Yuh-Feng Lin

National Taiwan University, T’ai-pei, Taipei, Taiwan

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Publications (97)260.12 Total impact

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    ABSTRACT: Introduction. Chronic kidney disease (CKD) is a health burden and an increasing public health issue. Prevalence is estimated to be 8–16% worldwide. The goal was to construct an easily-implemented model to predict CKD occurrence. We were especially interested in models that rely solely on information available to a clinical laboratory, enabling reporting the risk of CKD occurrence with clinical results. Methods. The study cohort included patients aged>18 years in the community between 2008 and 2013 with follow-up. CKD is defined as abnormalities of kidney function, present for >3 months. Individuals developed CKD defined by the glomerular filtration rate < 60 mL/min/1.73 m2. All subjects were followed-up from the date of cohort entry until they developed CKD or until the end of 2013. Data analysis was made using SAS Version 9.3. Results. There were 779 men and 873 women at baseline in the cohort. At follow-up, 25% (n=408) had developed CKD. In CKD group (N=408), the mean age was 63.9 ± 12.74 years. Age, diabetes mellitus, hypertension, medical history of gout, cardiovascular disease and genitourinary disease were significantly associated with the occurrence of CKD (P<0.05). The most fitted model for CKD occurrence included age, waist circumstance, anemia, hyperuricemia, medical history of gout, hypertension, and genitourinary disease. (AUC = 0.683). Conclusion. We evaluated predictors of CKD occurrence among individuals in the community and constructed a clinical model to predict the incidence of CKD progression. This prediction tool which may help to identify subjects at risk of CKD is routinely obtained history and laboratory examinations. Improved clinical prediction is a cornerstone of individualized medicine.
    142nd APHA Annual Meeting and Exposition 2014; 11/2014
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    ABSTRACT: Background/Aims: End-stage renal disease (ESRD) is simultaneously associated with immune activation, systemic inflammation and immune deficiency. Toll-like receptor 3 (TLR3), a receptor for viral double-stranded RNA, is involved in immune cell activation in renal diseases and may contribute to chronic inflammatory disease progression. To date, effects of TLR3 polymorphisms on ESRD remain unknown. Therefore, we determined the predictive value of TLR3 polymorphisms and further functionally studied ESRD. Methods: We performed a case-control association study and genotyped 616 ESRD patients and 813 healthy controls. Patients were genotyped for -7C/A, 1377C/T and 1234C/T polymorphisms of TLR3 using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The Haplotype association analysis was performed using the Haploview package. A luciferase reporter assay and real-time PCR were used to test the function of the -7C/A promoter polymorphism in TLR3 expression in human embryonic kidney 293 (HEK293) cells. Results: Genotype distributions of -7C/A and 1377C/T in TLR3 were significantly different in ESRD patients and healthy controls. The ATC haplotype of TLR3 was associated with a decreased risk of ESRD. We also found significant differences in TLR3 expression by dexamethasone treatment between various genotypes of -7C/A (p = 0.02). TLR3 transcriptional activity of the variant -7 C allele was higher than that of the -7 A allele after dexamethasone treatment. Conclusion: Results indicate that, in our population, the presence of the C allele of -7C/A in TLR3 increases the susceptibility to ESRD. In vitro studies demonstrated that -7C/A may be involved in ESRD development through transcriptional modulation of TLR3. © 2014 S. Karger AG, Basel.
    American journal of nephrology. 08/2014; 40(2):131-139.
