Yi-Chao Hsu

Antifibrotic effects of tetrandrine on hepatic stellate cells and rats with liver fibrosis

Background:  Anti‐inflammation strategies are one of the proposed therapeutic approaches to hepatic fibrosis. Tetrandrine (C38H42O8N2, molecular weight: 622; Tet), an alkaloid isolated from the Chinese medicinal herb Stephania tetrandra, has been shown to exert anti‐inflammatory activity in pulmonary diseases. The purpose of the present study was to investigate the in vitro and in vivo effects of Tet on hepatic fibrosis.

Increases in Fibrosis-Related Gene Transcripts in Livers of Dimethylnitrosamine-Intoxicated Rats

Fibrosis-related changes in livers of cirrhotic rats induced by dimethylnitrosamine (DMN) have not yet been fully clarified. The aim of this study was to investigate changes in molecular and biochemical markers in DMN-intoxicated rats. DMN was administered to Sprague-Dawley rats for 2 and 5 weeks to induce different degrees of hepatic fibrosis. Liver tissues were assessed for the degree of fibrosis and gene expression. Histological examination of the liver showed a progressive increase in fibrosis scores (1.33 ± 0.21 and 3.03 ± 0.29, respectively) and expansion of fibrous septa with collagen-staining fibers in rats after 2 and 5 weeks of DMN administration. Hepatic protein contents of α-smooth muscle actin (α-SMA) and total collagen were significantly higher in rats administered DMN for both 2 and 5 weeks compared with those in control rats. Hepatic mRNA expressions of α-SMA, transforming growth factor-β1 (TGF-β1), connective tissue growth factor, tissue inhibitor of metalloproteinase-1, and procollagen I and III were increased in DMN rats after 2 and 5 weeks. Abnormal increases in plasma alanine transaminase (ALT) and aspartate transaminase (AST) levels, plasma and mitochondrial MDA levels, and portal venous pressure were also noted in DMN rats. DMN administration to rats for 2 and 5 weeks induced progressive increases in hepatic fibrosis scores, hepatic mRNA expressions of TGF-β1 and procollagen I and III genes, plasma levels of ALT and AST, and portal venous pressure, as well as progressive decreases in both liver and body weights. Our results suggest that DMN administration in rats induces biochemical and molecular changes related to fibrogenesis in the liver.

Fluvastatin attenuates hepatic steatosis-induced fibrogenesis in rats through inhibiting paracrine effect of hepatocyte on hepatic stellate cells

BackgroundNon-alcoholic steatohepatitis (NASH) is associated with hepatic fibrogenesis. Despite well-known cholesterol-lowering action of statins, their mechanisms against NASH-mediated fibrogenesis remain unclear. This study aimed at investigating the in vitro and in vivo anti-fibrotic properties of fluvastatin (Flu).MethodsPalmitate (PA)-induced changes in intracellular hydrogen peroxide levels in primary rat hepatocytes (PRHs) and human hepatoma cell line (HepG2) were quantified by dichlorofluorescein diacetate (DCF-DA) dye assay, whereas changes in expressions of NADPH oxidase gp91phox subunit, α-smooth muscle actin (α-SMA), and NFκB p65 nuclear translocation were quantified with Western blotting. Quantitative real-time polymerase chain reaction (q-PCR) was used to investigate mRNA expressions of pro-inflammatory genes (ICAM-1, IL-6, TNF-α). Conditioned medium (CM) from PA-treated PRHs was applied to cultured rat hepatic stellate cell line, HSC-T6, with or without Flu-pretreatment for 2 h. Pro-fibrogenic gene expressions (COL1, TIMP-1, TGF-β1, α-SMA) and protein expression of α-SMA were analyzed. In vivo study using choline-deficient L-amino acid defined (CDAA) diet-induced rat NASH model was performed by randomly assigning Wistar rats (n = 28) to normal controls (n = 4), CDAA diet with vehicles, and CDAA diet with Flu (5 mg/kg or 10 mg/kg) (n = 8 each) through gavage for 4 or 8 weeks. Livers were harvested for histological, Western blot (α-SMA), and q-PCR analyses for expressions of pro-inflammatory (IL-6, iNOS, ICAM-1) and pro-fibrogenic (Col1, α-SMA, TIMP-1) genes.ResultsIn vitro, Flu (1–20 μM) inhibited PA-induced free-radical production, gp91phox expression, and NFκB p65 translocation in HepG2 and PRHs, while CM-induced α-SMA protein expression and pro-fibrogenic gene expressions in HSC-T6 were suppressed in Flu-pretreated cells compared to those without pretreatment. Moreover, α-SMA protein expression was significantly decreased in HSC-T6 cultured with CM from PA-Flu-treated PRHs compared to those cultured with CM from PA-treated PRHs. Flu also reduced steatosis and fibrosis scores, α-SMA protein expression, mRNA expression of pro-inflammatory and pro-fibrogenic genes in livers of CDAA rats.ConclusionsWe demonstrated PA-induced HSC activation through paracrine effect of hepatocyte in vitro that was significantly suppressed by pre-treating HSC with Flu. In vivo, Flu alleviated steatosis-induced HSC activation and hepatic fibrogenesis through mitigating inflammation and oxidative stress, suggesting possible therapeutic role of Flu against NASH.

