Hsi Chin Wu

Apoptotic effects of protocatechuic acid in human breast, lung, liver, cervix, and prostate cancer cells: potential mechanisms of action.

Apoptotic effects of protocatechuic acid (PCA) at 1, 2, 4, 8 micromol/L on human breast cancer MCF7 cell, lung cancer A549 cell, HepG2 cell, cervix HeLa cell, and prostate cancer LNCaP cell were examined. Results showed that PCA concentration-dependently decreased cell viability, increased lactate dehydrogenase leakage, enhanced DNA fragmentation, reduced mitochondrial membrane potential, and lowered Na(+)-K(+)-ATPase activity for these cancer cells (P < 0.05). PCA also concentration-dependently elevated caspase-3 activity in five cancer cells (P < 0.05), but this agent at 2-8 micromol/L significantly increased caspase-8 activity (P < 0.05). PCA concentration-dependently decreased intercellular adhesion molecule level in test cancer cells (P < 0.05) but significantly inhibited cell adhesion at 2-8 micromol/L (P < 0.05). PCA also concentration-dependently lowered the levels of interleukin (IL)-6 and IL-8 in five cancer cells (P < 0.05), but this agent at 2-8 micromol/L significantly suppressed vascular endothelial growth factor production (P < 0.05). These findings suggest that PCA is a potent anticancer agent to cause apoptosis or retard invasion and metastasis in these five cancer cells.

Stromal Cell-Derived Factor-1 Induces Matrix Metalloprotease- 13 Expression in Human Chondrocytes

The production of chemokine stromal cell-derived factor (SDF)-1 is significantly higher in synovial fluid of patients with osteoarthritis and rheumatoid arthritis. Matrix metalloproteinase (MMP)-13 may contribute to the breakdown of articular cartilage during arthritis. Here, we found that SDF-1α increased the secretion of MMP-13 in cultured human chondrocytes, as shown by reverse transcriptase-polymerase chain reaction, Western blot, and zymographic analysis. SDF-1α also increased the surface expression of CXCR4 receptor in human chondrocytes. CXCR4-neutralizing antibody, CXCR4-specific inhibitor [1-[[4-(1,4,8,11-tetrazacyclotetradec-1-ylmethyl)phenyl]methyl]-1,4,8,11-tetrazacyclotetradecane (AMD3100)], or small interfering RNA against CXCR4 inhibited the SDF-1α-induced increase of MMP-13 expression. The transcriptional regulation of MMP-13 by SDF-1α was mediated by phosphorylation of extracellular signal-regulated kinases (ERK) and activation of the activator protein (AP)-1 components of c-Fos and c-Jun. The binding of c-Fos and c-Jun to the activator protein (AP-1) element on the MMP-13 promoter and the increase in luciferase activity was enhanced by SDF-1α. Cotransfection with dominant-negative mutant of ERK2 or c-Fos and c-Jun antisense oligonucleotide inhibited the potentiating action of SDF-1α on MMP-13 promoter activity. Taken together, our results provide evidence that SDF-1α acts through CXCR4 to activate ERK and the downstream transcription factors (c-Fos and c-Jun), resulting in the activation of AP-1 on the MMP-13 promoter and contributing cartilage destruction during arthritis.

Involvement of oxidative stress-mediated ERK1/2 and p38 activation regulated mitochondria-dependent apoptotic signals in methylmercury-induced neuronal cell injury

Methylmercury (MeHg) is well-known for causing irreversible damage in the central nervous system as well as a risk factor for inducing neuronal degeneration. However, the molecular mechanisms of MeHg-induced neurotoxicity remain unclear. Here, we investigated the effects and possible mechanisms of MeHg in the mouse cerebrum (in vivo) and in cultured Neuro-2a cells (in vitro). In vivo study showed that the levels of LPO in the plasma and cerebral cortex significantly increased after administration of MeHg (50μg/kg/day) for 7 consecutive weeks. MeHg could also decrease glutathione level and increase the expressions of caspase-3, -7, and -9, accompanied by Bcl-2 down-regulation and up-regulation of Bax, Bak, and p53. Moreover, treatment of Neuro-2a cells with MeHg significantly reduced cell viability, increased oxidative stress damage, and induced several features of mitochondria-dependent apoptotic signals, including increased sub-G1 hypodiploids, mitochondrial dysfunctions, and the activation of PARP, and caspase cascades. These MeHg-induced apoptotic-related signals could be remarkably reversed by antioxidant NAC. MeHg also increased the phosphorylation of ERK1/2 and p38, but not JNK. Pharmacological inhibitors NAC, PD98059, and SB203580 attenuated MeHg-induced cytotoxicity, ERK1/2 and p38 activation, MMP loss, and caspase-3 activation in Neuro-2a cells. Taken together, these results suggest that the signals of ROS-mediated ERK1/2 and p38 activation regulated mitochondria-dependent apoptotic pathways that are involved in MeHg-induced neurotoxicity.

