TXNIP in liver sinusoidal endothelial cells ameliorates alcohol-associated liver disease via nitric oxide production.

Dysregulation of liver sinusoidal endothelial cell (LSEC) differentiation and function has been reported in alcohol-associated liver disease (ALD). Impaired nitric oxide (NO) production stimulates LSEC capillarization and dysfunction; however, the mechanism underlying NO production remains unclear. Here, we investigated the role of thioredoxin-interacting protein (TXNIP), an important regulator of redox homeostasis, in endothelial cell NO production and its subsequent effects on ALD progression. We found that hepatic TXNIP expression was upregulated in patients with ALD and in ethanol diet-fed mice with high expression in LSECs. Endothelial cell-specific Txnip deficiency (TxnipΔEC) in mice exacerbated alcohol-induced liver injury, inflammation, fibrosis, and hepatocellular carcinoma development. Deletion of Txnip in LSECs led to sinusoidal capillarization, downregulation of NO production, and increased release of proinflammatory cytokines and adhesion molecules, whereas TXNIP overexpression had the opposite effects. Mechanistically, TXNIP interacted with transforming growth factor ß-activated kinase 1 (TAK1) and subsequently suppressed the TAK1 pathway. Inhibition of TAK1 activation restored NO production and decreased the levels of proinflammatory cytokines, thereby, blocking liver injury and inflammation in TxnipΔEC mice. Our findings indicate that upregulated TXNIP expression in LSECs serves a protective role in ameliorating ALD. Enhancing TXNIP expression could, therefore, be a potential therapeutic approach for ALD.

Using community-based geographical information system (GIS) to recruit older Asian Americans in an Alzheimer's disease study.

OBJECTIVE: This study aims to show the usefulness of incorporating a community-based geographical information system (GIS) in recruiting research participants for the Asian Cohort for Alzheimer's Disease (ACAD) study for using the subgroup of Korean American (KA) older adults. The ACAD study is the first large study in the USA and Canada focusing on the recruitment of Chinese, Korean and Vietnamese older adults to address the issues of under-representation of Asian Americans in clinical research. METHODS: To promote clinical research participation of racial/ethnic minority older adults with and without dementia, we used GIS by collaborating with community members to delineate boundaries for geographical clusters and enclaves of church and senior networks, and KA serving ethnic clinics. In addition, we used socioeconomic data identified as recruitment factors unique to KA older adults which was analysed for developing recruitment strategies. RESULTS: GIS maps show a visualisation of the heterogeneity of the sociodemographic characteristics and the resources of faith-based organisations and KA serving local clinics. We addressed these factors that disproportionately affect participation in clinical research and successfully recruited the intended participants (N=60) in the proposed period. DISCUSSION: Using GIS maps to locate KA provided innovative inroads to successful research outreach efforts for a pilot study that may be expanded to other underserved populations across the USA in the future. We will use this tool subsequently on a large-scale clinical genetic epidemiology study. POLICY IMPLICATION: This approach responds to the call from the National Institute on Aging to develop strategies to improve the health status of older adults in diverse populations. Our study will offer a practical guidance to health researchers and policymakers in identifying understudied and hard-to-reach specific Asian American populations for clinical studies or initiatives. This would further contribute in reducing the health and research disparity gaps among older minority populations.

IL-17A promotes Helicobacter pylori-induced gastric carcinogenesis via interactions with IL-17RC.

