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1.
J Pers Med ; 12(7)2022 Jul 21.
Article in English | MEDLINE | ID: mdl-35887683

ABSTRACT

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.

2.
Healthcare (Basel) ; 8(3)2020 Sep 01.
Article in English | MEDLINE | ID: mdl-32882921

ABSTRACT

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.

3.
Clin Nucl Med ; 45(9): 727-729, 2020 Sep.
Article in English | MEDLINE | ID: mdl-32520499

ABSTRACT

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.


Subject(s)
Fluorodeoxyglucose F18 , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/secondary , Lysine/analogs & derivatives , Positron Emission Tomography Computed Tomography , Prostatic Neoplasms/pathology , Urea/analogs & derivatives , Disease Progression , Humans , Lung Neoplasms/drug therapy , Male , Middle Aged , Prednisone/therapeutic use
4.
Heart Surg Forum ; 23(3): E370-E375, 2020 May 29.
Article in English | MEDLINE | ID: mdl-32524986

ABSTRACT

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.


Subject(s)
Mitral Valve Insufficiency/etiology , Myocardial Ischemia/complications , Myocardial Revascularization/methods , Aged , Coronary Angiography , Echocardiography , Female , Follow-Up Studies , Humans , Male , Middle Aged , Mitral Valve Insufficiency/diagnosis , Mitral Valve Insufficiency/prevention & control , Myocardial Ischemia/diagnosis , Myocardial Ischemia/surgery , Retrospective Studies , Severity of Illness Index
5.
Eur J Prev Cardiol ; 27(18): 1934-1941, 2020 12.
Article in English | MEDLINE | ID: mdl-32122201

ABSTRACT

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.


Subject(s)
Atrial Fibrillation/etiology , Blood Glucose/metabolism , Insulin/blood , Risk Assessment/methods , Adult , Aged , Atrial Fibrillation/blood , Atrial Fibrillation/epidemiology , Biomarkers/blood , Diabetes Mellitus , Female , Follow-Up Studies , Humans , Incidence , Insulin Resistance , Male , Middle Aged , Obesity/complications , Obesity/epidemiology , Republic of Korea/epidemiology , Retrospective Studies , Risk Factors
6.
Ultrasonography ; 39(2): 144-151, 2020 Apr.
Article in English | MEDLINE | ID: mdl-32106664

ABSTRACT

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.

7.
PLoS One ; 15(1): e0227747, 2020.
Article in English | MEDLINE | ID: mdl-31978097

ABSTRACT

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.


Subject(s)
Brain Infarction/diagnosis , Brain/diagnostic imaging , Cerebral Arteries/physiopathology , Magnetic Resonance Angiography/methods , Perfusion Imaging/methods , Aged , Aged, 80 and over , Brain/blood supply , Brain Infarction/physiopathology , Cerebral Arteries/diagnostic imaging , Cerebral Blood Volume/physiology , Cerebrovascular Circulation/physiology , Feasibility Studies , Female , Humans , Male , Middle Aged , Retrospective Studies , Spin Labels
8.
Sci Rep ; 9(1): 11228, 2019 08 02.
Article in English | MEDLINE | ID: mdl-31375738

ABSTRACT

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.


Subject(s)
Atrial Fibrillation/physiopathology , Exercise/physiology , Heart Rate/physiology , Adult , Aged , Atrial Fibrillation/etiology , Female , Humans , Incidence , Male , Middle Aged , Republic of Korea/epidemiology , Risk Factors
9.
J Cardiol ; 74(6): 488-493, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31253525

ABSTRACT

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.


Subject(s)
Atrial Fibrillation/epidemiology , Respiratory Insufficiency/epidemiology , Adult , Aged , Atrial Fibrillation/etiology , Atrial Fibrillation/physiopathology , Electrocardiography , Female , Forced Expiratory Volume , Humans , Incidence , Lung/physiopathology , Male , Middle Aged , Prevalence , Proportional Hazards Models , Prospective Studies , Republic of Korea/epidemiology , Respiratory Function Tests , Respiratory Insufficiency/complications , Risk Assessment , Risk Factors , Vital Capacity
10.
Free Radic Biol Med ; 112: 567-577, 2017 11.
Article in English | MEDLINE | ID: mdl-28888620

ABSTRACT

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.


