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1.
BMC Health Serv Res ; 19(1): 838, 2019 Nov 14.
Article in English | MEDLINE | ID: mdl-31727066

ABSTRACT

BACKGROUND: According to the World Health Organization, an estimated 80% or more deaths in Pacific island countries, including Fiji, were related to non-communicable diseases (NCDs). Although competency-based approaches have been effective for developing healthcare workers' capabilities, there are only a few reports on competency scales of healthcare workers for NCD prevention. We aimed to develop a self-reported measurement scale on a potential component of competency in the healthcare staff engaged in the prevention and control of NCDs in Fiji. METHODS: There were 378 Ministry of Health and Medical Services staff members working on NCD prevention and control in Fiji included in this study, which was a cross-sectional survey of social factors, working situation factors, and competency. Exploratory factor analysis was conducted to assess potential competency components, whereas Cronbach's α coefficient and analysis of variance were used to assess the validity and reliability of the scale items, respectively. Multivariate regression analyses were conducted to analyze the respondents' factor scores relative to social status and work situations. RESULTS: The factor analysis revealed 16 items that identified competency in four work types: 1) work management, 2) monitoring and evaluation, 3) community partnership, and 4) community diagnosis. The monitoring and evaluation roles were related to ethnic background, community partnership was related to religion, and community diagnosis was related to academic qualifications. CONCLUSIONS: Based on the results, we developed a competency scale for the four work types. This scale can help healthcare workers engage in better management of residents with NCDs in Fiji.


Subject(s)
Clinical Competence/standards , Noncommunicable Diseases/prevention & control , Public Health Practice/standards , Self Report , Adult , Factor Analysis, Statistical , Female , Fiji/epidemiology , Health Surveys , Humans , Male
2.
BMC Geriatr ; 18(1): 133, 2018 06 04.
Article in English | MEDLINE | ID: mdl-29898680

ABSTRACT

BACKGROUND: Many survivors of the Great East Japan Earthquake that occurred in 2011 were at risk of deteriorating health, especially elderly people living in disaster-stricken areas. The objectives of this prospective study were: a) to clarify the different lifestyle and psychosocial factors associated with frailty by sex among the non-disabled elderly survivors, and b) to describe the differences in characteristics stratified by the degree of disaster-related housing damage. METHODS: We followed 2261 Japanese survivors aged ≥65 years (45.3% male; mean age, 71.7 years) without disability or frailty who completed a self-administered questionnaire at baseline. All participants completed a baseline questionnaire in 2011 and at least one identical follow-up questionnaire between 2012 and 2015 regarding lifestyle (smoking status, alcohol intake, physical activity, sedentary lifestyle, and dietary intake) and psychosocial factors (self-rated health, standard of living, psychological distress, and social networks). Frailty was defined as a score of ≥5 on the Kihon Checklist, which is used by the Japanese government to certify the need for long-term care insurance. Adjusted odds ratios and 95% confidence intervals with frailty as the dichotomous dependent variable and health factors as the independent variables were calculated using a multilevel model for repeated measures by sex, followed by stratification analyses by the degree of housing damage. RESULTS: Over the 4-year study period, 510 participants (22.6%) developed frailty. In the post-disaster setting, many of the psychosocial factors remained more prevalent 4 years later among survivors with extensive housing damage. The presence of risk factors regarding the development of frailty differed by the degree of housing damage. Among men, psychological distress, in parallel with a poor social network, was related to frailty among only the participants with extensive housing damage and those living in temporary housing, whereas among women, worsening psychological distress was associated only with no damage and no displaced survivors. Among women with extensive damage and displacement, health outcomes such as overweight and diabetes and poor social networks were strongly related to frailty. CONCLUSIONS: Lifestyle and psychosocial factors associated with the risk of frailty differ by sex and the degree of housing damage.


