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ABSTRACT: BACKGROUND: Sorafenib, a multikinase inhibitor approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma, has been reported inhibitory on the function of dendritic cells. This study was aimed to determine the effects of sorafenib on inducing autophagy and immunomodulatory activity and its implication on graft rejection. METHODS: Cell viability and surface antigens were examined by 7-amino-actinomycin D and flow cytometric analysis. Autophagy was characterized using light microscopy and transmission electron microscopy for morphology, Western blotting for LC3B-I lipidation and mammalian target of rapamycin signaling molecules, and immunofluorescence staining for endogenous LC3B, GFP-LC3 transfection, and acidic component vacuoles. Skin allograft in mice was used as an experimental transplantation rejection model. Soluble factors contained in culture medium and serum were measured by enzyme-linked immunosorbent assay. RESULTS: We found that sorafenib inhibited the viability of dendritic cells accompanied by morphologic changes characteristic of autophagy and immature differentiation. This autophagic effect induced by sorafenib was validated by LC3B-I lipidation and autophagosome accumulation. Sorafenib treatment was associated with the down-regulation of phosphorylated mammalian target of rapamycin and its downstream substrate p70S6K. We next performed skin graft model to testify the role of sorafenib-induced immature and autophagic dendritic cells. Intriguingly, sorafenib prolonged the survival of skin allograft without major toxicity. Blockade of autophagic flux by chloroquine partially diminished the protective effect of sorafenib, indicating an autophagy-related mechanism in vivo. CONCLUSION: This study suggests that sorafenib, in addition to being an anticancer agent, may have potential to be developed as a new category of immunosuppressant drugs acting via autophagy induction of dendritic cells.
Transplantation 01/2013; · 4.00 Impact Factor
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ABSTRACT: BACKGROUND: Sorafenib, a multi-kinase inhibitor approved for treatment of advanced renal cell carcinoma and other malignancies, has been shown as a modulator for dendritic cells. This study was designed to examine the effects of sorafenib on macrophages, the major ontogeny of innate immunity. MATERIALS AND METHODS: Macrophages were derived from sorted CD14(+) monocytes of human peripheral blood mononuclear cells. Cell viability and surface antigens were examined by trypan blue analysis. Autophagy was characterized by light microscopy and transmission electron microscopy for morphology, Western blotting for microtubule associated light chain protein 3B (LC-3B) I lipidation, and acridine orange staining for acidic component vacuoles. Soluble factors contained in culture medium and serum were measured by ELISA. RESULTS: We found that sorafenib inhibited the viability of macrophages accompanied by morphological changes characteristic of autophagy. This autophagy-inducing effect was validated by LC3B-I lipidation and autophagosome accumulation. The surface antigen expression and the function of activated macrophages were inhibited by sorafenib, including the expression of co-stimulatory molecule CD80, phagocytosis, and the production of reactive oxygen species. The secretion of IL-10, but not IL-6, TNF-α nor TGF-β, was reduced by sorafenib. CONCLUSION: Sorafenib, in addition to being a cancer targeted therapeutic agent, can induce autophagy and modulate the function of human macrophages.
International immunopharmacology 01/2013; · 2.21 Impact Factor
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Chih-Pei Lin,
Feng-Yen Lin,
Po-Hsun Huang,
Yuh-Lien Chen,
Wen-Chi Chen,
Huey-Yi Chen, Yu-Chuen Huang,
Wen-Ling Liao,
Huey-Chun Huang,
Po-Len Liu,
Yung-Hsiang Chen
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ABSTRACT: Endothelial progenitor cells (EPCs) move towards injured endothelium or inflamed tissues and incorporate into foci of neovascularisation, thereby improving blood flow and tissue repair. Patients with cardiovascular diseases have been shown to exhibit reduced EPC number and function. It has become increasingly apparent that these changes may be effected in response to enhanced oxidative stress, possibly as a result of systemic and localised inflammatory responses. The interplay between inflammation and oxidative stress affects the initiation, progression, and complications of cardiovascular diseases. Recent studies suggest that inflammation and oxidative stress modulate EPC bioactivity. Clinical medications with anti-inflammatory and antioxidant properties, such as statins, thiazolidinediones, angiotensin II receptor 1 blockers, and angiotensin-converting enzyme inhibitors, are currently administered to patients with cardiovascular diseases. These medications appear to exert beneficial effects on EPC biology. This review focuses on EPC biology and explores the links between oxidative stress, inflammation, and development of cardiovascular diseases.
