Empagliflozin Reduces the Progression of Hepatic Fibrosis in a Mouse Model and Inhibits the Activation of Hepatic Stellate Cells via the Hippo Signalling Pathway.

Hepatic fibrosis is the excessive production and deposition of the extracellular matrix, resulting in the activation of the fibrogenic phenotype of hepatic stellate cells (HSCs). The Hippo/Yes-associated protein (YAP) signalling pathway is a highly conserved kinase cascade that is critical in regulating cell proliferation, differentiation, and survival, and controls stellate cell activation. Empagliflozin, a sodium-glucose cotransporter type-2 inhibitor, is an antidiabetic drug that may prevent fibrotic progression by reducing hepatic steatosis and inflammation. However, little is known about its mechanism of action in liver fibrosis. In this study, we used male C57 BL/6 J mice fed a choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) as a model for hepatic fibrosis. For 5 weeks, the mice received either a vehicle or empagliflozin based on their assigned group. Empagliflozin attenuated CDAHFD-induced liver fibrosis. Thereafter, we identified the Hippo pathway, along with its effector, YAP, as a key pathway in the mouse liver. Hippo signalling is inactivated in the fibrotic liver, but empagliflozin treatment activated Hippo signalling and decreased YAP activity. In addition, empagliflozin downregulated the expression of pro-fibrogenic genes and activated Hippo signalling in HSCs. We identified a mechanism by which empagliflozin ameliorates liver fibrosis.

Nationwide population-based study showed that the rotavirus vaccination had no impact on the incidence of biliary atresia in Korea.

AIM: Rotaviruses have been associated with biliary atresia. This study investigated whether the rotavirus vaccine, which was introduced to Korea in 2008, had an impact on the incidence of biliary atresia. METHODS: We identified all rotavirus infections (n = 436 826) and biliary atresia cases (n = 528) diagnosed from 2006 to 2015 from insurance and health databases. The annual and seasonal incidence of biliary atresia and rotavirus infection rates in neonates and children were calculated. The difference in the risk of biliary atresia between rotavirus-infected and non-infected neonates was analysed. RESULTS: The incidence of rotavirus infections was 20.6 versus 13.4 per 1000 cases before (2006-2008) and after (2009-2015) vaccine implementation. However, neonatal rotavirus infection rates did not decrease, with an incidence of 14.5 versus 14.8 per 1000 cases before and after vaccination. The biliary atresia incidence remained constant at 12.0 per 100 000 cases. Rotavirus infections in neonates were a risk factor for biliary atresia (odds ratio 3.14, 95% confidence interval 1.87-5.26). CONCLUSION: Rotavirus vaccination had no impact on the incidence of biliary atresia, possibly because the vaccination did not change the neonatal rotavirus infection rate through herd immunity. However, rotavirus infections in neonates were significantly associated with biliary atresia.

Trends in the prescription of benzodiazepines for the elderly in Korea.

BACKGROUND: This study examined trends in the prescription of benzodiazepines for the elderly (age over 65 years) in Korea, a country with a higher level of spending on pharmaceuticals compared to that in other Organization for Economic Cooperation and Development (OECD) countries, and identified factors related to the inappropriate use of such drugs. METHODS: We used the National Health Insurance Claims Data (NHICD) for the period 2009-2013, including all reimbursed drug-prescribing information. Following the OECD's prescribing quality indicators (PQIs), we looked at the prevalence, quantities, durations, and inappropriate (long-term or high-quantity) use of benzodiazepines, some of the most widely prescribed, but potentially inappropriate, drugs for the elderly. We also performed multivariate logistic regression analyses to identify factors related to the inappropriate use of these drugs. RESULTS: The annual prevalence of benzodiazepine prescribing for elderly subjects decreased slightly over time but remained high (37.9% in 2009 and 35.1% in 2013). There were also small decreases in the inappropriate long-term use of benzodiazepines over the five years, with a 0.6 decrease in the Defined Daily Dose and a 4.1 per 1,000 decreases in elderly user-days. The proportion of subjects using long-acting benzodiazepines also fell from 263.6 to 220.4 per 1,000 elderly patients. The regression analyses found that the inappropriate long-term use of benzodiazepines in the elderly was significantly related to the patients visiting several institutions and physicians prescribing more than 30 days' worth of medication. CONCLUSIONS: The prevalence of prescribing potentially inappropriate drugs, such as benzodiazepines, remains high in Korea. Policy efforts, such as a periodic assessment of prescribing, restricting prescribing days, and more practical guidelines, are needed to improve the quality of prescribing.

Incidence, mortality, and causes of death in physician-diagnosed primary Sjögren's syndrome in Korea: A nationwide, population-based study.