Subject(s)
Disasters , Earthquakes , Frailty/epidemiology , Health Status , Housing/standards , Survivors , Aged , Aged, 80 and over , Disasters/economics , Earthquakes/economics , Exercise/physiology , Exercise/psychology , Female , Follow-Up Studies , Frailty/economics , Frailty/psychology , Housing/economics , Humans , Japan/epidemiology , Life Style , Longitudinal Studies , Male , Prospective Studies , Risk Factors , Surveys and Questionnaires , Survivors/psychology
4.
Infect Control Hosp Epidemiol ; 38(6): 651-657, 2017 06.
Article in English | MEDLINE | ID: mdl-28330512

ABSTRACT

OBJECTIVE Large-scale studies evaluating risk factors for Clostridium difficile infection (CDI), a leading cause of infectious diarrhea among patients undergoing stem cell transplantation (SCT), are lacking. We have evaluated risk factors for CDI among both autologous SCT (auto-SCT), and allogeneic SCT (allo-SCT) recipients using the National Inpatient Sample (NIS) database provided by the Healthcare Cost and Utilization Project (HCUP). METHODS We used patient data obtained from the NIS database for all adult patients admitted for auto- and allo-SCTs from January 2001 to December 2010. We performed multivariate logistic regression analyses to evaluate risk factors of CDI in auto- and allo-SCT patients. RESULTS Auto-SCTs constituted 61.5% of all SCTs performed during the study period. Of the 53,072 auto-SCT patients, 5.8% had CDI, whereas 8.5% of 33,189 allo-SCT patients had CDI. Univariate analyses identified age, gender, indication for SCT, radiation as part of the conditioning regimen, respiratory failure, septicemia, lengthy hospital stay, and multiple comorbidities as risk factors for CDI in both subsets. On multivariate analyses for auto-SCT, there was significant correlation between age and the indication for transplant (P=.003), but the indication for either auto- or allo-SCT was not associated with CDI on multivariate analyses. The following factors were found to be associated with CDI: septicemia (auto-SCT odds ratio [OR],=1.64; 95% confidence interval [CI], 1.35-2; and allo-SCT OR, 1.69; 95% CI, 1.36-2.1), male gender (auto-SCT OR, 1.29; 95% CI, 1.09-1.53; and allo-SCT OR, 1.36; 95% CI, 1.18-1.57), lengthy hospital stay (auto-SCT OR, 2.81; 95% CI, 2.29-3.45; and allo-SCT OR, 2.63; 95% CI, 2.15-3.22), and presence of multiple comorbidities (auto-SCT OR, 1.32; 95% CI, 1.11-1.57; and allo-SCT OR, 1.18; 95% CI, 1.0-1.4). CONCLUSIONS The prevalence of CDI was higher among patients undergoing allo-SCT. CDI was significantly associated with longer hospital stay, septicemia, and male gender for auto- and allo-SCT recipients. While this analysis did not permit us to directly ascribe the associations to be causative for CDI, it identifies the more vulnerable population for CDI and provides a rationale for the development of more effective approaches to preventing CDI. Infect Control Hosp Epidemiol 2017;38:651-657.


Subject(s)
Clostridioides difficile , Enterocolitis, Pseudomembranous/epidemiology , Stem Cell Transplantation/statistics & numerical data , Adolescent , Adult , Age Factors , Aged , Comorbidity , Databases, Factual , Female , Humans , Length of Stay/statistics & numerical data , Male , Middle Aged , Prevalence , Risk Factors , Sepsis/epidemiology , Sex Factors , Stem Cell Transplantation/adverse effects , Transplantation, Autologous/statistics & numerical data , Transplantation, Homologous/statistics & numerical data , United States/epidemiology , Young Adult
5.
Ann Transl Med ; 5(24): 482, 2017 Dec.
Article in English | MEDLINE | ID: mdl-29299444

ABSTRACT

BACKGROUND: Data on outcomes of ST-elevation myocardial infarction (STEMI) in patients with cancer are scarce. We investigated the nationwide trends in admissions for STEMI, utilization of percutaneous coronary intervention (PCI), and in-hospital outcomes in patients with the three most common cancer diagnoses (lung, breast, and colon) compared to patients without cancer. METHODS: We conducted an administrative database study using the Nationwide Inpatient Sample (NIS). All in-patient hospitalizations for STEMI from 2001 to 2011 were identified. Patients with concomitant diagnosis of lung, breast or colon cancer were identified using appropriate International classification of diagnosis (ICD 9-CM) codes. Primary outcome was utilization of PCI and in-hospital mortality in patients with cancer compared to those without cancer. RESULTS: Utilization of PCI was 30.8% (1,191/3,871), 20.2% (4,541/22,480) and 17.3% (1,716/9,944) in patients with breast, lung and colon cancer, respectively. Among patients without any of these cancers, use of PCI was 49.6%. In-hospital mortality was highest in patients with lung cancer (57.1%) and lowest in patients without cancer (25.7%). CONCLUSIONS: Patients with cancer have significantly worse in-hospital mortality compared to those without cancer, partly due to a relatively lower rate of PCI utilization in cancer patients with STEMI.

