Publications (61)283.64 Total impact
- [Show abstract] [Hide abstract] ABSTRACT: The skin of patients with atopic dermatitis (AD) has a unique predisposition for colonization by Staphylococcus aureus (S. aureus), which contributes to the inflammation and grim prognosis of AD. Although the mechanism underlying the S. aureus-induced exacerbation of AD remains unclear, recent studies have found a pivotal role for pattern recognition receptors in regulating the inflammatory responses in S. aureus infection. In the present study, we used a typical mouse model of AD-like skin inflammation and found that S. aureus-associated nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and toll-like receptor 2 (TLR2) ligands exacerbated AD-like symptoms, which were further deteriorated by the in vivo expansion of basophils and eosinophils. Subsequent histological analyses revealed that dermal fibroblasts were pervasive in the AD-like skin lesions. Co-culture of human dermal fibroblasts with basophils and eosinophils resulted in a vigorous cytokine/chemokine response to the NOD2/TLR2 ligands and the enhanced expression of intercellular adhesion molecule-1 on the dermal fibroblasts. Basophils and eosinophils were primarily responsible for the AD-related cytokine/chemokine expression in the co-cultures. Direct intercellular contact was necessary for the crosstalk between basophils and dermal fibroblasts, while soluble mediators were sufficient to mediate the eosinophil–fibroblast interactions. Moreover, the intracellular p38 mitogen-activated protein kinase, extracellular signal-regulated kinase, and nuclear factor-kappa B signaling pathways were essential for NOD2/TLR2 ligand-mediated activation of basophils, eosinophils, and dermal fibroblasts in AD-related inflammation. This study provides the evidence of NOD2/TLR2-mediated exacerbation of AD through activation of innate immune cells and therefore sheds light on a novel mechanistic pathway by which S. aureus contributes to the pathophysiology of AD.
- [Show abstract] [Hide abstract] ABSTRACT: Background: We have investigated the potential anticancer effects of karanjin, a principal furanoflavonol constituent of the Chinese medicine Fordia cauliflora, using cytotoxic assay, cell cycle arrest, and induction of apoptosis in three human cancer cell lines (A549, HepG2 and HL-60 cells). Results: MTT cytotoxic assay showed that karanjin could inhibit the proliferation and viability of all three cancer cells. The induction of cell cycle arrest was observed via a PI (propidium iodide)/RNase Staining Buffer detection kit and analyzed by flow cytometry: karanjin could dose-dependently induce cell cycle arrest at G2/M phase in the three cell lines. Cell apoptosis was assessed by Annexin V-FITC/PI staining: all three cancer cells treated with karanjin exhibited significantly increased apoptotic rates, especially in the percentage of late apoptosis cells. Conclusion: Karanjin can induce cancer cell death through cell cycle arrest and enhance apoptosis. This compound may be effective clinically for cancer pharmacotherapy.
- [Show abstract] [Hide abstract] ABSTRACT: Purpose - This study investigated influences of concentration and combination of excipients, commonly used in self-emulsifying drug delivery systems (SEDDS), on inhibition of human efflux transporter ABCC2 (MRP2). Ten commonly used excipients of SEDDS with inhibitory effect on MRP2 including Cremophor® EL, Cremophor® RH, Pluronic® F127, Maisine® 35-1, β-cyclodextrin, Labrasol®, Pluronic® F68, PEG 2000, PEG 400 and Transcutol® were studied with the Caco-2 cell model. Six excipients with inhibitory effect including Cremophor® EL, Cremophor® RH, Pluronic® F127, PEG 2000, PEG 400 and Transcutol® were further analyzed using the MRP2 vesicle assay and ATPase activity assay. Ultra-performance liquid-chromatography tandem mass spectrometry was used to measure scutellarin as the MRP2 substrate. In studying concentration-dependent effects, five excipients including Cremophor® EL, Cremophor® RH, Pluronic® F127, Maisine® 35-1 and β-cyclodextrin showed concentration-dependent decrease in efflux ratio of scutellarin. The other five excipients did not show such phenomenon, and their inhibitory effects were restricted to be above to certain critical or minimum concentrations. In studying combined effects, PEG 2000 and Pluronic® F127 both showed combined effect with Cremophor® EL on inhibiting MRP2. However, some combinations of excipients such as PEG 400 and Transcutol® with Cremophor® EL increased the scutellarin efflux ratio and decreased the transport of scutellarin and ATPase activity, compared to Cremophor® EL alone. The above results suggest that appropriate choice of excipients according to their concentration-dependent and combined effects on MRP2 inhibition can facilitate formulation of SEDDS for improving the bioavailability of drugs that are MRP2 substrates. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
- [Show abstract] [Hide abstract] ABSTRACT: Objective: This study aims to evaluate the relationship between tissue advanced glycation end products, as reflected by skin autofluorescence, and vascular calcification in chronic kidney disease. Approach and results: Three hundred patients with stage 3 to 5 chronic kidney disease underwent multislice computed tomography to estimate total coronary artery calcium score (CACS) and had tissue advanced glycation end product assessed using a skin autofluorescence reader. Intact parathyroid hormone (P<0.001) displaced estimated glomerular filtration rate as third most significant factor associated with skin autofluorescence after age (P<0.001) and diabetes mellitus (P<0.001) in multiple regression analysis. On univariate multinomial logistic regression analysis, every 1-U increase in skin autofluorescence was associated with a 7.43-fold (95% confidence intervals, 3.59-15.37; P<0.001) increased odds of having CACS ≥400 compared with those with zero CACS. Skin autofluorescence retained significance in predicting CACS ≥400 (odds ratio, 3.63; 95% confidence intervals, 1.44-9.18; P=0.006) when adjusting for age, sex, serum calcium, phosphate, albumin, C-reactive protein, lipids, blood pressure, estimated glomerular filtration rate, and intact parathyroid hormone but marginally lost significance when additionally adjusting for diabetes mellitus (odds ratio, 2.23; 95% confidence intervals, 0.81-6.14; P=0.1). Combination of diabetes mellitus and higher intact parathyroid hormone was associated with greater skin autofluorescence and CACS versus those without diabetes mellitus and having lower intact parathyroid hormone. Conclusions: Tissue advanced glycation end product, as reflected by skin autofluorescence, showed a significant novel association with vascular calcification in chronic kidney disease. These data suggest that increased tissue advanced glycation end product may contribute to vascular calcification in chronic kidney disease and diabetes mellitus and warrant further experimental investigation.
- [Show abstract] [Hide abstract] ABSTRACT: Allergic asthma can cause airway structural remodeling, involving the accumulation of extracellular matrix and thickening of smooth muscle. Tumor necrosis factor (TNF) family ligand LIGHT (TNFSF14) is a cytokine that binds herpesvirus entry mediator (HVEM)/TNFRSF14 and lymphotoxin β receptor (LT β R). LIGHT induces asthmatic cytokine IL-13 and fibrogenic cytokine transforming growth factor- β release from allergic asthma-related eosinophils expressing HVEM and alveolar macrophages expressing LT β R, respectively, thereby playing crucial roles in asthmatic airway remodeling. In this study, we investigated the effects of LIGHT on the coculture of human basophils/eosinophils and bronchial epithelial BEAS-2B cells. The expression of adhesion molecules, cytokines/chemokines, and matrix metalloproteinases (MMP) was measured by flow cytometry, multiplex, assay or ELISA. Results showed that LIGHT could significantly promote intercellular adhesion, cell surface expression of intercellular adhesion molecule-1, release of airway remodeling-related IL-6, CXCL8, and MMP-9 from BEAS-2B cells upon interaction with basophils/eosinophils, probably via the intercellular interaction, cell surface receptors HVEM and LT β R on BEAS-2B cells, and extracellular signal-regulated kinase, p38 mitogen activated protein kinase, and NF- κ B signaling pathways. The above results, therefore, enhance our understanding of the immunopathological roles of LIGHT in allergic asthma and shed light on the potential therapeutic targets for airway remodeling.
