Fluoxetine regulates cell growth inhibition of interferon-α.

Fluoxetine, a well-known anti-depression agent, may act as a chemosensitizer to assist and promote cancer therapy. However, how fluoxetine regulates cellular signaling to enhance cellular responses against tumor cell growth remains unclear. In the present study, addition of fluoxetine promoted growth inhibition of interferon-alpha (IFN-α) in human bladder carcinoma cells but not in normal uroepithelial cells through lessening the IFN-α-induced apoptosis but switching to cause G1 arrest, and maintaining the IFN-α-mediated reduction in G2/M phase. Activations and signal transducer and transactivator (STAT)-1 and peroxisome proliferator-activated receptor alpha (PPAR-α) were involved in this process. Chemical inhibitions of STAT-1 or PPAR-α partially rescued bladder carcinoma cells from IFN-α-mediated growth inhibition via blockades of G1 arrest, cyclin D1 reduction, p53 downregulation and p27 upregulation in the presence of fluoxetine. However, the functions of both proteins were not involved in the control of fluoxetine over apoptosis and maintained the declined G2/M phase of IFN-α. These results indicated that activation of PPAR-α and STAT-1 participated, at least in part, in growth inhibition of IFN-α in the presence of fluoxetine.

Endovascular salvage for contained rupture of gastroduodenal artery aneurysm presented with obstructive jaundice.

Gastroduodenal artery (GDA) aneurysms are rare but lethal conditions when ruptures develop. Most common clinical presentation are gastrointestinal hemorrhage and abdominal pain. Obstructive jaundice is unusual. Computed tomography and angiography are useful tools for diagnosis and treatment plan. Any GDA aneurysm should be considered for definitive treatment. Recently, endovascular intervention has gained popularity for its safety and efficacy. Here, we described a patient of GDA pseudoaneurysm presented with generalized jaundice and was treated successfully with endovascular intervention.

Fluoxetine a novel anti-hepatitis C virus agent via ROS-, JNK-, and PPARß/γ-dependent pathways.

More than 20% of chronic hepatitis C (CHC) patients receiving interferon-alpha (IFN-α)-based anti-hepatitis C virus (HCV) therapy experienced significant depression, which was relieved by treatment with fluoxetine. However, whether and how fluoxetine affected directly the anti-HCV therapy remained unclear. Here, we demonstrated that fluoxetine inhibited HCV infection and blocked the production of reactive oxygen species (ROS) and lipid accumulation in Huh7.5 cells. Fluoxetine facilitated the IFN-α-mediated antiviral actions via activations of signal transducer and activator of transcription (STAT)-1 and c-Jun amino-terminal kinases (JNK). Alternatively, fluoxetine elevated peroxisome proliferator-activated receptor (PPAR) response element activity under HCV infection. The inhibitory effects of fluoxetine on HCV infection and lipid accumulation, but not production of ROS, were partially reversed by the PPAR-ß, -γ, and JNK antagonists. Furthermore, fluoxetine intervention to the IFN-α-2b regimen facilitated to reduce HCV titer and alanine transaminase level for CHC patients. Therefore, fluoxetine intervention to the IFN-α-2b regimen improved the efficacy of anti-HCV treatment, which might be related to blockades of ROS generation and lipid accumulation and activation of host antiviral JNK/STAT-1 and PPARß/γ signals.

Rosiglitazone regulates anti-inflammation and growth inhibition via PTEN.