7.
Cardiol Res Pract ; 2016: 8956020, 2016.
Article in English | MEDLINE | ID: mdl-26966608

ABSTRACT

Atrial fibrillation (AF) is a common arrhythmia in adults associated with thromboembolic complications. External electrical cardioversion (DCCV) is a safe procedure used to convert AF to normal sinus rhythm. We sought to study factors that affect utilization of DCCV in hospitalized patients with AF. The study sample was drawn from the Nationwide Inpatient Sample (NIS) of the Healthcare Cost and Utilization Project in the United States. Patients with a primary discharge diagnosis of AF that received DCCV during hospitalization in the years 2000-2010 were included. An estimated 2,810,530 patients with a primary diagnosis of AF were hospitalized between 2001 and 2010, of which 1,19,840 (4.26%) received DCCV. The likelihood of receiving DCCV was higher in patients who were males, whites, privately insured, and aged < 40 years and those with fewer comorbid conditions. Higher CHADS2 score was found to have an inverse association with DCCV use. In-hospital stroke, in-hospital mortality, length of stay, and cost for hospitalization were significantly lower for patients undergoing DCCV during AF related hospitalization. Further research is required to study the contribution of other disease and patient related factors affecting the use of this procedure as well as postprocedure outcomes.

9.
J Cell Physiol ; 2015 May 07.
Article in English | MEDLINE | ID: mdl-25953328

ABSTRACT

The transcription of the ATP-binding cassette transporter A1 (ABCA1) gene, which plays a key anti-atherogenic role, is known to be induced by agonists of liver X receptors (LXRs). LXRs form obligate heterodimers with retinoid X receptors (RXRs) and interact with their recognition sequences in the regulatory regions of key genes implicated in the control of cholesterol, fatty acid and glucose homeostasis. We have previously shown a novel role for c-Jun N-terminal kinase (JNK) and phosphoinositide 3-kinase (PI3K) in the LXRs-mediated induction of macrophage gene expression. Protein kinase C (PKC) is often found to regulate the action of nuclear receptors and cross talk between this kinase family and JNK and/or PI3K has been shown in several settings. We have therefore investigated a potential role for PKC in the action of LXR/RXR agonist 22-(R)-hydroxycholesterol (22-(R)-HC)/9-cis-retinoic acid (9cRA) in THP-1 macrophages, including the induction of ABCA1 expression. The pan PKC inhibitor bisindoylmaleimide was found to attenuate the induction of ABCA1 protein expression, the activation of the JNK signaling pathway and the stimulation of activator protein-1 (AP-1) DNA binding activity in macrophages treated with 22-(R)-HC and 9cRA. The role of PKC in the action of these ligands was confirmed further by the use of more isotype-specific inhibitors. These studies therefore reveal a potentially important role for PKC in the action of 22-(R)-HC and 9cRA in human macrophages. This article is protected by copyright. All rights reserved.

10.
J Cell Biochem ; 116(9): 2032-8, 2015 Sep.
Article in English | MEDLINE | ID: mdl-25752819

ABSTRACT

The transcription of the ATP-binding cassette transporter A1 (ABCA1) gene, which plays a key anti-atherogenic role, is known to be induced by agonists of liver X receptors (LXRs). LXRs form obligate heterodimers with retinoid X receptors (RXRs) and interact with their recognition sequences in the regulatory regions of key genes implicated in the control of cholesterol, fatty acid and glucose homeostasis. We have previously shown a novel role for c-Jun N-terminal kinase (JNK) and phosphoinositide 3-kinase (PI3K) in the LXRs-mediated induction of macrophage gene expression. Protein kinase C (PKC) is often found to regulate the action of nuclear receptors and cross talk between this kinase family and JNK and/or PI3K has been shown in several settings. We have, therefore, investigated a potential role for PKC in the action of LXR/RXR agonist 22-(R)-hydroxycholesterol (22-(R)-HC)/9-cis-retinoic acid (9cRA) in THP-1 macrophages, including the induction of ABCA1 expression. The pan PKC inhibitor bisindoylmaleimide was found to attenuate the induction of ABCA1 protein expression, the activation of the JNK signaling pathway and the stimulation of activator protein-1 (AP-1) DNA binding activity in macrophages treated with 22-(R)-HC and 9cRA. The role of PKC in the action of these ligands was confirmed further by the use of more isotype-specific inhibitors. These studies, therefore, reveal a potentially important role for PKC in the action of 22-(R)-HC and 9cRA in human macrophages.