- [Show abstract] [Hide abstract] ABSTRACT: IL-32 is a proinflammatory cytokine associated with infections, autoimmune diseases, and allergic asthma. In the present study, we elucidated the synergistic effect of IL-32γ and NOD ligand on the activation of human eosinophils, principal effector cells for allergic inflammation, and the underlying mechanisms. Specific IL-32-binding protein, PR3, was found to localize on the cell surface and in the cytoplasm of eosinophils. IL-32γ was more capable of activating eosinophils than its isotype variant IL-32α and exhibited synergistic effect with NOD1 ligand iE-DAP and NOD2 ligand MDP on the induction of allergic inflammation-related IL-1β, TNF-α, and chemokines CXCL8, CCL3, and CCL4 (P<0.05). Moreover, IL-32γ and iE-DAP or MDP induced the significant up-regulation of the cell-surface expression of adhesion molecule CD18 and ICAM-1 on eosinophils. Synergism between IL-32γ and NOD ligands was dependent on the activation of intracellular caspase 1, ERKs, p38 MAPK, and NF-κB pathways in eosinophils. The further-enhanced CD18 and ICAM-1 expression and production of cytokines and chemokines were observed in eosinophils cocultured with human bronchial epithelial BEAS-2B cells. Furthermore, combined treatment of IL-32γ and NOD ligand could activate the release of eosinophil extracellular DNA traps, thereby implying the pathogen-defense mechanisms of eosinophils. Together, the above study provides pivotal immunological mechanisms by which bacterial infection-mediated activation of NOD1,2, together with IL-32γ, can synergize the activation of eosinophils interacting with bronchial epithelial cells.
- [Show abstract] [Hide abstract] ABSTRACT: Vitamin D seems to protect against cardiovascular disease, but the reported effects of vitamin D on patient outcomes in CKD are controversial. We conducted a prospective, double blind, randomized, placebo-controlled trial to determine whether oral activated vitamin D reduces left ventricular (LV) mass in patients with stages 3-5 CKD with LV hypertrophy. Subjects with echocardiographic criteria of LV hypertrophy were randomly assigned to receive either oral paricalcitol (1 μg) one time daily (n=30) or matching placebo (n=30) for 52 weeks. The primary end point was change in LV mass index over 52 weeks, which was measured by cardiac magnetic resonance imaging. Secondary end points included changes in LV volume, echocardiographic measures of systolic and diastolic function, biochemical parameters of mineral bone disease, and measures of renal function. Change in LV mass index did not differ significantly between groups (median [interquartile range], -2.59 [-6.13 to 0.32] g/m(2) with paricalcitol versus -4.85 [-9.89 to 1.10] g/m(2) with placebo). Changes in LV volume, ejection fraction, tissue Doppler-derived measures of early diastolic and systolic mitral annular velocities, and ratio of early mitral inflow velocity to early diastolic mitral annular velocity did not differ between the groups. However, paricalcitol treatment significantly reduced intact parathyroid hormone (P<0.001) and alkaline phosphatase (P=0.001) levels as well as the number of cardiovascular-related hospitalizations compared with placebo. In conclusion, 52 weeks of treatment with oral paricalcitol (1 μg one time daily) significantly improved secondary hyperparathyroidism but did not alter measures of LV structure and function in patients with severe CKD.
- [Show abstract] [Hide abstract] ABSTRACT: Since Macao's return of sovereignty to China in December 1999, the life style of Macao residents has changed. The aim of this study was to investigate changes of death patterns in Macao residents from 1986 to 2006 in order to identify the trends and patterns of major public health problems, which could provide the guidance for developing public health policies. A retrospective study was conducted for this investigation. Research data were collected from official websites and statistical yearbooks and classified by the International Classification of Diseases (ICD)-9. It was observed that mortality from the three major causes of (1) infectious, maternal and childhood diseases, (2) chronic non-communicable diseases, and (3) injury and poisoning were 17.7, 298.2 and 26.0 per 100 000, respectively. The largest decrease in death rate over the 21-year study-period was from infectious, maternal and childhood diseases (62.5%). The highest mortality rate was ischemic heart diseases (37.0%). The largest increase in mortality rate was lung cancer (46.9%). Mortality rate of Macao residents progressively decreased, but the constituent ratio of death from chronic non-communicable diseases was increasing. The mortality rate of lung cancer was clearly ascending, so emphasis should be put on tertiary prevention in future.