Distributions of p53 codon 72 polymorphism in bladder cancer - Proline form is prominent in invasive tumor

Abstract Abnormal function of p53 is commonly associated with various cancer formations. High-grade and late-stage bladder cancers have been reported to have mutated or become inactive p53 when using immunohistochemical stains. Recently, p53 codon 72 polymorphism was extensively studied to determine the risk factors responsible for cancer formation. There was a general population of codon 72 sequence polymorphism of the wild type p53. A single base change from G to C caused the alteration of amino acid residue 72 from arginine to proline. The arginine form is considered to be a significant risk factor in the development of cancer. However, various reports had indicated discrepancies with regard to this polymorphism; some showed no significant difference between the control and cancer groups, while other series were associated with high risks in the proline form homozygotes. To resolve the undefined distribution of this polymorphism in bladder cancers, 58 patients with bladder cancer were enrolled onto this study. When checked using the Chi-squared test (P=0.952) there were no differences between the control subjects and bladder cancer patients in the distribution of polymorphism. However, proline form homozygotes were more frequently found in the invasive group than the non-invasive group by Fishers exact test (25% and 2.9%, respectively, P < 0.001). More than 70% of the non-invasive bladder cancers were the arginine form homozygotes. This result is consistent with those reported for hepatocellular carcinoma that showed a history of chronic liver disease and proline form homozygotes in a report by Yu et al. Our data suggest that proline form homozygotes are associated with invasive bladder cancer.

Non-inferiority of silodosin to tamsulosin in treating patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH)

Study Type – Therapy (RCT)

Impotence evaluated by the use of prostaglandin E1

We screened 80 patients at our hospital for the differential diagnosis of impotence using intracavernous injection of prostaglandin E1 (20 micrograms). The rate of positive response was 78.8 per cent (63 patients). Neither systemic reactions nor priapism occurred. However, a considerable incidence (23.8 per cent, 19 of 80 patients) of tolerable injection pain was encountered. The 133xenon penile washout study was conducted routinely in impotent men for hemodynamic evaluation of penile vascularity. In 80 patients a positive correlation between the response of intracavernous prostaglandin E1 injection and the result of the washout study was found (r equals 0.381, p less than 0.0002). We selected 14 subjects randomly to receive additional intravenous infusions of prostaglandin E1 (6 ampules, 120 micrograms total) for 3 days, after which another 133xenon washout study was done. The washout studies before and after intravenous prostaglandin E1 infusion were compared, and 10 patients (71.4 per cent) appeared to obtain improvement in half-time clearance and penile blood flow. However, only 3 patients noticed improvement subjectively. We suggest that prostaglandin E1 could be a desirable alternative for the diagnosis and treatment of impotence.

p53 Gene Codon 72 Polymorphism but Not Tumor Necrosis Factor-α Gene Is Associated with Prostate Cancer

Objective: A polymorphism of gene p53 codon 72 is associated with various cancer formations. Tumor necrosis factor-α (TNF-α) one of the cytokines secreted by macrophages in response to inflammation and is also related to cancer formation. We aimed to evaluate the association between prostate cancer and the polymorphisms of the TNF-α gene promoter –308 and p53 gene codon 72. Patients and Methods: In our study, a normal control group of 126 healthy people and 96 patients with prostate cancer were examined. The polymorphism (G/A) of TNF-α gene was detected by polymerase chain reaction (PCR)-based restriction analysis (Nco I endonuclease) and the polymorphism of p53 gene was detected by two PCRs (one for proline and one for arginine form). Results: There was a significant difference in the distribution of codon 72 polymorphism the p53 gene between prostate cancer patients and the normal controls (p < 0.001). The proline form of p53 gene codon 72 was significantly higher than the arginine form, with an odds ratio of 2.606 (95% CI = 1.052–6.455). This difference was also revealed in the tumor staging (p = 0.035) as the proline form was significantly higher in the metastasis group of prostate cancer. There were no statistical differences in the distribution of –308 polymorphism of the TNF-α gene between cancer patients and the control subjects (p = 1.0). Conclusion: Prostate cancer appears to be associated with the p53 gene codon 72 polymorphisms, but not with the TNF-α gene. The proline form of p53 gene codon 72 might be a more significant risk factor for the development of metastasis than the arginine form.

