTN onset age increased across the four HTN groups (p for trend = 0.014). The AF onset age was significantly younger in participants in Group-H1 than in Groups-H2−H4. Early-onset HTN was associated with an increased risk of AF, and younger onset of AF in the general population. Surveillance for AF should be considered at a younger age in individuals with HTN.

Carbon monoxide promotes VEGF expression by increasing HIF-1alpha protein level via two distinct mechanisms, translational activation and stabilization of HIF-1alpha protein.

Carbon monoxide (CO) plays a significant role in vascular functions. We here examined the molecular mechanism by which CO regulates HIF-1 (hypoxia-inducible transcription factor-1)-dependent expression of vascular endothelial growth factor (VEGF), which is an important angiogenic factor. We found that astrocytes stimulated with CORM-2 (CO-releasing molecule) promoted angiogenesis by increasing VEGF expression and secretion. CORM-2 also induced HO-1 (hemeoxygenase-1) expression and increased nuclear HIF-1α protein level, without altering its promoter activity and mRNA level. VEGF expression was inhibited by treatment with HIF-1α siRNA and a hemeoxygenase inhibitor, indicating that CO stimulates VEGF expression via up-regulation of HIF-1α protein level, which is partially associated with HO-1 induction. CORM-2 activated the translational regulatory proteins p70(S6k) and eIF-4E as well as phosphorylating their upstream signal mediators Akt and ERK. These translational signal events and HIF-1α protein level were suppressed by inhibitors of phosphatidylinositol 3-kinase (PI3K), MEK, and mTOR, suggesting that the PI3K/Akt/mTOR and MEK/ERK pathways are involved in a translational increase in HIF-1α. In addition, CORM-2 also increased stability of the HIF-1α protein by suppressing its ubiquitination, without altering the proline hydroxylase-dependent HIF-1α degradation pathway. CORM-2 increased HIF-1α/HSP90α interaction, which is responsible for HIF-1α stabilization, and HSP90-specific inhibitors decreased this interaction, HIF-1α protein level, and VEGF expression. Furthermore, HSP90α knockdown suppressed CORM-2-induced increases in HIF-1α and VEGF protein levels. These results suggest that CO stimulates VEGF production by increasing HIF-1α protein level via two distinct mechanisms, translational stimulation and protein stabilization of HIF-1α.

Effect of recombinant IL-10 on cultured fetal rat alveolar type II cells exposed to 65%-hyperoxia.

BACKGROUND: Hyperoxia plays an important role in the genesis of lung injury in preterm infants. Although alveolar type II cells are the main target of hyperoxic lung injury, the exact mechanisms whereby hyperoxia on fetal alveolar type II cells contributes to the genesis of lung injury are not fully defined, and there have been no specific measures for protection of fetal alveolar type II cells. OBJECTIVE: The aim of this study was to investigate (a) cell death response and inflammatory response in fetal alveolar type II cells in the transitional period from canalicular to saccular stages during 65%-hyperoxia and (b) whether the injurious stimulus is promoted by creating an imbalance between pro- and anti-inflammatory cytokines and (c) whether treatment with an anti-inflammatory cytokine may be effective for protection of fetal alveolar type II cells from injury secondary to 65%-hyperoxia. METHODS: Fetal alveolar type II cells were isolated on embryonic day 19 and exposed to 65%-oxygen for 24 h and 36 h. Cells in room air were used as controls. Cellular necrosis was assessed by lactate dehydrogenase-release and flow cytometry, and apoptosis was analyzed by TUNEL assay and flow cytometry, and cell proliferation was studied by BrdU incorporation. Release of cytokines including VEGF was analyzed by ELISA, and their gene expressions were investigated by qRT-PCR. RESULTS: 65%-hyperoxia increased cellular necrosis, whereas it decreased cell proliferation in a time-dependent manner compared to controls. 65%-hyperoxia stimulated IL-8-release in a time-dependent fashion, whereas the anti-inflammatory cytokine, IL-10, showed an opposite response. 65%-hyperoxia induced a significant decrease of VEGF-release compared to controls, and similar findings were observed on IL-8/IL-10/VEGF genes expression. Preincubation of recombinant IL-10 prior to 65%-hyperoxia decreased cellular necrosis and IL-8-release, and increased VEGF-release and cell proliferation significantly compared to hyperoxic cells without IL-10. CONCLUSIONS: The present study provides an experimental evidence that IL-10 may play a potential role in protection of fetal alveolar type II cells from injury induced by 65%-hyperoxia.