BACKGROUND: Gastric cancer (GC) is a common malignancy worldwide, with a major attribution to Helicobacter pylori. Interleukin (IL)-17A has been reported to be up-regulated in serum and tumor of GC patients, but the precise mechanisms underlying its involvement in gastric tumorigenesis are yet to be established. Here, we investigated the roles of IL-17A in the pathogenesis of H. pylori-induced GC. METHODS: GC was induced in IL-17A knockout (KO) and wild-type (WT) mice via N-methyl-N-nitrosourea (MNU) treatment and H. pylori infection. At 50 weeks after treatment, gastric tissues were examined by histopathology, immunohistochemistry, and immunoblot analyses. In vitro experiments on the human GC cell lines were additionally performed to elucidate the underlying mechanisms. RESULTS: Deletion of IL-17A suppressed MNU and H. pylori-induced gastric tumor development accompanied by a decrease in gastric epithelial cell growth, oxidative stress, and expression of gastric epithelial stem cells markers. In AGS cells, recombinant human IL-17A (rhIL-17A) inhibited apoptosis and G1/S phase transition arrest while promoting reactive oxygen species production, sphere formation ability of cancer stem cells (CSC), and expression of stemness-related genes. In addition, rhIL-17A induced expression of IL-17RC, leading to NF-κB activation and increased NADPH oxidase 1 (NOX1) levels. Inhibition of NOX1 with GKT136901 attenuated rhIL-17A-mediated elevation of GC cell growth, ROS generation, and CSC stemness. Clinically, IL-17RC expressions were significantly upregulated in human GC compared with normal gastric tissues. CONCLUSION: Our results suggest that IL-17A promotes gastric carcinogenesis, in part, by regulating IL-17RC/NF-κB/NOX1 pathway, supporting its potential as a target in human GC therapy.

Inhibitory effects of Hydrocotyle ramiflora on testosterone-induced benign prostatic hyperplasia in rats.

PURPOSE: Benign prostatic hyperplasia (BPH) is a urogenital disorder that affects approximately 85% of males who are over 50 years of age. Hydrocotyle ramiflora (HR), belonging to Apiaceae family, is used to treat urinary system diseases such as urine retention in traditional Chinese herbal medicine. In this study, we evaluated the effects of HR in the BPH animal model. METHODS: We induced BPH in rats via subcutaneous (sc) injections of testosterone propionate (TP, 3 mg/kg). Rats were also administered HR (150 mg/kg), finasteride (10 mg/kg), or vehicle via oral gavage. After induction, prostate glands were collected, weighed, and processed for further analysis, including histopathological examination and immunohistochemistry. In addition, the mRNA expression of inflammatory cytokines in prostatic tissues was determined by quantitative real-time PCR (qRT-PCR). The protein expression of pro-apoptotic markers was examined using western blotting. RESULTS: HR treatment significantly reduced the prostate weight, epithelial thickness, and proliferating cell nuclear antigen (PCNA) expression, with the levels of cleaved caspase-3 and Bcl-2-associated X (Bax) protein considerably increased compared to BPH group. HR also decreased inflammatory cell infiltration and pro-inflammatory cytokine levels compared with BPH group. Furthermore, the expression of phosphor-nuclear factor-κB (NF-κB), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) were reduced by HR treatment. CONCLUSION: These results indicate that HR suppresses the development of BPH associated with anti-proliferative, pro-apoptotic, and anti-inflammatory effects, suggesting it is a potential alternative therapeutic agent for BPH.

Anti-inflammatory effect of Gyeji-tang in a chronic obstructive pulmonary disease mouse model induced by cigarette smoke and lipopolysaccharide.

CONTEXT: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease associated with respiratory symptoms and narrowing of airways. Gyeji-tang (GJT) is a traditional Asian medicine that has been used to relieve early-stage cold symptoms, headache, and chills. OBJECTIVE: We examined the effect and potential molecular action mechanism of GJT in a mouse model of COPD induced by cigarette smoke (CS) plus lipopolysaccharide (LPS). MATERIALS AND METHODS: COPD was induced in C57BL/6J mice via daily exposure to CS for 1 h for 8 weeks and intranasal administration of LPS on weeks 1, 3, 5, and 7. GJT (100 or 200 mg/kg) or roflumilast (5 mg/kg) was administrated daily for the final 4 weeks of COPD induction. RESULTS: Administration of GJT significantly suppressed the CS/LPS-induced increases in: the numbers of total cells and macrophages in bronchoalveolar lavage fluid; the expression levels of tumour necrosis factor-α, interleukin (IL)-6, IL-1ß, and IL-8; the activities (phosphorylation) of nuclear factor kappa B and signal transducer and activator of transcription 3; and the expression levels of the structural remodelling markers, transforming growth factor beta, matrix metallopeptidase (MMP)-7, and MMP-9. DISCUSSION AND CONCLUSIONS: These results demonstrate that GJT prevents the lung inflammation and airway remodelling induced by CS plus LPS exposure in mice, suggesting that GJT may have therapeutic potential for the treatment of COPD.

