Comparative toxicity of silicon dioxide,silver and iron oxide nanoparticles after repeated oral administration to rats

Although silicon dioxide (SiO₂), silver (Ag) and iron oxide (Fe₂O₃) nanoparticles are widely used in diverse applications from food to biomedicine, in vivo toxicities of these nanoparticles exposed via the oral route remain highly controversial. To examine the systemic toxicity of these nanoparticles, well‐dispersed nanoparticles were orally administered to Sprague–Dawley rats daily over a 13‐week period. Based on the results of an acute toxicity and a 14‐day repeated toxicity study, 975.9, 1030.5 and 1000 mg kg^–1 were selected as the highest dose of the SiO₂, Ag and Fe₂O₃ nanoparticles, respectively, for the 13‐week repeated oral toxicity study. The SiO₂ and Fe₂O₃ nanoparticles did not induce dose‐related changes in a number of parameters associated with the systemic toxicity up to 975.9 and 1000 mg kg^–1, respectively, whereas the Ag nanoparticles resulted in increases in serum alkaline phosphatase and calcium as well as lymphocyte infiltration in liver and kidney, raising the possibility of liver and kidney toxicity induced by the Ag nanoparticles. Compared with the SiO₂ and Fe₂O₃ nanoparticles showing no systemic distribution in all tissues tested, the Ag concentration in sampled blood and organs in the Ag nanoparticle‐treated group significantly increased with a positive and/or dose‐related trend, meaning that the systemic toxicity of the Ag nanoparticles, including liver and kidney toxicity, might be explained by extensive systemic distribution of Ag originating from the Ag nanoparticles. Our current results suggest that further study is required to identify that Ag detected outside the gastrointestinal tract were indeed a nanoparticle form or ionized form. Copyright © 2015 John Wiley & Sons, Ltd.     

The chloroform fraction of Solanum nigrum suppresses nitric oxide and tumor necrosis factor-α in LPS-stimulated mouse peritoneal macrophages through inhibition of p38, JNK and ERK1/2

Solanum nigrum L., commonly known as black nightshade, is used worldwide for the treatment of skin and mucosal ulcers, liver cirrhosis and edema. We aimed to determine the anti-inflammatory active fraction of S. nigrum by serial extractions. S. nigrum was first extracted with methanol, then fractionated with chloroform and water. The effects of S. nigrum fractions, diosgenin and α-solanine on LPS/interferon-gamma-induced nitric oxide (NO) and inducible NO synthase (iNOS), or LPS-induced tumor necrosis factor-α (TNF-α) and interleukin (IL)-6, in mouse peritoneal macrophages were determined. Western blotting analysis was used to detect LPS-induced phosphorylation of p38, JNK and ERK1/2. The chloroform fraction of S. nigrum was cytotoxic in a time and concentration dependent manner; however, the methanol and water fractions were not. The chloroform fraction reduced NO through inhibition of iNOS synthesis and inhibited TNF-α and IL-6 at the level of protein secretion; the methanol and water fractions showed a weak or no effect. The chloroform fraction also suppressed p38, JNK and ERK1/2. Diosgenin and α-solanine were cytotoxic at a high concentration. In particular, diosgenin was able to inhibit TNF-α and IL-6, but both compounds did not affect LPS-induced iNOS expression. These results indicate that the anti-inflammatory compounds of S. nigrum exist preferentially in the nonpolar fraction, ruling out the possibility that diosgenin and α-solanine are the likely candidates. The inhibition of iNOS, TNF-α and IL-6 by the chloroform fraction may be partly due to the suppression of p38, JNK and ERK1/2. Further study is required to identify the active compounds of S. nigrum.     

Antiproliferative triterpenes from the leaves and twigs of Juglans sinensis on HSC-T6 cells

Bioassay-guided fractionation of an 80% MeOH extract of leaves and twigs of Juglan sinensis has resulted in the isolation of four new triterpenes (1-4) and 17 known triterpenes (5-21). The new compounds were determined to be 1-oxo-3β,23-dihydroxyolean-12-en-28-oic acid 28-O-β-D-glucopyranoside (1), 1-oxo-3β-hydroxyolean-18-ene (2), 3β,23-dihydroxyurs-12-en-28-oic acid 28-O-β-D-glucopyranoside (3), and 3β,22α-dihydroxyurs-12-en-28-oic acid 28-O-β-D-glucopyranoside (4) by spectroscopic analysis. Compounds 2, 13, 15, and 21 showed antiproliferative activities (14.2, 14.8, 15.6, and 11.0% at 100 μM, respectively) in HSC-T6 cells. Flow cytometry assays revealed that these compounds inhibited HSC-T6 proliferation by inducing apoptosis.     