BioMed research international. 01/2013; 2013:845037.
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ABSTRACT: Purpose: To identify genetic variants that predispose to type 2 diabetes (T2D) with cataract. Patients and methods: Genome-wide association study (GWAS) of T2D patients with cataract, as graded by Lens Opacities Classification System (LOCS). A total of 109 T2D patients with cataract score equal to or above 10 designated as the study group, 649 T2D patients with cataract score equal to or below 3 as the control group. Single nucleotide polymorphisms (SNPs) with p-values < 10(-5) were considered to be putatively associated with the diabetic cataract. Results: Fifteen SNPs were found to be putatively associated with diabetic cataract. These variants were located near the following genes: PPARD, CCDC102A, GBA3, NEDD9, GABRR1/2, RPS6KA2, tcag7.1163, TAC1, GALNTL1 and KIAA1671. We defined haplotype 1 to haplotype 4 from the alternative alleles of related polymorphisms. Distribution of haplotype 2 on chromosome 4 and haplotype 4 on chromosome 7 revealed significant differences (OR = 1.86 and 1.69, respectively; 95% confidence interval were 1.26-2.76 and 1.23-2.31, respectively). Conclusions: The 15 loci coded on chromosomes 4, 6, 7, 14, 16 and 22 were associated with diabetic cataract. Gene functions are either with mechanisms of regulating blood sugar or formation of cataract. High linkage disequilibrium appeared on chromosome 4p15.31 and chromosome 7q21.3.
Ophthalmic Genetics 11/2012; · 0.93 Impact Factor
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ABSTRACT: Stem cells are capable of self-renewal and differentiation into a wide range of cell types with multiple clinical and therapeutic applications. Stem cells are providing hope for many diseases that currently lack effective therapeutic methods, including stroke, amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. Embryonic stem (ES) cells were originally targeted for differentiation into functional dopamine neurons for cell therapy. Today, induced pluripotent stem (iPS) cells are being tested for such purposes as generating functional dopamine neurons and treating a rat model of Parkinson's disease. In addition, neural stem cell and mesenchymal stem cells are also being used in neurodegenerative disorder therapies for stroke and Parkinson's disease. Although stem cell therapy is still in its infancy, it will likely become a powerful tool for many diseases that currently do not have effective therapeutic approaches. In this article we discuss current research on the potential application of neural stem cells, mesenchymal stem cells, ES cells, and iPS cells to neurodegenerative disorders.
Cell Transplantation 10/2012; · 5.13 Impact Factor
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ABSTRACT: The pegylated liposomal doxorubicin (PLD) has been widely accepted in treatment of various cancers. However, the composition of two currently marketed PLD nanoparticles differs in structure and composition of lipids, and their differential effects remain unknown. Macrophages of the mononuclear phagocyte system are pivotal in determining PLD clearance in vivo. The aim of this study was to compare the effect of these two PLDs on drug uptake, cell viability, morphology and immune function of human macrophages.
Two PLD nanoparticles were used in this study. The major difference between PLD-D and PLD-H is that their phospholipid bilayers are composed of distearoyl phosphatidylcholine (DSPC) and hydrogenated soybean phosphatidylcholine (HSPC), respectively. Human CD14+ monocytes were isolated from peripheral blood to prepare macrophages. Comparative assays included: flow cytometry for detection of doxorubicin penetration into cells, MTT for cell viability, Trypan blue exclusion for cell membrane integrity, Liu's stain for morphologic evaluation, and inactivated yeast co-culture for phagocytosis.
The uptake of PLD-H was rapidly detected at 10 min and kept increasing to 4 h followed by a decline thereafter, whereas that of PLD-D had similar profile with much less doxorubicin fluorescence detected, indicating a greater amount of doxorubicin retention of PLD-H. PLD-H, at higher concentration, decreased the viability and impaired cell membrane integrity of macrophages with an extent greater than PLD-D. The morphological observation showed a more extensive necrosis in PLD-H-treated macrophages. The phagocytosis function of macrophage was inhibited with a greater extent in PLD-H-treated macrophages.
The PLD containing HSPC may cause retention of doxorubicin with greater amount and longer period in human macrophages than that containing DSPC. This effect was accompanied by greater toxicity and more profound dysfunction. The correlation of this differential effect to clinical outcome remains to be extensively investigated by performing in vivo experiments or conducting clinical trials.