A Large-Scale Study Indicates Increase in the Risk of Epilepsy in Patients With Different Risk Factors, Including Rheumatoid Arthritis.

AbstractPeripheral neuropathy and inflammatory reactions of the central nervous system may accompany rheumatoid arthritis (RA). Inflammatory processes play a critical role in epilepsy. Therefore, we conducted this study to determine the risk of epilepsy in patients with RA.The RA cohort comprised patients ages 20 years and older who were newly diagnosed with RA between 2000 and 2011, with data obtained from the Registry of Catastrophic Illnesses Patient Database. Patients without RA were frequency matched with an RA cohort at a 1:1 ratio according to age, sex, and year of RA diagnosis.The overall crude hazard ratio (HR) for epilepsy was 1.27-fold higher in the RA cohort compared with that in the controls. After adjustment for age, sex, comorbidities, and medications, the patients with RA were associated with an increased risk of epilepsy compared with those without RA (adjusted HR [aHR] = 1.52, 95% confidence interval [CI] = 1.12–2.07). Compared with the RA patients with ⩽ 560 days of nonsteroidal anti-inflammatory drug (NSAID) use, the RA patients with 1181 to 2145 and >2145 days of NSAID use had a significantly lower risk of epilepsy (aHR = 0.35, 95% CI = 0.24–0.52 and aHR = 0.15, 95% CI = 0.09–0.24, respectively).This study provides compelling evidence of an increased risk of epilepsy in patients with RA. The period of NSAID treatment is negatively associated with the risk of epilepsy in RA patients.

Association of Periodontitis and Subsequent Depression: A Nationwide Population-Based Study.

AbstractPeriodontitis is a systemic and chronic inflammatory disease associated with multiple physical conditions. Distress and depression are other problems affecting the progression of periodontitis. However, the causal relationship between depression and periodontitis has not been adequately investigated. This aim of this study was to determine the association between periodontitis and the subsequent development of depression.We identified 12,708 patients with newly diagnosed periodontitis from 2000 to 2005 and 50,832 frequency-matched individuals without periodontitis. Both groups were followed until diagnosed with depression, withdrawal from the National Health Insurance program, or the end of 2011. The association between periodontitis and depressio was analyzed using Cox proportional hazard regression models.The incidence density rate of depression was higher in the periodontitis group than in the nonperiodontitis group, with an adjusted hazard ratio of 1.73 (95% confidence interval 1.58–1.89) when adjusting for sex, age, and comorbidity. Cox models revealed that periodontitis was an independent risk factor for depression in patients, except for comorbidities of diabetes mellitus (DM), alcohol abuse, and cancer.Periodontitis may increase the risk of subsequent depression and was suggested an independent risk factor regardless of sex, age, and most comorbidities. However, DM, alcohol abuse, and cancer may prevent the development of subsequent depression because of DM treatment, the paradoxical effect of alcohol, and emotional distress to cancer, respectively. Prospective studies on the relationship between periodontitis and depression are warranted.

Increased Subsequent Risk of Peptic Ulcer Diseases in Patients With Bipolar Disorders

Abstract Previous studies have reported that patients with bipolar disorders (BDs) exhibit increased physical comorbidity and psychological distress. Studies have shown that schizophrenia and anxiety increase the risk of peptic ulcer diseases (PUDs). Therefore, we conducted this study to determine the association between these 2 diseases and examine the possible risk factors. We used patients diagnosed with BDs from the Taiwan National Health Insurance Research Database. A comparison cohort comprising patients without BDs was frequency matched by age, sex, and comorbidities, and the occurrence of PUDs was evaluated in both the cohorts. The BD and non-BD cohort consisted of 21,060 patients with BDs and 84,240 frequency-matched patients without BDs, respectively. The incidence of PUDs (hazard ratio, 1.51; 95% confidence interval, 1.43–1.59; P < 0.001) was higher among the patients with BDs than the control patients. Cox models showed that irrespective of comorbidities, BDs were an independent risk factor for PUDs. Patients with BDs exhibit a substantially higher risk for developing PUDs. According to our data, we suggest that, following a diagnosis of BD, practitioners could notice the occurrence of PUD and associated prevention. Further prospective clinical studies investigating the relationship between BDs and PUDs are warranted.

Depression and the Risk of Peptic Ulcer Disease: A Nationwide Population-Based Study.

