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Dive into the research topics where Shao-Chun Lu is active.

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Featured researches published by Shao-Chun Lu.


FEBS Letters | 2002

Lipopolysaccharide increases resistin gene expression in vivo and in vitro.

Shao-Chun Lu; Wei-Yeong Shieh; Chia-Ying Chen; Shu-Ching Hsu; Hui-Ling Chen

Although resistin has been thought to be an important link between obesity and diabetes, recent results do not support this hypothesis. We speculated that resistin may be involved in inflammatory processes and be induced by inflammatory stimuli. In this study, we tested whether lipopolysaccharide (LPS) induced resistin expression in rats. The results show that resistin mRNA levels in white adipose tissue and white blood cells were increased by LPS treatment. LPS also increased resistin mRNA levels in 3T3‐L1 adipocytes and human peripheral blood monocytes. The results suggest that resistin is involved in insulin resistance and probably in other inflammatory responses.


Circulation Research | 2008

Homocysteine inhibits arterial endothelial cell growth through transcriptional downregulation of fibroblast growth factor-2 involving G protein and DNA methylation

Po Yuan Chang; Shao-Chun Lu; Chii-Ming Lee; Yi Jie Chen; Tracey A. Dugan; Wen Huei Huang; Shwu Fen Chang; Warren S L Liao; Chu-Huang Chen; Yuan-Teh Lee

Homocysteine (Hcy) contributes to atherogenesis and angiostasis by altering the phenotype of arterial endothelial cells (ECs). The present study was aimed at elucidating potential mechanisms by which Hcy can slow EC proliferation and induce EC apoptosis, thereby disrupting endothelial integrity. Given the strong mitogenic and antiapoptotic properties of fibroblast growth factor (FGF)2, we examined whether Hcy can modulate its expression. In cultured human coronary and bovine aortic ECs, Hcy exerted time- and concentration-dependent (0 to 500 &mgr;mol/L) reduction of the mRNA and protein levels of FGF2, whereas vascular endothelial growth factor expression was not affected until Hcy reached a proapoptotic 500 &mgr;mol/L. By testing a panel of signal transduction inhibitors, we found that the Hcy-induced downregulation of FGF2 was specifically attenuated by pertussis toxin, an inhibitor of Gi protein signaling. Hcy induced cell cycle arrest at the G1/S transition and increased TUNEL-positive apoptotic cells in a graded manner. These effects were effectively counteracted by exogenous FGF2. Reporter gene assays showed that Hcy downregulated FGF2 by transcriptional repression of the gene promoter encompassed in a CpG dinucleotide-rich island. This region was heavily methylated at the cytosine residues by Hcy despite decreased methylation potential (S-adenosylmethionine to S-adenosylhomocysteine ratio). Normal levels of FGF2 transcription were restored to ECs simultaneously exposed to Hcy and 5-aza-deoxycytidine. We conclude that homocysteine disrupts the growth and survival of ECs through a G protein–mediated pathway associated with altered promoter DNA methylation and the transcriptional repression of FGF2.


Journal of Cellular Physiology | 2015

IL‐1β Promotes Malignant Transformation and Tumor Aggressiveness in Oral Cancer

Chia Huei Lee; Jeffrey S. Chang; Shih Han Syu; Thian Sze Wong; Jimmy Yu-Wai Chan; Ya Chu Tang; Zhi Ping Yang; Wen Chan Yang; Chiung Tong Chen; Shao-Chun Lu; Pei Hua Tang; Tzu Ching Yang; Pei Yi Chu; Jenn Ren Hsiao; Ko Jiunn Liu