- [Show abstract] [Hide abstract] ABSTRACT: Key intracytosolic pattern recognition receptors of innate immunity against bacterial infections are nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs). We elucidated the NOD1 and NOD2-mediated activation of human eosinophils, the principal effector cells for allergic inflammation, upon interacting with human bronchial epithelial BEAS-2B cells in allergic asthma. Eosinophils constitutively expressed NOD1,2 but exhibited nonsignificant responses to release chemokines upon the stimulation by NOD1 ligand γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP) and NOD2 ligand muramyl dipeptide (MDP). However, iE-DAP and MDP could significantly upregulate cell surface expression of CD18 and intercellular adhesion molecule (ICAM)-1 on eosinophils and ICAM-1 on BEAS-2B cells, as well as induce chemokines CCL2 and CXCL8 release in the coculture system (all P<0.05). Both eosinophils and BEAS-2B cells were the main source for CXCL8 and CCL2 release in the coculture system upon iE-DAP or MDP stimulation. Direct interaction between eosinophils and BEAS-2B cells is responsible for CCL2 release, and soluble mediators are implicated in CXCL8 release. ERK and NF-κB play regulatory roles for the expression of adhesion molecules and chemokines in coculture. Treatment with NOD1,2 ligand could induce the subepithelial fibrosis and significantly enhance the serum concentration of total IgE, chemokine CCL5 for eosinophils and T helper type 2 (Th2) cells and asthma Th2 cytokine IL-13 in bronchoalveolar lavage fluid of ovalbumin-sensitized allergic asthmatic mice (all P<0.05). This study provides further evidence of bacterial infection-mediated activation of NOD1,2 in triggering allergic asthma via the activation of eosinophils interacting with bronchial epithelial cells at inflammatory airway.Cellular & Molecular Immunology advance online publication, 25 March 2013; doi:10.1038/cmi.2012.77.
- [Show abstract] [Hide abstract] ABSTRACT: BACKGROUND: Heart failure is one of the most frequent complications in dialysis patients. However, little is known of the significance of the entity "heart failure with preserved ejection fraction" (HFPEF) in this population. This study aimed to determine the prevalence, clinical profiles, and long-term outcomes of peritoneal dialysis patients with HFPEF. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 220 patients treated with peritoneal dialysis were recruited from a university teaching hospital in Hong Kong. PREDICTOR: Heart failure was defined clinically based on the presence of: (1) symptoms and signs, including dyspnea, increased jugular venous pressure, and basal crepitations; (2) radiographic evidence of pulmonary venous congestion or interstitial edema; and (3) resolution of symptoms, signs, and radiographic changes with hypertonic peritoneal dialysis exchanges. Based on a combination of clinical history of heart failure and echocardiography-derived ejection fraction, patients were classified as having no heart failure, HFPEF, and heart failure with reduced ejection fraction (HFREF). OUTCOMES: All-cause mortality, cardiac death, heart failure, and fatal or nonfatal cardiovascular events. MEASUREMENTS: All patients underwent 2-dimensional echocardiography and tissue Doppler imaging at baseline and were followed up prospectively for clinical events for 4 years. RESULTS: 86 (39%) patients had heart failure, of whom 54.7% had preserved ejection fraction ≥50% and 45.3% had reduced ejection fraction <50%. Patients with HFPEF were intermediate between those with no heart failure and those with HFREF in terms of blood pressure, prevalence of coronary artery disease, diabetes, cardiac biomarkers, left ventricular mass, volume, and ratio of early mitral inflow velocity to peak mitral annulus velocity. In the multivariable Cox regression analysis, patients with HFPEF showed an increased adjusted HR for cardiac death (2.57; 95% CI, 1.20-5.50), heart failure (HR, 2.25; 95% CI, 1.28-3.96), and fatal or nonfatal cardiovascular event (HR, 2.01; 95% CI, 1.26-3.21) compared with those with no heart failure, but the risk was lower compared with those with HFREF. LIMITATIONS: The study included prevalent peritoneal dialysis patients and may introduce survival bias. CONCLUSIONS: HFPEF is common in peritoneal dialysis patients (∼55% of all heart failure) and is associated with increased risk of mortality and adverse cardiovascular outcomes compared with those with no heart failure, although the risk was lower than in patients with HFREF. This entity needs to be more recognized in peritoneal dialysis patients.
- [Show abstract] [Hide abstract] ABSTRACT: The aim of this study was to investigate the multidrug resistance related protein-2 (MRP2) inhibition effect of excipients commonly employed in the formulation of self-emulsifying drug delivery systems (SEDDS). Cytotoxicity and safe dosages of fifteen excipients, including five surfactants, three oils, three co-surfactants and four solid carriers, were compared using MTT assay. Caco-2 cell permeability and MRP2 vesicles transport assays were used in the inhibition analysis. Scutellarin was shown to be a substrate of MRP2 and used as a probe in the inhibition assay. Twelve excipients decreased efflux ratio of scutellarin in Caco-2 model, among them six excipients showed inhibition effect on MRP2 in MRP2 transport model. In Caco-2 model, Cremophor® EL, Maisine® 35-1, PEG 2000 and β-cyclodextrin reduced efflux ratio of scutellarin the most in the four different excipients groups. The efflux reduction mechanism was further validated by MRP2 transport assay in inhibiting MRP2 activity in Cremophor® EL and PEG 2000. It is suggested that scutellarin quantified by LC-MS can be used as a model drug for MRP2 inhibition analysis using Caco-2 permeability and vesicles transport analyses. Together they constitute a sensitive and rapid screening method for assessing interactions between excipients and MRP2 in SEDDS formulation.