Subject(s)
BH3 Interacting Domain Death Agonist Protein/genetics , Caspase 8/genetics , Cytochromes c/genetics , Mitochondria, Liver/metabolism , Reactive Oxygen Species/metabolism , Animals , Apoptosis/genetics , BH3 Interacting Domain Death Agonist Protein/metabolism , Caspase 8/metabolism , Cell Line, Tumor , Cytochromes c/metabolism , Fas-Associated Death Domain Protein/genetics , Fas-Associated Death Domain Protein/metabolism , Gene Expression Regulation , HeLa Cells , Humans , Jurkat Cells , Liver/cytology , Liver/metabolism , Mice , Mice, Inbred C57BL , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Signal Transduction , TNF-Related Apoptosis-Inducing Ligand/genetics , TNF-Related Apoptosis-Inducing Ligand/metabolism , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , bcl-X Protein/genetics , bcl-X Protein/metabolism
11.
Clin Nucl Med ; 41(4): 296-301, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26756099

ABSTRACT

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.


Subject(s)
Carcinoma, Hepatocellular/diagnostic imaging , Fluorodeoxyglucose F18 , Liver Neoplasms/diagnostic imaging , Perfusion Imaging , Portal System/diagnostic imaging , Positron-Emission Tomography , Radiopharmaceuticals , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Multimodal Imaging , Tomography, X-Ray Computed
12.
Clin Nucl Med ; 40(8): 632-6, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26018720

ABSTRACT

PURPOSE: This study was to evaluate the relationship among FDG uptake in the pituitary gland (FDGp), FDG uptake in the thyroid gland (FDGt), and serum thyroid-stimulating hormone (TSH) levels in patients with diffuse FDGt incidentally noted on positron emission tomography/computed tomography (PET/CT). PATIENTS AND METHODS: We retrospectively reviewed FDG PET/CT scans of 2,945 subjects who underwent health screening. Of these, 44 subjects had diffuse FDGt and available thyroid function tests. FDGt and FDGp were correlated with serum TSH. FDGp in 44 paired control subjects without FDGt and 15 thyroid cancer patients undergoing thyroid hormone withdrawal were additionally measured, and compared with FDGp in the 44 subjects with FDGt divided into 3 groups according to serum TSH levels. RESULTS: In the 44 subjects, there was a strong correlation found between FDGp and TSH (P < 0.001, r = 0.618). As well, there were statistically significant differences in FDGp between the low, normal, and high TSH groups (P < 0.001). FDGp in the paired control subjects was not different from that in the normal TSH group (P = 0.384), and FDGp in the TSH-stimulated thyroid cancer patients was not different from that in the high TSH group (P = 0.463). CONCLUSION: We found a strong positive correlation between pituitary FDG uptake and serum TSH. Pituitary FDG uptake seems to hold an important clue to the functional status of the thyroid in subjects with diffuse thyroid FDG uptake. Furthermore, physiologic FDG uptake in the pituitary gland caused by hypothyroidism should not be confused with pathologic conditions such as macroadenoma or metastases.


Subject(s)
Fluorodeoxyglucose F18/pharmacokinetics , Pituitary Gland/diagnostic imaging , Positron-Emission Tomography , Radiopharmaceuticals/pharmacokinetics , Thyroid Gland/diagnostic imaging , Thyrotropin/blood , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Multimodal Imaging , Tomography, X-Ray Computed
13.
Vascul Pharmacol ; 63(1): 19-28, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24998908

