Formation of intermediate gel-liquid crystalline phase on medium-chain phosphatidylcholine bilayers: Phase transitions depending on the bilayer packing.

The bilayer phase transitions of medium-chain phosphatidylcholines with linear saturated acyl chains (Cn = 12, 13 and 14) were measured by high-pressure light-transmittance measurements and differential scanning calorimetry to investigate the formation of intermediate gel-liquid crystalline phase called Lx phase. The constructed phase diagrams showed that there existed a distinct region of the Lx phase between ripple gel (Pß') and liquid crystalline (Lα) phase for multilamellar vesicle bilayers of C12PC and C13PC. The Lx phase of the C12PC bilayer was metastable at all pressures and disappeared at a higher pressure. In the C13PC bilayer, the Lx phase was stable and also disappeared at a higher pressure but its region markedly shrunk. By contrast, the Lx phase was not detected for the C14PC bilayer. Effects of other factors such as vesicle size and solvent substitution on the Lx phase of the C13PC bilayer were also examined. A decrease in vesicle size and solvent substitution from water to 50 wt% ethylene glycol solution promoted the Lx-phase formation as opposed to the effects of acyl-chain elongation and pressurization. The fluorescence data of the C13PC bilayer with different vesicle sizes showed that the Lx phase is caused by the difference of local packing in the bilayer. Considering these facts, we concluded that the Lx phase is an intermediate gel-Lα phase that has gel-phase monolayers with negative curvature and Lα-phase monolayers with positive curvature. The formation mechanism of the Lx-phase in stacked bilayers and dispersed vesicles is also explainable by this difference in packing state.

Verification of the diagnostic strategy for anterior mediastinal tumors.

BACKGROUND: For thymic epithelial tumors (TETs), the National Comprehensive Cancer Network guideline has suggested that complete excision of the tumor should be performed without a preoperative biopsy when resectable. However, little evidence has been provided to support this strategy. The purpose of this study was to review our diagnostic process and to evaluate the validity of radical resection of anterior mediastinal masses (AMMs) without pathological confirmation. METHODS: A total of 254 patients underwent surgical resection for AMMs between 2004 and 2015. This study included 181 patients with likely TETs according to clinical features, serum levels of tumor markers and autoimmune-antibodies, and radiological findings. In addition, AMMs likely TETs were classified into resectable or unresectable tumors. We retrospectively reviewed the diagnostic process of those patients and validated surgical resection of AMMs without a definitive diagnosis. RESULTS: Among 254 patients, 181 were suspected of having a TET based on the serum levels of tumor markers and autoimmune-antibodies and the radiological findings. Of them, 157 patients were deemed resectable and underwent surgical resection without histological confirmation, and 144 (92%) were diagnosed with TETs in the final pathological examinations. In 13 patients with non-TETs, the tumors were difficult to differentiate from TETs by imaging and clinical findings alone. CONCLUSIONS: A total of 92% of patients suspected of having a TET and who underwent complete resection without pathological confirmation were accurately diagnosed and properly treated. Surgical resection without a definitive diagnosis was feasible in patients suspected of having a TET when they were considered resectable.

Oral Administration of Collagen Hydrolysates Improves Glucose Tolerance in Normal Mice Through GLP-1-Dependent and GLP-1-Independent Mechanisms.

The aim of this study was to evaluate the antidiabetic properties of collagen hydrolysates (CHs). CHs exhibited dipeptidyl peptidase-IV inhibitory activity and stimulated glucagon-like-peptide-1 (GLP-1) secretion in vitro. We also determined whether CHs improve glucose tolerance in normal mice. Oral administration of CHs suppressed the glycemic response during the oral and intraperitoneal glucose tolerance tests (OGTT and IPGTT), but the effects were weaker in IPGTT than in OGTT. CHs had no effect on the gastric emptying rate. A pretreatment with the GLP-1 receptor antagonist, exendin 9-39 (Ex9), partially reversed the glucose-lowering effects of CHs, but only when coadministered with glucose. CHs administered 45 min before the glucose load potentiated the glucose-stimulated insulin secretion. This potentiating effect on insulin secretion was not reversed by the pretreatment with Ex9, it appeared to be enhanced. These results suggest that CHs improve glucose tolerance by inhibiting intestinal glucose uptake and enhancing insulin secretion, and also demonstrated that GLP-1 was partially involved in the inhibition of glucose uptake, but not essential for the enhancement of insulin secretion.

Rivaroxaban, a factor Xa inhibitor, induces the secondary prevention of cardiovascular events after myocardial ischemia reperfusion injury in mice.

OBJECTIVES: Rivaroxaban has been shown to reduce overall death from cardiovascular causes in patients with recent acute coronary syndrome. Therefore, we evaluated the secondary prevention of cardiovascular events after myocardial ischemia reperfusion injury and its mechanisms in mice. METHODS: After myocardial reperfusion injury, C57BL/6J mice were randomized to receive either no treatment or treatment for 14days with low and high doses of rivaroxaban. After 7days, mice were administered tissue factor as a secondary event. RESULTS: Based on a Kaplan-Meier curve analysis, the high-dose rivaroxaban group showed a significantly higher % survival than the no-treatment group from day 7 (after the administration of tissue factor) to day 14 (at the end of the experimental period). Left ventricular (LV) ejection fraction in both the low- and high-dose rivaroxaban groups improved compared to that in the no-treatment group. Moreover, mRNA levels of interleukin-6 and collagens 1α2 and 3α1 in the LV in the high-dose group were significantly suppressed compared to those in the no-treatment group. CONCLUSIONS: Rivaroxaban improved the survival rate, probably by improving cardiac function through the reduction of inflammatory and fibrotic factors in the LV. This effect may be due to the pleiotropic effects of rivaroxaban beyond its main effect as an anti-coagulant.