- [Show abstract] [Hide abstract] ABSTRACT: Background Left atrial enlargement (LAE) reflects diastolic dysfunction and predicts mortality in end-stage renal disease patients. However, little is known of its prevalence and factors associated with subclinical LAE in earlier stages of chronic kidney disease (CKD).Methods We conducted a prospective, cross-sectional study in 261 Stage 3-5 non-dialysis CKD patients without symptomatic cardiovascular disease with two-dimensional echocardiography performed to estimate left atrial volume index and other cardiac parameters.ResultsOne hundred and nine (41.8%) patients had LAE. Mild and moderate/severe LAEs were observed in 22.9 and 41.3% of patients with left ventricular (LV) hypertrophy (n = 109) versus 13.2 and 12.5% of patients with no LV hypertrophy (n = 152), respectively (P < 0.001). On univariate analysis, plasma sodium concentration showed a significant association with LAE [odds ratio (OR) 1.22, 95% confidence interval (95% CI) 1.09-1.37; P = 0.001]. In the stepwise multiple logistic regression, plasma sodium concentration emerged as one of the most significant factors associated with LAE (adjusted OR 1.29, 95% CI 1.14-1.47; P < 0.001]. Its significance was well maintained (adjusted OR 1.23, 95% CI 1.07-1.43; P = 0.005) when including LV mass and volume index and N-terminal pro-brain natriuretic peptide in the model, while blood haemoglobin and systolic blood pressure were displaced.Conclusions This study for the first time alerted to a very high prevalence of subclinical LAE and reported a strong novel, independent relationship between plasma sodium concentration and subclinical LAE in Stage 3-5 CKD patients. Longitudinal studies are needed to establish causality between high plasma sodium concentration and LAE and their usefulness as therapeutic targets in CKD.
- [Show abstract] [Hide abstract] ABSTRACT: Solid self-microemulsifying drug delivery systems (SMEDDS) have been used increasingly for improving the bioavailability of hydrophobic drugs. Labrasol® and Transcutol® are used widely as surfactant and solubilizer in the formulation of solid SMEDDS. We investigated the effects of spray-drying and the use of different solid carriers on concentrations of Labrasol® and Transcutol® in solid SMEDDS with scutellarin as the formulated drug. Liquid and gas chromatography tandem mass spectrometry (LC-MS and GC-MS) methods were developed for measuring low concentrations of Labrasol® and Transcutol®. In the preparation of solid SMEDDS, lactose, hydroxypropylmethyl cellulose (HPMC) and microcrystalline cellulose (MCC) were used as solid carriers. Judging from the retention ratios of Labrasol® and Transcutol®, the droplet size of solid SMEDDS increased after spray-drying of liquid SMEDDS, and concentrations of these excipients decreased after the solidifying procedure. In such reduction, Lactose and HPMC were found to preserve Labrasol® and Transcutol® better than MCC during spray-drying, and the resultant droplet sizes were smaller than that of MCC. Labrasol® and Transcutol® showed good thermal stability at 60 °C degree for 10 days. It can be concluded that spray-drying could increase the droplet size of solid SMEDDS and decreased the concentration of Labrasol® and Transcutol® therein, while water-soluble solid carriers could preserve Labrasol® and Transcutol® better than insoluble carriers in the solid SMEDDS.
- [Show abstract] [Hide abstract] ABSTRACT: Mortality in dialysis patients remains high due to excessive cardiovascular disease burden from coronary artery disease, left ventricular hypertrophy, and heart failure. Thus, cardiovascular risk stratification is an important aspect in managing dialysis patients; it may enable early identification of high-risk patients to optimize therapeutic interventions that may ultimately lower their cardiovascular morbidity and mortality. In particular, serum cardiac biomarkers that are readily measured, inexpensive, reproducible with high sensitivity and specificity, may have potential for cardiovascular risk prediction and stratification. Cardiac troponin represents a highly sensitive and specific marker of myocardial damage and is a current gold standard test for diagnosing acute myocardial infarction in the general population. On the other hand, natriuretic peptides, released from the heart secondary to increased left ventricular wall stress, have emerged as a diagnostic marker for heart failure in the general population. These two biomarkers reflect unique pathology of the myocardium and are powerful prognostic markers in the dialysis population. This article reviews the diagnostic potentials of these two cardiac biomarkers and their clinical application in the dialysis population.
