Ming-Che Lee

Tzu Chi University, Hua-lien, Taiwan, Taiwan

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Publications (33)105.44 Total impact

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    ABSTRACT: Hepatocyte growth factor (HGF) and its receptor c-Met were frequently deregulated in hepatocellular carcinoma (HCC). Signaling pathways activated by HGF-c-Met are promising targets for preventing HCC progression. HGF can induce the reactive oxygen species (ROS) signaling for cell adhesion, migration and invasion of tumors including HCC. On the other hand, extracellular signal-regulated kinases (ERK), member of mitogen activated kinase, can be activated by ROS for a lot of cellular processes. As expected, HGF-induced phosphorylation of ERK and progression of HCC cell HepG2 were suppressed by ROS scavengers. By N-(biotinoyl)-N'-(iodoacetyl)-ethylenediamine (BIAM) labeling method, a lot of cysteine (-SH)-containing proteins with M.W. 50-75 kD were decreased in HepG2 treated with HGF or two other ROS generators, 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and phenazine methosulfate. These redox sensitive proteins were identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Among them, two chaperones, heat shock protein 60 (HSP60) and protein disulfide isomerase (PDI), were found to be the most common redox sensitive proteins in responding to all three agonists. Affinity blot of BIAM-labeled, immunoprecipitated HSP60 and PDI verified that HGF can decrease the cysteine (-SH) containing HSP60 and PDI. On the other hand, HGF and TPA increased cysteinyl glutathione-containing HSP60, consistent with the decrease of cysteine (-SH)-containing HSP60. Moreover, depletion of HSP60 and PDI or expression of dominant negative mutant of HSP60 with alteration of Cys, effectively prevented HGF-induced ERK phosphorylation and HepG2 migration.In conclusion, the redox sensitive HSP60 and PDI are required for HGF-induced ROS signaling and potential targets for preventing HCC progressions.
    No preview · Article · Feb 2016 · Oncotarget
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    ABSTRACT: Arterial stiffness is recognized as an independent risk factor for cardiovascular morbidity and mortality. Recent studies found that osteoprotegerin (OPG) is associated with arterial stiffness and may reflect endothelial dysfunction. The aim of this study was to evaluate the relationship between fasting serum OPG levels and the aortic augmentation index (AIx) in renal transplant recipients.
    Preview · Article · Feb 2016 · Tzu Chi Medical Journal
  • Wen-Yao Yin · Ming-Che Lee · Hsien-Bin Huang · Ming-Chi Lu
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    ABSTRACT: We aimed to investigate the roles of cytokines during polyomavirus BK (BKV) reactivation in renal transplant patients. Forty-eight renal allograft recipients were enrolled and their sera BKV viral load and mRNA expression levels of cytokines in peripheral blood mononuclear cells were measured by real-time polymerase chain reaction. Patient's age and gene expression levels of interleukin (IL)-2 (10.04 ± 2.63 vs. 8.70 ± 2.40, P = 0.049) and transforming growth factor (TGF)-β (12.58 ± 2.59 vs. 10.89 ± 1.91, P = 0.015) were significantly higher in BKV viremia (+) renal transplant patients. Multivariate logistic regression analysis revealed that age and mRNA expression levels of TGF-β, but not IL-2, significantly correlated with the presence of BKV viremia. Sera BKV viral loads showed a positive correlation with patient age and the levels of TGF-β and IL-6 mRNA. After adjusting for age and sex in the regression model, both age and TGF-β mRNA levels maintained a significant positive association with sera BKV viral loads. Serum TGF-β concentration tended to be higher in BKV viremia (+) patients (P = 0.079). In conclusion, expression levels of TGF-β were found to correlate with both BKV viremia positivity and sera BKV viral loads in renal transplant patients. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Clinical Transplantation