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    ABSTRACT: A recent study demonstrated that an increased risk of chronic kidney disease (CKD) was associated with high urinary total arsenic levels. However, whether genomic instability is related to CKD remains unclear. An association between CKD and genetic polymorphisms of regulation enzymes of the renin-angiotensin-aldosterone system (RAAS), such as angiotensin-converting enzyme (ACE), angiotensinogen (AGT), angiotensin II type I receptor (AT1R), and aldosterone synthase (CYP11B2) has not been shown. The aim of the present study was to investigate the relationship between arsenic, genetic polymorphisms of RAAS enzymes and CKD. A total of 233 patients and 449 age- and gender-matched controls were recruited from the Taipei Medical University Hospital, Taipei Municipal Wan Fang Hospital and the Shin Kong Wu Ho-Su Memorial Hospital. Concentrations of urinary arsenic were determined by a high-performance liquid chromatography-linked hydride generator, and atomic absorption spectrometry. Polymorphisms of ACE(I/D), AGT(A[-20]C), (T174M), (M235T), AT1R(A1166C) and CYP11B2(C[-344]T) were examined by polymerase chain reaction and restriction fragment length polymorphism. Subjects carrying the CYP11B2 TT genotype had a higher odds ratio (OR), 1.39 (0.96 - 2.01), of CKD; while those with the AGT (A[-20]C) CC genotype had an inverse OR of CKD (0.20 (0.05 - 0.81)), and a high-risk genotype was defined as A/A+A/C for AGT(A[-20C]) and T/T for CYP11B2(C[-344]T)). The trend test showed a higher OR for CKD in patients who had either high urinary total arsenic levels or carried the high-risk genotype, or both, compared to patients with low urinary total arsenic levels, who carried the low-risk genotype, and could also be affected by the hypertension or diabetes status.
    Toxicology and Applied Pharmacology 06/2014; · 3.98 Impact Factor
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    05/2014; 29 Suppl 3:iii90-iii101.
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    ABSTRACT: Membranous nephropathy (MN) is a common cause of nephrotic syndrome that may progress to end-stage renal disease (ESRD). The formation of MN involves the in situ formation of subepithelial immune deposits and leads to albuminuria; however, the underlying mechanism of how MN leads to ESRD remains unclear. The aim of this study was to investigate the expression and biological functions of phosphotriesterase-related protein (PTER) in MN. The PTER expression level was assessed by immunohistochemical staining, quantitative real-time PCR and Western blot analysis in MN mouse model and clinical cases. Results. The relationship between PTER and albuminuria was determined by in vitro albuminuria tubular cell model. In the progression of MN, the expression of PTER was increased significantly and mainly expressed in the renal tubular cells. Both mRNA and protein expression levels of PTER were increased in a concentration- and time-dependent manner in the in vitro albuminuria tubular cell model. Silencing the expression of PTER by RNA interference diminished albuminuria-induced inflammatory and pro-fibrotic cytokines production. Conclusions Our findings reveal that PTER may sense albuminuria in the progression of MN, induce tubular cell activation and lead to ESRD.
    Journal of Biomedical Science 04/2014; 21(1):32. · 2.46 Impact Factor
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    ABSTRACT: The safety and efficacy of continuous infusion vs bolus injection of intravenous loop diuretics to treat acute decompensated heart failure were debated. Our aim is to compare the administration routes of diuretics in hospitalized patients with acute decompensated heart failure. A systematic review and meta-analysis of randomized controlled trials was performed to evaluate the effects of continuous infusion vs bolus administration of loop diuretics in patients with acute decompensated heart failure. The primary end points were urine outputs, body weight loss, all causes of mortality, and death from cardiovascular causes. Secondary end points were electrolyte imbalance, change in creatinine levels, tinnitus or hearing loss, and days of hospitalization. Ten randomized controlled trials with 518 patients were identified. Continuous infusion of diuretics was associated with a significantly greater weight loss (weighted mean difference, 0.78; 95% confidence interval, 0.03-1.54) compared with bolus injection. Urine output, the incidence of electrolyte imbalance, change in creatinine level, length of hospitalization, the incidence of ototoxicity, cardiac mortality, and all-cause mortality showed no significant differences between the 2 groups. Meta-analysis of the existing limited studies did not confirm any significant differences in the safety and efficacy with continuous administration of loop diuretic, compared with bolus injection in patients with acute decompensated heart failure.
    Journal of critical care 02/2014; 29(1):2-9. · 2.13 Impact Factor
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    ABSTRACT: The yam tuber is a traditional Chinese medicine used in long-term treatment as a juvenescent substance. The purified yam tuber's major water-soluble protein, dioscorin, and its protease hydrolysates have been reported to have several biological activities. In this study, D-galactose (Gal) was subcutaneously injected into the dorsal necks of BALB/c mice daily for 10 weeks (Gal group) to induce oxidative stress. By the fifth week, 20 or 80 mg dioscorin/kg was orally administered daily combined with a daily Gal injection until the end of the study. The plasma malondialdehyde (MDA) level and advanced glycation end-products obtained after dioscorin oral administrations were lower compared to the Gal group. In addition, the latency and swimming distance in the mice that received dioscorin administration were significantly improved compared to the Gal group in the Morris water maze. Dioscorin administration resulted in higher GSH levels and oxygen radical antioxidant capacity (ORAC) activity and lower MDA and inducible nitric oxide synthase (iNOS) levels in the brain compared to mice in the Gal group. These elevated antioxidant activities following oral administration of yam dioscorin in vivo may reflect traditional juvenescent uses with the potential for anti-aging treatments.
    Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 01/2014; · 2.99 Impact Factor
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    ABSTRACT: The aberrant activation of Wnt/β-catenin signaling plays an important role in the carcinogenesis and progression of hepatocellular carcinoma (HCC). Therefore, the Wnt/β-catenin signaling molecules are attractive candidates for the development of targeted therapies for this disease. The present study showed that destruxin B (DB) inhibits the proliferation and induces the apoptosis of HCC cells by decreasing the protein expression of anti-apoptotic Bcl-2 and Bcl-xL and increasing the expression of the proapoptotic protein Bax. More importantly, DB also attenuates Wnt-signaling in HCC cells by downregulating β-catenin, Tcf4, and β-catenin/Tcf4 transcriptional activity, which results in the decreased expression of β-catenin target genes, such as cyclin D1, c-myc, and survivin. Furthermore, DB affects the migratory and invasive abilities of Sk-Hep1 cells through the suppression of markers of the epithelial-mesenchymal transition (EMT). A synergistic anti-proliferative and migratory effect was achieved using the combination of DB and sorafenib in Sk-Hep1 cells. In conclusion, DB acts as a novel Wnt/β-catenin inhibitor and reduces the aggressiveness and invasive potential of HCC by altering the cells' EMT status and mobility. DB in combination with sorafenib may be considered for future clinical use for the management of metastatic HCC.
    Toxicology in Vitro 01/2014; · 2.65 Impact Factor
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    ABSTRACT: Transcriptional repressor activating transcription factor 3 (ATF3) is induced by various stress stimuli, including inflammation-induced renal injury. In addition, ATF3 also down-regulates adhesion molecules like intercellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), and monocyte chemotactic protein-1 (MCP-1). However, the relation between up-regulated ATF3 after renal ischemia/reperfusion (I/R) injury and MCP-1 is not completely understood. In this study, we demonstrated that, in renal I/R induced inflammation, induction of adhesion molecules (interleukin-6, P-selectin, E-selectin, ICAM, VCAM, and MCP-1) was higher in ATF3-knockout mice than in wild-type animals. Molecular and biochemical analyses revealed that ATF3 binds to the ATF/CRE sites in the MCP-1 promoter and inhibits the secretion of MCP-1 from renal epithelial cells after I/R injury. Urinary exosome containing ATF3 RNA was 60-fold higher in patients with acute kidney injury than in normal controls, but no difference in total urinary ATF3 RNA levels was found. In addition, in vitro study showed that exosome containing ATF3 RNA derived from epithelial cells also inhibits MCP-1 expression in the epithelial cells and macrophage migration. Furthermore, direct administration of the epithelium-derived exosomal ATF3 RNA attenuates I/R induced kidney injury. Together, our studies reveal a novel regulatory mechanism of MCP-1 expression mediated by the exosomal ATF3 RNA under renal I/R insult and suggest a potential targeted therapy for I/R induced acute kidney injury. J. Cell. Physiol. 9999: XX-XX, 2014. © 2014 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 01/2014; · 4.22 Impact Factor
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    ABSTRACT: The present study was designed to explore the effects of GAS6 and AXL gene polymorphisms on adiposity, systemic inflammation, and insulin resistance in adolescents. After multistage sampling from the data of the Taipei Children Heart Study-III, we collected 358 boys and 369 girls with an average age of 13.3 years. We genotyped the adolescents' GAS6 rs8191973, GAS6 rs8191974, AXL rs4802113, and AXL rs2304232 polymorphisms. Significantly higher body mass index (BMI), waist circumference (WC), and hsCRP levels were found in boys with the GG genotype of GAS6 rs8191974 than A allele carriers; higher IL-6 and insulin levels and increased HOMA-IR were found in boys with the GG genotype of AXL rs2304232 than the A allele carriers. There was a significant difference in hsCRP levels of boys with the TT, TC, and CC genotypes of AXL rs4802113. Boys with both the GG genotype of GAS6 rs8191973 and the GG genotype of GAS6 rs8191974 exhibited higher BMI, WC, IL-6, and hsCRP levels than the boys carrying both the C allele of the GAS6 rs8191973 and the A allele of the GAS6 rs8191974. In conclusion, GAS6 and AXL polymorphisms are associated with adiposity, systemic inflammation, and insulin resistance in adolescents, especially in boys.
