Chao-Bin Yeh

Antimetastatic effects of norcantharidin on hepatocellular carcinoma by transcriptional inhibition of MMP-9 through modulation of NF-Kb activity

Background The rate of morbidity and mortality of hepatocellular carcinoma (HCC) in Taiwan has not lessened because of difficulty in treating tumor metastasis. Norcantharidin (NCTD) is currently used as an anticancer drug for hepatoma, breast cancer, and colorectal adenocarcinoma. NCTD possesses various biological anticancer activities, including apoptosis. However, detailed effects and molecular mechanisms of NCTD on metastasis are unclear. Thus, HCC cells were subjected to treatment with NCTD and then analyzed to determine the effects of NCTD on cell metastasis. Methodology/Principal Findings Modified Boyden chamber assays revealed that NCTD treatment inhibited cell migration and invasion capacities of HCC cells substantially. Results of zymography and western blotting showed that activities and protein levels of matrix metalloproteinase-9 (MMP-9) and urokinase plasminogen activator (u-PA) were inhibited by NCTD. Western blot analysis showed that NCTD inhibits phosphorylation of ERK1/2. Testing of mRNA level, quantitative real-time PCR, and promoter assays evaluated the inhibitory effects of NCTD on MMP-9 and u-PA expression in HCC cells. The chromatin immunoprecipitation (ChIP) assay for analyzing the genomic DNA sequences bound to these proteins was reactive to the transcription protein nuclear factor (NF)-kappaB, which was inhibited by NCTD. The expression of NF-kappa B was measured by western blot analysis, which revealed decreased nuclear-factor DNA-binding activity after NCTD treatment. Conclusions NCTD inhibited MMP-9 and u-PA expression through the phosphorylation of ERK1/2 and NF-kappaB signaling pathway which serves as a powerful chemopreventive agent in HCC cell metastasis.

The Antimetastatic Effects of Resveratrol on Hepatocellular Carcinoma through the Downregulation of a Metastasis-Associated Protease by SP-1 Modulation

Background The mortality and morbidity rates from cancer metastasis have not declined in Taiwan, especially because of hepatocellular carcinoma (HCC). Resveratrol has been shown to have benefits such as cardioprotection, providing antioxidative, anti-inflammatory, anti-cancer properties in previous studies. Therefore, HCC cells were subjected to treatment with resveratrol and then analyzed to determine the effects of resveratrol on the migration and invasion. Methodology and Principal Findings Modified Boyden chamber assays revealed that resveratrol treatment significantly inhibited cell migration and invasion capacities of Huh7 cell lines that have low cytotoxicity in vitro, even at a high concentration of 100 µM. The results of casein zymography and western blotting revealed that the activities and protein levels of the urokinase-type plasminogen activator (u-PA) were inhibited by resveratrol. Western blot analysis also showed that resveratrol inhibits phosphorylation of JNK1/2. Tests of the mRNA level, real-time PCR, and promoter assays evaluated the inhibitory effects of resveratrol on u-PA expression in HCC cells. The chromatin immunoprecipitation (ChIP) assay showed that reactive in transcription protein of nuclear factor SP-1 was inhibited by resveratrol. Conclusions Resveratrol inhibits u-PA expression and the metastasis of HCC cells and is a powerful chemopreventive agent. The inhibitory effects were associated with the downregulation of the transcription factors of SP-1 signaling pathways.

Corrigendum to “Terminalia catappa Exerts Antimetastatic Effects on Hepatocellular Carcinoma through Transcriptional Inhibition of Matrix Metalloproteinase-9 by Modulating NF-κB and AP-1 Activity”

High mortality and morbidity rates for hepatocellular carcinoma (HCC) in Taiwan primarily result from uncontrolled tumor metastasis. Previous studies have identified that Terminalia catappa leaf extracts (TCE) exert hepatoprotective, antioxidative, antiinflammatory, anticancer, and antimetastatic activities. However, the effects of TCE on HCC and the underlying molecular mechanisms of its activities have yet to be fully elucidated. The present studys findings demonstrate that TCE concentration dependently inhibits human HCC migration/invasion. Zymographic and western blot analyses revealed that TCE inhibited the activities and expression of matrix metalloproteinase-9 (MMP-9). Assessment of mRNA levels, using reverse transcriptase polymerase chain reaction (PCR) and real-time PCR, and promoter assays confirmed the inhibitory effects of TCE on MMP-9 expression in HCC cells. The inhibitory effects of TCE on MMP-9 proceeded by upregulating tissue inhibitor of metalloproteinase-1 (TIMP-1), as well as suppressing nuclear translocation and DNA binding activity of nuclear factor-kappa B (NF-κB) and activating protein-1 (AP-1) on the MMP-9 promoter in Huh7 cells. In conclusion, TCE inhibits MMP-9 expression and HCC cell metastasis and, thus, has potential use as a chemopreventive agent. Its inhibitory effects are associated with downregulation of the binding activities of the transcription factors NF-κB and AP-1.