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    ABSTRACT: Osteoprotegerin (OPG) is a cytokine that regulates bone resorption by inhibiting osteoclastogenesis, and OPG has been implicated in the process that causes vascular stiffness. An increase in serum OPG level has been associated with the development of arterial stiffness. Kidney transplant (KT) patients are susceptible to aortic stiffness, which is considered to be a predictor of cardiovascular events in this patient population. Carotid-femoral pulse wave velocity (cfPWV) has emerged as a gold standard for non-invasive evaluation of aortic stiffness. The aim of this study was to evaluate the relationship between serum OPG concentration and cfPWV among KT patients. Fasting blood samples were obtained from 57 KT patients and their cfPWV was measured using applanation tonometry. The serum OPG levels were measured using an enzyme-linked immunosorbent assay. Univariable linear regression analysis showed that the cfPWV in KT patients was significantly and positively correlated with age, body weight, waist circumference, body mass index, log-creatinine, systolic blood pressure, diastolic blood pressure, pulse pressure, and the log-OPG concentration. KT patients with metabolic syndrome had higher cfPWV values than those without metabolic syndrome (P = 0.036), which indicates a higher incidence of aortic stiffness in this patient population. Multivariable forward stepwise linear regression analysis of the significant variables showed that the log-OPG (P = 0.001), the log-creatinine (P = 0.004), and the SBP (P = 0.005) remained as independent and positive predictors of cfPWV values. These findings indicate that serum OPG levels are positively associated with cfPWV in KT patients.
    Full-text · Article · Jul 2015 · The Tohoku Journal of Experimental Medicine
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    ABSTRACT: One of the signaling components involved in hepatocellular carcinoma (HCC) progression is the focal adhesion adaptor paxillin. Hydrogen peroxide inducible clone-5 (Hic-5), one of the paralogs of paxillin, exhibits many biological functions distinct from paxillin, but may cooperate with paxillin to trigger tumor progression. Screening of Hic-5 in 145 surgical HCCs demonstrated overexpression of Hic-5 correlated well with intra- and extra-hepatic metastasis. Hic-5 highly expressed in the patient derived HCCs with high motility such as HCC329 and HCC353 but not in the HCCs with low motility such as HCC340. Blockade of Hic-5 expression prevented constitutive migration of HCC329 and HCC353 and HGF-induced cell migration of HCC340. HCC329Hic-5(-), HCC353Hic-5(-), HCC372Hic-5(-), the HCCs stably depleted of Hic-5, exhibited reduced motility compared with each HCC expressing Scramble shRNA. Moreover, intra/extrahepatic metastasis of HCC329Hic-5(-) in SCID mice greatly decreased compared with HCC329Scramble. On the other hand, ectopic Hic-5 expression in HCC340 promoted its progression. Constitutive and HGF-induced Hic-5 expression in HCCs were suppressed by the reactive oxygen species (ROS) scavengers catalase and dithiotheritol and c-Jun N-terminal kinase (JNK) inhibitor SP600125. On the contrary, depletion of Hic-5 blocked constitutive and HGF-induced ROS generation and JNK phosphorylation in HCCs. Also, ectopic expression of Hic-5 enhanced ROS generation and JNK phosphorylation. These highlighted that Hic-5 plays a central role in the positive feedback ROS-JNK signal cascade. Finally, the Chinese herbal derived anti-HCC peptide LZ-8 suppressed constitutive Hic-5 expression and JNK phosphorylation. In conclusion, Hic-5 mediates ROS-JNK signaling and may serve as a therapeutic target for prevention of HCC progression.