    International Journal of Endocrinology 01/2014; 2014:674069. · 2.52 Impact Factor
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    ABSTRACT: To determine if expenditures for dentistry (DENT) correlate with severity of chronic kidney disease (CKD). A total of 10,457 subjects were enrolled from January 2008 to December 2010, divided into three groups: healthy control (HC) group (n = 1,438), high risk (HR) group (n = 3,392), and CKD group (n = 5,627). Five stages were further categorized for the CKD group. OPD utilization and expenditures for western medicine (WM), DENT, and TCM (traditional Chinese medicine) were analyzed retrospectively (2000-2008) using Taiwan's National Health Insurance Research Database. Three major areas were analyzed among groups CKD, HR and HC in this study: 1) demographic data and medical history; 2) utilization (visits/person/year) and expenditures (9-year cumulative expenditure, expenditure/person/year) for OPD services in WM, DENT, and TCM; and 3) utilization and expenditures for dental OPD services, particularly in dental filling, root canal and periodontal therapy. OPD utilization and expenditures of WM increased significantly for the CKD group compared with the HR and HC groups, and increased steadily along with the severity of CKD stages. However, overall DENT and TCM utilization and expenditures did not increase for the CKD group. In comparison among different CKD stages, the average expenditures and utilization for DENT including restorative filling and periodontal therapy, but not root canal therapy, showed significant decreases according to severity of CKD stage, indicating less DENT OPD utilization with progression of CKD. Patients with advanced CKD used DENT OPD service less frequently. However, the connection between CKD and DENT service utilization requires further study.
    PLoS ONE 01/2014; 9(2):e88418. · 3.53 Impact Factor
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    ABSTRACT: A recent study demonstrated that an increased risk of chronic kidney disease (CKD) was associated with high urinary total arsenic levels. However, whether genomic instability is related to CKD remains unclear. An association between CKD and genetic polymorphisms of regulation enzymes of the renin–angiotensin–aldosterone system (RAAS), such as angiotensin-converting enzyme (ACE), angiotensinogen (AGT), angiotensin II type I receptor (AT1R), and aldosterone synthase (CYP11B2) has not been shown. The aim of the present study was to investigate the relationship between arsenic, genetic polymorphisms of RAAS enzymes and CKD. A total of 233 patients and 449 age- and gender-matched controls were recruited from the Taipei Medical University Hospital, Taipei Municipal Wan Fang Hospital and the Shin Kong Wu Ho-Su Memorial Hospital. Concentrations of urinary arsenic were determined by a high-performance liquid chromatography-linked hydride generator, and atomic absorption spectrometry. Polymorphisms of ACE(I/D), AGT(A[− 20]C), (T174M), (M235T), AT1R(A1166C) and CYP11B2(C[− 344]T) were examined by polymerase chain reaction and restriction fragment length polymorphism. Subjects carrying the CYP11B2 TT genotype had a higher odds ratio (OR), 1.39 (0.96–2.01), of CKD; while those with the AGT(A[− 20]C) CC genotype had an inverse OR of CKD (0.20 (0.05–0.81)), and a high-risk genotype was defined as A/A + A/C for AGT(A[− 20C]) and T/T for CYP11B2(C[− 344]T). The trend test showed a higher OR for CKD in patients who had either high urinary total arsenic levels or carried the high-risk genotype, or both, compared to patients with low urinary total arsenic levels, who carried the low-risk genotype, and could also be affected by the hypertension or diabetes status.