Chronic inflammation, coupled with alcohol, betel quid, and cigarette consumption, is associated with oral squamous cell carcinoma (OSCC). Interleukin‐1 beta (IL‐1β) is a critical mediator of chronic inflammation and implicated in many cancers. In this study, we showed that increased pro‐IL‐1β expression was associated with the severity of oral malignant transformation in a mouse OSCC model induced by 4‐Nitroquinolin‐1‐oxide (4‐NQO) and arecoline, two carcinogens related to tobacco and betel quid, respectively. Using microarray and quantitative PCR assay, we showed that pro‐IL‐1β was upregulated in human OSCC tumors associated with tobacco and betel quid consumption. In a human OSCC cell line TW2.6, we demonstrated nicotine‐derived nitrosamine ketone (NNK) and arecoline stimulated IL‐1β secretion in an inflammasome‐dependent manner. IL‐1β treatment significantly increased the proliferation and dysregulated the Akt signaling pathways of dysplastic oral keratinocytes (DOKs). Using cytokine antibodies and inflammation cytometric bead arrays, we found that DOK and OSCC cells secreted high levels of IL‐6, IL‐8, and growth‐regulated oncogene‐α following IL‐1β stimulation. The conditioned medium of IL‐1β‐treated OSCC cells exerted significant proangiogenic effects. Crucially, IL‐1β increased the invasiveness of OSCC cells through the epithelial‐mesenchymal transition (EMT), characterized by downregulation of E‐cadherin, upregulation of Snail, Slug, and Vimentin, and alterations in morphology. These findings provide novel insights into the mechanism underlying OSCC tumorigenesis. Our study suggested that IL‐1β can be induced by tobacco and betel quid‐related carcinogens, and participates in the early and late stages of oral carcinogenesis by increasing the proliferation of dysplasia oral cells, stimulating oncogenic cytokines, and promoting aggressiveness of OSCC. J. Cell. Physiol. 230: 875–884, 2015.


Cardiovascular Research | 2013

Aspirin protects human coronary artery endothelial cells against atherogenic electronegative LDL via an epigenetic mechanism: a novel cytoprotective role of aspirin in acute myocardial infarction

Po Yuan Chang; Yi Jie Chen; Fu Hsiung Chang; Jonathan Lu; Wen Huei Huang; Tzu Ching Yang; Yuan-Teh Lee; Shwu Fen Chang; Shao-Chun Lu; Chu-Huang Chen

AIMS L5 is the most negatively charged subfraction of human low-density lipoprotein (LDL) and is the only subfraction of LDL capable of inducing apoptosis in cultured vascular endothelial cells (ECs) by inhibiting fibroblast growth factor-2 (FGF2) transcription. We examined whether plasma L5 levels are elevated in patients with ST-segment elevation myocardial infarction (STEMI) and whether aspirin provides epigenetic protection of human coronary artery ECs (HCAECs) exposed to L5. METHODS AND RESULTS Plasma L5 levels were compared between patients with STEMI (n = 10) and control subjects with chest pain syndrome but a normal coronary arteriogram (n = 5). L5 was isolated from the plasma of STEMI patients and control subjects, and apoptosis, FGF2 expression, and FGF2 promoter methylation were examined in HCAECs treated with L5 and aspirin. Plasma L5 levels were significantly higher in STEMI patients than in control subjects (P < 0.001). Treatment of HCAECs with L5 resulted in reduced survival and FGF2 expression and increased CpG methylation of the FGF2 promoter. Co-treatment of HCAECs with L5 and a physiologically relevant, low concentration of aspirin (0.2 mM) attenuated the adverse effects of L5 on HCAEC survival, FGF2 expression, and FGF2 promoter methylation. In contrast, high concentrations of aspirin (≥1.0 mM) accentuated the effects of L5. CONCLUSIONS Our results show that L5 levels are significantly increased in STEMI patients. Furthermore, L5 impairs HCAEC function through CpG methylation of the FGF2 promoter, which is suppressed in the presence of low-concentration aspirin. Our results provide evidence of a novel mechanism of aspirin in the prevention of MI.


American Journal of Physiology-cell Physiology | 2009

The essential role of Oct-2 in LPS-induced expression of iNOS in RAW 264.7 macrophages and its regulation by trichostatin A.