- [Show abstract] [Hide abstract] ABSTRACT: There is an increasing global recognition of nutritional vitamin D deficiency in patients with chronic kidney disease (CKD). Yet, there is not much data in the Chinese population. We performed this prospective cross-sectional survey, with an aim to determine the prevalence of vitamin D deficiency (defined as serum 25-hydroxyvitamin D [25(OH)D] level <30ng/mL) in a cohort of Chinese stage 3-5 CKD patients and factors associated with its deficiency. Two-hundred and fifty (157 men and 93 women) stage 3-5 CKD patients (mean age: 57±12 years) were invited to have blood taking for 25(OH)D levels and other biochemical parameters and were asked to record the average number of hours of outdoor sunlight exposure per day during weekday and weekend in the week before blood taking. The mean glomerular filtration rate (GFR) estimated by the MDRD equation was 25±13 ml/min per 1.73m2, with 84, 91 and 75 patients having stage 3, 4 and 5 CKD. Two hundred and twenty-six patients (90%) were confirmed to be 25(OH)D deficient with 97% of the women having 25(OH)D deficiency as compared to 87% of men. In the univariate analysis, both weekday and weekend outdoor sunlight exposure showed significant positive association with serum 25(OH)D levels. In the multiple linear regression analysis, younger age (P<0.001), fewer weekday sun exposure hours (P<0.001) and female gender (P=0.001) were found to be the most significant factors associated with lower serum 25(OH)D levels.In conclusion, our study confirmed an extremely high prevalence of vitamin D deficiency and an important association between outdoor sunlight exposure and 25(OH)D deficiency in Chinese stage 3-5 CKD patients. Further study is needed to determine whether increasing daily outdoor sunlight exposure may represent a cost-free treatment for correcting nutritional 25(OH)D deficiency in the CKD population.
- [Show abstract] [Hide abstract] ABSTRACT: Plasma adiponectin (ADPN) is markedly elevated in end-stage renal disease (ESRD) patients compared to healthy controls. In this study, we aimed to evaluate clinical correlates of plasma ADPN and its importance in predicting clinical outcomes in chronic peritoneal dialysis (PD) patients. Furthermore, we evaluated the relationship between ADPN and C-reactive protein (CRP) in predicting outcomes of these patients. We prospectively measured plasma ADPN, CRP and other biochemical parameters and body composition in 238 ESRD patients on maintenance PD ≥3 months. Patients were followed for a median of 48 months. The plasma ADPN was 24.6 (13.9, 39.8) and 23.0 (13.9, 32.7)μg/ml for men and women, respectively (P=0.42). Multiple linear regression analysis showed that log-transformed ADPN was correlated with body fat mass (P=0.008), residual glomerular filtration rate (P=0.005), log-CRP (P < 0.001), serum albumin (P=0.004), triglyceride (P < 0.001) and HDL-cholesterol (P < 0.001). Univariate Cox regression analysis showed that plasma ADPN showed no significant association with all-cause mortality and cardiovascular death. However, stratifying patients into 4 groups on the basis of high or low CRP and high or low ADPN (stratified by their median levels), those with high CRP and high ADPN were dialyzed for the longest duration, had the lowest serum albumin, lowest LDL-cholesterol and residual GFR but highest CRP among the four groups. Body mass index and body fat mass were the highest among patients with high CRP, low ADPN. In the multivariable Cox regression analysis controlling for confounding covariates, patients with high CRP and high ADPN showed a 2.33-fold (95% CI, 1.24–4.35; P=0.008) and 2.47-fold (95% CI, 1.09–5.63; P=0.031) increased risk of mortality and cardiovascular death, respectively compared to those with low CRP and high ADPN while those with high CRP and low ADPN were not associated with a significantly increased risk of mortality and cardiovascular death.