The farnesyltransferase inhibitor LB42708 suppresses vascular endothelial growth factor-induced angiogenesis by inhibiting ras-dependent mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt signal pathways.

Farnesyltransferase (FTase) inhibitors induce growth arrest and apoptosis in various human cancer cells by inhibiting the post-translational activation of Ras. FTase inhibitors also function to suppress the release of vascular endothelial growth factor (VEGF) from tumor cells by inhibiting Ras activation; however, the effects of FTase inhibitors on VEGF-induced angiogenesis in endothelial cells have not been studied. We have investigated the antiangiogenic effect and molecular mechanism of 4-((1-((1-((4-bromophenyl)methyl)-1H-imidazol-5-yl)methyl)-4-(1-napthalenyl)-1H-pyrrol-3-yl)carbonyl)-(9C1)-morpholine (LB42708), a selective nonpeptidic FTase inhibitor, using in vitro and in vivo assay systems. LB42708 inhibited VEGF-induced Ras activation and subsequently suppressed angiogenesis in vitro and in vivo by blocking the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase/p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt/endothelial nitric-oxide synthase pathways in endothelial cells without altering FAK/Src activation. In addition, this inhibitor suppressed VEGF-induced endothelial cell cycle progression at the G(1) phase by suppressing cyclin D1 expression and retinoblastoma phosphorylation as well as up-regulating the cyclin-dependent kinase inhibitors p21 and p27. Knockdown of Ras by short interfering RNA revealed similar inhibitory effects on VEGF-induced angiogenic signal events compared with LB42708. Moreover, the inhibitory effects of LB42708 were significantly higher than those of 4-(2-(4-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo-(5,6)-cyclohepta(1,2-b)-pyridin-11(R)-yl)-1-piperidinyl)-2-oxo-ethyl)-1-piperidinecarboxamide (SCH66336), a well known FTase inhibitor. LB42708 suppressed tumor growth and tumor angiogenesis in both xenograft tumor models of Ras-mutated HCT116 cells and its wild-type Caco-2 cells, indicating its potential application in the treatment of both Ras-mutated and wild type tumors. These data indicate that the antitumor effect of LB42708 can be associated with direct inhibition of VEGF-induced tumor angiogenesis by blocking Ras-dependent MAPK and PI3K/Akt signal pathways in tumor-associated endothelial cells.

Elasticity of torn supraspinatus tendons measured by shear wave elastography: a potential surrogate marker of chronicity?

PURPOSE: This study investigated whether shear wave elastography (SWE) could be used to estimate the chronicity of supraspinatus tendon (SST) tears. METHODS: A retrospective study was performed. From November 2015 to July 2016, 113 patients (52 men, 61 women; age range, 21 to 79 years) with persistent shoulder pain underwent 119 rotator cuff tendon examinations by routine B-mode ultrasonography, while SST elasticity was measured using SWE. Following the exclusion of eight suboptimal examinations, four examinations with missing SST measurements, and 27 examinations of patients with other conditions, 80 examinations were analyzed. A torn SST was found in 54 examinations (27 with a partial-thickness tear and 27 with a full-thickness tear). Elasticity values were compared in multiple ways. The results were analyzed using the Mann-Whitney U test or Kruskal-Wallis test. RESULTS: No statistically significant difference in elasticity values (in kPa) was found between normal (median, 94.65; interquartile range [IQR], 87.43 to 105.47) and torn SSTs (median, 96.79; IQR, 86.71 to 108.56) or between full-thickness tears (median, 93.80; IQR, 82.50 to 108.33) and partial-thickness tears (median, 96.83; IQR, 90.60 to 112.20). However, there was a statistically significant difference in elasticity according to whether the duration of symptoms was 1 year or less (median, 92.20; IQR, 84.01 to 104.38) or longer than 1 year (median, 105.10; IQR, 100.41 to 116.03; P=0.032). CONCLUSION: Elasticity values were significantly higher in torn SSTs in patients with chronic shoulder pain that had persisted for more than 1 year. Further studies with larger samples seem warranted to determine whether elasticity values measured by SWE can be used preoperatively as a surrogate marker of the chronicity of a rotator cuff tendon tear.

Prostate Cancer Lymphangitic Pulmonary Carcinomatosis: Appearance on 18F-FDG PET/CT and 18F-DCFPyL PET/CT.