    No preview · Article · Jul 2015 · Oncotarget
  • Wen-Yao Yin · Ming-Che Lee · Ning-Sheng Lai · Ming-Chi Lu
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    ABSTRACT: Renal transplant patients have high risk for bladder cancer. The reactivation of BK virus is common in renal transplant patients especially in the urinary tract. There was some evidence suggesting that the reactivation of BK virus (BKV) in renal transplant patients may associate with the development of bladder cancer. Here we demonstrated that a patient that had persistent elevated BKV viruria (urine BKV DNA concentration more than 10(11) copies/ml) after renal transplantation. Then, bladder cancer was found in 13 months after kidney transplantation. The urine BKV DNA concentration was detected by real-time PCR and the BKV DNA in the bladder tumor was detected by PCR. BKV DNA was found in the marginal and central part of the bladder tumor. After removal of the bladder cancer, the urine BKV viral load in this patients dropped dramatically to <10(2) copies/ml. However, the urine viral load had increased modestly to 10(6) copies/ml in 3 months after surgery. Since there is a close correlation between the urine BK viral load and the presence of bladder cancer, we suggested that there might be a causal relationship between the reactivation of BKV and the development of bladder cancer in renal transplant patient. Copyright © 2012. Published by Elsevier B.V.
    No preview · Article · Apr 2015 · Journal of the Formosan Medical Association
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    ABSTRACT: Hepatocellular carcinoma (HCC) is among the most lethal cancers. Mounting studies highlighted the essential role of the HGF/c-MET axis in driving HCC tumor progression. Therefore, c-Met is a potential therapeutic target for HCC. However, several concerns remain unresolved in c-Met targeting. First, the status of active c-Met in HCC must be screened to determine patients suitable for therapy. Second, resistance and side effects have been observed frequently when using conventional c-Met inhibitors. Thus, a preclinical system for screening the status of c-Met signaling and identifying efficient and safe anti-HCC agents is urgently required. In this study, immunohistochemical staining of phosphorylated c-Met (Tyr1234) on tissue sections indicated that HCCs with positive c-Met signaling accounted for approximately 46% in 26 cases. Second, many patient-derived HCC cell lines were established and characterized according to motility and c-Met signaling status. Moreover, LZ8, a medicinal peptide purified from the herb Lingzhi, featuring immunomodulatory and anticancer properties, was capable of suppressing cell migration and slightly reducing the survival rate of both c-Met positive and negative HCCs, HCC372, and HCC329, respectively. LZ8 also suppressed the intrahepatic metastasis of HCC329 in SCID mice. On the molecular level, LZ8 suppressed the expression of c-Met and phosphorylation of c-Met, ERK and AKT in HCC372, and suppressed the phosphorylation of JNK, ERK, and AKT in HCC329. According to receptor array screening, the major receptor tyrosine kinase activated in HCC329 was found to be the epidermal growth factor receptor (EGFR). Moreover, tyrosine-phosphorylated EGFR (the active EGFR) was greatly suppressed in HCC329 by LZ8 treatment. In addition, LZ8 blocked HGF-induced cell migration and c-Met-dependent signaling in HepG2. In summary, we designed a preclinical trial using LZ8 to prevent the tumor progression of patient-derived HCCs with c-Met-positive or -negative signaling.
    Preview · Article · Jan 2015 · PLoS ONE
  • Wen-Yao Yin · Malcolm Koo · Ming-Che Lee · Ming-Chi Lu

    No preview · Article · Oct 2014 · Transplantation
  • Kuei-Chun Chou · Ming-Che Lee
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    ABSTRACT: Kidney transplantation is one strategy for treating end-stage renal disease. Recent advances in perioperative management and immunosuppressive agents as well as improved understanding of transplant immunology have improved the post-surgery quality of life of kidney recipients dramatically. However, lifelong monitoring of renal functions and potential complications is essential to ensure optimal medical outcomes. Furthermore, the self-care competency of transplant recipients is a significant factor affecting survival of the graft and the patient over the long term. All kidney transplant recipients should comply with the self-care instructions provided by transplantation medical personnel and work to improve their self-care abilities in order to prevent / detect post-transplant complications such as rejection, infection, and medical comorbidities as early as possible. The purpose of this study is to explore the current management and care issues faced by kidney transplant recipients.