Journal of Nanoscience and Nanotechnology 10/2012; 12(10):7739-46. · 1.56 Impact Factor
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ABSTRACT: Purpose: Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus (DM). The susceptibility genes responsible for increasing the risk for DR in type 2 diabetes (T2D) were sought in this study. Methods: A case-control study was carried out, comprising 749 unrelated T2D individuals with (n = 174) and without (n = 575) DR. Genotypic distributions of single nucleotide polymorphisms (SNPs) were determined for subjects with and without DR. Results: Eight chromosome 6 SNPs, having the most significant differences, were delineated: rs10499298, rs10499299, rs17827966, rs1224329, rs1150790, rs713050, rs2518344 and rs487083; all were associated with genes TMEM217, MRPL14 and GRIK2. After adjusting for the duration of DM and levels of hemoglobin A(1c), the TT genotype of rs713050, and the AG + AA genotypes of rs2518344 and rs10499298, differed significantly between those with and without DR. Haplotype analysis revealed haplotype C-A-C, residing in rs10499299, rs10499298 and rs17827966, to have significant linkage disequilibrium. Conclusions: We identified new loci on chromosome 6 associated to DR; all loci showed high levels of linkage disequilibrium.
Ophthalmologica 09/2012; · 1.42 Impact Factor
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ABSTRACT: A significant percentage of Taiwanese neonatal HB immunization recipients have subsequently exhibited low anti-HB titers at non-protective or undetectable levels. Several mechanisms have been proposed to explain this phenomenon, including low vaccination responsiveness, deficient lymphocyte function, inappropriate antigen processing and presentation, and abnormal cytokine secretion.
To determine genetic influences resulting in high anti-HB titers, we divided a study cohort of 183 individuals into an anti-HBs≥1000 mIU/mL group and a 10-1000 mIU/mL anti-HBs titer group. Chi-square tests were used to compare genotype and allelic frequencies between the two groups.
Data from univariate and multivariate regression analyses of cytokine and cytokine receptor gene variants indicate (a) increased potential of high anti-HB titers in the presence of the TT genotype of the IL-4 rs2243250 SNP (OR=3.19; p=0.012) and the AA genotype of the IL-4R rs1805010 SNP (OR=2.25; p=0.048), and (b) individuals carrying the TT genotype of the IL-4 rs2243250 SNP had anti-HB titers at levels that were almost twice as high as those in individuals carrying the CC genotype (478.8 mIU/mL and 290.3 mIU/mL, respectively; p=0.033).
Genetic determinants, especially IL-4 and IL-4R, may contribute to high anti-HB titers in immune responses to HB vaccinations.
Clinica chimica acta; international journal of clinical chemistry 03/2012; 413(15-16):1194-8. · 2.54 Impact Factor
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ABSTRACT: Diabetic retinopathy (DR) is a microvascular complication of diabetes with a complex multifactorial pathogenesis. We aimed to investigate whether chromosome 15q21-22-related gene polymorphisms could be used as markers of DR susceptibility in type 2 diabetic (T2D) individuals.
Individuals were divided into three groups: (1) T2D with nonproliferative DR (NPDR; n=102); (2) T2D with proliferative DR (PDR; n=72); (3) T2D without DR (n=573). Six single-nucleotide polymorphisms (SNPs) (rs7174997, rs3751624, rs8025011, rs17818837, rs2922220, and rs2414520) lying within chromosome 15q21-22 region were genotyped by using Illumina HumanHap550-Duo BeadChips. Genotypes/allelic frequencies and haplotypes for these polymorphisms in each group were compared.
The MYO5C related SNP (rs3751624)*A related genotype and allele are associated with higher susceptibilities to DR, including PDR and NPDR. The rs3751624*GG/AA+AG percentages in each group are (1) 75.5%/24.5%, (2) 73.6%/26.4%, and (3) 82.5%/17.5%. In contrast, the other five SNPs in each group were not significantly different. One haplotype (G-A-G-G-T-G) appears significantly different between T2D individuals with and without DR. Other haplotype distributions were not significantly different between each group.
The MYO5C related SNP (rs3751624)*A related genotype/allele and haplotype (G-A-G-G-T-G) might be associated with susceptibility for retinopathy in T2D individuals. Some chromosome 15q21-22* related genetic variations might contribute to the pathogenesis of DR.