A 51-year-old man diagnosed with high-grade, high-volume metastatic castration-sensitive prostate adenocarcinoma received pelvic radiation, androgen deprivation therapy, and intravenous docetaxel. Serum prostate-specific antigen became undetectable following treatment. Within a year, his cancer progressed to castration-resistant disease, and he was treated with oral abiraterone acetate 1000 mg and prednisone 10 mg daily. Despite this, the serum prostate-specific antigen rose from 0.03 to 1.39 µg/L, and F-DCFPyL and F-FDG PET/CT showed progression. While F-DCFPyL uptake may be seen in aggressive disease, F-FDG portends poor prognosis. Despite intravenous platinum-based chemotherapy, the patient died of respiratory failure 20 months after his initial diagnosis.

A novel visual ranking system based on arterial spin labeling perfusion imaging for evaluating perfusion disturbance in patients with ischemic stroke.

We developed a visual ranking system by combining the parenchymal perfusion deficits (PPD) and hyperintense vessel signals (HVS) on arterial spin labeling (ASL) imaging. This study aimed to assess the performance of this ranking system by correlating with subtypes classified based on dynamic susceptibility contrast (DSC) imaging for evaluating the perfusion disturbance observed in patients with ischemic stroke. 32 patients with acute or subacute infarcts detected by DSC imaging were reviewed. Each patient's brain was divided into 12 areas. ASL ranks were defined by the presence (+) or absence (-) of PPD/HVS as follows; I:-/-, II:-/+, III: +/+, and IV: +/-. DSC imaging findings were categorized based on cerebral blood flow (CBF) and time to peak (TTP) as normal (normal CBF/TTP), mismatched (normal CBF/delayed TTP), and matched (decreased CBF/delayed TTP). Two reviewers rated perfusion abnormalities in the total of 384 areas. The four ASL ranks correlated well with the DSC subtypes (Spearman's r = 0.82). The performance of ASL ranking system was excellent as indicated by the area under the curve value of 0.94 using either matched or mismatched DSC subtype as the gold standard and 0.97 using only the matched DSC subtype as the gold standard. The two methods were in good-to-excellent agreement (maximum κ-values, 0.86). Inter-observer agreement was excellent (κ-value, 0.98). Although the number of patients was small and the number of dropouts was high, our proposed, ASL-based visual ranking system represented by PPD and HVS provides good, graded estimates of perfusion disturbance that agree well with those obtained by DSC perfusion imaging.

The Relationship between Poor Pulmonary Function and Irregular Pulse in the Elderly: Findings from a Nationwide Cross-Sectional Survey in Korea.

Arrhythmia may be caused by reduced pulmonary function, and pulse palpation is a useful screening method for the early detection of cardiac arrhythmia. The aim of this study was to investigate the association between reduced pulmonary function and abnormal findings on pulse palpation in 2347 subjects aged ≥65 years using data from a nationwide survey. Pulse palpation was initially performed for 15 s and, if felt to be abnormal, it was performed again for 60 s. The prevalence of irregular pulse (IP) determined by the 60-second palpation was 61 (2.6%). The mean age of subjects with an IP was 73.0 (95% CI 71.7-74.3) years, and 45.8% were male. After adjustment for covariates, forced vital capacity (FVC)/predicted FVC, forced expiratory volume in one second (FEV1)/predicted FEV1, and the lowest FEV1 remained significant risk factors for IP. A restrictive or obstructive spirometry pattern was also an independent risk factor for IP. In summary, an IP is more prevalent when pulmonary function is reduced in the elderly, in whom careful pulse palpation may be necessary for the early detection of arrhythmia.

Association between insulin resistance and risk of atrial fibrillation in non-diabetics.

AIMS: Previous studies from Western countries have been unable to demonstrate a relationship between insulin resistance and new-onset atrial fibrillation. We aimed to evaluate this relationship in the nondiabetic Asian population. METHODS: Between 2001-2003, 8175 adults (mean age 51.5 years, 53% women) without both existing atrial fibrillation and diabetes and with insulin resistance measures at baseline were enrolled and were followed by biennial electrocardiograms thereafter until 2014. We constructed multivariable-adjusted Cox proportional hazard models for risk of incident atrial fibrillation. RESULTS: Over a median follow-up of 12.3 years, 136 participants (1.89/1000 person-years) developed atrial fibrillation. Higher homeostasis model assessment of insulin resistance (HOMA-IR) was independently associated with newly developed atrial fibrillation (hazard ratio 1.61, 95% confidence interval 1.14-2.28). Atrial fibrillation development increased at the HOMA-IR levels approximately between 1-2.5, and then plateaued afterwards (p = 0.031). CONCLUSION: There is a significant relationship between insulin resistance and atrial fibrillation development independent of other known risk factors, including obesity in a nondiabetic Asian population.