Subject(s)
ATP Binding Cassette Transporter 1/metabolism , Hydroxycholesterols/pharmacology , Macrophages/drug effects , Protein Kinase C/metabolism , Tretinoin/pharmacology , ATP Binding Cassette Transporter 1/antagonists & inhibitors , Alitretinoin , Cell Line , Gene Expression Regulation/drug effects , Humans , Indoles/pharmacology , Liver X Receptors , MAP Kinase Signaling System/drug effects , Macrophages/cytology , Maleimides/pharmacology , Orphan Nuclear Receptors/agonists , Orphan Nuclear Receptors/metabolism , Retinoid X Receptors/agonists , Retinoid X Receptors/metabolism
11.
Eur J Clin Nutr ; 69(4): 482-8, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25585600

ABSTRACT

BACKGROUND/OBJECTIVES: There have been few studies on the association of fruit and vegetable (FV) intake with cardiovascular disease (CVD) risk in Asian populations where both dietary habits and disease structure are different from western countries. No study in Asia has found its significant association with stroke. We examined associations of FV intake with mortality risk from total CVD, stroke and coronary heart diseases (CHDs) in a representative Japanese sample. METHODS: A total of 9112 participants aged from 24-year follow-up data in the NIPPON DATA80, of which baseline data were obtained in the National Nutrition Survey Japan in 1980, were studied. Dietary data were obtained from 3-day weighing dietary records. Participants were divided into sex-specific quartiles of energy adjusted intake of FV. Multivariate-adjusted hazard ratios (HRs) were calculated between strata of the total of FV intake, fruit intake and vegetable intake. The adjustment included age, sex, smoking, drinking habit and energy adjusted intakes of sodium and some other food groups. RESULTS: Participants with higher FV intake were older, ate more fish, milk and dairy products and soybeans and legumes and ate less meat. Multivariate-adjusted HR (95% confidence interval; P; P for trend) for the highest versus the lowest quartile of the total of FV intake was 0.74 (0.61-0.91; 0.004; 0.003) for total CVD, 0.80 (0.59-1.09; 0.105; 0.036) for stroke and 0.57 (0.37-0.87; 0.010; 0.109) for CHD. CONCLUSIONS: The results showed that higher total intake of FVs was significantly associated with reduced risk of CVD mortality in Japan.


Subject(s)
Cardiovascular Diseases/mortality , Fruit , Vegetables , Adult , Aged , Asian People , Body Mass Index , Diet , Diet Records , Diet Surveys , Endpoint Determination , Female , Follow-Up Studies , Humans , Japan/epidemiology , Male , Middle Aged , Multivariate Analysis , Nutrition Surveys , Proportional Hazards Models , Prospective Studies , Risk Factors , Stroke/mortality
12.
Biol Blood Marrow Transplant ; 20(6): 852-857, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24607557

ABSTRACT

Trials have shown benefits of palifermin in reducing the incidence and severity of oral mucositis in patients with hematological malignancies undergoing autologous hematopoietic stem cell transplantation (HSCT) with total body irradiation (TBI)-based conditioning regimens. Similar outcome data are lacking for patients receiving non-TBI-based regimens. We performed a retrospective evaluation on the pharmacoeconomic benefit of palifermin in the setting of non-TBI-based conditioning and autologous HSCT. Between January 2002 and December 2010, 524 patients undergoing autologous HSCT for myeloma (melphalan 200 mg/m²) and lymphoma (high-dose busulfan, cyclophosphamide, and etoposide) as preparative regimen were analyzed. Use of patient-controlled analgesia (PCA) was significantly lower in the palifermin-treated groups (myeloma: 13% versus 53%, P < .001; lymphoma: 46% versus 68%, P < .001). Median total transplant charges were significantly higher in the palifermin-treated group, after controlling for inflation (myeloma: $167,820 versus $143,200, P < .001; lymphoma: $168,570 versus $148,590, P < .001). Palifermin treatment was not associated with a difference in days to neutrophil engraftment, length of stay, and overall survival and was associated with an additional cost of $5.5K (myeloma) and $14K (lymphoma) per day of PCA avoided. Future studies are suggested to evaluate the cost-effectiveness of palifermin compared with other symptomatic treatments to reduce transplant toxicity using validated measures for pain and quality of life.