Genetic Testing and Molecular Biomarkers 03/2012; 16(5):442-8. · 1.11 Impact Factor
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ABSTRACT: Zoledronic acid (ZOL), an effective nitrogen-containing bisphosphonate used to prevent excessive bone loss in clinical practice, has been shown to affect the development of dendritic cells by redirecting differentiation toward a state of atypical maturation. The study was aimed to examine whether ZOL can reduce acute rejection of skin allografts.
A skin transplantation model using C57BL/6 to BALB/c mice was used. ZOL was injected intraperitoneally into transplant recipients post-surgically. Graft survival, body weight, leukocyte count, hepatic and renal functions were assessed.
ZOL treatment significantly prolonged skin allograft survival in mice. In terms of toxicity, there were no significant differences in body weight, leukocyte count, plasma alanine aminotransferase or creatinine levels between the ZOL-treated and control groups. Histopathology showed that the loss of skin integrity seen in control group was prevented by ZOL treatment. In draining lymph nodes and spleen, the number and clustering extent of mononuclear cells were markedly declined by ZOL treatment. The plasma IL-6 levels were reduced by treatment of ZOL.
ZOL can prolong skin allograft survival without major toxicity.
Clinical and investigative medicine. Medecine clinique et experimentale 01/2012; 35(4):E165-72. · 1.15 Impact Factor
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ABSTRACT: In 2006, induced pluripotent stem (iPS) cells were generated from somatic cells by introducing Oct4, Sox2, c-Myc and Klf4. The original process was inefficient; maintaining the pluripotency of embryonic stem (ES) and iPS cell cultures required an expensive reagent-leukemia induced factor (LIF). Our goal is to find a pure compound that not only maintains ES and iPS cell pluripotency, but also increases iPS cell generation efficiency. From 15 candidate compounds we determined that 10 µg/ml n-Butylidenephthalide (BP), an Angelica sinensis extract, triggers the up-regulation of Oct4 and Sox2 gene expression levels in MEF cells. We used ES and iPS cells treated with different concentrations of BP to test its usefulness for maintaining stem cell pluripotency. Results indicate higher expression levels of several stem cell markers in BP-treated ES and iPS cells compared to controls that did not contain LIF, including alkaline phosphatase, SSEA1, and Nanog. Embryoid body formation and differentiation results confirm that BP containing medium culture was capable of maintaining ES cell pluripotency after six time passage. Microarray analysis data identified PPAR, ECM, and Jak-Stat signaling as the top three deregulated pathways. We subsequently determined that phosphorylated Jak2 and phosphorylated Stat3 protein levels increased following BP treatment and suppressed with the Jak2 inhibitor, AG490. The gene expression levels of cytokines associated with the Jak2-Stat3 pathway were also up-regulated. Last, we used pou5f1-GFP MEF cells to test iPS generation efficiency following BP treatment. Our data demonstrate the ability of BP to maintain stem cell pluripotency via the Jak2-Stat3 pathway by inducing cytokine expression levels, at the same time improving iPS generation efficiency.
PLoS ONE 01/2012; 7(9):e44024. · 4.09 Impact Factor
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ABSTRACT: Diabetic retinopathy (DR) is a chronic retinal disorder, in which the retinal microvasculature is gradually altered, ultimately leading to blindness. Previous observations on clinical variations of the onset and severity of DR in various patients and populations suggest that genetic polymorphisms contribute to DR development. The present study was undertaken in an attempt to uncover new genetic factors contributing to the development of DR in a Taiwanese population. A well-defined Taiwanese population comprising persons with type 2 diabetes mellitus (T2DM) (n=749) was recruited for this study. We conducted a genome-wide association study in an independent set of 174 patients with DR and 575 without DR, using Illumina HumanHap550-Duo BeadChip. Eleven single nucleotide polymorphisms (SNPs) with the most significant test statistics (p≤1 × 10−5) were selected from one of the models. Of the selected SNPs, rs832882 (G/A) (p=2.29 × 10−6; odds ratio (OR)=1.49; 95% confidence interval (CI)=1.11–2.00) and rs3742872 (G/A) (P=1.19 × 10−15; OR=1.95; 95% CI=1.02–3.72), both identified as having the most significant association with DR, are located in the intronic region of the gene encoding the pleckstrin homology (PH) domain-containing proteins family O member 2 (PLEKHO2) and family H member 1 (PLEKHH1), respectively. Functional prediction analysis strengthened the likelihood of participation of PLEKHO2 and PLEKHH1 in the development of DR. The current findings suggest that the rs832882 and rs3742872 polymorphisms may be harbouring retinopathy susceptibility in a Taiwanese population, and implicate the pathological role of PH domain-containing proteins in DR development.