ABSTRACT

The therapeutic effects of stem cell transplantation in ischemic disease are mediated by the production of paracrine bioactive factors. However, the bioactive factors secreted by human mesenchymal stem cells (hMSCs) and their angiogenic activity are not clearly identified or determined. We here found that hMSC-derived conditioned media (hMSC-CdM) stimulated in vitro angiogenic activity of endothelial cells and contained significant levels of various growth factors and cytokines, such as vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), and transforming growth factor-beta1 (TGF-ß1). The angiogenic activity of hMSC-CdM was significantly inhibited by pretreatment with neutralizing antibodies against VEGF, MCP-1, and IL-6, but not against TGF-ß1 and HGF. A mixture of those inhibitory antibodies blocked CdM-mediated activation of angiogenic signals, as well as inhibited CdM-mediated in vivo angiogenesis. Moreover, local injection of CdM increased angiogenesis and promoted blood flow in mice with hindlimb ischemia, and these effects were inhibited by co-treatment with these inhibitory antibodies. These results indicate that hMSC-CdM represents a promising cell-free therapeutic strategy for neovascularization in ischemic diseases. These results suggest the combination of VEGF, MCP-1, and IL-6 as a commercial application for therapeutic angiogenesis.


Subject(s)
Ischemia/therapy , Mesenchymal Stem Cells/metabolism , Neovascularization, Physiologic/physiology , Paracrine Communication/physiology , Adult , Animals , Chemokine CCL2/metabolism , Cytokines/metabolism , Hindlimb/blood supply , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Interleukin-6/metabolism , Male , Mice , Mice, Inbred C57BL , Middle Aged , Vascular Endothelial Growth Factor A/metabolism
14.
Hepatology ; 59(5): 1750-60, 2014 May.
Article in English | MEDLINE | ID: mdl-24038081

ABSTRACT

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.


Subject(s)
Fatty Liver/drug therapy , PPAR gamma/genetics , Receptors, Cytoplasmic and Nuclear/physiology , Tretinoin/therapeutic use , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Blood Glucose/analysis , Fatty Liver/metabolism , Gene Expression Regulation , Lipid Metabolism , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease , Receptors, Retinoic Acid/physiology , Repressor Proteins/genetics , Retinoic Acid Receptor alpha , Transcription, Genetic , Tretinoin/pharmacology
15.
Yonsei Med J ; 54(2): 445-52, 2013 Mar 01.
Article in English | MEDLINE | ID: mdl-23364980

ABSTRACT

PURPOSE: Hyperoxia has the chief biological effect of cell death. We have previously reported that cathepsin B (CB) is related to fetal alveolar type II cell (FATIIC) death and pretreatment of recombinant IL-10 (rIL-10) attenuates type II cell death during 65%-hyperoixa. In this study, we investigated what kinds of changes of CB expression are induced in FATIICs at different concentrations of hyperoxia (65%- and 85%-hyperoxia) and whether pretreatment with rIL-10 reduces the expression of CB in FATIICs during hyperoxia. MATERIALS AND METHODS: Isolated embryonic day 19 fetal rat alveolar type II cells were cultured and exposed to 65%- and 85%-hyperoxia for 12 h and 24 h. Cells in room air were used as controls. Cytotoxicity was assessed by lactate dehydrogenase (LDH) released into the supernatant. Expression of CB was analyzed by fluorescence-based assay upon cell lysis and western blotting, and LDH-release was re-analyzed after preincubation of cathepsin B-inhibitor (CBI). IL-10 production was analyzed by ELISA, and LDH-release was re-assessed after preincubation with rIL-10 and CB expression was re-analyzed by western blotting and real-time PCR. RESULTS: LDH-release and CB expression in FATIICs were enhanced significantly in an oxygen-concentration-dependent manner during hyperoxia, whereas caspase-3 was not activated. Preincubation of FATIICs with CBI significantly reduced LDH-release during hyperoxia. IL-10-release decreased in an oxygen-concentration-dependent fashion, and preincubation of the cells with rIL-10 significantly reduced cellular necrosis and expression of CB in FATIICs which were exposed to 65%- and 85%-hyperoxia. CONCLUSION: Our study suggests that CB is enhanced in an oxygen- concentration-dependent manner, and IL-10 has an inhibitory effect on CB expression in FATIICs during hyperoxia.


