TRAIL Enhances Apoptosis of Human Hepatocellular Carcinoma Cells Sensitized by Hepatitis C Virus Infection: Therapeutic Implications

Hepatitis C virus (HCV) infection causes chronic liver diseases leading to hepatocellular carcinoma (HCC) and liver failure. We have previously shown that HCV sensitizes hepatocytes to mitochondrial apoptosis via the TRAIL death receptors DR4 and DR5. Although TRAIL and its receptors are selective targets for cancer therapy, their potential against HCC with chronic HCV infection has not been explored yet. Here we show that HCV induces DR4/DR5-dependent activation of caspase-8 leading to elevation of apoptotic signaling in infected cells and also present TRAIL effect in HCV-induced apoptotic signaling. HCV induced proteolytic cleavage of caspase-9 by stimulating DR4 and DR5, resulting in subsequent cleavage of caspase-3. Further, HCV-induced proteolytic cleavage in caspase-8, caspase-9, and caspase-3 was enhanced in the presence of recombinant TRAIL. HCV-induced cleavage in caspase-9 and increase in caspase-3/7 activity was completely suppressed by silencing of either DR4 or DR5. Perturbing DR4/DR5-caspase-8 signaling complex by silencing DR4 and DR5 or by chemical inhibitor specific to caspase-8 led to decrease of HCV-induced cleavage of poly(ADP-ribose) polymerase (PARP), a substrate for caspase-3 during apoptosis, indicating the functional role of caspase-8 in HCV-induced apoptotic signaling network. Furthermore, TRAIL enhanced PARP cleavage in apoptotic response induced by HCV infection, indicating the effect of TRAIL for the induction of selective apoptosis of HCC cells infected with HCV. Given the importance of apoptosis in HCC development, our data suggest that HCV-induced DR4 and DR5 may be considered as an attractive target for TRAIL therapy against HCC with chronic HCV infection

Establishment of Efficacy and Safety Assessment of Human Adipose Tissue-Derived Mesenchymal Stem Cells (hATMSCs) in a Nude Rat Femoral Segmental Defect Model

Human adipose tissue-derived mesenchymal stem cell (hATMSC) have emerged as a potentially powerful tool for bone repair, but an appropriate evaluation system has not been established. The purpose of this study was to establish a preclinical assessment system to evaluate the efficacy and safety of cell therapies in a nude rat bone defect model. Segmental defects (5 mm) were created in the femoral diaphyses and transplanted with cell media (control), hydroxyapatite/tricalcium phosphate scaffolds (HA/TCP, Group I), hATMSCs (Group II), or three cell-loading density of hATMSC-loaded HA/TCP (Group III-V). Healing response was evaluated by serial radiography, micro-computed tomography and histology at 16 weeks. To address safety-concerns, we conducted a GLP-compliant toxicity study. Scanning electron microscopy studies showed that hATMSCs filled the pores/surfaces of scaffolds in a cell-loading density-dependent manner. We detected significant increases in bone formation in the hATMSC-loaded HA/TCP groups compared with other groups. The amount of new bone formation increased with increases in loaded cell number. In a toxicity study, no significant hATMSC-related changes were found in body weights, clinical signs, hematological/biochemical values, organ weights, or histopathological findings. In conclusion, hATMSCs loaded on HA/TCP enhance the repair of bone defects and was found to be safe under our preclinical efficacy/safety hybrid assessment system

Marine Alga Ecklonia cava Extract and Dieckol Attenuate Prostaglandin E2 Production in HaCaT Keratinocytes Exposed to Airborne Particulate Matter

Atmospheric particulate matter (PM) is an important cause of skin damage, and an increasing number of studies have been conducted to discover safe, natural materials that can alleviate the oxidative stress and inflammation caused by PM. It has been previously shown that the extract of Ecklonia cava Kjellman, a perennial brown macroalga, can alleviate oxidative stress in epidermal keratinocytes exposed to PM less than 10 microns in diameter (PM10). The present study was undertaken to further examine the anti-inflammatory effects of E. cava extract and its major polyphenolic constituent, dieckol. HaCaT keratinocytes were exposed to PM10 in the presence or absence of E. cava extract or dieckol and analyzed for their viability, prostaglandin E2 (PGE2) release, and gene expression of cyclooxygenase (COX)-1, COX-2, microsomal prostaglandin E2 synthase (mPGES)-1, mPGES-2, and cytosolic prostaglandin E2 synthase (cPGES). PM10 treatment decreased cell viability and increased the production of PGE2, and these changes were partially abrogated by E. cava extract. E. cava extract also attenuated the expression of COX-1, COX-2, and mPGES-2 stimulated by PM10. Dieckol attenuated PGE2 production and the gene expression of COX-1, COX-2, and mPGES-1 stimulated by PM10. This study demonstrates that E. cava extract and dieckol alleviate airborne PM10-induced PGE2 production in keratinocytes through the inhibition of gene expression of COX-1, COX-2, mPGES-1, and/or mPGES-2. Thus, E. cava extract and dieckol are potentially useful natural cosmetic ingredients for counteracting the pro-inflammatory effects of airborne PM