AbstractThe risk of peptic ulcer disease (PUD) among patients with depression has raised concern. This study determined the association between depression and the subsequent development of PUD using claims data.Patients newly diagnosed with depression in 2000 to 2010 were identified as depression cohort from the Taiwan National Health Insurance Research Database. The comparison cohort was randomly selected from subjects without depression, frequency matched by age and gender and diagnosis date, with a size 2-fold of the size of the depression cohort. The incidence of PUD was evaluated for both cohorts by the end of 2011. We calculated the hazard ratios (HRs) and 95% confidence intervals (CIs) of PUD using the Cox proportional hazards regression model.The depression cohort consisted of 23,536 subjects (129,751 person-years), and the comparison cohort consisted of 47,069 subjects (285,592 person-years). The incidence of PUD was 2-fold higher in the depression cohort than in the comparison cohort (33.2 vs 16.8 per 1000 person-years) with an age adjusted HR of 1.97 (95% CI = 1.89–2.06) or a multivariable adjusted HR of 1.35 (95% CI = 1.29–1.42).Depression might increase the risk of developing PUD. Prospective clinical studies of the relationship between depression and PUD are warranted.

Association of Dementia and Peptic Ulcer Disease A Nationwide Population-Based Study

Objective: We determine the association between dementia and the subsequent peptic ulcer disease (PUD). Methods: We identified patients with diagnosed dementia in the Taiwan National Health Insurance Research Database. A comparison cohort without dementia was frequency-matched by age, sex, and comorbidities, and the occurrence of PUD was evaluated in both cohorts. Results: The dementia and control cohort consisted of 6014 patients with dementia and 17 830 frequency-matched patients without dementia, respectively. The incidence of PUD (hazard ratio, 1.27; 95% confidence interval, 1.18-1.37; P < .001) was higher among patients with dementia. Cox models showed that being female, diabetes mellitus, chronic kidney disease, coronary artery disease, and chronic obstructive pulmonary disease were independent risk factors for PUD in patients with dementia. Conclusion: Dementia might increase the risk of developing PUD.

Increased risk of incident nasopharyngeal carcinoma with exposure to air pollution

Background Nasopharyngeal carcinoma (NPC) is a race-specific malignancy. The nasal cavity is the main entry point for air pollutants or poisonous gases into the human body. However, the risk of NPC in populations exposed to air pollution remains unknown. Methods We combined data from the Taiwan Air Quality Monitoring Database (TAQMD) and the Longitudinal Health Insurance Database (LHID) to assess the risk of NPC in a population exposed to air pollution. Results Multivariate analysis revealed positive trends for the association between the risk of NPC and exposure to air pollution. After adjusting for potential covariates, the risk of developing NPC increased with the increase in nitrogen dioxide (NO2) and fine particulate matter (PM2.5) exposure concentrations from 1.39 to 2.28 and 2.01 to 1.97, respectively, compared to the risks at the lowest concentration levels. Conclusions We identified a significant risk of NPC in a population exposed to air pollution. However, this study had several limitations. Moreover, additional experimental and clinical studies on the associations between environmental factors and NPC risk are warranted.

HBV infection increases the risk of macular degeneration: the roles of HBx-mediated sensitization of retinal pigment epithelial cells to UV and blue light irradiation

BackgroundHepatitis B virus (HBV) infection is strongly associated with hepatocellular carcinoma due to the main pathogenic X protein of HBV (HBx). Whether HBV infection and the HBx protein could result in macular degeneration (MD) is not known. The aim of this study is to assess the association and underlying mechanisms between HBV infection and MD.MethodsThe National Health Research Institutes in Taiwan built a large database, the National Health Insurance Research Database (NHIRD), which includes the claims data from the Taiwan National Health Insurance (NHI) program. The Taiwan NHI is a single-payer, compulsory health insurance program for Taiwan citizens. The data for the present study were derived from the Longitudinal Health Insurance Database, which contains the claims data of 1 million insured people within the NHIRD, including beneficiary registration, inpatient and outpatient files, drug use, and other medical services. In this study, we first investigated the association of HBV infection and the risk of MD by a population-based cohorts study enrolling 39,796 HBV-infected patients and 159,184 non-HBV-infected patients.ResultsAfter adjustment of age, sex, and comorbidities, the risk of MD was significantly higher in the HBV-infected cohort than in the non-HBV-infected cohort (adjusted HR = 1.31; 95% CI = 1.17–1.46). In vitro, we provided evidence to demonstrate that overexpression of HBx in the human retinal pigment epithelial (RPE) cell line, ARPE19, significantly reduced cell viability and clonogenic survival upon UV and blue light irradiation. By gene microarray analysis, we further showed that almost all genes in DNA repair pathways including base excision repair, nucleotide excision repair, mismatch repair, and homologous recombination were significantly down-regulated in the UV-induced cell death of HBx-transfected ARPE19 cells.ConclusionsThe HBx protein may sensitize RPE cells to UV and blue light irradiation and increase the risk of HBV-infection-associated MD through down-regulation of multiple DNA repair pathways.