Genetic polymorphism of CCR2-64I increased the susceptibility of hepatocellular carcinoma†

The purpose of this study was to investigate genetic impact of monocyte chemoattractant protein‐1 (MCP‐1) and its receptor chemokine receptor‐2 (CCR2) gene polymorphisms on the susceptibility and clinicopathological characteristics of hepatocellular carcinoma (HCC).

Therapeutic effects of cantharidin analogues without bridging ether oxygen on human hepatocellular carcinoma cells.

Previous research indicates that cantharidin, norcantharidin and their analogues exhibit anticancer activity due to their inhibition of cancer cell lines such as HL60, HT29 and L1210. The anticancer activities of cantharidin, norcantharidin and their analogues involve the suppression of serine/threonine protein phosphatases (PPs) activity. However, cantharidin is not suitable for cancer therapy because of its high cytotoxicity in vitro (IC(50) = 21 microM in primary cultured rat hepatocytes). In this study, synthetic cantharidin analogues with a structure of aminothiazole compounds 3-9 and a structure of anhydride compounds 10-12 were screened for anticancer activities and cytotoxic effects on human hepatocellular carcinoma cell (HCC) lines HepG2, Sk-Hep1, and primary cultured rat hepatocytes. Experimental results indicated that compounds 3-9 did not perform as expected with regard to anticancer activity and exhibited lower cytotoxicity. Compound 10 promoted apoptosis in HepG2 (IC(50) = 62 microM) and SK-Hep1(IC(50) = 151 microM) cell lines. Compounds 11 and 12 had anticancer potential similar to that of compound 10. After treatment with compounds 3-12, primary cultured rat hepatocytes exhibited no cytotoxicity (IC(50) > 200 microM). By investigating the structure-activity relationship (SAR) of these analogues as a whole, this study suggests that the anhydride ether oxygen such as in cantharidin, norcantharidin and compounds 10-12 may be correlated with HCC survival suppression. The results further suggest that the elimination of bridging ether oxygen on the ring, such as in compounds 10-12, can decrease cytotoxicity.

Effect of RECK gene polymorphisms on hepatocellular carcinoma susceptibility and clinicopathologic features

Background The reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) down-regulation has been confirmed in numerous human cancers and is clinically associated with metastasis. This study investigates the potential associations of RECK single-nucleotide polymorphisms (SNPs) with hepatocellular carcinoma (HCC) susceptibility and its clinicopathologic characteristics. Methodology/Principal Findings A total of 135 HCC cancer patients and 501 cancer-free controls were analyzed for four RECK SNPs (rs10814325, rs16932912, rs11788747, and rs10972727) using real-time PCR and PCR-RFLP genotyping analysis. After adjusting for other co-variants, the individuals carrying RECK promoter rs10814325 inheriting at least one C allele had a 1.85-fold [95% confidence interval (CI), 1.03–3.36] risk of developing HCC compared to TT wild type carriers. The HCC patients, who carried rs11788747 with at least one G allele, had a higher distant metastasis risk than wild type probands. Conclusions RECK gene polymorphisms might be a risk factor increasing HCC susceptibility and distant metastasis in Taiwan.

Relationship of interleukin-8 gene polymorphisms with hepatocellular carcinoma susceptibility and pathological development†

Hepatocellular carcinoma (HCC) is one of the most frequent malignant neoplasms worldwide, and the second leading cause of death from cancer in Taiwan. Interleukin‐8 (IL‐8) is an angiogenic chemokine with important roles in the development and progression of many human malignancies including HCC. This study investigates the effects of single‐nucleotide polymorphisms (SNPs) in the IL‐8 gene on the susceptibility and clinicopathological characteristics of HCC.

Risk of Stroke-Associated Pneumonia With Acid-Suppressive Drugs: A Population-Based Cohort Study.