Shao-Chun Lu; Hsiao Wen Wu; Yen Jen Lin; Shwu Fen Chang

This article reports on a study of the effect of trichostatin A (TSA), an inhibitor of histone deacetylase, on lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase (iNOS) in RAW 264.7 macrophages and its underlying mechanisms. TSA pretreatment potently diminishes LPS-stimulated nitric oxide (NO) release and both mRNA and protein levels of iNOS in macrophages. The effects of TSA and LPS on transcription factors binding to two LPS-responsive elements within the iNOS promoter, one binding the NF-kappaB site and the other the octamer element, were investigated. Results show that TSA did not alter the LPS-activated NF-kappaB activity demonstrated by the nuclear translocation of p50 and p65 and by a NF-kappaB-driven reporter gene expression system. In addition, neither TSA nor LPS changed the expression of Oct-1, a ubiquitously expressed octamer binding protein. However, TSA suppressed the LPS-induced expression of Oct-2, another octamer binding protein, at both mRNA and protein levels. Chromatin immunoprecipitation assays revealed that binding of Oct-2 to the iNOS promoter was enhanced by LPS treatment; however, pretreatment with TSA resulted in loss of this binding. Moreover, forced expression of Oct-2 by transfection of pCG-Oct-2 plasmid restored the TSA-suppressed iNOS expression elevated by LPS stimulation, further indicating that Oct-2 activation is a crucial step for transcriptional activation of the iNOS gene in response to LPS stimulation in macrophages. This study demonstrates that TSA diminishes iNOS expression in LPS-treated macrophages by inhibiting Oct-2 expression and thus reducing the production of NO.


Biochemical Journal | 2006

Identification of three crucial histidine residues (His115, His132 and His297) in porcine deoxyribonuclease II

Yu-Che Cheng; Chin-Chen Hsueh; Shao-Chun Lu; Ta-Hsiu Liao

DNase II is an acid endonuclease that is involved in the degradation of exogenous DNA and is important for DNA fragmentation and degradation during cell death. In an effort to understand its catalytic mechanism, we constructed plasmids encoding nine different histidine (H)-to-leucine (L) mutants for porcine DNase II and examined the enzyme properties of the expressed mutant proteins. Of the mutants, all but H132L were secreted into the medium of expressing cells. Six of the mutated DNase II proteins (H41L, H109L, H206L, H207L, H274L and H322L) showed enzyme activity, whereas the H115L, H132L and H297L mutants exhibited very little activity. The H115L and H297L mutants were found to undergo correct protein folding, but were inactive. To further examine these mutants, we expressed H115A and H297A DNase II mutants; these mutants were inactive, but their DNase activities could be rescued with imidazole, indicating that His115 and His297 are likely to function as a general acid and a general base respectively in the catalytic centre of the enzyme. In contrast with the secreted mutants, the H132L mutant protein was found in cell lysates within 16 h after transfection. This protein was inactive, improperly folded and was drastically degraded via the proteosomal pathway after 24 h. The polypeptide of another substitution for His132 with lysine resulted in the misfolded form being retained in endoplasmic reticulum.


Journal of Biomedical Science | 2014

Malondialdehyde mediates oxidized LDL-induced coronary toxicity through the Akt-FGF2 pathway via DNA methylation

Tzu Ching Yang; Yi Jie Chen; Shwu Fen Chang; Chu-Huang Chen; Po Yuan Chang; Shao-Chun Lu