    Toxicology and Applied Pharmacology 01/2014; · 3.98 Impact Factor
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    ABSTRACT: Objective. In this study, we investigated whether RAAS gene single nucleotide polymorphisms (SNPs) and their interactions were associated with end-stage renal stage (ESRD). Methodology and Results. This was a case-control study for 647 ESRD cases and 644 controls. AGT (M235T (rs699) and T174M (rs4762)), AGTR1 (A1166C (rs5186) and C573T (rs5182)), ACE (I/D (rs1799752) and G2350A (rs4343)), and CYP11B2 C-344T (rs1799998) were genotyped and compared between cases and controls to identify SNPs associated with ESRD susceptibility. Multifactor dimensionality reduction (MDR) was used to identify gene-gene interactions. Several RAAS genes were associated with ESRD: AGT M235T, ACE I/D, ACE G2350A, and CYP11B2 C-344T. By MDR analysis, a three-locus model (ACE ID/ACE G2350A/CYP11B2 C-344T) of gene-gene interaction was the best for predicting ESRD risk, and its maximum testing accuracy was 56.08% and maximum cross-validation consistency was 9/10. ESRD risk was higher with the simultaneous occurrence of ACE I/D DD-ACE G2350A AA. AGT, ACE, and CYP11B2 gene polymorphisms are associated with ESRD. Conclusions. The gene-gene interaction effects of ACE I/D, ACE G2350A, and CYP11B2 C-344T polymorphisms are more important than individual factors for ESRD development among Han Chinese.
    TheScientificWorldJournal. 01/2014; 2014:169798.
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    ABSTRACT: Associations between angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphisms and chronic kidney disease (CKD) have been extensively studied, with most studies reporting that individuals with the D allele have a higher risk. Although some factors, such as ethnicity, may moderate the association between ACE I/D polymorphisms and CKD risk, gender-dependent effects on the CKD risk remain controversial. This study investigated the gender-dependent effects of ACE I/D polymorphisms on CKD risk. PubMed, the Cochrane library, and EMBASE were searched for studies published before January 2013. Cross-sectional surveys and case-control studies analyzing ACE I/D polymorphisms and CKD were included. They were required to match the following criteria: age >18 years, absence of rare diseases, and Asian or Caucasian ethnicity. The effect of carrying the D allele on CKD risk was assessed by meta-analysis and meta-regression using random-effects models. ETHNICITY [ODDS RATIO (OR): 1.24; 95% confidence interval (CI): 1.08-1.42] and hypertension (OR: 1.55; 95% CI: 1.04-2.32) had significant moderate effects on the association between ACE I/D polymorphisms and CKD risk, but they were not significant in the diabetic nephropathy subgroup. Males had higher OR for the association between ACE I/D polymorphisms and CKD risk than females in Asians but not Caucasians, regardless of adjustment for hypertension (p<0.05). In subgroup analyses, this result was significant in the nondiabetic nephropathy group. Compared with the I allele, the D allele had the highest risk (OR: 3.75; 95% CI: 1.84-7.65) for CKD in hypertensive Asian males. The ACE I/D polymorphisms may incur the highest risk for increasing CKD in hypertensive Asian males.
    PLoS ONE 01/2014; 9(1):e87604. · 3.53 Impact Factor
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    ABSTRACT: Zhibai Dihuang Wan (ZDW) is an ancient traditional Chinese medicine composed of eight herbal ingredients and has been used to treat chronic kidney inflammation and diabetes for thousands of years. Nonetheless, the influence of ZDW on acute kidney injury is still unknown. We intended to identify the influence of ZDW on cell growth and gentamicin-induced apoptotic injury in renal tubular cells. We extracted ZDW with artificial intestinal fluid and treated rat renal tubular cells (NRK-52E) with various concentrations of the ZDW extraction. Cell proliferation and gentamicin-induced apoptosis of NRK-52E cells were evaluated using real-time proliferation monitoring and annexin V staining, respectively. Western blotting was used to evaluate the levels of Bcl-2 and caspase-3 expression. The effect of ZDW on gentamicin-induced kidney injury was also monitored in mice using the terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) assay, and the measurement of serum creatinine and blood urea nitrogen. We found that 30μg/ml of ZDW promoted cell proliferation of the rat renal tubular cells. ZDW also expressed a dose-dependent protective effect against gentamicin-induced apoptosis in the cells. Pretreatment with 3μg/ml or 30μg/ml of ZDW maximally increased Bcl-2 and decreased cleaved caspase-3 in the gentamicin-treated NRK-52E cells. Among the herbal ingredients of ZDW, only Phellodendron amurense Rupr., bark (Cortex Phellodendri), and Anemarrhena asphodeloides Bunge, rhizome inhibited both the gentamicin-induced Bcl-2 decrease and cleaved caspase-3 increase. Phellodendron amurense Rupr., bark and Anemarrhena asphodeloides Bunge, rhizome also inhibited gentamicin-induced apoptosis at particular concentrations; however, these two ingredients were less effective than ZDW. In the mouse model of gentamicin-induced nephropathy, the ZDW treatment significantly reduced apoptotic cells in the renal cortex and improved renal function. Our results suggest that ZDW at adequate doses attenuates gentamicin-induced apoptotic injury in renal tubular cells and also protects kidneys from gentamicin-induced injury in mice.