Development of cyclosporin A-loaded hyaluronic microsphere with enhanced oral bioavailability

To develop a hyaluronic microsphere with the improved oral bioavailability of poorly water-soluble cyclosporin A (CsA), the microspheres were prepared with varying ratios of sodium hyaluronate (HA)/sodium lauryl sulfate (SLS)/CsA using a spray-drying technique. The effects of HA and SLS on the dissolution and solubility of CsA in microspheres were investigated. The CsA-microsphere prepared with HA/SLS/CsA at the ratio of 4/2/1 gave the highest solubility and dissolution rate of CsA among those formulae tested. As solubility and dissolution rate of CsA were increased about 17- and 2-fold compared to CsA powder, respectively, this CsA-microsphere was selected as an optimal formula for oral delivery in rats. The CsA-microsphere and Sandimmun neoral sol gave significantly higher blood levels compared with CsA powder alone. Moreover, the AUC, T(max) and C(max) values of CsA in CsA-microsphere were not significantly different from those in Sandimmun neoral sol in rats, indicating that CsA-microsphere was bioequivalent to the commercial product in rats. Our results demonstrated that the CsA-microsphere prepared with HA and SLS, with improved bioavailability of CsA, might have been useful to deliver a poorly water-soluble CsA.     

Role of adjuvant chemoradiotherapy and chemotherapy in patients with resected gallbladder carcinoma: a multi-institutional analysis (KROG 19-04)

Objective:The effectiveness of adjuvant treatments for resected gallbladder carcinoma (GBC) has remained unclear due to lack of randomized controlled trials; thus, the aim of present study was to evaluate the role of adjuvant treatments, including chemoradiotherapy (CRT) and/or chemotherapy (CTx), in patients with resected GBC.Methods:A total of 733 GBC patients who received curative-intent surgical resection were identified in a multi-institutional database. Of 733 patients, 372 (50.8%) did not receive adjuvant treatment, whereas 215 (29.3%) and 146 (19.9%) received adjuvant CTx and CRT, respectively. The locoregional recurrence-free survival (LRFS), recurrence-free survival (RFS), and overall survival (OS) of the adjuvant treatment groups were compared according to tumor stage (stage II vs. stage III–IV).Results:In stage II disease (n = 381), the 5-year LRFS, RFS, and OS were not significantly different among the no-adjuvant therapy, CTx, and CRT groups, and positive resection margin, presence of perineural invasion, and Nx classification were consistently associated with worse LRFS, RFS, and OS in the multivariate analysis (P < 0.05). For stage III–IV (n = 352), the CRT group had significantly higher 5-year LRFS, RFS, and OS than the no-adjuvant therapy and CTx groups (67.8%, 45.2%, and 56.9%; 37.9%, 28.8%, and 35.4%; and 45.0%, 30.0%, and 45.7%, respectively) (P < 0.05).Conclusions:CRT has value as adjuvant treatment for resected GBC with stage III–IV disease. Further study is needed for stage II disease with high-risk features.     

Triple Therapy-Based on Tegoprazan,a New Potassium-Competitive Acid Blocker,for First-Line Treatment of Helicobacter pylori Infection: A Randomized,Double-Blind,Phase III,Clinical Trial

Background/AimsWe examined the efficacy and safety of tegoprazan as a part of first-line triple therapy for Helicobacter pylori eradication.MethodsA randomized, double-blind, controlled, multicenter study was performed to evaluate whether tegoprazan (50 mg)-based triple therapy (TPZ) was noninferior to lansoprazole (30 mg)-based triple therapy (LPZ) (with amoxicillin 1 g and clarithromycin 500 mg; all administered twice daily for 7 days) for treating H. pylori. The primary endpoint was the H. pylori eradication rate. Subgroup analyses were performed according to the cytochrome P450 (CYP) 2C19 genotype, the minimum inhibitory concentration (MIC) of amoxicillin and clarithromycin, and underlying gastric diseases.ResultsIn total, 350 H. pylori-positive patients were randomly allocated to the TPZ or LPZ group. The H. pylori eradication rates in the TPZ and LPZ groups were 62.86% (110/175) and 60.57% (106/175) in an intention-to-treat analysis and 69.33% (104/150) and 67.33% (101/150) in a per-protocol analysis (non-inferiority test, p=0.009 and p=0.013), respectively. Subgroup analyses according to MICs or CYP2C19 did not show remarkable differences in eradication rate. Both first-line triple therapies were well-tolerated with no notable differences.ConclusionsTPZ is as effective as proton pump inhibitor-based triple therapy and is as safe as first-line H. pylori eradication therapy but does not overcome the clarithromycin resistance of H. pylori in Korea (ClinicalTrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT03317223","term_id":"NCT03317223"}}NCT03317223).     