Subject(s)
Fibroblast Growth Factor 7/economics , Fibroblast Growth Factor 7/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Mucositis/prevention & control , Adolescent , Adult , Aged , Economics, Pharmaceutical , Female , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Lymphoma/therapy , Male , Middle Aged , Mucositis/economics , Mucositis/etiology , Multiple Myeloma/therapy , Retrospective Studies , Transplantation Conditioning/adverse effects , Transplantation Conditioning/methods , Transplantation, Autologous , Young Adult
13.
Neuroscience ; 260: 149-57, 2014 Feb 28.
Article in English | MEDLINE | ID: mdl-24361738

ABSTRACT

High fructose intake is associated with increased plasma triglyceride concentration, hepatic steatosis, impaired glucose tolerance, insulin resistance, and high blood pressure. In addition, increased fructose intake has recently been supposed to be a risk factor for dementia. However, direct effects of fructose on the brain function remain to be clarified. The localization of glucose transporter 5 (Glut5), a representative transporter of fructose, was immunohistochemically examined in the brains of humans, rats, and mice to clarify whether fructose was transported from the blood into the brain. Glut5 immunoreactivity was demonstrated to be located in the epithelial cells of the choroid plexus and the ependymal cells in the brains of humans and rats using commercial antibodies for Glut5. In addition, mRNA expression of mouse Glut5 was confirmed in the brains of mice. Immunohistochemical examination using a custom-made antibody against two regions of amino acid sequences of mouse Glut5 revealed that Glut5 immunoreactivity was also seen in the epithelial cells of the choroid plexus and the ependymal cells in the brains of mice. These findings show that Glut5 immunoreactivity is located in the epithelial cells of the choroid plexus and the ependymal cells, suggesting the possibility of the direct transportation of intravascular fructose into the brain parenchyma.


Subject(s)
Choroid Plexus/chemistry , Epithelial Cells/chemistry , Glucose Transporter Type 5/analysis , Adult , Aged , Animals , Choroid Plexus/metabolism , Epithelial Cells/metabolism , Female , Glucose Transporter Type 5/genetics , Glucose Transporter Type 5/immunology , Glucose Transporter Type 5/metabolism , Humans , Immunohistochemistry , Male , Mice , Mice, Inbred C3H , Middle Aged , RNA, Messenger/metabolism , Rats , Rats, Inbred WKY
14.
Placenta ; 33(10): 885-7, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22877695

ABSTRACT

Galectin 4 (Gal4) is abundantly expressed in the epithelium of the gastrointestinal tract, and functional analysis has concentrated on its roles associated with polarized membrane trafficking. This study aimed to investigate the expression of Gal4 in placentation. The expression level of Gal4 was revealed to be lower in differentiated Rcho-1 cells (a model system of rat trophoblast differentiation) than in proliferative cells. In the rat placenta, immunohistochemical analysis showed that Gal4 is preferentially located in the maternal-fetal junctional zone. These results suggest that down-regulation of Gal4 may be involved in the promotion of trophoblast cell differentiation.


Subject(s)
Galectin 4/biosynthesis , Placentation/physiology , Animals , Cell Differentiation/physiology , Down-Regulation , Female , Placenta/metabolism , Pregnancy , Rats
15.
Neuropathol Appl Neurobiol ; 37(7): 727-37, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21418266

ABSTRACT

AIMS: The class B scavenger receptor CD36, the receptor for oxidized low-density lipoprotein, mediates free radical production and brain injury in cerebral ischaemia. Free radical production is known to be involved in the remodelling of the cerebral vasculature of stroke-prone spontaneously hypertensive rats (SHRSP). Accordingly, we examined whether the expression of CD36 is increased in the vasculature with blood-brain barrier (BBB) impairment and collagen deposition of SHRSP. METHODS: The gene and protein expression of CD36 was examined in the vessels of the hippocampus of SHRSP with BBB impairment and those of Wistar Kyoto rats without the impairment, by real-time RT-PCR, Western blotting and immunohistochemical techniques. RESULTS: The gene and protein expression of CD36 was increased in the hippocampus of SHRSP compared with that of Wistar Kyoto rats. Confocal microscopic examination revealed CD36 immunoreactivity in perivascular microglial cells immunopositive for ED1. Immunoelectron microscopic examination revealed that the immunosignals for CD36 were located mainly in the cytoplasm of perivascular cells in vessels showing increased vascular permeability and a few in the cytoplasmic membranes of endothelial cells. CONCLUSIONS: These findings indicate that the expression of CD36 was increased in vessels with BBB impairment in the hippocampus of SHRSP and was mainly seen in the cytoplasm of perivascular microglial cells, suggesting a role of CD36 in cerebrovascular injury.


