[Show abstract][Hide abstract] ABSTRACT: Microalbuminuria is an indicator of renal disease and is known to be related to obesity. The aim of this study is to investigate the association between the cross-sectional area of visceral adipose tissue (VAT) and the prevalence of microalbuminuria. We conducted a cross-sectional study of 1154 subjects who underwent routine checkups, including computed tomography (CT) scans of abdominal adipose tissue. We used the lowest tertile as a reference of abdominal fat. The highest tertile of VAT was related to the highest prevalence of microalbuminuria (odds ratio (OR): 1.96; 95% CI: 1.12-3.43). Subcutaneous adipose tissue (SAT) was not associated with microalbuminuria. In men, the highest tertile for VAT was associated with the highest prevalence of microalbuminuria (OR: 2.74; 95% CI: 1.44-5.22). In women, VAT or SAT was not associated with microalbuminuria. In nondiabetic subjects, the highest tertile for VAT was associated with the highest prevalence of microalbuminuria (OR: 2.23; 95% CI: 1.15-4.32). Among subjects without metabolic syndrome or with body mass index <25 kg m(-2), the highest tertile for VAT was associated with microalbuminuria in age- and sex-adjusted model, respectively (OR: 1.62; 95% CI: 1.01-2.31; OR: 2.21; 95% CI: 1.05-4.65). The analysis of the association of VAT and insulin resistance (IR) indicated that a higher VAT was associated with a higher IR (highest tertile for VAT-OR: 2.91; 95% CI: 1.70-4.96). In conclusion, the highest VAT of the current study was significantly correlated with the highest prevalence of microalbuminuria, even in traditionally low-risk subjects without diabetes, and this association is potentially related with a higher IR.Hypertension Research advance online publication, 20 March 2014; doi:10.1038/hr.2014.47.
Hypertension Research 03/2014; · 2.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Elevated serum level of fibroblast growth factor-23 (FGF23) is associated with adverse outcomes in dialyzed patients.Objectives: The CUPID study compared the efficacy of a cinacalcet-based regimen with conventional care (vitamin D and P binders) for achieving the stringent NKF-K/DOQI targets for peritoneal dialysis (PD) patients. Additionally, we analyzed change in FGF23 levels between two treatments to explore the cinacalcet effect in lowering FGF23. DESIGN: Multicenter, open-labeled, randomized controlled studySetting: Seven university-affiliated hospitals in KoreaParticipants: Overall, 66 peritoneal dialysis patients were enrolledIntervention: Sixty six patients were randomly assigned to treatment with either cinacalcet + oral vitamin D (cinacalcet group, n = 33) or oral vitamin D alone (control group, n = 33) to achieve K/DOQI targets. CUPID included a 4-week screening for vitamin D washout, a 12-week dose-titration, and a 4-week assessment phases. We calculated mean values of iPTH, Ca, P, Ca x P, during assessment phase and final FGF23 to assess the outcome.Main outcome measures: Achievement of >30% reduction of iPTH from baseline (primary) and FGF23 reduction (secondary). RESULTS: 72.7% (n = 24) of the cinacalcet group and 93.9% (n = 31) of the control group completed the study. Cinacalcet group received 30.2 +/- 18.0 mg/day of cinacalcet and 0.13 +/- 0.32 mug/d oral vitamin D (P < 0.001 vs. control with 0.27 +/- 0.18 mug/d vitamin D). The proportion of patients who reached the primary endpoint was not statistically different (48.5% vs. 51.5%, cinacalcet vs. control, P = 1.000). After treatment, cinacalcet group experienced a significant reduction in FGF23 levels (median value from 3,960 to 2,325 RU/ml, P = 0.002), while an insignificant change was shown for control group (from 2,085 to 2,415 RU/ml). The percent change of FGF23 after treatment was also significantly different between the two groups (- 42.54% vs. 15.83%, P = 0.008). After adjustment, cinacalcet treatment was independently associated with the serum FGF23 reduction. CONCLUSION: Cinacalcet treatment was independently associated with the reduction of FGF23 in our PD patients.Trial registration: Controlled trials NCT01101113 (http://www.clinicaltrials.gov).