Subject(s)
Cathepsin B/genetics , Down-Regulation , Hyperoxia/genetics , Interleukin-10/pharmacology , Animals , Cathepsin B/metabolism , Gene Expression Regulation , Interleukin-10/physiology , L-Lactate Dehydrogenase/metabolism , Necrosis/chemically induced , Oxygen/metabolism , Rats
16.
J Ethnopharmacol ; 146(2): 515-24, 2013 Mar 27.
Article in English | MEDLINE | ID: mdl-23353895

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: The fruit of Rubus coreanus has been used as a traditional herbal medicine for alleviation of inflammatory and vascular diseases in Asian countries. AIM OF THE STUDY: The anti-atherogenic effect of unripe Rubus coreanus fruit extract (URFE) and its underlying mechanism were analyzed in mice fed a high-fat diet (HFD) and in cell culture system. MATERIALS AND METHODS: Mouse was freely given HFD alone or supplemented with URFE for 14 weeks, followed by analysis of atherosclerotic lesions and serum lipid levels. For in vitro assay, macrophages were pretreated with URFE, followed by stimulation with lipopolysaccharide (LPS). Expression levels of inflammatory genes (TNF-α, IL-1ß, and iNOS) and phase II genes (heme oxygenase-1, glutamate cysteine lygase, and peroxiredoxine-1) as well as intracellular reactive oxygen species (ROS) level and NF-κB activation pathway were analyzed in cultured macrophages as well as mouse sera and aortic tissues. RESULTS: URFE supplementation reduced HFD-induced atherosclerotic lesion formation which was correlated with decreased levels of lipids, lipid peroxides, and inflammatory mediators (TNF-α, IL-1ß, and nitric oxide) in sera as well as suppression of inflammatory gene in aortic tissues. In addition, pre-treatment of macrophages with URFE also suppressed LPS-induced NF-κB activation, ROS production, and inflammatory and phase II gene expressions. Inhibition of phase II enzyme and protein activities attenuated the suppressive effects URFE on ROS production, NF-κB activation, and inflammatory gene expression. CONCLUSION: These results suggest that URFE attenuates atherosclerosis by improving blood lipid profile and inhibiting NF-κB activation via phase II antioxidant gene expression.


Subject(s)
Atherosclerosis/drug therapy , Plant Extracts/therapeutic use , Rosaceae , Animals , Aorta/metabolism , Atherosclerosis/genetics , Atherosclerosis/metabolism , Cell Line , Cholesterol/blood , Fruit , Gene Expression Regulation/drug effects , Glutamate-Cysteine Ligase/genetics , Heme Oxygenase-1/genetics , Homeodomain Proteins/genetics , Interleukin-1beta/metabolism , Male , Membrane Proteins/genetics , Mice , Mice, Inbred C57BL , NF-E2-Related Factor 2/metabolism , NF-kappa B/antagonists & inhibitors , NF-kappa B/metabolism , Nitric Oxide Synthase Type II/metabolism , Phytotherapy , Plant Extracts/pharmacology , Tumor Necrosis Factor-alpha/metabolism
17.
Article in English | MEDLINE | ID: mdl-23243449

ABSTRACT

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.

18.
Respir Res ; 12: 68, 2011 May 24.
Article in English | MEDLINE | ID: mdl-21609457

ABSTRACT

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.


Subject(s)
Alveolar Epithelial Cells/drug effects , Anti-Inflammatory Agents/pharmacology , Hyperoxia/drug therapy , Interleukin-10/pharmacology , Pulmonary Alveoli/drug effects , Alveolar Epithelial Cells/immunology , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/pathology , Animals , Apoptosis/drug effects , Biomarkers/metabolism , Cell Proliferation/drug effects , Cells, Cultured , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Gestational Age , Hyperoxia/genetics , Hyperoxia/immunology , Hyperoxia/metabolism , Hyperoxia/pathology , In Situ Nick-End Labeling , Interleukin-10/genetics , Interleukin-10/metabolism , Interleukin-8/genetics , Interleukin-8/metabolism , L-Lactate Dehydrogenase/metabolism , Necrosis , Pulmonary Alveoli/embryology , Pulmonary Alveoli/immunology , Pulmonary Alveoli/metabolism , Pulmonary Alveoli/pathology , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Recombinant Proteins/pharmacology , Reverse Transcriptase Polymerase Chain Reaction , Time Factors , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/metabolism
19.
Exp Mol Med ; 43(4): 223-9, 2011 Apr 30.
Article in English | MEDLINE | ID: mdl-21415591

