Fimasartan Ameliorates Deteriorations in Glucose Metabolism in a High Glucose State by Regulating Skeletal Muscle and Liver Cells

PurposeSince diabetes and hypertension frequently occur together, it is thought that these conditions may have a common pathogenesis. This study was designed to evaluate the anti-diabetic function of the anti-hypertensive drug fimasartan on C2C12 mouse skeletal muscle and HepG2 human liver cells in a high glucose state.Materials and MethodsThe anti-diabetic effects and mechanism of fimasartan were identified using Western blot, glucose uptake tests, oxygen consumption rate (OCR) analysis, adenosine 5′-triphosphate (ATP) enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining for diabetic biomarkers in C2C12 cells. Protein biomarkers for glycogenolysis and glycogenesis were evaluated by Western blotting and ELISA in HepG2 cells.ResultsThe protein levels of phosphorylated 5′ adenosine monophosphate-activated protein kinase (p-AMPK), p-AKT, insulin receptor substrate-1 (IRS-1), and glucose transporter type 4 (Glut4) were elevated in C2C12 cells treated with fimasartan. These increases were reversed by peroxisome proliferator-activated receptor delta (PPARδ) antagonist. ATP, OCR, and glucose uptake were increased in cells treated with 200 µM fimasartan. Protein levels of glycogen phosphorylase, glucose synthase, phosphorylated glycogen synthase, and glycogen synthase kinase-3 (GSK-3) were decreased in HepG2 cells treated with fimasartan. However, these effects were reversed following the addition of the PPARδ antagonist GSK0660.ConclusionIn conclusion, fimasartan ameliorates deteriorations in glucose metabolism as a result of a high glucose state by regulating PPARδ in skeletal muscle and liver cells.     

Current Landscape and Future Perspectives of Abbreviated MRI for Hepatocellular Carcinoma Surveillance

While ultrasound (US) is considered an important tool for hepatocellular carcinoma (HCC) surveillance, it has limited sensitivity for detecting early-stage HCC. Abbreviated MRI (AMRI) has recently gained popularity owing to better sensitivity in its detection of early-stage HCC than US, while also minimizing the time and cost in comparison to complete contrast-enhanced MRI, as AMRI includes only a few essential sequences tailored for detecting HCC. Currently, three AMRI protocols exist, namely gadoxetic acid-enhanced hepatobiliary-phase AMRI, dynamic contrast-enhanced AMRI, and non-enhanced AMRI. In this study, we discussed the rationale and technical details of AMRI techniques for achieving optimal surveillance performance. The strengths, weaknesses, and current issues of each AMRI protocol were also elucidated. Moreover, we scrutinized previously performed AMRI studies regarding clinical and technical factors. Reporting and recall strategies were discussed while considering the differences in AMRI protocols. A risk-stratified approach for the target population should be taken to maximize the benefits of AMRI and the cost-effectiveness should be considered. In the era of multiple HCC surveillance tools, patients need to be fully informed about their choices for better adherence to a surveillance program.     

Comparative effect of genistein and daidzein on the expression of MCP-1, eNOS, and cell adhesion molecules in TNF-��-stimulated HUVECs

We compared the effects of genistein and daidzein on the expression of chemokines, cell adhesion molecules (CAMs), and endothelial nitric oxide synthase (eNOS) in tumor necrosis factor (TNF)-α-stimulated human umbilical vascular endothelial cells (HUVECs). TNF-α exposure significantly increased expression of monocyte chemoattractant protein (MCP)-1, vascular adhesion molecule (VCAM)-1, and intercellular adhesion molecule-1. Genistein significantly decreased MCP-1 and VCAM-1 production in a dose-dependent manner, whereas CAM expression was not significantly lowered by genistein treatment. However, daidzein slightly decreased MCP-1 production. The effects of genistein and daidzein on MCP-1 secretion coincided with mRNA expression. Pre-treatment with either genistein or daidzein elevated eNOS expression and nitric oxide production disturbed by TNF-α exposure. A low concentration of isoflavones significantly inhibited nuclear factor (NF)κB activation, whereas a high dose slightly ameliorated these inhibitive effects. These results suggest that genistein had a stronger effect on MCP-1 and eNOS expression than that of daidzein. Additionally, NFκB transactivation might be partially related to the down-regulation of these mRNAs in TNF-α-stimulated HUVECs.     