Subject(s)
Blood-Brain Barrier/metabolism , CD36 Antigens/metabolism , Endothelium, Vascular/metabolism , Hippocampus/blood supply , Hypertension/metabolism , Stroke/metabolism , Animals , Blood-Brain Barrier/physiopathology , Endothelial Cells/metabolism , Endothelium, Vascular/physiopathology , Hippocampus/metabolism , Hippocampus/physiopathology , Hypertension/physiopathology , Male , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Stroke/physiopathology
16.
Int J Biochem Cell Biol ; 43(5): 805-11, 2011 May.
Article in English | MEDLINE | ID: mdl-21334453

ABSTRACT

Atherosclerosis is an inflammatory disorder of the vasculature that is orchestrated by the action of cytokines. Macrophages play a prominent role in all stages of this disease, including foam cell formation, production of reactive oxygen species, modulation of the inflammatory response and the regulation of the stability of atherosclerotic plaques. The role of the matrix metalloproteinase family in the control of plaque stability is well established. A disintegrin and metalloproteinase with thrombospondin motif (ADAMTS) family has been implicated in several diseases and the expression of ADAMTS-4 in macrophages of atherosclerotic lesions has suggested a potential role for this protease in atherosclerosis. However, the action of cytokines on the expression of ADAMTS-4 in macrophages is poorly understood. We have investigated here the effect of transforming growth factor-ß (TGF-ß) on ADAMTS-4 expression in macrophages along with the regulatory mechanisms underlying its actions. Consistent with the anti-atherogenic role of TGF-ß, this cytokine decreased the expression of ADAMTS-4 mRNA and protein in human macrophages. Transient transfection assays showed that the -100 to +10 promoter region contained the minimal TGF-ß response elements. Small-interfering RNA-mediated knockdown revealed a critical role for Smads, p38 mitogen-activated protein kinase and c-Jun in the action of TGF-ß on ADAMTS-4 mRNA expression. These studies show for the first time that TGF-ß inhibits the expression of ADAMTS-4 in human macrophages and identifies the signalling pathways underlying this response. The inhibition of macrophage ADAMTS-4 expression is likely to contribute to the anti-atherogenic, plaque stabilisation action of TGF-ß.


Subject(s)
ADAM Proteins/metabolism , Gene Expression Regulation, Enzymologic/drug effects , JNK Mitogen-Activated Protein Kinases/metabolism , Macrophages/drug effects , Procollagen N-Endopeptidase/metabolism , Smad Proteins/metabolism , Transforming Growth Factor beta1/pharmacology , p38 Mitogen-Activated Protein Kinases/metabolism , ADAM Proteins/genetics , ADAMTS4 Protein , Atherosclerosis/drug therapy , Atherosclerosis/metabolism , Cell Line, Tumor , Down-Regulation/drug effects , Humans , Macrophages/metabolism , Procollagen N-Endopeptidase/genetics , Promoter Regions, Genetic/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Transforming Growth Factor beta1/therapeutic use
17.
Cell Signal ; 23(3): 542-9, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21070853