    No preview · Article · Aug 2014 · Hu li za zhi The journal of nursing
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    ABSTRACT: Background: Adiponectin is a fat-derived hormone produced and secreted exclusively by adipocytes that have anti-atherosclerotic effects. The aim of this study was to evaluate the relationship between fasting serum adiponectin levels and arterial stiffness among kidney transplant (KT) patients. Methods: Fasting blood samples were obtained from 69 KT patients. Brachial-ankle pulse wave velocity (baPWV) was measured in the right or left brachial artery to the ankle segments using an automatic pulse wave analyzer. Plasma adiponectin levels were measured using a commercial enzyme-linked immunosorbent assay kit. Left or right baPWV values of >14.0 m/s were used to define the high arterial stiffness group. Results: Thirty-five KT patients (35/69; 50.7 %) were defined in high arterial stiffness group. Diabetes (P = 0.013), smoking (P = 0.001), KT duration (P < 0.001), body weight (P = 0.013), waist circumference (P = 0.013), body mass index (P = 0.001), fasting glucose (P = 0.013), systolic blood pressure (P < 0.001), diastolic blood pressure (P = 0.008), and pulse pressure (P = 0.003) were higher, while serum adiponectin level (P = 0.004) was lower in high arterial stiffness group compared with low arterial stiffness group. Multivariate logistic regression analysis showed that adiponectin (odds ratio 0.90, 95 % confidence interval 0.81-0.99, P = 0.034) was still the independent predictors of arterial stiffness among the KT patients. Conclusion: Serum fasting adiponectin level was inversely associated with arterial stiffness among KT patients.
    Full-text · Article · Jul 2014 · Clinical and Experimental Nephrology

  • No preview · Article · May 2014 · Gastroenterology
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    ABSTRACT: Peripheral arterial diseases associated with an increased risk of death in kidney transplant patients. Natriuretic peptide has anti-atherosclerotic effects. We sought to evaluate the relation between ankle-brachial index and fasting serum long-acting natriuretic peptide concentrations in kidney transplant patients. Fasting blood samples were obtained from 69 kidney transplant patients. Serum long-acting natriuretic peptide concentrations were measured using a commercially available enzyme immunoassay kit. Left or right ankle-brachial index values that were < 0.9 were included in the low ankle-brachial index group. Fifteen patients (21.7%) were enrolled in the low ankle-brachial index group. Increased waist circumference (P = .013), higher serum total cholesterol levels (P = .019), higher triglyceride levels (P = .002), and decreased serum long-acting natriuretic peptide concentrations (P = .006) were noted in the low ankle-brachial index group. Univariate linear regression analysis indicated that the left/right ankle-brachial index values of the subjects were negatively correlated with serum triglycerides (P = .008 or P < .001) and fasting glucose levels (P = .034 or P = .012), but were positively correlated with long-acting natriuretic peptide concentrations (P = .011 or P = .011). Multivariate forward stepwise linear regression analyses of the significant variables revealed that serum triglycerides and long-acting natriuretic peptide levels were independent predictors of the left/right ankle-brachial index values of kidney transplant patients. Serum long-acting natriuretic peptide concentrations correlate positively with anklebrachial index values among the kidney transplant patients.
    Full-text · Article · Aug 2013
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    ABSTRACT: Objectives Renal transplant patients receive calcineurin inhibitors to suppress the calcineurin-nuclear factor of activated T cells (NFAT) pathway. The DNA binding activity of NFAT and its relationship to the reactivation of BK virus (BKV) has not been evaluated in renal transplant patients.Patients and Methods The DNA binding activity of NFAT cytoplasmic 1 (NFATc1) was measured by enzyme-linked immunosorbent assay in peripheral blood mononuclear cells from 26 renal transplant patients and 26 healthy controls. At the same time, their urinary BKV viral load was measured by real-time polymerase chain reaction.ResultsThe activity of NFATc1 was lower in renal transplant patients without BKV viruria [BKV (−)] than in healthy controls, while it trended to be higher in renal transplant patients with BKV viruria [BKV (+)] than in BKV (−) patients. The tacrolimus blood levels did not differ between BKV (+) and BKV (−) renal transplant patients or correlate with NFATc1 activity.ConclusionNFATc1 DNA binding activity was lower in renal transplant patients without BKV viruria than in those who were BKV (+). However, there was no relationship between tacrolimus blood levels and NFATc1 activity in renal transplant patients.