Diagnosis and Prevention of Hypersensitivity Reactions to Iodinated Contrast Media

Iodinated contrast media (ICM) have become one of the major causes of drug hypersensitivity reactions (HSRs) related to increasing numbers of ICM-based radiological imaging procedures. Strategies for diagnosing and preventing ICM-induced HSRs have not been uniformly standardized yet. However, advances have been made based on the results of recent research. A previous history of hypersensitivity to ICM is the most significant risk factor for developing HSR by ICM. Avoidance of culprit agents and premedication is the main strategy to prevent recurrences of HSRs in high-risk patients. In addition, we strongly recommend identifying sensitized ICM using skin tests to determine immunoglobulin E-mediated or delayed-type allergy and to guide the choice of an alternative contrast agent. ICM provocation test procedures have been established and are helpful in selected cases. In this paper, we review how to evaluate patients who have experienced immediate or delayed HSRs caused by ICM to minimize the risk of recurrence and discuss unmet needs that require further research.     

Association between Micronutrient Intake and Breast Cancer Risk According to Body Mass Index in South Korean Adult Women: A Cohort Study

This study investigated the association between micronutrient intake and breast cancer risk in South Korean adult women. This association was stratified according to body mass index (BMI) categories. Data from the Korean Genome and Epidemiology Study (KoGES) and the Health Examinee Study were analyzed. Altogether, 63,337 individuals (aged ≥40 years) completed the baseline and first follow-up surveys; 40,432 women without a history of cancer at baseline were included in this study. The association between micronutrient intake and breast cancer was determined by estimating the hazard ratio (HR) and 95% confidence interval (CI) using the Cox proportional hazard regression model. A stratified analysis by BMI (<25 kg/m² and ≥25 kg/m²) was performed. The an analysis of 15 micronutrients and breast cancer risk revealed that none of the micronutrients were associated with breast cancer risk after adjusting for covariates. In obese women, the risk of breast cancer was significantly reduced in the group that consumed vitamin C more than the recommended level (HR = 0.54, 95% CI: 0.31–0.93) and vitamin B6 levels above the recommended level (HR = 0.48, 95% CI: 0.25–0.89). In obese women, exceeding the recommended daily intake levels of vitamin C and vitamin B6 was associated with a lower risk of breast cancer. However, other micronutrients were not associated with breast cancer risk in these women.     

Prevalence and risk of colorectal polyps among the Korean population under 50 years

Colorectal cancer is a common cancer; generally, adults aged ≥ 50 years are screened using stool occult blood tests and colonoscopy. However, colorectal adenoma and cancer have been found in patients under the aged of 50, and studies on characteristics and risk factors in young patients are lacking. We evaluated the prevalence and risk factors of colorectal adenoma and cancer in young adults aged under 50 years.We retrospectively analyzed 570 individuals aged under 50 years who underwent colonoscopy at the Haeundae Paik Hospital, Korea, from January to June 2018. Logistic regression model was used to identify the risk factors for colorectal adenoma and colorectal cancer.The prevalence of colorectal adenoma in group of 19–29 years was 3.2% (1 of 31), 30–39 years was 13.8% (30 of 217) and in the group of 40–49 years was 21.1% (68 of 322) (P = .009). In multivariable analysis, age over 45 years (adjusted odds ratio [OR], 1.941; 95% confidence interval [CI], 1.187–3.172; P = .008) and male sex (adjusted OR, 1.711; 95% CI, 1.044–2.806; P = .033) were independent risk factors for colorectal neoplasia including cancer.The prevalence of colorectal adenoma increases as the age increased in young adults under 50 years of age, especially after the age of 45 years, the risk of colorectal neoplasia increases; hence, early screening should be considered before the age of 50 years.