ABSTRACT

Liver X receptors (LXRs) are ligand-dependent transcription factors that are activated by metabolites of cholesterol, oxysterols, and a number of synthetic agonists. LXRs play potent anti-atherogenic roles in part by stimulating the efflux of cholesterol from macrophage foam cells. The LXR-induced expression of ATP-binding cassette transporter (ABC)-A1 and Apolipoprotein E (ApoE) in macrophages is essential for the stimulation of cholesterol efflux and the prevention of atherosclerotic development. Unfortunately, the signaling pathways underlying such regulation are poorly understood and were therefore investigated in human macrophages. The expression of ApoE and ABCA1 induced by synthetic or natural LXR ligands [TO901317, GW3965, and 22-(R)-hydroxycholesterol (22-(R)-HC), respectively] was attenuated by inhibitors of c-Jun N-terminal kinase (JNK) (curcumin and SP600125) and phosphoinositide 3-kinase (PI3K) (LY294002). Similar results were obtained with ABCG1 and LXR-α, two other LXR target genes. LXR agonists activated several components of the JNK pathway (SEK1, JNK and c-Jun) along with AKT, a downstream target for PI3K. In addition, dominant negative mutants of JNK and PI3K pathways inhibited the LXR-agonists-induced activity of the ABCA1 and LXR-α gene promoters in transfected cells. LXR agonists also induced the binding of activator protein-1 (AP-1), a key transcription factor family regulated by JNK, to recognition sequences present in the regulatory regions of the ApoE and ABCA1 genes. These studies reveal a novel role for JNK and PI3K/AKT signaling in the LXR-regulated expression in macrophages of several key genes implicated in atherosclerosis.


Subject(s)
JNK Mitogen-Activated Protein Kinases/physiology , Macrophages/enzymology , Orphan Nuclear Receptors/metabolism , Phosphatidylinositol 3-Kinases/physiology , ATP Binding Cassette Transporter 1 , ATP-Binding Cassette Transporters/biosynthesis , ATP-Binding Cassette Transporters/genetics , Cells, Cultured , Cholesterol/metabolism , Humans , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Liver X Receptors , Macrophages/drug effects , Orphan Nuclear Receptors/agonists , Orphan Nuclear Receptors/genetics , Phosphoinositide-3 Kinase Inhibitors , Signal Transduction , Transcription Factor AP-1/metabolism , Transcriptional Activation
18.
J Immunol ; 184(10): 5827-34, 2010 May 15.
Article in English | MEDLINE | ID: mdl-20410491

ABSTRACT

TNF-like protein 1A (TL1A), a TNF superfamily cytokine that binds to death receptor 3 (DR3), is highly expressed in macrophage foam cell-rich regions of atherosclerotic plaques, although its role in foam cell formation has yet to be elucidated. We investigated whether TL1A can directly stimulate macrophage foam cell formation in both THP-1 and primary human monocyte-derived macrophages with the underlying mechanisms involved. We demonstrated that TL1A promotes foam cell formation in human macrophages in vitro by increasing both acetylated and oxidized low-density lipoprotein uptake, by enhancing intracellular total and esterified cholesterol levels and reducing cholesterol efflux. This imbalance in cholesterol homeostasis is orchestrated by TL1A-mediated changes in the mRNA and protein expression of several genes implicated in the uptake and efflux of cholesterol, such as scavenger receptor A and ATP-binding cassette transporter A1. Furthermore, through the use of virally delivered DR3 short-hairpin RNA and bone marrow-derived macrophages from DR3 knockout mice, we demonstrate that DR3 can regulate foam cell formation and contributes significantly to the action of TL1A in this process in vitro. We show, for the first time, a novel proatherogenic role for both TL1A and DR3 that implicates this pathway as a target for the therapeutic intervention of atherosclerosis.


Subject(s)
Cell Differentiation/immunology , Foam Cells/cytology , Foam Cells/immunology , Receptors, Tumor Necrosis Factor, Member 25/physiology , Signal Transduction/immunology , Tumor Necrosis Factor Ligand Superfamily Member 15/physiology , Animals , Atherosclerosis/immunology , Atherosclerosis/pathology , Biological Transport/immunology , Cell Line, Tumor , Cells, Cultured , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Cholesterol Ester Transfer Proteins/metabolism , Female , Foam Cells/pathology , Humans , Intracellular Fluid/immunology , Intracellular Fluid/metabolism , Lipoproteins, LDL/metabolism , Mice , Mice, Knockout , Receptors, Tumor Necrosis Factor, Member 25/deficiency , Up-Regulation/immunology
19.
Int J Biochem Cell Biol ; 42(1): 113-9, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19800021