    Journal of ethnopharmacology 11/2013; · 2.32 Impact Factor
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    ABSTRACT: A T60M mutation in the thiazide-sensitive sodium chloride cotransporter (NCC) is common in patients with Gitelman's syndrome (GS). This mutation prevents Ste20-related proline and alanine-rich kinase (SPAK)/oxidative stress responsive kinase-1 (OSR1)-mediated phosphorylation of NCC and alters NCC transporter activity in vitro. Here, we examined the physiologic effects of NCC phosphorylation in vivo using a novel Ncc T58M (human T60M) knock-in mouse model. Ncc(T58M/T58M) mice exhibited typical features of GS with a blunted response to thiazide diuretics. Despite expressing normal levels of Ncc mRNA, these mice had lower levels of total Ncc and p-Ncc protein that did not change with a low-salt diet that increased p-Spak. In contrast to wild-type Ncc, which localized to the apical membrane of distal convoluted tubule cells, T58M Ncc localized primarily to the cytosolic region and caused an increase in late distal convoluted tubule volume. In MDCK cells, exogenous expression of phosphorylation-defective NCC mutants reduced total protein expression levels and membrane stability. Furthermore, our analysis found diminished total urine NCC excretion in a cohort of GS patients with homozygous NCC T60M mutations. When Wnk4(D561A/+) mice, a model of pseudohypoaldosteronism type II expressing an activated Spak/Osr1-Ncc, were crossed with Ncc(T58M/T58M) mice, total Ncc and p-Ncc protein levels decreased and the GS phenotype persisted over the hypertensive phenotype. Overall, these data suggest that SPAK-mediated phosphorylation of NCC at T60 regulates NCC stability and function, and defective phosphorylation at this residue corrects the phenotype of pseudohypoaldosteronism type II.
    Journal of the American Society of Nephrology 07/2013; · 8.99 Impact Factor
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    ABSTRACT: We previously reported that heat stroke induces autophagy as a protection mechanism against neurodegeneration in the brain. Heme oxygenase (HO)-1 is a stress protein and can be induced by heat stress (HS). Cerebellar Purkinje cells are selectively vulnerable to heat-induced injury. In this study, we first validated an animal model of HS (38 for 4 h) in which sustained increase of Purkinje cell injury, HO-1 expression up to 24 h post HS (HS24), and hyperthermia reaching a rectal temperature 41.52 ± 0.32 were observed. In subsequent experiments, we investigated the effects of HO-1 on HS-induced Purkinje cell injury. Rats were divided into four groups: one normothermic control group receiving saline vehicle (1 mL/kg, intraperitoneal [i.p.]) and exposed to 25 for 4 h; and three HS groups receiving saline, or HO-1 inducer haemin (30 mg/kg, i.p.) or HO-1 inhibitor tin protoporphyrin (SnPP, 30 mg/kg, i.p.), respectively, at 12 h prior to HS. HS-induced Purkinje cell injury was further enhanced by HO-1 inducer but attenuated by HO-1 inhibitor as evaluated by immunoreactivity of apoptosis marker (active caspase-3) as well as Fluoro-Jade B histochemistry (staining for degenerating neurons), suggesting a detrimental role of HO-1. Interestingly, the protective autophagy was reduced by HO-1 inducer but enhanced by HO-1 inhibitor as demonstrated by autophagy markers including Beclin-1 and microtubule-associated protein light chain 3 in Purkinje cells. Double immunofluorescent labelling of Beclin-1 or 8-hydroxydeoxyguanosine (an oxidative DNA damage marker) with HO-1 immunoreactivity not only demonstrated their co-localization, but also confirmed that HO-1 negatively regulated Beclin-1 but increased oxidative stress in the same Purkinje cell. Taken together, our results indicate that HO-1 aggravates HS injury in cerebellar Purkinje cells. Our findings shed new light on cell damage mechanisms by HS in central nervous system and may help to provide potential therapeutic foci.