Co-localization of inducible nitric oxide synthase and phosphorylated Akt in the lesional skins of patients with melasma.

Activation of the inducible nitric oxide synthase (iNOS)/nitric oxide (NO) pathway in keratinocytes has been reported to be associated with the pathogenesis of melanogenesis. Akt activation plays an important role in the activation of the transcription factor nuclear factor (NF)-kappaB and subsequent elevation of iNOS expression. In the present study, we highly detected both iNOS protein and Akt phosphorylation in keratinocytes of the basal layer of the epidermis at the junction with the dermis of melasma skin biopsy specimens, but not in normal skin tissues, from nine patients using immunohistological analysis. iNOS protein and phosphorylated Akt were co-localized in the lesional skins, and their levels were highly correlated R2= 0.69). Furthermore, iNOS mRNA was also detected in an additional three skin biopsy specimens, but not in normal skin, by reverse transcription polymerase chain reaction. Our results describe that iNOS expression is elevated in human melasma lesions, probably via activation of the Akt/NF-kappaB pathway, indicating that NO production plays an important role in the mechanism of hyperpigmentation in human facial melasma.

Independent effect of physical activity and resting heart rate on the incidence of atrial fibrillation in the general population.

While physical activity (PA) may influence resting heart rate (RHR), and a low RHR may be a risk factor for atrial fibrillation (AF), controversy exists regarding the association between PA and development of AF. Using data from a Korean, prospective population cohort, we investigated the independent effect of PA and RHR on the incidence of AF in the general population. A total of 8,811 participants aged 40-69 years were analyzed. Total PA assessed based on questionnaires was divided into quartiles, with the lowest to the highest being Q1, Q2, Q3, and Q4. During a median follow-up of 139 months, AF developed in 167 participants (1.9%). Q3 of total PA was associated with a significantly lower risk of AF than Q1 even after adjusting for RHR as a covariate, but Q4 was not. The risk of AF was higher in participants with RHR < 60 bpm than in those with RHR 70-85 bpm, and the significance persisted after adjusting for PA as a covariate. This study showed that a moderate amount of total PA was associated with a lower risk of incident AF independent of RHR and that low RHR was an independent risk factor for AF in the general Korean population.

The relationship between decreased pulmonary function and atrial fibrillation in general population: Findings from Ansung-Ansan cohort of the Korean Genome and Epidemiology Study.

BACKGROUND: Decreased pulmonary function is a possible risk factor for atrial fibrillation (AF). However, data on this relationship in Asian populations are scant. The aim of this study was to evaluate the relationship between decreased pulmonary function and the incidence of AF in a prospective cohort of Koreans aged 40-69 years. METHODS: We assessed AF in 9631 Korean people enrolled in the community-based cohort who were followed for up to 12 years. AF at baseline was identified by electrocardiography (ECG) performed during the baseline visit and/or the self-reported history of physician-determined diagnosis made before the baseline visit. Similarly, AF newly developed after the baseline visit was also identified by biennially performed ECGs and/or the self-reported history of physician-determined diagnosis that occurred between each biennial visit. If AF was identified by both ECGs and the history in the same subject, the earlier identification date was considered the time of AF development. RESULTS: The median age was 50 (interquartile range, 44-60) years, and 4633 (48.1%) were male. The prevalence of AF at baseline was significantly higher in subjects with lower quartiles of forced expiratory volume in second (FEV1)% predicted (1.2% in the lowest quartile versus 0.3% in the highest quartile; p<0.001). After adjustment for cardiovascular risk factors, FEV1% predicted and forced vital capacity (FVC)% predicted were independent risk factors for AF at baseline. Over a median follow-up period of 138 (interquartile range, 70-141) months, AF was newly documented in 162 subjects (1.7%). The lowest quartiles of FEV1% predicted (adjusted hazard ratio, 1.59; 95% confidence interval, 1.02-2.50) was associated with a higher risk of incident AF than the highest quartiles. CONCLUSIONS: In this large community-based cohort study with a long-term follow-up, decreased pulmonary function was found to be an independent risk factor for AF in the general Korean population.