ScienceAsia 01/2012; 38(4):340-348. · 0.34 Impact Factor
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ABSTRACT: Membranous glomerulonephritis (MGN) is one of common causes of idiopathic nephrotic syndrome in adults, and 25% of MGN patients proceed to end-stage renal disease. STAT4 gene polymorphisms have been reported to be associated with many inflammatory diseases. The objective of this study was to clarify the relationship between STAT4 gene polymorphisms and the pathogenesis of MGN.
We investigated the association of three STAT4 gene polymorphisms (rs3024912, rs3024908, and rs3024877) with the susceptibility to MGN in 403 Taiwanese populations (138 MGN patients and 265 controls).
The results indicated that the statistically significant difference in genotype frequency distribution was found at rs3024908 SNP in MGN patients and control groups (p=0.014). In addition, the individuals with the GG genotype at rs3024912 SNP may have a higher risk in kidney failure of MGN patients (adjusted odds ratio [OR]=3.255; 95% confidence interval [CI]=1.155-9.176, p=0.026).
Our data provide a new information that the STAT4 (rs3024912 and rs3024908) polymorphisms may be the underlying cause of MGN, and these polymorphisms revealed by this study warrant further investigation.
Clinica chimica acta; international journal of clinical chemistry 10/2011; 412(21-22):1899-904. · 2.54 Impact Factor
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ABSTRACT: Cantharidin (CTD), a naturally occurring small molecule isolated from a medicinal insect, possesses anti-cancer and pro-inflammatory properties. We aimed to examine the effect of CTD on human myeloid dendritic cells (DCs) by examining immature DCs differentiated and maturated from CD14+ monocytes. CTD added into a culture of starting CD14+ monocytes markedly and dose-dependently reduced viability of harvested DC. Mature DCs differentiated in the presence of CTD had much fewer, shorter membranous projections than those without CTD. Changes in morphological features characteristic of necrotic cells were also evident. Furthermore, CTD affected DC differentiation and maturation phenotypes including down-regulation of surface CD1a, CD83 and DC-SIGN. DCs derived in the presence of CTD possessed an impaired allostimulatory activity on naive CD4+CD45+RA+T cell in terms of proliferation and interferon-γ production. It suggests that CTD may redirect DC differentiation toward a less mature stage and that this effect is not solely due to its cytotoxicity. Whether this effect refers to immune suppression or tolerance to disease treatments with unwanted immune reactions needs further evaluation.
Toxicology in Vitro 09/2011; 25(8):1740-7. · 2.78 Impact Factor
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ABSTRACT: To examine the effects of norcantharidin (NCTD) on development of human myeloid dendritic cells (DCs) in vitro and in skin allograft transplantation in vivo.
Human CD14(+) monocytes were isolated and triggered differentiation and maturation toward myeloid DCs with and without NCTD. The cell morphology, viability, cell death, expression of surface markers and co-stimulatory molecules, allostimulatory activity, and cytokine production were examined for characterization of DCs. The rejection of mice skin allograft model was used to translate the in vitro effect of cantharidin (CTD) and NCTD on DCs.
DCs developed in the presence of NCTD showed decreased viability, cell death with necrosis, and lower expression of CD1a and CD83. DCs triggered in the presence of NCTD possessed a greater allostimulatory activity in naive CD4(+)CD45RA(+) T cells. NCTD modulated DCs through calcineurin phosphatase but not through mammalian target of rapamycin or downstream molecule p70S6 kinase. In vivo, NCTD caused accumulation and co-localization of antigen-presenting cells and regulatory T cells in the interfollicular area of the recipients' spleens. CTD and NCTD prolonged skin allograft survival along with less severe histopathological inflammatory reactions. CTD, but not NCTD, treatment caused elevation of serum alanine aminotransferase and evident mortality of the recipients.
NCTD modulated the differentiation and maturation of human myeloid DCs and caused deviation of standard DC differentiation toward a tolerogenic phenotype through calcineurin phosphatase inhibition. In vivo, both drugs effectively prolonged skin allograft survival. NCTD was less toxic than CTD, and thus, has potential for development as an immunosuppressant for transplant rejection.