Texture Modification of 3D-Printed Maltitol Candy by Changing Internal Design

The purpose of this study is to show more diverse texture modifications by changing the material of a food 3D-printed structure conducted only with soft materials (in this case, potatoes and chocolate) to a hard material (in this case, maltitol here). However, unlike previous 3D-printed food materials, sweetener materials such as sucrose and maltitol are sensitively caramelized at a high melting temperature. As such, there is no commercialized printing equipment. Therefore, a printing process experiment was conducted first in this case. To do this, a high-temperature syringe pump-based extrusion device was designed, and process tests according to the temperature and environment were conducted. An assessment of the internal structural changes according to the infill patterns and infill percentages was conducted based on the acquired process conditions. The texture strength increased as the infill percentage increased. Depending on the infill patterns, the texture strength increased in the order of the Hilbert curve, honeycomb, and rectilinear samples here. As a result, a change in the texture strength was determined through a change in the internal structure of a hard food material using 3D printing, which showed a wider range of change than in conventional soft food materials

Luteolin 7-Sulfate Attenuates Melanin Synthesis through Inhibition of CREB- and MITF-Mediated Tyrosinase Expression

Antioxidants with antimelanogenic activity are potentially useful for the attenuation of skin hyperpigmentation disorders. In a previous study, luteolin 7-sulfate isolated from Phyllospadix iwatensis Makino, a marine plant, was shown to inhibit cellular melanin synthesis. The aim of the present study was to examine its action mechanism, focusing on the regulation of tyrosinase (TYR) expression in cells. Cell-based assay was undertaken using murine melanoma B16-F10 cells and primary human epidermal melanocytes (HEMs). Luteolin 7-sulfate showed lower toxicity compared to luteolin in B16-F10 cells. At the non-toxic concentration ranges, luteolin 7-sulfate attenuated melanin synthesis, stimulated by α-melanocyte-stimulating hormone or forskolin. Luteolin 7-sulfate attenuated forskolin-induced microphthalmia-associated transcription factor (MITF) and TYR expressions at the mRNA and protein levels in B16-F10 cells. It also attenuated the phosphorylation of cAMP-responsive element binding protein (CREB) stimulated by forskolin. Luteolin 7-sulfate also attenuated melanin synthesis in primary HEMs. This study demonstrates that luteolin 7-sulfate attenuates TYR gene expression through the intervention of a CREB- and MITF-mediated signaling pathway, leading to the decreased melanin synthesis

Adhesion Strength Analysis of Synthetic Polymer Rubberized Gel on Diversely Wetted Concrete Surfaces

In this study, the relationship between viscosity of synthetic polymer rubberized gel (SPRG) used for waterproofing and adhesive strength on varying degrees of wetted surfaces is examined. First, SPRG specimens of different ratios of viscosity modifiers were prepared (3% to 10%, interval of 1% per specimen type). These specimens were installed onto substrate surfaces of varying degrees of humidity ratio (0%, 10%, 20%, 30%, 50%, 70% and 100%). Upon following the standard installation procedure of the SPRG specimens, standard pull-off tests were conducted. Results of the test showed that a consistent relationship exists between the viscosity of synthetic polymer rubberized gel (SPRG) and its adhesive strength on different degrees of wetted surfaces. Linear regression analysis and subsequent calculation of the respective coefficient of determination leads to the result that viscosity is a relevant factor for achieving stable adhesion when it comes to the usage of SPRG waterproofing. The findings of this study could have significant implications for the development and application of adhesive gel waterproofing materials in various industries

Effects of hormone therapy on the clinical outcomes of endoscopic intervention in patients with endometriosis-related ureteral obstruction