The non-provitamin A carotenoid, lutein, inhibits NF-kappaB-dependent gene expression through redox-based regulation of the phosphatidylinositol 3-kinase/PTEN/Akt and NF-kappaB-inducing kinase pathways: role of H(2)O(2) in NF-kappaB activation.

Reactive oxygen species (ROS) have been implicated in the regulation of NF-kappaB activation, which plays an important role in inflammation and cell survival. However, the molecular mechanisms of ROS in NF-kappaB activation remain poorly defined. We found that the non-provitamin A carotenoid, lutein, decreased intracellular H(2)O(2) accumulation by scavenging superoxide and H(2)O(2) and the NF-kappaB-regulated inflammatory genes, iNOS, TNF-alpha, IL-1beta, and cyclooxygenase-2, in lipopolysaccharide (LPS)-stimulated macrophages. Lutein inhibited LPS-induced NF-kappaB activation, which highly correlated with its inhibitory effect on LPS-induced IkappaB kinase (IKK) activation, IkappaB degradation, nuclear translocation of NF-kappaB, and binding of NF-kappaB to the kappaB motif of the iNOS promoter. This compound inhibited LPS- and H(2)O(2)-induced increases in phosphatidylinositol 3-kinase (PI3K) activity, PTEN inactivation, NF-kappaB-inducing kinase (NIK), and Akt phosphorylation, which are all upstream of IKK activation, but did not affect the interaction between Toll-like receptor 4 and MyD88 and the activation of mitogen-activated protein kinases. The NADPH oxidase inhibitor apocynin and gp91(phox) deletion reduced the LPS-induced NF-kappaB signaling pathway as lutein did. Moreover, lutein treatment and gp91(phox) deletion decreased the expressional levels of the inflammatory genes in vivo and protected mice from LPS-induced lethality. Our data suggest that H(2)O(2) modulates IKK-dependent NF-kappaB activation by promoting the redox-sensitive activation of the PI3K/PTEN/Akt and NIK/IKK pathways. These findings further provide new insights into the pathophysiological role of intracellular H(2)O(2) in the NF-kappaB signal pathway and inflammatory process.

Icariin stimulates angiogenesis by activating the MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways in human endothelial cells.

We investigated the molecular effect and signal pathway of icariin, a major flavonoid of Epimedium koreanum Nakai, on angiogenesis. Icariin stimulated in vitro endothelial cell proliferation, migration, and tubulogenesis, which are typical phenomena of angiogenesis, as well as increased in vivo angiogenesis. Icariin activated the angiogenic signal modulators, ERK, phosphatidylinositol 3-kinase (PI3K), Akt, and endothelial nitric oxide synthase (eNOS), and increased NO production, without affecting VEGF expression, indicating that icariin may directly stimulate angiogenesis. Icariin-induced ERK activation and angiogenic events were significantly inhibited by the MEK inhibitor PD98059, without affecting Akt and eNOS phosphorylation. The PI3K inhibitor Wortmannin suppressed icariin-mediated angiogenesis and Akt and eNOS activation without affecting ERK phosphorylation. Moreover, the NOS inhibitor NMA partially reduced the angiogenic activity of icariin. These results suggest that icariin stimulated angiogenesis by activating the MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways and may be a useful drug for angiogenic therapy.

The caspase-8/Bid/cytochrome c axis links signals from death receptors to mitochondrial reactive oxygen species production.

Ligation of the death receptors for TNF-α, FasL, and TRAIL triggers two common pathways, caspase-dependent intrinsic apoptosis and intracellular reactive oxygen species (ROS) generation. The apoptotic pathway is well characterized; however, a signaling linker between the death receptor and ROS production has not been clearly elucidated. Here, we found that death receptor-induced ROS generation was strongly inhibited by mitochondrial complex I and II inhibitors, but not by inhibitors of NADPH oxidase, lipoxygenase, cyclooxygenase or xanthine oxidase, indicating that ROS are mostly generated by the impairment of the mitochondrial respiratory chain. ROS generation was accompanied by caspase-8 activation, Bid cleavage, and cytochrome c release; it was blocked in FADD- and caspase-8-deficient cells, as well as by caspase-8 knockdown and inhibitor. Moreover, Bid knockdown abrogated TNF-α- or TRAIL-induced ROS generation, whereas overexpression of truncated Bid (tBid) or knockdown of cytochrome c spontaneously elevated ROS production. In addition, p53-overexpressing cells accumulated intracellular ROS via cytochrome c release mediated by the BH3-only protein Noxa induction. In a cell-free reconstitution system, caspase-8-mediated Bid cleavage and recombinant tBid induced mitochondrial cytochrome c release and ROS generation, which were blocked by Bcl-xL and antioxidant enzymes. These data suggest that anti-apoptotic Bcl-2 proteins play an important role in mitochondrial ROS generation by preventing cytochrome c release. These data provide evidence that the FADD/caspase-8/Bid/cytochrome c axis is a crucial linker between death receptors and mitochondria, where they play a role in ROS generation and apoptosis.