BackgroundOxidized LDL (oxLDL) is involved in the development of atherosclerotic heart disease through a mechanism that is not fully understood. In this study, we examined the role of malondialdehyde (MDA), an important oxidative stress epitope of oxLDL, in mediating coronary endothelial cytotoxicity.ResultsHuman coronary artery endothelial cells (HCAECs) were treated with oxLDL in the presence or absence of antibody against MDA (anti-MDA) or apoB100 (anti-apoB100). In HCAECs treated with oxLDL (100 μg/ml) alone, DNA synthesis, cell viability, and expression of prosurvival fibroblast growth factor 2 (FGF2) were significantly reduced (P < 0.01 vs phosphate buffered saline–treated cells). These inhibitory effects of oxLDL were significantly attenuated in HCAECs cotreated with anti-MDA (0.15 μg/ml; P < 0.05 vs oxLDL-treated cells), but not in those cotreated with anti-apoB100. When we tested the effects of a panel of signal transduction modifiers on the signal transduction pathways of MDA in oxLDL-treated HCAECs, we found that MDA-induced cytotoxicity was mediated partly through the Akt pathway. Using a reporter gene assay, we identified an oxLDL-response element in the FGF2 promoter that was responsible for the transcriptional repression of FGF2 by oxLDL. The results of bisulfite genomic DNA sequencing showed that in HCAECs treated with oxLDL, the GC-rich promoter of FGF2 was heavily methylated at cytosine residues, whereas cotreatment with anti-MDA markedly reduced oxLDL-induced FGF2 promoter methylation.ConclusionOxLDL disrupts the growth and survival of HCAECs through an MDA-dependent pathway involving methylation of the FGF2 promoter and repression of FGF2 transcription. This novel epigenetic mechanism of oxLDL may underlie its atherogenicity in patients with atherosclerotic cardiovascular disease.


PLOS ONE | 2014

A Vaccine Targeted at CETP Alleviates High Fat and High Cholesterol Diet-Induced Atherosclerosis and Non-Alcoholic Steatohepatitis in Rabbit

Yi Wei Liaw; Chi Yu Lin; Yu Sheng Lai; Tzu Chung Yang; Chau-Jong Wang; Jacqueline Whang-Peng; Leroy F. Liu; Chia Po Lin; Shin Nieh; Shao-Chun Lu; Jaulang Hwang

Low HDL-C levels are associated with atherosclerosis and non-alcoholic steatohepatitis, and increased levels may reduce the risk of these diseases. Inhibition of cholesteryl ester transfer protein (CETP) activity is considered a promising strategy for increasing HDL-C levels. Since CETP is a self-antigen with low immunogenicity, we developed a novel CETP vaccine (Fc-CETP6) to overcome the low immunogenicity of CETP and for long-term inhibition of CETP activity. The vaccine consists of a rabbit IgG Fc domain for antigen delivery to antigen-presenting cells fused to a linear array of 6 repeats of a CETP epitope to efficiently activate B cells. Rabbits were fed a high fat/cholesterol (HFC) diet to induce atherosclerosis and NASH, and immunized with Fc-CETP6 vaccine. The Fc-CETP6 vaccine successfully elicited anti-CETP antibodies and lowered plasma CETP activity. The levels of plasma HDL-C and ApoA-I were higher, and plasma ox-LDL lower, in the Fc-CETP6-immunized rabbits as compared to the unimmunized HFC diet-fed rabbits. Pathological analyses revealed less lipid accumulation and inflammation in the aorta and liver of the Fc-CETP6-immunized rabbits. These results show that the Fc-CETP6 vaccine efficiently elicited antibodies against CETP and reduced susceptibility to both atherosclerosis and steatohepatitis induced by the HFC diet. Our findings suggest that the Fc-CETP6 vaccine may improve atherosclerosis and NASH and has high potential for clinical use.


FEBS Journal | 2011

Rapamycin inhibits lipopolysaccharide induction of granulocyte‐colony stimulating factor and inducible nitric oxide synthase expression in macrophages by reducing the levels of octamer‐binding factor‐2