Purpose: We investigated whether endoscopic interventions, including laser endoureterotomy and balloon dilatation following hormone therapy, are a good choice to treat ureteral obstruction due to ureteral endometriosis instead of laparoscopic or open surgery. Materials and Methods: Patients with ureteral obstruction due to endometriosis who underwent endoscopic intervention between 2004 and 2021 were reviewed. Patients with other causes of ureteral obstruction or previous ureteral surgery were excluded from the study. The primary endpoint was the 3-month success rate of endoscopic intervention with or without hormone therapy. Secondary endpoints were the success rate of endoscopic intervention between the hormone-treated and hormone-untreated groups at 6 months and the success rate according to the hormone therapy response of endometriosis at 3 and 6 months. Results: Eighteen patients with 19 ureter units were evaluated in this study, including 12 patients receiving hormone therapy and six patients not receiving hormone therapy. Among patients receiving hormone therapy, one patient had bilateral ureteral obstruction. The success rate of endoscopic intervention was higher in patients who received hormone therapy than in those who did not receive hormone therapy three months after endoscopic intervention (76.9% vs. 0.0%, p=0.003). The same result was also found 6 months after endoscopic intervention (75.0% vs. 0.0%, p=0.005). In addition, the success rates were higher in the hormone-responsive group than in the non-responsive group (100.0% vs. 57.1%), although the difference was not statistically significant (p=0.122). Conclusions: Ureteral obstruction caused by endometriosis can be effectively treated by endoscopic intervention with hormone therapy in select patients

Spexin-based galanin receptor 2 agonist improves renal injury in mice with type 2 diabetes

ABSTRACTThe spexin-based GALR2 agonist (NS200) is a novel drug, which has shown antidepressant and anxiolytic action in a recent experimental study. In this study, we investigated the effects of NS200 on renal injury in an animal model of type 2 diabetes. Eight-week-old diabetic db/db mice were administered NS200 for 12 weeks. NS200 was intraperitoneally administered at a dose of 1.0 mg/kg/day. Metabolic parameters and structural and molecular changes in the kidneys were compared among the three groups: non-diabetic db/m control, db/db mice, and NS200-treated db/db mice. In db/db mice, NS200 administration did not impact the body weight, food and water intake, urinary volume, fasting blood glucose level, or HbA1c levels. Insulin and glucose tolerance were also unaffected by NS200 treatment. However, NS200 improved urinary albumin excretion and glomerulosclerosis in diabetic kidneys. Activation of TGFβ1 and insulin signaling pathways, such as PI3 K /AKT/ERK, were inhibited by NS200. In conclusion, a spexin-based GALR2 agonist attenuated diabetic nephropathy by alleviating renal fibrosis in mice with type 2 diabetes. Spexin-based GALR2 agonists have considerable potential as novel treatment agents in diabetic nephropathy

The Acute and Short-Term Inhalation of Carbon Nanofiber in Sprague-Dawley Rats

The inhalation toxicity of carbon nanofibers (CNFs) is not clearly known due to relatively few related studies reported. An acute inhalation study and short-term inhalation study (5 days) were therefore conducted using Sprague-Dawley rats. In the acute inhalation study, the rats were grouped and exposed to a fresh air control or to low (0.238 ± 0.197), moderate (1.935 ± 0.159), or high (24.696 ± 6.336 mg/m3) CNF concentrations for 6 h and thereafter sacrificed at 14 days. For the short-term inhalation study, the rats were grouped and exposed to a fresh air control or low (0.593 ± 0.019), moderate (2.487 ± 0.213), or high (10.345 ± 0.541 mg/m3) CNF concentrations for 6 h/day for 5 days and sacrificed at 1, 3, and 21 days post-exposure. No mortality was observed in the acute inhalation study. Thus, the CNF LC50 was higher than 25 mg/m3. No significant body or organ weight changes were noted during the 5 days short-term inhalation study or during the post-exposure period. No significant effects of toxicological importance were observed in the hematological, blood biochemical, and coagulation tests. In addition, the bronchoalveolar lavage (BAL) fluid cell differential counts and BAL inflammatory markers showed no CNF-exposure-relevant changes. The histopathological examination also found no CNF-exposure-relevant histopathological lesions. Thus, neither acute nor 5 days inhalation exposure to CNFs induced any noticeable toxicological responses