Catechin-7-O-α-L-rhamnopyranoside can reduce α-MSH-induced melanogenesis in B16F10 melanoma cells through competitive inhibition of tyrosinase

Although melanogenesis is a defense mechanism against ultraviolet (UV)-induced skin damage, abnormally excessive melanin production causes pigmentation disorders. Tyrosinase, as a key factor for melanin synthesis, plays an important role in inducing skin pigmentation. Therefore, the inhibition of tyrosinase is crucial in preventing skin pigmentation in the cosmetics and medicine fields. However, the majority of well-known tyrosinase inhibitors have been discontinued due to toxic effects on the skin or lack of selectivity and/or stability. In this study, we evaluated possible anti-melanogenic effects of catechin-7-O-α-L-rhamnopyranoside (C7R) isolated from the stem bark of Ulmus parvifolia, to discover a new tyrosinase inhibitor that has both safety and stability. When C7R was pretreated in B16F10 melanoma cells stimulated by α-melanocyte-stimulating hormone, this compound reduced melanin accumulation and murine tyrosinase activity. In line with these results, C7R inhibits tyrosinase purified from a mushroom in vitro like kojic acid and arbutin. Furthermore, C7R exhibited a competitive inhibition on a Lineweaver-Burk plot. Next, the underlying mechanisms of the C7R-mediated tyrosinase inhibitory effect were sought through docking simulation and pharmacophore analysis between tyrosinase residues and C7R. The results of these analyses showed that C7R had binding energy of -14.5kcal/mol, and indicated that C7R interacts with tyrosinase through an aromatic ring and various hydrophobic and hydrogen bonds. Together, our results suggest that C7R can be applied as a novel natural anti-melanogenic agent that inhibits tyrosinase.     

Total arch repair versus hemiarch repair in the management of acute DeBakey type I aortic dissection

Objective: In acute DeBakey type I aortic dissection, it is still controversial whether to perform extended aortic replacement to improve long-term outcome or to use a conservative strategy with ascending aortic and hemiarch replacement to palliate a life-threatening condition. Methods: Between 1999 and 2009, 188 consecutive patients (93 women; mean age, 57.4 ± 11.7 years) with acute DeBakey type I aortic dissection underwent hemiarch (Hemiarch group; n = 144) or total arch replacement (Total arch group; n = 44) in conjunction with ascending aorta replacement. Clinical outcomes were compared after adjustment for baseline characteristics using inverse-probability-of-treatment weighting. Results: Median follow-up was 47.5 months (range 0–130.4 months) and was 92.0% (n = 173) complete. Five-year unadjusted survival and permanent-neurologic-injury-free survival rates were 65.8 ± 8.3% and 43.1 ± 9.7% in the Total arch group, and 83.2 ± 3.3% and 75.2 ± 4.0% in the Hemiarch group, respectively (P = 0.013 and <0.001). After adjustment, the Total arch group patients were at greater risks of death (hazard ratio (HR) 2.38, 95% confidence interval (CI) 1.21–4.67; P = 0.012), and permanent neurologic injury (HR 3.25, 95% CI 1.31–8.04; P = 0.011) compared to the Hemiarch group patients. The risks of the re-operation for aortic pathology or distal aortic dilatation (>55 mm) were similar for both groups (HR 0.33, 95% CI 0.08–1.43; P = 0.14). Conclusions: Total arch repair was associated with greater morbidity and mortality compared with hemiarch repair in acute DeBakey type I aortic dissection. Rates of aortic re-operation or aortic dilatation were not significantly different between the two surgical strategies. These findings support a conservative surgical approach to circumvent this life-threatening situation.     