ABSTRACT

Alveolar type II cells are main target of hyperoxia-induced lung injury. The authors investigated whether lysosomal protease, cathepsin B (CB), is activated in fetal alveolar type II cells in the transitional period from the canalicular to saccular stages during 65%-hyperoxia and whether CB is related to fetal alveolar type II cell (FATIIC) death secondary to hyperoxia. FATIICs were isolated from embryonic day 19 rats and exposed to 65%-oxygen for 24 h and 36 h. The cells exposed to room air were used as controls. Cell cytotoxicity was assessed by lactate dehydrogenase-release and flow cytometry, and apoptosis was analyzed by TUNEL assay and flow cytometry. CB activity was assessed by colorimetric assay, qRT-PCR and western blots. 65%-hyperoxia induced FATIIC death via necrosis and apoptosis. Interestingly, caspase-3 activities were not enhanced in FATIICs during 65%-hyperoxia, whereas CB activities were greatly increased during 65%-hyperoxia in a time-dependent manner, and similar findings were observed with qRT-PCR and western blots. In addition, the preincubation of CB inhibitor prior to 65%-hyperoxia reduced FATIIC death significantly. Our studies suggest that CB activation secondary to hyperoxia might have a relevant role in executing the cell death program in FATIICs during the acute stage of 65%-hyperoxia.


Subject(s)
Alveolar Epithelial Cells/metabolism , Cathepsin B/metabolism , Pulmonary Alveoli/enzymology , Alveolar Epithelial Cells/cytology , Animals , Caspase 3 , Cell Death , Cell Hypoxia , Enzyme Activation , Female , In Situ Nick-End Labeling , L-Lactate Dehydrogenase/analysis , Lung/metabolism , Necrosis/metabolism , Oxygen , Polymerase Chain Reaction , Pregnancy , Pulmonary Alveoli/cytology , Pulmonary Alveoli/embryology , Rats , Rats, Sprague-Dawley
20.
Atherosclerosis ; 213(1): 109-14, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20850747

ABSTRACT

OBJECTIVE: Psychological stress has been shown to contribute to the development of atherosclerosis; however its underlying mechanism has not been clearly elucidated. We here studied the mechanism by which immobilization stress causes endothelial dysfunction with specific aim of identifying the role of angiotensin II and its type I (AT(1)) receptor signaling pathway. METHODS AND RESULTS: Rats (n=30) were subjected to immobilization stress (120 min/day) for 14 days using a restrainer. During immobilized period, rats were orally administrated with or without the angiotensin converting enzyme (ACE) inhibitor ramipril (3 mg/kg/day, n=10) or AT(1) receptor inhibitor losartan (9 mg/kg/day, n=10). Immobilization significantly increased systolic blood pressure and decreased acetylcholine-induced ex vivo relaxation of arteries compared with those of control animals (n=10). Immobilization increased the plasma levels of angiotensin II and ACE activity that were inhibited by treatment with ramipril, but not losartan. Furthermore, immobilization increased the plasma level of malondialdehyde and expression of gp91(phox) and Rho-associated kinase-1 in arteries, and decreased the arterial eNOS mRNA and oxidized products of NO (nitrite plus nitrate). These functional and biochemical alterations induced by immobilization were significantly reversed by administration of ramipril or losartan. CONCLUSIONS: Immobilization stress induces vascular oxidative stress by activating the angiotensin II/AT(1) receptor signaling pathway, thereby provoking endothelial dysfunction which can contribute to the development of atherosclerosis and hypertension.


Subject(s)
Angiotensin II/metabolism , Atherosclerosis/metabolism , Immobilization , Oxidative Stress , Acetylcholine/metabolism , Angiotensin II Type 1 Receptor Blockers/pharmacology , Animals , Antihypertensive Agents/pharmacology , Arteries/metabolism , Losartan/pharmacology , Male , Nitric Oxide Synthase Type III/metabolism , Ramipril/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Angiotensin/metabolism
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