Transplantation 08/2011; 92(8):848-57. · 4.00 Impact Factor
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Huang-Chi Chen,
Wen-Chi Chen,
Kai-Huang Lin,
Yung-Hsiang Chen,
Lun-Chien Lo,
Tsung-Chieh Lee,
Te-Chun Hsia,
Chu-Hsien Wang,
Shin-Hwar Wu,
Hsin-Whae Hsu,
Yu-Jun Chang, Yu-Chuen Huang,
Tien-Hsiung Ku,
Ming-Hwarng Horng
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ABSTRACT: Even though there are continually upgraded recommendations for managing sepsis, such as "Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock", mortality is still high. Si-ni-tang, a remedy documented in Shanghan Lun, a medical collection from ancient China, is used for treating patients with sepsis and septic shock. Using a well-designed clinical trial, we are eager to survey the effectiveness of the concurrent use of this remedy in restoring these patients' hemodynamic status, or "Yang Qi".
Patients admitted to our medical intensive care units with the diagnosis of septic shock, defined as persistent hypotension induced by sepsis despite adequate fluid resuscitation, are eligible for participation. The inclusion criteria include: age from 20 to 85 years, conditions meeting the definition of septic shock, use of vasopressors within 24 hours of entering the study, and use of a nasogastric tube for feeding. The enrolled patients are randomly allocated either to the si-ni-tang group or the placebo group. The prescription of the trial drugs (si-ni-tang/placebo) is 2.25 grams 4 times a day for 7 days or till shock reversal (if shock reversal occurs in less than 7 days). Data, including duration of vasopressor infusion, gender, age, co-morbidities, APACHE II score, predicted mortality, ICU mortality, ICU length of stay, hospital mortality, hospital length of stay, source of sepsis, and culture results, are collected for the following analysis.
Si-ni-tang is composed of processed Zingiber officinale, Glycyrrhiza uralensis, and Aconitum carmichaeli. Zingiber officinale and Glycyrrhiza uralensis are found to have the ability to reduce pro-inflammatory cytokine production, to inhibit lipopolisaccharide-induced macrophage activation and function, and to lessen the bacterial load and suppress acute and chronic inflammation. Aconitum carmichaeli is known to have vasopressor activity, and positive chronotropic and inotropic effects. As this remedy has a potential benefit in treating septic shock patients, we designed a double-blind, prospective, randomized controlled trial and would like to publish the results and conclusions later.
ClinicalTrials.gov: NCT01223430.
Trials 08/2011; 12:199. · 2.02 Impact Factor
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Marcelo Chen,
Chiao-Wei Ho, Yu-Chuen Huang,
Kuen-Yuh Wu,
Ming-Tseng Wu,
Hueiwang Anna Jeng,
Chiou-Jong Chen,
Tung-Sheng Shih,
Ching-Huang Lai,
Chih-Hong Pan,
Yi-Ming Arthur Chen
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ABSTRACT: The object of this study was to assess the modulating effects of genetic polymorphisms of glycine N-methyltransferase (GNMT) genotypes on 1-hydroxypyrene (1-OHP) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in urine from coke-oven workers, consistently exposed to polycyclic aromatic hydrocarbons (PAHs).
The study participants included 289 coke-oven workers from a steel company in Taiwan. Personal air samples, spot urine samples, peripheral blood samples, and questionnaires were used to quantify PAH exposure, oxidative DNA damage, GNMT gene polymorphisms, demographic data, and environmental pollutants.
Urinary 1-OHP level, GNMT STRP1 genotype, and worksite were significant predictors of urinary 8-OHdG levels after adjustments were made for covariates.
This study suggests that GNMT STRP1 could modulate urinary 1-OHP and 8-OHdG levels in coke-oven workers exposed to PAHs.
Journal of occupational and environmental medicine / American College of Occupational and Environmental Medicine 06/2011; 53(7):812-9. · 1.88 Impact Factor
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ABSTRACT: Diabetic retinopathy (DR) is a microvascular complication of diabetes with a complex multifactorial pathogenesis. The aim of this study was to identify the susceptibility genes that increase the risk of DR in type 2 diabetes (T2D) and to further elucidate the underlying mechanism of DR pathogenesis.
A case-control study.
We included 749 unrelated individuals with T2D (174 with DR and 575 without DR) and 100 nondiabetic controls.
We conducted a genome-wide association study using Illumina HumanHap550-Duo BeadChips.
Compared with the genotypic distribution of single nucleotide polymorphisms (SNPs) between subjects with DR and without DR.