Eriochloa villosa Alleviates Progression of Benign Prostatic Hyperplasia in vitro and in vivo.

Introduction: Benign prostatic hyperplasia (BPH) is a non-neoplastic proliferative disease of the prostate. Eriochloa villosa (EV) reportedly possesses various pharmacological activities, including anti-lipase activity and modulation of various antioxidative enzymes. In this study, we investigate the therapeutic potential of EV against BPH in a testosterone-induced BPH rat model. Methods: Rats were subjected to a daily subcutaneous injection of testosterone (3 mg kg-1) for 4 weeks to induce BPH. Along with testosterone, rats in the treatment group were administered finasteride (10 mg kg-1) or EV (150 mg kg-1) via oral gavage. Prostatic cancer (LNCaP) cell line was used to examine the effect of EV. Results: Finasteride and EV significantly decrease the relative prostate weight, serum levels of dihydrotestosterone and testosterone, and prostate epithelial thickness. Testosterone injection induced prostatic hyperplasia and proliferating cell nuclear antigen expression; however, EV treatment significantly attenuated these effects. Moreover, finasteride- and EV-treated rats exhibit an increase in the number of TUNEL-positive cells and reduced Bcl-2 expression in the prostate tissues compared with the testosterone-treated animals. Furthermore, EV suppresses inflammatory cytokines, including interleukin (IL)-6 and IL-8, in the prostate tissues. Meanwhile, the expression of inflammatory mediator cyclooxygenase-2 is consistently upregulated in testosterone-treated rats, whereas EV treatment significantly reverses this effect. Notably, EV treatment suppresses malondialdehyde (MDA) levels and upregulates testosterone-induced catalase (CAT) expression. In addition, EV suppresses expression of androgen receptor (AR) and prostate-specific antigen (PSA) induced by testosterone in LNCaP cells. Conclusion: The present study results suggest that EV regulates prostatic proliferation, apoptosis, response to inflammation, and oxidative stress in the BPH rat model, and may, therefore, serve as a useful therapeutic agent for BPH.

Yijin-Tang Attenuates Cigarette Smoke and Lipopolysaccharide-Induced Chronic Obstructive Pulmonary Disease in Mice.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) refers to a lung disorder associated with symptoms of dyspnea, cough, and sputum production. Traditionally, Yijin-tang (YJT), a mixture of Pinellia ternate, Poria cocos, ginger, Chinese liquorice, and tangerine peel, has been prescribed for the treatment of respiratory system diseases caused by dampness phlegm. This experiment investigated the therapeutic effect of YJT in a mouse model of cigarette smoke (CS)- and lipopolysaccharide (LPS)-induced COPD. METHODS: COPD was induced by exposing mice to CS for 1 hour per day for 8 weeks, with intranasal delivery of LPS on weeks 1, 3, 5, and 7. YJT was administered at doses of 100 and 200 mg/kg 1 hour before CS exposure for the last 4 weeks. RESULTS: YJT significantly suppressed CS- and LPS-induced increases in inflammatory cell counts and reduced interleukin-1 beta (IL-1ß), IL-6, tumor necrosis factor-alpha (TNF-α), and monocyte chemoattractant protein-1 (MCP-1) levels in bronchoalveolar lavage fluid (BALF) and lung tissue. In addition, YJT not only decreased airway wall thickness, average alveolar intercept, and lung fibrosis, but it also suppressed the expression of matrix metallopeptidase (MMP)-7, MMP-9, and transforming growth factor-B (TGF-ß) and collagen deposition. Moreover, YJT suppressed phosphorylation of nuclear factor-kappa B (NF-κB) as well as expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). CONCLUSION: Collectively, our findings show that YJT attenuates respiratory inflammation and airway remodeling caused by CS and LPS exposure; therefore, therapeutic applications in COPD can be considered.