    No preview · Article · Jun 2013 · Tzu Chi Medical Journal
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    ABSTRACT: Aim: Arterial stiffness is an established cardiovascular risk marker and an independent predictor of cardiovascular events and mortality in various groups of patients, including renal transplant recipients. Recent studies have noted that B-type natriuretic peptide (BNP) acts as a local paracrine molecule that modulates endothelial permeability and regeneration. The aim of this study was to evaluate the relationship between the serum N-terminal pro-BNP (NT-pro-BNP) level and arterial stiffness in renal transplant recipients. Methods: Fasting blood samples were obtained from 66 renal transplant recipients. The cardio-ankle vascular index was calculated using the waveform device (CAVI-VaSera VS-1000). The serum NTpro-BNP levels were measured using an electrochemiluminescence immunoassay. A CAVI value of ≥9 was used to define a high level of arterial stiffness. Results: Thirty-two patients (48.5%) were classified into the high arterial stiffness group. Diabetes (p=0.030), smoking (p<0.001), duration of kidney transplantation (p=0.001), body weight (p=0.014), waist circumference (p=0.022), body mass index (p=0.001) and the fasting glucose (p=0.021) and serum NT-pro-BNP (p<0.001) levels were higher in the high arterial stiffness group than in the low arterial stiffness group. A multivariate forward stepwise linear regression analysis showed that the log-NT-pro-BNP level (β: 0.459, p<0.001) remained an independent predictor of the CAVI value in the renal transplant recipients. Conclusions: The serum fasting NT-pro-BNP level is associated with arterial stiffness in renal transplant recipients.
    No preview · Article · May 2013 · Journal of atherosclerosis and thrombosis

  • No preview · Article · May 2013 · Gastroenterology
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    ABSTRACT: Objective: Muscarinic receptors mediate contraction of the human gallbladder through unclear receptor subtypes. The aim of the present study was to characterize muscarinic acetylcholine receptors mediating contraction of the human gallbladder. Materials and methods: Contraction of human gallbladder muscle strips caused by agonists carbachol and muscarine was measured and the inhibition of carbachol-induced contraction by muscarinic receptor antagonists was evaluated. Reverse transcription polymerase chain reaction was performed to determine the existence of muscarinic receptor subtypes. Results: Carbachol and muscarine caused concentration-dependent contraction of gallbladder strips. Four receptor antagonists, including atropine, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), methoctramine, and pirenzepine, inhibited the carbachol-induced contraction. The relative inhibitory potency of these receptor antagonists was atropine > 4-DAMP > methoctramine > pirenzepine. The antagonist affinity estimates (pA(2) values) correlated with the known affinities at M(3), M(4), and M(5) muscarinic receptors. In addition, the M(4)-selective antagonist muscarinic toxin 3 did not inhibit and the M(5)-selective positive allosteric modulator VU0238429 did not potentiate carbachol-induced gallbladder contraction. This suggests that M(3) muscarinic receptors mediate the muscarinic response predominantly. The contractile response of carbachol was attenuated by the voltage-gated Ca(2+) channel inhibitor nifedipine and Rho-kinase inhibitor H-1152, but not affected by protein kinase C inhibitor chelerythrine. This implies the involvement of voltage-gated Ca(2+) channel and Rho kinase but not protein kinase C. Conclusions: These results suggest a major role of M(3) muscarinic receptors mediating the human gallbladder contraction through voltage-gated Ca(2+) channels and Rho kinase. M(3)-selective muscarinic receptor antagonists could be of therapeutic importance in the treatment of biliary motility disorders.