Yoga Training Improves Metabolic Parameters in Obese Boys

Yoga has been known to have stimulatory or inhibitory effects on the metabolic parameters and to be uncomplicated therapy for obesity. The purpose of the present study was to test the effect of an 8-week of yoga-asana training on body composition, lipid profile, and insulin resistance (IR) in obese adolescent boys. Twenty volunteers with body mass index (BMI) greater than the 95th percentile were randomly assigned to yoga (age 14.7±0.5 years, n=10) and control groups (age 14.6±1.0 years, n=10). The yoga group performed exercises three times per week at 40~60% of heart-rate reserve (HRR) for 8 weeks. IR was determined with the homeostasis model assessment of insulin resistance (HOMA-IR). After yoga training, body weight, BMI, fat mass (FM), and body fat % (BF %) were significantly decreased, and fat-free mass and basal metabolic rate were significantly increased than baseline values. FM and BF % were significantly improved in the yoga group compared with the control group (p<0.05). Total cholesterol (TC) was significantly decreased in the yoga group (p<0.01). HDL-cholesterol was decreased in both groups (p<0.05). No significant changes were observed between or within groups for triglycerides, LDL-cholesterol, glucose, insulin, and HOMA-IR. Our findings show that an 8-week of yoga training improves body composition and TC levels in obese adolescent boys, suggesting that yoga training may be effective in controlling some metabolic syndrome factors in obese adolescent boys.     

Development and validation of an LC–ESI–MS/MS method for simultaneous determination of levodopa, dopamine, L-α-methyldopa and 3-O-methyldopa in rat plasma

Parkinson??s disease (PD) is a progressive degenerative disorder of the central nervous system. Levodopa (L-dopa), dopamine precursor is the most effective therapeutic drug for PD patients. Levodopa (LDP) and its three metabolites in rat plasma were determined using high performance liquid chromatography coupled with tandem mass spectrometry (LC?CMS/MS). Method validation was conducted in terms of linearity, accuracy, precision, recovery, specificity, limit of detection, limit of quantification and stability. Correlation coefficients (r ²) were above 0.9965. The intra-day accuracy values at LLOQ (low limit of quantification), LQC (low quality control), MQC (medium quality control) and HQC (high quality control) levels were 85.7?C103.3, 96.5?C105.1, 90.7?C100.1 and 94.2?C101.3?%, respectively. The inter-day accuracy values at LLOQ, LQC, MQC and HQC levels were 77.6?C112.0, 91.1?C109.3, 84.3?C101.0 and 88.2?C103.9?%, respectively. The coefficient of variation (RSD) values of both intra- and inter-day results were within 6.7 and 8.5?%, respectively. The recoveries (mean?±?%SD) for LLOQ, LQC, MQC and HQC were 82.7?±?3.7?C113?±?2.8?%, 86.6?±?5.7?C110.3±3.4?%, 90.9?±?3.6?C106?±?6.5 and 89.7?±?4.5?C97.4?±?6.7?%, respectively. The coefficient of variation (RSD) values of both intra- and inter-day results were within 6.7 and 8.5?%, respectively. The validated LC?CMS/MS method was applied successfully to the measurement of LDP and its metabolites in the rat plasma samples.     

Pharmaceutical perspectives for the delivery of TNF-α in cancer therapy

TNF-?? is an endogenous signaling protein which controls physiological activities and participates in immune response. It is known to interact with TNF receptors (TNFR), of which have two kinds leading to totally different effects. Binding of TNF-?? to TNFR1 can induce either cell proliferation or cell death, i.e., necroptosis, depending on the kinds of protein to which it binds during the signaling cascade. On the contrary, binding of TNF-?? to TNFR2 induces only cell death process. TNF-?? can also cause antiviral effect by inducing interferon, and can inhibit tumor growth. Moreover, TNF-?? helps action of immune cells and it leads to increasement of tumor cell lysis. TNF-?? also makes tumor vessels more permeable and induces coagulation and thrombosis in the tumor vessels, which ultimately contribute to antitumor effect. However, TNF-?? also has several toxic effects, which include the change in redox status of antioxidant factors, induction of excess inflammation response, and action as pro-inflammatory cytokine of itself. These toxicities need to be considered when developing TNF-?? as an anticancer agent. In this review, pharmaceutical approaches to optimize and utilize its antitumor activity of TNF-?? as well as to decrease its adverse effect are discussed.