Effects of Environmental Air Pollution on Pulmonary Function Level of Residents in Korean Industrial Complexes.

This study aims to identify environmental air pollution adversely affecting pulmonary function among a community-based general population living in Korean industrial complexes. A total of 1963 residents participated in a pulmonary function test (PFT). The sample population consisted of an exposed group (n = 1487) living within a radius of 5 km of industrial complexes and a control group (n = 476) living over a radius of 10 km from the industrial complexes in Gwangyang and Yeosu cities. PFT results were calculated for each resident of the study population. On-site questionnaire surveys with face-to-face interviews were also conducted to collect more detailed information on personal lifestyles, medical history, exposure to air pollution, and respiratory disease and related symptoms. A total of 486 measured samples were collected by eight automated air-monitoring stations installed in four counties of Gwangyang and four counties of Yeosu in South Korea from January 2006 to February 2007. Mean levels of SO2 (0.012 ppm), CO (0.648 ppm), NO2 (0.02 ppm), O3 (0.034 ppm), and PM10 (43.07 μg/m³), collected within a radius of 5 km, were significantly higher than those collected over a radius of 10 km from Gwangyang and Yeosu industrial complexes. Prevalence odds ratio (OR) of abnormal pulmonary function in the exposed group of residents (<5 km) was elevated at 1.24 (95% CI 0.71⁻1.96), but not statistically significant (p > 0.05). In multiple linear regression analysis, forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) levels significantly declined as SO2, CO, and O3 levels increased when adjusting for age, sex, body mass index (BMI), alcohol, smoking, secondhand smoke, and respiratory disease and related symptoms (n = 1963) (p < 0.05). These results suggest that exposure to air pollution affects pulmonary function levels of residents living in Korean industrial complexes.

Income-related health inequalities across regions in Korea.

INTRODUCTION: In addition to economic inequalities, there has been growing concern over socioeconomic inequalities in health across income levels and/or regions. This study measures income-related health inequalities within and between regions and assesses the possibility of convergence of socioeconomic inequalities in health as regional incomes converge. METHODS: We considered a total of 45,233 subjects (≥ 19 years) drawn from the four waves of the Korean National Health and Nutrition Examination Survey (KNHANES). We considered true health as a latent variable following a lognormal distribution. We obtained ill-health scores by matching self-rated health (SRH) to its distribution and used the Gini Coefficient (GC) and an income-related ill-health Concentration Index (CI) to examine inequalities in income and health, respectively. RESULTS: The GC estimates were 0.3763 and 0.0657 for overall and spatial inequalities, respectively. The overall CI was -0.1309, and the spatial CI was -0.0473. The spatial GC and CI estimates were smaller than their counterparts, indicating substantial inequalities in income (from 0.3199 in Daejeon to 0.4233 Chungnam) and income-related health inequalities (from -0.1596 in Jeju and -0.0844 in Ulsan) within regions.The results indicate a positive relationship between the GC and the average ill-health and a negative relationship between the CI and the average ill-health. Those regions with a low level of health tended to show an unequal distribution of income and health. In addition, there was a negative relationship between the GC and the CI, that is, the larger the income inequalities, the larger the health inequalities were. The GC was negatively related to the average regional income, indicating that an increase in a region's average income reduced income inequalities in the region. On the other hand, the CI showed a positive relationship, indicating that an increase in a region's average income reduced health inequalities in the region. CONCLUSION: The results suggest that reducing health inequalities across regions require a more equitable distribution of income and a higher level of average income and that the higher the region's average income, the smaller its health inequalities are.