OBJECTIVES: The objective of this study was to investigate the epidemiological features of primary Sjögren's syndrome (pSS) in Korea at a national level, including the incidence, mortality, and causes of death. METHODS: We used a national, population-based registry database called the Rare Intractable Disease Registration Program from the Health Insurance Review and Assessment Service to obtain pSS patient data for the period between 2010 and 2014. pSS was diagnosed by a physician based on uniform criteria. We also used data from Statistics Korea to confirm the mortality and causes of death. RESULTS: Between 2010 and 2014, the total number of patients newly diagnosed with pSS was 5891, resulting in an annual incidence of 2.34 per 100,000 individuals. The female-to-male ratio was 14.5:1. A total of 114 pSS patients died during the study period. The overall survival rate of pSS patients was 99.0%, and the 1-year, 2-year, and 5-year survival rates were 98.7%, 98.1%, and 97.1%, respectively, and the standardized mortality ratio (SMR) was 1.47 (2.14 for males and 1.35 for females). The most common causes of death were respiratory disease (n = 25; 21.9%) followed by circulatory diseases (n = 21; 18.4%), musculoskeletal connective tissue diseases (n = 21; 18.4%), and cancer (n=19; 16.7%). CONCLUSIONS: The national incidence of pSS in Korea presented in this study was lower in comparison with reports from other countries. However, the mortality rate was significantly higher than the corresponding values in the age- and gender-matched general population. The higher mortality in pSS patients is attributable to respiratory diseases and lung cancer.

Incidence, prevalence, mortality and causes of death in Takayasu Arteritis in Korea - A nationwide, population-based study.

BACKGROUND: Studies investigating the epidemiology and mortality of Takayasu Arteritis (TA) are scarce. The objective of this study was to provide information regarding the epidemiology of TA, such as the incidence, prevalence, survival and cause of death in Korea. METHODS: We used a national, population-based database maintained by the Rare Intractable Disease registration program and the Health Insurance Review and Assessment Service, which includes information on all TA patients, diagnosed based on uniform criteria. We also used data from Statistics Korea linked with RID database to confirm survival and cause of death. We analyzed data for the period 2008-2012. RESULTS: During study period, there were 612 new patients with TA, with a female-to-male ratio of 4.3:1. The annual mean incidence was 0.24 per 105 people, and the prevalence was 2.82 per 105 people in 2012. The average annual mortality rate was 0.02 per 105 people, and the standardized mortality ratio was 3.1. The overall survival of patients with TA was 96.6%, which was significantly lower than that in the general population. Cardiovascular disease was the most common cause of death, accounting for 29 of the 64 deaths (45.3%), followed by neoplasms in 9 patients (14.1%). CONCLUSIONS: The incidence and prevalence presented in this study are the highest ever reported. The survival of patients with TA was significantly lower than that of the general population, and the main cause of death was cardiovascular disease. This study reflects the need for greater awareness of TA, especially in Asian countries.

Prevalence, Age at Diagnosis, Mortality, and Cause of Death in Retinitis Pigmentosa in Korea-A Nationwide Population-based Study.

PURPOSE: To determine the prevalence and mortality of retinitis pigmentosa (RP) patients in Korea. DESIGN: Population-based retrospective cohort study. METHODS: We used data covering the 2011-2014 period from the Rare Intractable Disease (RID) registry and Health Insurance Review and Assessment (HIRA) service, which include information on all patients diagnosed with RP based on predefined diagnostic criteria. Using the HIRA-RID database, we evaluated the prevalence and age at diagnosis of RP patients across the entire Korean population. We further linked the data from Statistics Korea to the HIRA-RID database to confirm mortality and causes of death. RESULTS: The prevalence in the total population across all ages was 11.09 per 105 people, and the prevalence in those over the age of 40 was 16.16 per 105 people. The age at diagnosis ranged from 0 to 95 and, on average, was 44.8. The standardized mortality ratio (SMR) was 1.56 for all ages, peaking at 2.61 in men aged 40-59, which was attributed to 6.6-fold higher suicide rates than the same age group in the general male population. CONCLUSIONS: This is the first nationwide epidemiologic study of RP patients covering the entire population of all ages. The results suggest that the prevalence of RP in Korea is about 1 in 9000 for all ages and 1 in 6000 for those over 40 years of age. The higher mortality of RP patients than that of the general population is attributable to a high suicide rate in male RP patients of working ages, which necessitates a careful attention to their mental health.

Specific intracellular uptake of herceptin-conjugated CdSe/ZnS quantum dots into breast cancer cells.