    No preview · Article · Dec 2012 · Scandinavian Journal of Gastroenterology
  • Yen-Cheng Chen · Guan-Jin Ho · Ying-Chin Yang · Ming-Che Lee
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    ABSTRACT: Surgical portosystemic shunts are safe and effective for treating rebleeding gastric varices (GV) in portal hypertensive patients with well-preserved liver function. The aim of this study is to investigate the clinical outcomes of using selected surgical shunts for managing rebleeding GV at a single institution in eastern Taiwan.Materials and Methods We retrospectively recruited 12 patients who received distal splenorenal shunts (DSRS) following the indication of rebleeding GV or hypersplenism from January 2001 through December 2010. Their demographic data, etiology of portal hypertension, associated treatments, perioperative complications and clinical outcomes were reviewed.ResultsAll patients received DSRS, including 10 adults and two children, and were examined for a median follow-up period of 53 months. No postoperative encephalopathy, major complications, or surgical mortality occurred. Two of the patients were waiting for liver transplants. Late rebleeding in esophageal varices developed in two patients who were successfully managed using endoscopic treatment. The etiology of portal hypertension had no significant impact on the postoperative complications.Conclusion Although there were a limited number of cases in this series, our results indicate that the DSRS is an effective treatment for rebleeding GV, especially for patients with well-preserved liver function and taking into account the realities of organ shortages.
    No preview · Article · Jun 2012 · Tzu Chi Medical Journal
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    ABSTRACT: Background: BK virus (BKV) is known to be associated with nephropathy. Here, we investigated the relationships between BKV levels, T-cell activation, and kidney function in kidney transplant recipients. Materials and methods: In renal transplant patients and controls, urine BKV levels were detected by quantitative real-time PCR, and the percentage of activated T lymphocytes in blood was determined by flow cytometry. The correlations between viral load, activated T cell percentage, and renal function were determined. Results: Urine BKV viral loads and the activated T cell percentage were significantly elevated in transplant recipients. Correlational analysis indicated that transplant recipients that had BKV levels of more than 10(6) copies/mL and an activated T lymphocyte percentage of less than 20% were likely to have poor renal function. Conclusions: Urine BKV levels and the percentage of activated T lymphocytes can be used as clinical indices to optimize the dosage of immunosuppressive drugs.
    No preview · Article · May 2012 · Journal of Surgical Research

  • No preview · Article · May 2012 · Gastroenterology
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    Jing-Liang Chen · Ming-Che Lee · Hann-Chorng Kuo
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    ABSTRACT: Reduced bladder capacity and compliance in patients with end-stage renal disease (ESRD) may affect storage and voiding function after kidney transplantation. This study evaluated the bladder capacity, compliance, and lower urinary tract dysfunction in ESRD patients with duration after dialysis and anuria. Adults with ESRD on kidney transplantation waiting list were consecutively enrolled. The survey items included videourodynamic study (VUDS), renal ultrasound, and cystoscopy. The analytical variables assessed included the duration of dialysis, the duration of anuria, cystometric bladder capacity and bladder compliance, voiding phases in VUDS, and cystoscopic findings. A total of 62 patients with a mean dialysis duration of 58.9 ± 6.3 months were enrolled. The mean cystometric bladder capacity was 178 ± 14 mL and decreased significantly with duration of dialysis (p < 0.001). Anuria was diagnosed in 26 patients, and the mean cystometric bladder capacity decreased significantly with the duration of anuria (p = 0.002). Among the 26 patients with anuria, 16 had a poor bladder compliance. VUDS revealed abnormal storage function in 44 (71.0%) patients and bladder outlet obstruction due to bladder neck dysfunction or urethral narrowing in the voiding phase in 32 (51.6%). Abnormal cystoscopic findings were also noted in 30 (48.4%) patients. Cystometric bladder capacity and bladder compliance decreased with longer duration of dialysis, and the presence of anuria contributed to further decreases in cystometric bladder capacity and bladder compliance. More than two-thirds of patients with ESRD had abnormal findings on VUDS.
    Preview · Article · Apr 2012 · Journal of the Formosan Medical Association