Peroxisome proliferator-activated receptor gamma (PPARγ) agonist has anti-inflammatory and anticancer properties. However, the mechanisms by which PPARγ agonist rosiglitazone interferes with inflammation and cancer via phosphatase and tensin homolog-(PTEN)-dependent pathway remain unclear. We found that lower doses (<25 µ M) of rosiglitazone significantly inhibited lipopolysaccharide-(LPS)-induced nitric oxide (NO) release (via inducible nitric oxide synthase, iNOS), prostaglandin E2 (PGE2) production (via cyclooxygenase-2, COX-2), and activation of Akt in RAW 264.7 murine macrophages. However, rosiglitazone did not inhibit the production of reactive oxygen species (ROS). In PTEN knockdown (shPTEN) cells exposed to LPS, rosiglitazone did not inhibit NO release, PGE2 production, and activation of Akt. These cells had elevated basal levels of iNOS, COX-2, and ROS. However, higher doses (25-100 µ M) of rosiglitazone, without LPS stimulation, did not block NO release and PGE2 productions, but they inhibited p38 MAPK phosphorylation and blocked ROS generation in shPTEN cells. In addition, rosiglitazone caused G1 arrest and reduced the number of cells in S + G2/M phase, leading to growth inhibition. These results indicate that the anti-inflammatory property of rosiglitazone is related to regulation of PTEN independent of inhibition on ROS production. However, rosiglitazone affected the dependence of PTEN-deficient cell growth on ROS.

Blockade of reactive oxygen species and Akt activation is critical for anti-inflammation and growth inhibition of metformin in phosphatase and tensin homolog-deficient RAW264.7 cells.

CONTEXT: Metformin is widely used for treatment of type 2 diabetes and has a potential application on the treatment of inflammation and cancer. Phosphatase and tensin homolog (PTEN) plays a critical role in cancer cell growth and inflammation; however, precise mechanisms remain unclear. OBJECTIVE: We aimed to investigate the possible mechanisms of how PTEN regulates metformin against cell growth and inflammation. MATERIALS AND METHODS: We established PTEN knockdown in RAW264.7 murine macrophages (shPTEN cells) to detect inflammatory mediators using commercial kits, production of reactive oxygen species (ROS) by flow cytometry, cell growth by MTT assay and phosphorylated levels of signal molecules by western blot. RESULTS: The shPTEN cells had a significant large amount of inflammatory mediators, such as inducible nitric oxide synthase (iNOS)/nitric oxide (NO) and cyclooxygenase-2 (COX-2)/prostaglandin E(2) (PGE(2)); and also elevated the production of ROS and increased cell proliferation. These effects were accompanied with the activation of Akt and p38 mitogen-activated protein kinase (MAPK), and the inactivation of an AMP-activated protein kinase (AMPK) activator and extracellular signal-regulated kinase 1/2. Pretreatment with metformin not only blocked these inflammatory mediators, but also caused growth inhibition induced by significant apoptosis. Furthermore, inactivation of Akt, blockade of ROS generation and independence of activations of AMPK and MAPK by metformin were also observed. CONCLUSION: Macrophages with PTEN deficiency developed a continuous inflammatory microenvironment, which further aggravated tumor cell growth. Moreover, metformin affected PTEN-deficient cells dependent of inhibition of ROS production and Akt activation against enlarged inflammatory mediators and/or cell growth in shPTEN cells.

Evaluation of the appropriate age range of colorectal cancer screening based on the changing epidemiology in the past 20 years in taiwan.

Introduction. According to the recommendation of the United States Preventative Services Task Force, most countries provide average-risk screening for colorectal cancers (CRCs) between the ages of 50 and 75 years. However, the age range of screening should be modified because of an increasing life span. Methods. Totally 124,314 CRC cases were registered in Taiwan Cancer Registry from 1988 to 2007. The 20-year study period was divided into four 5-year increments. We divided the patients into four age groups (under age 50, age 50-74, age 74-84, and over age 85) in each increment to determine whether there were changes in the age distribution. Results. In the subgroup of patients under age 50, the number of CRC cases increased, but they accounted for a decreasing proportion of the total CRCs. In the 50-74 age group, the proportion of CRC cases also dropped. In contrast, the proportion increased in the 75-84 age group. Therefore, 43.63% of CRC patients would not be delegated to screen in the period of 2003-2007 if the CRC screening were restricted in the 50-74 age group. Conclusions. CRC screening for healthy individuals aged over 75 years is necessary.

Ethnic-specific prevalence of hepatitis B/C virus infection in Pin-Jen, Taiwan.