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: Frameshift mutations in coding mononucleotide repeats (cMNRs) are common in tumors with high microsatellite instability (MSI-H). These mutations generate mRNAs containing abnormal coding sequences and premature termination codons (PTCs). Normally, mRNAs containing PTCs are degraded by NMD. However, mRNAs containing PTCs located in the last exon are not subject to degradation by NMD (NMD-irrelevant). This study aimed to discover whether genes with frameshift mutations in the last exon generate truncated mutant proteins. EXPERIMENTAL DESIGN: We identified 66 genes containing cMNRs in the last exon by bioinformatic analysis. We found frequent insertion/deletion mutations in the cMNRs of 29 genes in 10 MSI-H cancer cell lines and in the cMNRs of 3 genes in 19 MSI-H cancer tissues. We selected seven genes (TTK, TCF7L2, MARCKS, ASTE1, INO80E, CYHR1, and EBPL) for mutant mRNA expression analysis and three genes (TTK, TCF7L2, and MARCKS) for mutant protein expression analysis. RESULTS: The PTC-containing NMD-irrelevant mRNAs from mutated genes were not degraded. However, only faint amounts of endogenous mutant TTK and TCF7L2 were detected, and we failed to detect endogenous mutant MARCKS. By polysome analysis, we demonstrated that mRNAs from genomic mutant MARCKS constructs are normally translated. After inhibiting three protein degradation pathways, we found that only inhibition of the proteasomal pathway facilitated the rescue of endogenous mutant TTK, TCF7L2, and MARCKS. CONCLUSIONS: Our findings indicate that cancer cells scavenge potentially harmful neopeptide-containing mutant proteins derived from NMD-irrelevant abnormal mRNAs via the ubiquitin-proteasome system, and these mutant proteins may be important substrates for tumor-specific antigens.
Clinical Cancer Research 05/2013; · 7.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Periodontitis and chronic kidney disease (CKD) are important health issues; however, the association between periodontitis and CKD markers, especially in Korean adults, remains elusive.
Data on 15,729 Korean adults were obtained from the Korean National Health and Nutritional Examination Surveys IV and V. The CKD markers included a decreased estimated glomerular filtration rate (eGFR;<60 mL/min/1.73 m2), proteinuria, and hematuria. Odds ratios (ORs) and 95% confidence intervals were measured using stepwise multivariate logistic regression analyses for CKD markers based on the presence of periodontitis.
Patients with periodontitis had greater unadjusted ORs for CKD markers compared to those without periodontitis, as follows: decreased eGFR, 4.07 (3.11–5.33); proteinuria, 2.12 (1.48–3.05); and hematuria, 1.25 (1.13–1.39; (all P<0.001). Periodontitis was a significant predictor of decreased eGFR independent of all covariates [1.39 (1.03–1.89), P=0.034]. However, the effect of periodontitis on decreased eGFR seemed to be affected by hypertension and diabetes mellitus. Periodontitis was not an independent predictor of proteinuria; the significance disappeared after adjusting for hypertension and diabetes mellitus. Periodontitis was significantly correlated with hematuria, leading to similar ORs regardless of the adjustment for covariates [1.29 (1.15–1.46), P<0.001].
This study confirms the correlation between periodontitis and CKD markers, including decreased eGFR, proteinuria, and hematuria in Korean adults.
[Show abstract][Hide abstract] ABSTRACT: High mobility group box-1 (HMGB1), a nuclear protein, is overexpressed and secreted in cancer cells. Phosphorylation on two different nuclear localization signal regions are known to be important for the nuclear-to-cytoplasmic transport and secretion of HMGB1. However, little is known about the biochemical mechanism of HMGB1 modifications and its subsequent secretion from cancer cells. To identify the specific enzyme and important sites for HMGB1 phosphorylation, we screened the protein kinase C (PKC) family in a colon cancer cell line (HCT116) for HMGB1 binding by pull-down experiments using a 3XFLAG-HMGB1 construct. Strong interactions between atypical PKCs (PKC-ζ, λ, and ι) and cytoplasmic HMGB1 were observed in HCT116 cells. We further identified the most critical PKC isotype that regulates HMGB1 secretion is PKC-ζ by using PKC inhibitors and siRNA experiments. The serine residues at S39, S53 and S181 of HMGB1 were related to enhancing HMGB1 secretion. We also demonstrated overexpression and activation of PKC-ζ in colon cancer tissues. Our findings suggest that PKC-ζ is involved in the phosphorylation of HMGB1, and the phosphorylation of specific serine residues in the nuclear localization signal regions is related to enhanced HMGB1 secretion in colon cancer cells.