ABSTRACT

Elevated circulating levels of acute phase proteins (APP) are associated with inflammation and inflammatory disorders such as cardiovascular disease. APP are mainly synthesised by hepatocytes and their transcription is induced by pro-inflammatory cytokines such as interleukin-1 (IL-1). The molecular mechanisms underlying the IL-1-induced expression of key transcription factors implicated in the regulation of APP are poorly understood. We have investigated this aspect using the CCAAT/enhancer binding protein-delta (C/EBPdelta) as a model gene. IL-1 induced the expression of C/EBPdelta mRNA and protein in the human hepatoma Hep3B cell line, a widely employed model system for studies on cytokine signalling in relation to the expression of APP. The IL-1-mediated induction of C/EBPdelta expression was attenuated in the presence of pharmacological inhibitors against c-Jun N-terminal kinase (JNK) (curcumin and SP600125), casein kinase 2 (CK2) (apigenin) and nuclear factor-kappaB (NF-kappaB) (NF-kappaB activation inhibitor). RNA interference assays showed significant attenuation of the IL-1-induced expression of C/EBPdelta following knockdown of the p50 and p65 subunits of NF-kappaB. IL-1 induced NF-kappaB DNA binding and activation by this transcription factor and this was attenuated by curcumin and apigenin. Taken together, these results suggest a potentially crucial role for NF-kappaB in the IL-1-induced expression of C/EBPdelta, and thereby downstream APP genes regulated by this transcription factor.


Subject(s)
CCAAT-Enhancer-Binding Protein-delta/genetics , Gene Expression Regulation, Neoplastic/drug effects , Hepatocytes/drug effects , Hepatocytes/metabolism , Interleukin-1beta/pharmacology , NF-kappa B/metabolism , Signal Transduction/drug effects , Apigenin/pharmacology , Binding Sites , CCAAT-Enhancer-Binding Protein-delta/metabolism , Casein Kinase II/antagonists & inhibitors , Cell Line, Tumor , Curcumin/pharmacology , DNA/metabolism , Enzyme Activation/drug effects , Gene Knockdown Techniques , Humans , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , NF-kappa B/antagonists & inhibitors , Protein Binding/drug effects , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Small Interfering/metabolism , Time Factors , Transcriptional Activation/drug effects , Transcriptional Activation/genetics
20.
Int J Biochem Cell Biol ; 41(5): 1189-97, 2009 May.
Article in English | MEDLINE | ID: mdl-19027873

ABSTRACT

Tumour necrosis factor-alpha (TNF-alpha) is a key regulator of the immune and inflammatory responses along with numerous other cellular changes during physiological and pathophysiological conditions. The cellular actions of TNF-alpha are associated with both the activation and the inhibition of gene transcription. In contrast to gene activation, the mechanisms underlying the TNF-alpha-mediated transcriptional inhibition remain largely unclear. We have investigated this aspect using the transcription factor CCAAT/enhancer binding protein-alpha (C/EBPalpha) as a model gene. TNF-alpha decreased the expression of C/EBPalpha mRNA and protein in the human hepatoma Hep3B cell line. The activity of the proximal promoter of both the human and the Xenopus C/EBPalpha genes in transfected Hep3B cells was inhibited by TNF-alpha. Transient transfection assays using various Xenopus C/EBPalpha promoter-luciferase DNA constructs showed that a C/EBP recognition sequence was essential for the TNF-alpha response. Electrophoretic mobility shift assays showed that C/EBPalpha bound to this site and co-transfection assays revealed that it was a major activator of the promoter and its transactivation potential was reduced by TNF-alpha. The potential role of nuclear factor kappaB (NF-kappaB) in the response was also investigated in the light of its pivotal role in TNF-alpha signalling. Inhibition of NF-kappaB using pharmacological agents or by transfection of a plasmid specifying for a superrepressor attenuated the TNF-alpha-inhibited C/EBPalpha promoter activity. In addition, an involvement of NF-kappaB in DNA-protein interactions at the C/EBP recognition sequence was identified.


Subject(s)
CCAAT-Enhancer-Binding Protein-alpha/genetics , Hepatocytes/physiology , NF-kappa B/physiology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Animals , CCAAT-Enhancer-Binding Protein-alpha/antagonists & inhibitors , CCAAT-Enhancer-Binding Protein-alpha/metabolism , Cell Line, Tumor , Electrophoretic Mobility Shift Assay , Hepatocytes/metabolism , Humans , NF-kappa B/genetics , NF-kappa B/metabolism , NF-kappa B/pharmacology , Promoter Regions, Genetic , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Transfection , Tumor Necrosis Factor-alpha/physiology , Up-Regulation , Xenopus laevis
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