Herceptin, a typical monoclonal antibody, was immobilized on the surface of CdSe/ZnS core-shell quantum dots (QDs) to enhance their specific interactions with breast cancer cells (SK-BR3). The mean size of the core-shell quantum dots (28 nm), as determined by dynamic light scattering, increased to 86 nm after herceptin immobilization. The in vitro cell culture experiment showed that the keratin forming cancer cells (KB) proliferated well in the presence of herceptin-conjugated QDs (QD-Her, 5 nmol/mL), whereas most of the breast cancer cells (SK-BR3) had died. To clarify the mechanism of cell death, the interaction of SK-BR3 cells with QD-Her was examined by confocal laser scanning microscopy. As a result, the QD-Her bound specifically to the membrane of SK-BR3, which became almost saturated after 6 hours incubation. This suggests that the growth signal of breast cancer cells is inhibited completely by the specific binding of herceptin to the Her-2 receptor of SK-BR3 membrane, resulting in cell death.

Organic solar cells with plasmonic layers formed by laser nanofabrication.

A method for the synthesis of metal nanoparticle coatings for plasmonic solar cells which can meet large scale industrial demands is demonstrated. A UV pulsed laser is utilized to fabricate Au and Ag nanoparticles on the surface of polymer materials which form the substrates for plasmonic organic photovoltaic devices to enhance their performance. Control of the particles' size and density is demonstrated. The optical and electrical effects of these embedded particles on the power conversion efficiency are examined rigorously using both experimental and computer simulation. Gold nanoparticles of particular size and spatial distribution enhance the device efficiency. Based on our findings, we propose design considerations for utilizing the entire AM1.5 spectrum using plasmonic structures towards enhancing the efficiency of polymer solar cells using broad spectrum plasmonics.

Enhanced osteoblast responses to poly(methyl methacrylate)/hydroxyapatite electrospun nanocomposites for bone tissue engineering.

Hydroxyapatite (HA)-containing polymers have been proposed for improving the biological properties of bone cements. Poly(methyl methacrylate) (PMMA) has long been used to secure orthopedic implants to skeletal bones. The aim of this study was to determine whether the incorporation of HA nanoparticles into the PMMA nanofibrous scaffolds enhances the biological functions of osteoblasts. The number of osteoblasts adhered and proliferated on the PMMA/HA nanofibrous scaffolds was significantly larger than that on the PMMA alone. The cytoskeletal organization and alkaline phosphatase (ALP) activity of the osteoblasts on the PMMA/HA nanofibrous scaffolds were clearly higher than that on the PMMA control. The amount of calcium ions released from 20 wt% HA-containing PMMA nanofibrous scaffolds (PMMA/HA20) was much higher than that released from 10 wt% HA-containing PMMA nanofibrous scaffolds (PMMA/HA10) (HA, 10 wt%). These findings suggested that osteoblast differentiation was accelerated by the incorporation of HA into the PMMA nanofibrous scaffolds. Therefore, the incorporation of HA into the PMMA nanofibrous scaffolds could be a useful method. This can be used for providing PMMA scaffolds with enhanced osteogenic properties.

High-speed atomic force microscope lithography using a piezo tube scanner driven by a sinusoidal waveform.

Improving the throughput of atomic force microscope (AFM) lithography is an important success factor for employing it in nanolithography applications. The conventional motion of the AFM tube scanner is usually driven by triangular-shaped signals, but it is limited in speed due to mechanical instability of the scanner at the turning points. Here, we show that high-speed lithography is achievable using not only a piezo tube driven by a sinusoidal waveform signal but also highly sensitive noble organic resists including a photo acid generator. Cross-linked polymer nanostructures applying sinusoidal waveform driving have also shown improvements in the linearity and uniformity of line patterns.

Real-time atomic force microscopy using mechanical resonator type scanner.

The real-time atomic force microscope for biological sample is a challenging research field. We have demonstrated a real-time atomic force microscope by implementing a mechanical resonator type scanner called by "microscanner" The microscanner was designed to have a resonance frequency in the range of 5-10 kHz and an amplitude of 1-3 microm. The resonant vibration of the microscanner was served as a fast-scan directional motion, and an image acquisition rate of 30 frames/s with 256x256 pixels per frame was achieved. Time-varying sequential images of a poly(ethylene-oxide) sample were taken as a demonstration of potential for excellence in real-time imaging a moving nano-object.

The involvement of caspase-11 in TPEN-induced apoptosis.

The depletion of intracellular zinc with N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) induces protein synthesis-dependent apoptosis. Here we examined the involvement of caspase induction in apoptosis. Among the examined caspases, only caspase-11 was increased by TPEN. Caspase-11 activity also increased, which resulted in caspase-3 activation. Cycloheximide or actinomycin D blocked caspase-11 induction, reduced caspase-11 and -3 activation, and attenuated TPEN-induced neuronal apoptosis. Blockade of caspase-11 by a chemical inhibitor or genetic deletion attenuated TPEN-induced apoptosis, indicating a critical role of caspase-11 in TPEN-induced apoptosis. Although mitochondria-mediated caspase-9/-3 activation also contributed to TPEN-induced apoptosis, caspase-11 is likely a key inducible apoptosis-inducing protein.