Increased 18F-FDG Uptake on PET/CT is Associated With Poor Arterial and Portal Perfusion on Multiphase CT.

PURPOSE: To correlate 18F-FDG uptake on PET/CT with patterns of arterial and portal perfusion on multi-detector CT (MDCT) in patients with hepatocellular carcinoma (HCC) and to assess the value of variables from PET/CT and MDCT in predicting histological grades and overall survival. METHODS: We retrospectively analyzed MDCT and PET/CT of 66 patients with HCC who underwent surgical treatment. Tumor peak standard uptake value (SUV) was divided by the mean liver SUV (T/LSUV). The mean tumor Hounsfield unit (HU) to mean liver HU was calculated for arterial (T/LHU-A) and portal phases (T/LHU-P). All patients were divided into three groups: I, T/LHU-A ≤l and T/LHU-P <1; II, T/LHU-A >1 and T/LHU-P <1; and III, T/LHU-A >1 and T/LHU-P ≥1. The relationships between the CT perfusion groups and T/LSUV were assessed. Multivariate logistic regression analyses were performed using clinical and imaging parameters for predicting histological grade. Overall survival curves stratified by T/LSUV and CT perfusion groups were estimated using the Kaplan-Meier method. RESULTS: Statistically significant differences in T/LSUV were noted between groups I and II (2.29 [range 1.74-3.60] vs. 1.20 [range 1.07-1.58], P < 0.001) and groups I and III (2.29 [range 1.74-3.60] vs. 1.30 [range 1.07-1.43], P < 0.001). In multivariate analysis, a T/LSUV cutoff of >1.46 was the only independent predictor of tumor grade, with an odds ratio of 8.462 (95% confidence interval 1.799-39.803). Kaplan-Meier curves showed significant differences in OS according to T/LSUV >1.62, group I perfusion pattern, and T/LSUV >1.62 plus group I perfusion pattern (P = 0.04, P = 0.021, and P = 0.002, respectively). CONCLUSION: 18F-FDG PET/CT is not commonly used for detecting HCC due to its limited sensitivity. We found that increased 18F-FDG uptake is associated with decreased arterial and portal perfusion on MDCT. This can be used to preselect patients who would benefit the most from PET/CT. Meanwhile, 18F-FDG uptake remained as the only independent predictor of histological grade, and higher 18F-FDG uptake and lower perfusion pattern on MDCT were significantly related to shorter OS.

Prostaglandin E2 stimulates angiogenesis by activating the nitric oxide/cGMP pathway in human umbilical vein endothelial cells.

Prostaglandin E2 (PGE2), a major product of cyclooxygenase, has been implicated in modulating angiogenesis, vascular function, and inflammatory processes, but the underlying mechanism is not clearly elucidated. We here investigated the molecular mechanism by which PGE2 regulates angiogenesis. Treatment of human umbilical vein endothelial cells (HUVEC) with PGE2 increased angiogenesis. PGE2 increased phosphorylation of Akt and endothelial nitric oxide synthase (eNOS), eNOS activity, and nitric oxide (NO) production by the activation of cAMP-dependent protein kinase (PKA) and phosphatidylinositol 3-kinase (PI3K). Dibutyryl cAMP (DB-cAMP) mimicked the role of PGE2 in angiogenesis and the signaling pathway, suggesting that cAMP is a down-stream mediator of PGE2. Furthermore, PGE2 increased endothelial cell sprouting from normal murine aortic segments, but not from eNOS-deficient ones, on Matrigel. The angiogenic effects of PGE2 were inhibited by the inhibitors of PKA, PI3K, eNOS, and soluble guanylate cyclase, but not by phospholipase C inhibitor. These results clearly show that PGE2 increased angiogenesis by activating the NO/cGMP signaling pathway through PKA/PI3K/Akt-dependent increase in eNOS activity.