Abstract Acid-suppressive drugs, including histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs), are common medications used for treating upper gastrointestinal tract disorders. However, acid-suppressive drugs have been reported to increase the risk of pneumonia in numerous disease populations. However, the relationship between acid-suppressive drugs and stroke-associated pneumonia (SAP) remains controversial. The purpose of this study was to investigate the association between acid-suppressive drug usage and pneumonia among patients with stroke by using a nationwide data set. A population-based cohort study was conducted using a data set from the Taiwanese National Health Insurance Research Database. Data on patients with new-onset stroke from 2010 to 2011 were collected. Patients with and without acid-suppressive drug usage were followed up to identify the occurrence of any type of pneumonia. We estimated the adjusted hazard ratios (HRs) by using the Cox proportional hazards model. The study cohort comprised 7965 patients with new-onset stroke. The incidence of pneumonia was 6.9% (552/7965) and more than 40% (225/552) of patients developed pneumonia within 3 months after an acute stroke. Acid-suppressive drug usage was an independent risk factor of pneumonia. The adjusted HR for the risk of pneumonia in patients with new-onset stroke using acid-suppressive drugs was 1.44 (95% confidence interval [CI] = 1.18–1.75, P < 0.01). Only PPI usage increased risk of chronic SAP (adjusted HR = 1.46, 95% CI = 1.04–2.05). Acid-suppressive drug usage was associated with a slightly increased risk of SAP. Physicians should exercise caution when prescribing acid-suppressive drugs to patients with stroke, particularly at the chronic stage.

Population-based cohort study on the risk of pneumonia in patients with non-traumatic intracranial haemorrhage who use proton pump inhibitors

Objectives This nationwide cohort study investigated the association between proton pump inhibitor (PPI) usage and the risk of pneumonia in patients with non-traumatic intracranial haemorrhage (ICH). Design Nationwide population-based cohort study. Setting Longitudinal Health Insurance Database 2010 (LHID2010) sampled from the Taiwan National Health Insurance Research Database. Participants 4644 patients with non-traumatic ICH from 2010 to 2011 were identified. Patients aged <18 years and newly diagnosed with non-traumatic ICH complicated with pneumonia during the same admission period were excluded. A total of 2170 participants were eligible for the final analysis. Main outcome measure Patients using PPIs or not during the study period were tracked to identify the occurrence of any type of pneumonia. Results The adjusted HR of the risk of pneumonia for ICH patients who used PPIs was 1.61 (95% CI 1.32 to 1.97, p<0.001). The risk of pneumonia was positively associated with the administration of PPIs. We observed a greater risk of pneumonia in patients who used PPIs than in those who did not. Moreover, we observed that the risk of pneumonia in patients who used PPIs was 2.60 and 2.04 (95% CI 2.01 to 3.38, p<0.001; 95% CI 1.34 to 3.10, p<0.001) greater than that in patients who did not use PPIs when the defined daily dose was <30 and 30−60, respectively. Conclusions The results of this study indicate that the use of PPIs in patients with non-traumatic ICH is associated with an increased risk of pneumonia, and the severity of this risk depends on the defined daily dose. Physicians should exercise caution when prescribing PPIs for patients with non-traumatic ICH.

Usefulness of Plasma YKL-40 in Management of Community-Acquired Pneumonia Severity in Patients

Plasma YKL-40 level has been reported as playing a significant role in community-acquired pneumonia (CAP). However, the correlation between plasma level of YKL-40 and the severity of CAP has not been reported. This study identifies the relationship between plasma level changes of the YKL-40 gene in adult patients hospitalized with CAP. The ELISA was used to measure the plasma YKL-40 level from 61 adult CAP patients before and after antibiotic treatment and from 60 healthy controls. The plasma YKL-40 levels were significantly increased in patients with CAP compared to normal controls. Moreover, the plasma concentration of YKL-40 correlated with the severity of CAP based on the pneumonia severity index (PSI) score (r = 0.630, p < 0.001), the CURB-65 (confusion, uremia, respiratory rate, BP, age 65 years) score (r = 0.640, p < 0.001), the Acute Physiology And Chronic Health Evaluation II (APACHE II) score (r = 0.539, p < 0.001) and length of hospital stay (r = 0.321, p = 0.011), respectively. In conclusion, plasma YKL-40 may play a role in the diagnosis and clinical assessment of CAP severity, which could potentially guide the development of treatment strategies.