    Experimental Biology and Medicine 06/2013; · 2.80 Impact Factor
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    ABSTRACT: BACKGROUND: Several polymorphisms in the angiotensin-converting enzyme (ACE) and ACE2 genes are associated with the development of end-stage renal disease (ESRD). Certain genetic polymorphisms may modify the deleterious effects of environmental factors such as cigarette smoking and may also modify the inherited risk. We investigated the association of six ACE and ACE2 polymorphisms with ESRD to determine whether a relationship exists between gene-smoking interactions and ESRD. MATERIALS AND METHODS: We performed a case-control association study and genotyped 683 ESRD patients and 653 healthy controls. All subjects were genotyped for ACE (I/D, G2350A and A-240T) and ACE2 (G8790A, A1075G and G16854C) gene polymorphisms by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS: Significant associations were observed between ACE I/D and G2350A polymorphisms and ESRD. There was no difference in ACE2 genotype distribution between ESRD patients and healthy controls. Haplotype analysis showed that DAA and DAT haplotypes were risk factors for ESRD. Moreover, a gene-environment interaction was observed between ACE I/D polymorphism and cigarette smoking. CONCLUSION: ACE I/D and ACE G2350A polymorphisms were associated with the development of ESRD. The interaction between ACE I/D polymorphism and smoking is also associated with an enhanced risk of ESRD.
    Journal of Renin-Angiotensin-Aldosterone System 03/2013; · 2.29 Impact Factor
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    ABSTRACT: OBJECTIVE: Glucose-regulated protein 78 (Grp78) is an endoplasmic reticulum chaperone; it maintains endoplasmic reticulum homeostasis and modulates unfolded protein response. The protein is overexpressed in various cancer types, including renal cell carcinoma (RCC). Increased Grp78 expression in patients with RCC is correlated with more aggressive tumors and poorer prognoses. This study investigated the role of Grp78 in regulating tumorigenesis and evaluated the potential of Grp78-targeted therapy for RCC. METHODS: The expression level of Grp78 was examined in von Hippel-Lindau (VHL)-intact or VHL-null RCC cell lines by reverse transcription polymerase chain reaction and Western blot. Specific Grp78 ribonucleic acid interference was applied as a molecularly Grp78-targeted therapeutic approach. This method enabled us to assess the effects of manipulating Grp78 expression to regulate RCC cell growth. RESULTS: The Grp78 messenger ribonucleic acid and protein were expressed in both VHL-intact and VHL-null RCC cell lines. The specific inhibition of Grp78 expression suppressed RCC cell growth and colony formation significantly, and induced G1 cell-cycle arrest. We also showed that inhibiting Grp78 expression increased the cells' resistance to the cytotoxicity of the S-phase-specific anticancer drug 5-fluorouracil. This effect was regulated by the unfolded protein response-induced suppression of G1/S transition-related cyclins (D1, E1, and E2) and cyclin-dependent kinase (CDK4 and CDK6) protein expression. CONCLUSION: Overall, our findings indicate the regulatory function of Grp78 in RCC cell proliferation, and provide a molecular-based mechanism of Grp78 positivity in the progression of RCC.
    Urologic Oncology 02/2013; · 3.65 Impact Factor

Publication Stats

695 Citations
260.12 Total Impact Points

Institutions

  • 2014
    • National Taiwan University
      • Graduate Institute of Epidemiology and Preventive Medicine
      T’ai-pei, Taipei, Taiwan
  • 2010–2014
    • Taipei Medical University
      • • Division of Nephrology
      • • School of Medicine
      • • Graduate Institute of Biomedical Materials
      T’ai-pei, Taipei, Taiwan
    • Chi-Mei Medical Center
      臺南市, Taiwan, Taiwan
  • 1998–2014
    • National Defense Medical Center
      • • Tri-Service General Hospital
      • • Department of Pathology
      • • Graduate Institute of Life Sciences
      T’ai-pei, Taipei, Taiwan
  • 2013
    • National Taiwan University of Science and Technology
      • School of Management
      T’ai-pei, Taipei, Taiwan
  • 1996–2013
    • Tri-Service General Hospital
      T’ai-pei, Taipei, Taiwan
  • 2011
    • Fu Jen Catholic University
      • School of Medicine
      Taipei, Taipei, Taiwan