Using statistical models, we selected a total of 12 SNPs with P-values <1 × 10(-6) that were associated with DR. After controlling for diabetes duration and hemoglobin A(1C), 9 of the 12 SNPs located on 5 chromosomal regions were found to be associated with DR. Five loci not previously associated with DR susceptibility were identified in and around the following genes: MYSM1 (Myb-like, SWIRM, and MPN domains 1) located on chromosome 1p (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.03-2.20); PLXDC2 (plexin domain-containing 2) located on the chromosome 10p (OR, 1.67; 95% CI, 1.06-2.65); ARHGAP22 (Rho GTPase-activating protein 22) located on chromosome 10q (OR, 1.65; 95% CI, 1.05-2.60); and HS6ST3 (heparan sulfate 6-O-sulfotransferase 3) located on chromosome 13q (OR, 2.33; 95% CI, 1.13-4.77). The SNPs rs13163610 and rs17376456 located in the unknown gene on chromosome 5q were also associated with DR (OR, 3.63; 95% CI, 1.38-9.58).
We identified a genetic association for susceptibility to DR in 5 novel chromosomal regions and PLXDC2 and ARHGAP22, the latter 2 of which are genes implicated in endothelial cell angiogenesis and increased capillary permeability. These findings suggest unsuspected pathways in the pathogenesis of DR.
Ophthalmology 02/2011; 118(4):642-8. · 5.45 Impact Factor
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Shih-Yin Chen,
Lei Wan,
Chung-Ming Huang, Yu-Chuen Huang,
Jim Jinn-Chyuan Sheu,
Ying-Ju Lin,
Shih-Ping Liu,
Yu-Ching Lan,
Chih-Ho Lai,
Cheng-Wen Lin,
Chang-Hai Tsai,
Fuu-Jen Tsai
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ABSTRACT: Rheumatoid arthritis (RA) is a chronic autoimmune disease and can lead to deformities and severe disabilities, due to irreversible damage of tendons, joints, and bones. Previous study indicated that DNA repair system was involved in the pathology of RA. In this study, we investigated the association of two 8-oxoguanine glycosylase 1 (OGG1) gene polymorphisms (rs159153 and rs3219008) with the susceptibility to RA in 384 Taiwanese individuals (192 patients with RA and 192 controls). Our data showed that statistically significant difference in genotype frequency distributions was found at rs3219008 SNP between patients with RA and control groups (P = 5.6E-0.5). Our data also indicated that individuals with the AG genotype at rs3219008 SNP may have a higher risk of developing RA. We did not observe any statistically significant association of OGG1 haplotype frequencies (rs159153 and rs3219008) with RA progression. The study suggested that OGG1 polymorphisms (rs159153 and rs3219008) are associated with RA progression and that these may be used as molecular markers of RA.
Rheumatology International 01/2011; 32(5):1165-9. · 1.88 Impact Factor
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ABSTRACT: Lapatinib is an oral, small-molecule, dual tyrosine kinase inhibitor of epidermal growth factor receptors (EGFR, or ErbB/Her) in solid tumors. Little is known about the effect of lapatinib on leukemia. Using human chronic myelogenous leukemia (CML) K562 cells as an experimental model, we found that lapatinib simultaneously induced morphological changes resembling apoptosis, autophagy, and megakaryocytic differentiation. Lapatinib-induced apoptosis was accompanied by a decrease in mitochondrial transmembrane potential and was attenuated by the pancaspase inhibitor z-VAD-fmk, indicating a mitochondria-mediated and caspase-dependent pathway. Lapatinib-induced autophagic cell death was verified by LC3-II conversion, and upregulation of Beclin-1. Further, autophagy inhibitor 3-methyladenine as well as autophagy-related proteins Beclin-1 (ATG6), ATG7, and ATG5 shRNA knockdown rescued the cells from lapatinib-induced growth inhibition. A moderate number of lapatinib-treated K562 cells exhibited features of megakaryocytic differentiation. In summary, lapatinib inhibited viability and induced multiple cellular events including apoptosis, autophagic cell death, and megakaryocytic differentiation in human CML K562 cells. This distinct activity of lapatinib against CML cells suggests potential for lapatinib as a therapeutic agent for treatment of CML. Further validation of lapatinib activity in vivo is warranted.
PLoS ONE 01/2011; 6(12):e29014. · 4.09 Impact Factor