OBJECTIVES: The study aimed to estimate prevalence rate of hepatitis B/C virus infection by three ethnic groups including Hakka, Minnan, and Mainlander in Taiwan where there was a high incidence of hepatocellular carcinoma. METHODS: We enrolled a total of 5007 people aged 30 years or older who participated in Li-Shin Out-Reaching Neighboring Screening (LIONS) project in 2004-2005 in Pin-Jen township of Taoyuan county. The ethnic group was classified in the current study by using the criteria on the basis of the ethnicity of mother of participants. We collected the character of participants, hepatitis B/C virus infection, and life-style factors for the comparison across three ethnic groups. RESULTS: The highest positive rate of hepatitis B virus infection was seen in Minnan descendants (15.1%), followed by Hakka descendants (11.4%), and Mainlander descendants (6.6%). The difference by three groups was statistically significant (P<.001). Positive hepatitis B virus infection declined with age whereas positive hepatitis C virus infection increased with age regardless of ethnic group. By using ecological analysis, the higher proportion of Minnan was positively correlated to the elevated incidence of hepatocellular carcinoma (HCC) (correlation coefficient=.46, P=.03). CONCLUSIONS: Our population-based study shows prevalence rate of hepatitis B and C virus infection varies with ethnic group, with higher rate in Minnan. This finding was consistent with the ecological result, the higher the composition of Minnan the higher the incidence of HCC.

Marked elevation of liver transaminases after high-dose fluvastatin unmasks chronic hepatitis C: safety and re-challenge.

The statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have emerged as the drugs of choice for patients with dyslipidemia and have been shown to reduce major cardiovascular adverse events in large-scale clinical trials for both primary and secondary prevention. Statins are generally safe; however, the results of clinical trials do demonstrate possibilities of significant adverse effects in liver and muscle. Moreover, the numbers from the trials may not reflect the real situation in daily practice because individuals at increased risk for hepatotoxicity are usually deliberately and carefully excluded in clinical trials. We presented an 85-year-old woman who had a marked elevation of ALT (up to 409 U/L) after treatment with fluvastatin 80 mg/day for 6 weeks. Hepatitis C was identified after this episode. The elevation of ALT resolved 10 weeks after discontinuation of fluvastatin. Re-institution of fluvastatin from 40 to 80 mg/day for 2 months only cause mild elevation of ALT. This case suggests that elevation of transaminases during statin therapy may not be solely ascribed to statins. Re-challenge with the same statin at lower doses or with other statins may help to identify the patients who can still be treated with drugs of this category.

Therapeutic plasma exchange in patients with hyperlipidemic pancreatitis.

AIM: To clarify the effectiveness of plasma exchange by comparing the mortality and morbidity before and after the intervention of plasma exchange. METHODS: Plasma exchange has been available as an optional therapy for hyperlipidemic pancreatitis since August 1999 in our hospital. The patients were assorted into 2 groups (group I: before August 1999 and group II: after August 1999). Group I consisted of 34 patients (before the availability of plasma exchange). Group II consisted of 60 patients (after the availability of plasma exchange). Twenty patients in group II received plasma exchange after giving their consent. The mortality and morbidity were compared between group I and group II. Furthermore, the patients with severe hyperlipidemic pancreatitis (Ranson's score > or = 3) were analyzed separately. The mortality and morbidity were also compared between those receiving plasma exchange (group A) and those who did not receive plasma exchange (group B). RESULTS: There was no statistical difference in the mortality, systemic and local complications between group I and group II. When the patients with severe hyperlipidemic pancreatitis were analyzed separately, there was no statistical difference between group A and group B. CONCLUSION: Plasma exchange can not ameliorate the overall mortality or morbidity of hyperlipidemic pancreatitis. The time of plasma exchange might be the critical point. If patients with hyperlipidemic pancreatitis can receive plasma exchange as soon as possible, better result may be predicted. Further study with more cases is needed to clarify the role of plasma exchange in the treatment of hyperlipidemic pancreatitis.