Yuan Yi Chou; Jhen I. Gao; Shwu Fen Chang; Po Yuan Chang; Shao-Chun Lu

This article reports an inhibitory effect of rapamycin on the lipopolysaccharide (LPS)‐induced expression of both inducible nitric oxide synthase (iNOS) and granulocyte‐colony stimulating factor (G‐CSF) in macrophages and its underlying mechanism. The study arose from an observation that rapamycin inhibited the LPS‐induced increase in octamer‐binding factor‐2 (Oct‐2) protein levels through a mammalian target of rapamycin (mTOR)‐dependent pathway in mouse RAW264.7 macrophages. As both iNOS and G‐CSF are potential Oct‐2 target genes, we tested the effect of rapamycin on their expression and found that it reduced the LPS‐induced increase in iNOS and G‐CSF mRNA levels and iNOS and G‐CSF protein levels. Blocking of mTOR‐signaling using a dominant‐negative mTOR expression plasmid resulted in inhibition of the LPS‐induced increase in iNOS and G‐CSF protein levels, supporting the essential role of mTOR. Forced expression of Oct‐2 using the pCG–Oct‐2 plasmid overcame the inhibitory effect of rapamycin on the LPS‐induced increase in iNOS and G‐CSF mRNA levels. Chromatin immunoprecipitation assays showed that LPS enhanced the binding of Oct‐2 to the iNOS and G‐CSF promoters and that this effect was inhibited by pretreatment with rapamycin. Moreover, RNA interference knockdown of Oct‐2 reduced iNOS and G‐CSF expression in LPS‐treated cells. The inhibitory effect of rapamycin on the LPS‐induced increase in Oct‐2 protein levels and on the iNOS and G‐CSF mRNA levels was also detected in human THP‐1 monocyte‐derived macrophages. This study demonstrates that rapamycin reduces iNOS and G‐CSF expression at the transcription level in LPS‐treated macrophages by inhibiting Oct‐2 expression.


Hepatology | 2009

A novel nonsynonymous variant of matrix metalloproteinase-7 confers risk of liver cirrhosis†

Tzu-Min Hung; Shin C. Chang; Wei-Hsuan Yu; Yu-Wen Wang; Cheng Huang; Shao-Chun Lu; Po-Huang Lee; Ming-Fu Chang

Liver cirrhosis is characterized by progressive accumulation of extracellular matrix following chronic liver injuries. In the extracellular space, the constant turnover of liver matrix is regulated by the matrix metalloproteinase (MMP) class of enzyme. To assess whether genetic variations in MMP would result in diversity of liver cirrhosis, a case‐control study of 320 patients with hepatocellular carcinoma, with or without cirrhosis, was conducted. Ten single‐nucleotide polymorphism markers from four potential fibrosis‐associated genes were selected for genotyping. Among these genes, a nonsynonymous single‐nucleotide polymorphism which generates the variation of Gly‐137 and Asp‐137 in the MMP‐7 gene was found to be strongly associated with the development of liver cirrhosis. In contrast to MMP‐7(Gly‐137) that predominantly secretes out into the cell culture medium, the cirrhosis‐associated MMP‐7(Asp‐137) variant is preferentially localized on the extracellular membranes where it exerts its proteolytic activity on pericellular substrates. Functional analysis demonstrated an increased ability of the MMP‐7(Asp‐137) variant to associate with the cell surface CD151 molecule. In wound‐healing and Boyden chamber assays, cell motility was specifically enhanced with the expression of MMP‐7(Asp‐137) as compared to the cells expressing MMP‐7(Gly‐137). These results demonstrate that the MMP‐7(Asp‐137) variant confers a gain‐of‐function phenotype for MMP‐7. Conclusion: We have identified a novel genetic association of MMP‐7(Asp‐137) variant with liver cirrhosis in patients with hepatocellular carcinoma. Whether the MMP‐7 variant can be a new marker for liver cirrhosis will be further studied. (HEPATOLOGY 2009.)

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Po-Yuan Chang

National Taiwan University

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Shwu Fen Chang

Taipei Medical University

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Hui-Ling Chen

National Taiwan University

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Tzu-Ching Yang

National Taiwan University

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Yuan-Teh Lee

National Taiwan University

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Chu-Huang Chen

The Texas Heart Institute

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Po Yuan Chang

National Taiwan University

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Yi-Jie Chen

National Taiwan University

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Tzu Ching Yang

National Taiwan University

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Yuan Yi Chou

National Taiwan University

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