Biochemical and Biophysical Research Communications 06/2012; 424(2):321-6. · 2.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: High mobility group box 1 protein (HMGB1), a nuclear protein, can be translocated to the cytoplasm and secreted in colon cancer cells. However, the diagnostic significance of HMGB1 has not been evaluated in colorectal carcinomas. For this purpose, we have screened the expression and secretion of HMGB1 in 10 colon cancer cell lines and 1 control cell line and found that HMGB1 was detected in the culture medium. To evaluate the diagnostic value of HMGB1, we performed an enzyme-linked immunosorbent assay to measure HMGB1 levels and compared them to carcinoembryonic antigen (CEA) levels in the serum samples of 219 colorectal carcinoma patients and 75 healthy control subjects. We found that the serum HMGB1 level was increased by 1.5-fold in patients with colorectal carcinoma compared to those in healthy controls. When HMGB1 and CEA levels were compared, HMGB1 had similar efficacy as CEA regarding cancer detection (the sensitivity was 20.1% for HMGB1 vs. 25.6% for CEA, and the specificity was 96% for HMGB1 vs. 90.7% for CEA). Moreover, the diagnostic accuracy of HMGB1 for stage I cancer was significantly higher than that of CEA (sensitivity: 41.2% vs. 5.9%; specificity: 96% vs. 90.7). When we combined HMGB1 and CEA, the overall diagnostic sensitivity was higher than that of CEA alone (42% vs. 25.6%), and the diagnostic sensitivity for stage I was also elevated (47% vs. 5.9%). However, the prognosis of patients was not related with serum HMGB1 concentrations. Our findings indicate that serum HMGB1 levels are increased in a subset of colorectal carcinomas, suggesting their potential utility as a supportive diagnostic marker for colorectal carcinomas.
PLoS ONE 01/2012; 7(4):e34318. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Frameshift mutations at coding mononucleotide repeats (cMNR) are frequent in high-microsatellite instability (MSI-H) cancers. Frameshift mutations in cMNR result in the formation of a premature termination codon (PTC) in the transcribed mRNA, and these abnormal mRNAs are generally degraded by nonsense mediated mRNA decay (NMD). We have identified novel genes that are frequently mutated at their cMNR by blocking NMD in two MSI-H cancer cell lines. After blocking NMD, we screened for differentially expressed genes using DNA microarrays, and then used database analysis to select 28 candidate genes containing cMNR with more than 9 nucleotide repeats. cMNR mutations have not been previously reported in MSI-H cancers for 15 of the 28 genes. We analyzed the cMNR mutation of each of the 15 genes in 10 MSI-H cell lines and 21 MSI-H cancers, and found frequent mutations of 12 genes in MSI-H cell lines and cancers, but not in microsatellite stable (MSS) cancers. Among these genes, the most frequently mutated in MSI-H cell lines were MLL3 (70%), PHACTR4 (70%), RUFY2 (50%) and TBC1D23 (50%). MLL3, which has already been implicated in cancer, had the highest mutation frequency in MSI-H cancers (48%). Our combined approach of NMD block, database search, and mutation analysis has identified a large number of genes mutated in their cMNR in MSI-H cancers. The identified mutations are expected to contribute to MSI-H tumorigenesis by causing an absence of gene expression or low gene dosage effects.
International Journal of Cancer 06/2011; 128(12):2872-80. · 6.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: HMGB1 is a nuclear protein that is overexpressed and secreted in cancer cells. However, little is known about the roles of HMGB1 in the cytoplasm and secretory pathway in cancer cells. To clarify this aspect of HMGB1 function, we fractionated the cytoplasm of HCT116 colon cancer cells and used a proteomic approach to analyze cytoplasmic HMGB1-binding proteins. Pull-down experiments using recombinant HMGB1 protein as bait, followed by mass spectrometry analysis identified 162 interacting proteins. Among them were 74 proteins known to be localized exclusively to the extra-nuclear region, and 60 proteins known to be localized to both nuclear and extranuclear regions. The functions of these binding proteins include involvement in cell-cycle progression, cell proliferation, anti-apoptosis, and angiogenesis. In addition, nine of the identified proteins are related to protein translocation and secretion. These include annexin A2, myosin IC isoform a, myosin-9, and Ras-related protein Rab10, which are involved in unconventional protein secretion. Cytoplasmic HMGB1 was primarily associated with the lysosomal cytosol fraction and was colocalized with the lysosomal marker LAMP1. Our findings suggest that cytoplasmic HMGB1 binds to a number of molecules related to cancer progression and the unconventional secretory pathway.
Journal of Proteome Research 09/2010; 9(9):4661-70. · 5.06 Impact Factor