Leptin increases motility and integrin up‐regulation in human prostate cancer cells

Prostate cancer is the most commonly diagnosed malignancy in men and shows a predilection for metastasis to distant organs. Leptin, an adipocyte‐derived cytokine that is closely associated with obesity, has recently been shown to be involved in carcinogenesis and cancer progression. The aim of this study was to investigate whether leptin is associated with the motility of prostate cancer cells. We found that leptin increased the migration of human prostate cancer cells and expression of αvβ3 integrin on these cells. Leptin‐mediated migration and increased integrin expression were attenuated by OBRl receptor antisense oligonucleotide (ODN). Activation of insulin receptor substrate (IRS‐1), phosphatidylinositol 3‐kinase (PI3K), Akt, and NF‐κB pathways after leptin treatment was demonstrated. Furthermore, leptin‐induced integrin expression and migration activity were inhibited by specific inhibitors; small interfering RNAs (siRNAs); and mutants of the IRS‐1, PI3K, Akt, and NF‐κB cascades. Therefore, this study shows that leptin stimulates the migration of human prostate cancer cells, one of the mechanisms underlying leptin‐directed migration was transcriptional up‐regulation of αvβ3 integrin expression through the OBR1/IRS‐1/PI3K/Akt/NF‐κB signal transduction pathway. J. Cell. Physiol. 226: 1274–1282, 2011.

Excess mortality after hip fracture among the elderly in Taiwan: A nationwide population-based cohort study

Osteoporotic hip fractures cause high mortality in the elderly population. However, few population studies reported the long-term mortality of hip fracture among the elderly in Asian population. This study assessed the incidence, excess mortality, and risk factors after osteoporotic hip fractures through inpatients aged 60 years or older. A total of 143,595 patients with hip fracture were selected from Taiwan National Health Insurance database in the years 1999 to 2009 and followed up until the end of 2010. Annual incidence, mortality and SMR, and mortality and SMR at different periods after fracture were measured. From 1999 to 2005, hip fracture incidence gradually increased and then fluctuated after 2006. From 1999 to 2009, the male-to-female ratio of annual incidence increased from 0.60 to 0.66, annual mortality for hip fracture decreased from 18.10% to 13.98%, male-to-female ratio of annual mortality increased from 1.38 to 1.64, and annual SMR decreased from 13.80 to 2.98. Follow-up SMR at one, two, five, and ten years post-fracture was 9.67, 5.28, 3.31, and 2.89, respectively. Females had higher follow-up SMR in the younger age groups (60-69 yr of age) but lower follow-up SMR in the older age groups (over 80 yr of age) compared with males. Among the studied patients, incidence is gradually decreasing along with annual mortality and SMR. Hip fracture affects short-term but not long-term mortality.

p21 gene codon 31 polymorphism is associated with bladder cancer

The function of p21 is related to cell apoptosis, progression and malignancies. It is thought that p21 is related to cancer formation but is not related to tumor grade. We aimed to investigative the polymorphism of p21 codon 31 as a candidate for the genetic marker of bladder cancer and its progression. The distribution was analyzed in 53 bladder cancer patients, 119 healthy controls in Taiwanese patients. Polymerase chain reaction based restriction analysis was used for the study of the association of p21 codon 31 polymorphism with bladder cancer. There was a significant difference in p21 codon 31 polymorphism between the control and the cancer patients (p < 0.01). The arginine form was prominent in the cancer patient (per copy of the A allele, odds ratio = 2.03, 95% confidence interval = 1.23-3.37). Furthermore, the distribution of this polymorphism was significantly different from non-invasive to invasive bladder cancer (p < 0.05). Serine heterozygote was more prominent in the invasive group with 25 to 1% respectively when compared with the non-invasive group. The polymorphism of p21 codon 31 is associated with bladder cancer. An individual possessing one allele of arginine form in p21 codon 31 has a higher risk of developing bladder cancer than the serine form. Although the mechanism is unclear, our results show p21 gene is associated with tumor grade.