- [Show abstract] [Hide abstract] ABSTRACT: Abbreviations: eos%, circulating eosinophil percentage; FLG, filaggrin; GMDR, generalized multifactor dimensionality reduction; GWAS, genome-wide association study; logIgE, logarithm-transformed plasma total IgE concentration; MAF, minor allele frequency; SNP, single-nucleotide polymorphism
- [Show abstract] [Hide abstract] ABSTRACT: IL-31 is a pruritogenic cytokine, and IL-33 is an alarmin for damaging inflammation. They together relate to the pathogenesis of atopic dermatitis (AD). Eosinophil infiltration into the inner dermal compartment is a predominant pathological feature of AD. We herein investigated the in vitro inflammatory effects of IL-31 and IL-33 on the activation of human eosinophils and dermal fibroblasts. Receptors, adhesion molecules and signaling molecules were assessed by Western blot or flow cytometry. Chemokines and cytokine were quantitated by multiplex assay. Functional IL-31 receptor component IL-31RA, OSMR-β and IL-33 receptor component ST2 were constitutively expressed on the surface of eosinophils. Co-culture of eosinophils and fibroblasts significantly induced pro-inflammatory cytokine IL-6 and AD-related chemokines CXCL1, CXCL10, CCL2 and CCL5. Such inductions were further enhanced with IL-31 and IL-33 stimulation. IL-31 and IL-33 could significantly provoke the release of CXCL8 from eosinophils and fibroblasts, respectively, which was further enhanced upon co-culture. In co-culture, eosinophils and fibroblasts were the main source for the release of CCL5, and IL-6, CXCL1, CXCL8, CXCL10 and CCL2, respectively. Direct interaction between eosinophils and fibroblasts was required for CXCL1, CXCL10, CXCL8 and CCL5 release. Cell surface expression of intercellular adhesion molecule-1 on eosinophils and fibroblasts was up-regulated in co-culture upon IL-31 and IL-33 stimulation. The interaction between eosinophils and fibroblasts under IL-31 and IL-33 stimulation differentially activated extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase, nuclear factor-κB and phosphatidylinositol 3-kinase-Akt pathways. Using specific signaling molecule inhibitors, the differential induction of IL-31 and IL-33-mediated release of cytokines and chemokines such as IL-6 and CXCL8 from co-culture should be related to their distinct activation profile of intracellular signaling pathways. The above findings suggest a crucial immunopathological role of IL-31 and IL-33 in AD through the activation of eosinophils-fibroblasts interaction via differential intracellular signaling mechanisms.
- [Show abstract] [Hide abstract] ABSTRACT: The progression to type 2 diabetes mellitus (DM) and other long-term cardiometabolic risks in Chinese women with prior history of gestational diabetes (GD) was studied at 15 years postpartum. 139 Chinese women (45 with GD and 94 with normal glucose tolerance (NGT) at the index pregnancy) who had their insulin sensitivity and β-cell functions examined at 8 years postpartum were again followed up at 15 years for the investigation of the rate of type 2 DM, hypertension and metabolic syndrome. Women with prior history of GD had a significantly higher rate of hypertension (35.6% vs. 16.0%, p = 0.01), type 2 DM (24.4% vs. 5.3%, p < 0.001) and impaired glucose regulation (26.6% vs. 14.9%, p < 0.001) than women with NGT during the index pregnancy. The Matsuda insulin sensitivity index and the quantitative insulin sensitivity check index at 8 years postpartum were independent predictors of both DM and metabolic syndrome at 15 years postpartum. The conversion rate of type 2 DM increased at an average rate of 1.6% per year after a pregnancy affected by GD. Insulin resistance at 8 years postpartum could refine a future diabetic risk in women with prior history of GD.
- [Show abstract] [Hide abstract] ABSTRACT: Sinomenine, an alkaloid isolated from the root of Sinomenium acutum, has been used to alleviate the symptoms of rheumatic diseases. Liang Miao San (LMS), composed of the herbs Rhizoma Atractylodis (Cangzhu) and Cotex Phellodendri (Huangbai), is another traditional Chinese medicine formula for rheumatoid arthritis (RA) treatment. Although numerous studies have demonstrated the potential anti-inflammatory activities of sinomenine and LMS, the underlying intracellular mechanisms regulating the anti-inflammatory activities of sinomenine and LMS on human primary fibroblast-like synoviocytes (FLS) from RA patients and normal control subjects have not been elucidated.
The Chinese University of Hong Kong
Hong Kong, Hong Kong
- • Department of Chemical Pathology
- • Prince of Wales Hospital
Prince of Wales Hospital, Hong KongChiu-lung, Kowloon City, Hong Kong