Mucosal immune features to phosphorylcholine by nasal Flt3 ligand cDNA-based vaccination.

Phosphorylcholine (PC) is an immunodominant epitope in some pathogens including Streptococcus pneumoniae and it is well-known that PC-specific antibodies (Abs) play a key role in the induction of protective immunity against pneumococcal infection. In this study, we examined whether nasal administration of DNA plasmid encoding Flt3 ligand gene (pFL) as a mucosal adjuvant plus PC-conjugated keyhole limpet hemocyanin (PC-KLH), would elicit PC-specific immune responses, and characterized mucosal immune responses to PC induced by this nasal vaccination. Nasal immunization with pFL plus PC-KLH enhanced induction of PC-specific IgA and IgM Abs in airway secretions when compared with mice given PC-KLH with or without empty plasmid gene (pORF) as controls; in addition to the mucosal immune responses, PC-specific immune responses in serum were also induced. Furthermore, the mucosal and serum IgA and IgM Abs in mice given pFL plus PC-KLH nasally, exhibited high-specificity for the PC molecule. Of interest, the PC-specific Abs bound dose-dependently to anti-T15 idiotype (AB1-2). Thus, the inhibition of S. pneumoniae colonization on the nasal cavity and lungs after nasal challenge with the live organism was significantly elicited in mice immunized with pFL plus PC-KLH compared to that of mice immunized with antigen with pORF. Taken together, these findings show that nasal administration of pFL with PC-KLH elicited T15-like anti-PC IgA and IgM Abs in the respiratory tracts, and further attenuated S. pneumoniae colonization on the respiratory tracts. Nasal administration of Flt3 ligand cDNA with PC may contribute to the development of nasal vaccination for prevention of S. pneumoniae infection.

Reduced hyperthermia-induced cutaneous vasodilation and enhanced exercise-induced plasma water loss at simulated high altitude (3,200 m) in humans.

We examined whether less convective heat loss during exercise at high altitude than at sea level was partially caused by reduced cutaneous vasodilation due to enhanced plasma water loss into contracting muscles and whether it was caused by hypoxia rather than by hypobaria. Seven young men performed cycling exercise for 40 min at 50% peak aerobic power in normoxia at (710 mmHg) 610 m, determined before the experiments, in three trials: 1) normobaric normoxia at 610 m (CNT), 2) hypobaric hypoxia [low pressure and low oxygen (LPLO)] at 3,200 m (510 mmHg), 3) normobaric hypoxia [normal pressure and low oxygen (NPLO)] at 610 m, in an artificial climate chamber where atmospheric temperature and relative humidity were maintained at 30°C and 50%, respectively. Subjects in CNT and LPLO breathed room air, whereas those in NPLO breathed a mixed gas of 14% O2 balanced N2, equivalent to the gas composition in LPLO. We measured change in PV (ΔPV), oxygen consumption rate (Vo2), mean arterial blood pressure (MBP), esophageal temperature (T(es)), mean skin temperature (T(sk)), forearm skin blood flow (FBF), and sweat rate (SR) during exercise. Although Vo2, MBP, T(sk), and SR responses during exercise were similar between trials (P > 0.05), the sensitivity of forearm vascular conductance (FBF/MBP) in response to increased T(es) was lower in LPLO and NPLO than in CNT (P < 0.05), whereas that of SR was not, resulting in a greater increase in T(es) from minute 5 to 40 of exercise in LPLO and NPLO than in CNT (P = 0.026 and P = 0.011, respectively). ΔPV during exercise was twofold greater in LPLO and NPLO than in CNT. These variables were not significantly different between LPLO and NPLO. Thus reduced convective heat loss during exercise at 3,200 m was partially caused by reduced cutaneous vasodilation due to enhanced PV loss. Moreover, this may be caused by hypoxia rather than by hypobaria.

Protein and carbohydrate supplementation during 5-day aerobic training enhanced plasma volume expansion and thermoregulatory adaptation in young men.

We examined whether protein and carbohydrate (CHO) supplementation during 5-day training enhanced plasma volume (PV) expansion and thermoregulatory and cardiovascular adaptations in young men. Eighteen men [age 23 ± 4 (SD) yr] were divided into two groups according to supplements: placebo (CNT: 0.93 kcal/kg, 0.00 g protein/kg, n = 9) and protein and CHO (Pro-CHO: 3.6 kcal/kg, 0.36 protein/kg, n = 9). Subjects in both groups performed a cycling exercise at 70% peak oxygen consumption rate (VO2peak), 30 min/day, for 5 consecutive days at 30°C ambient temperature and 50% relative humidity and took either a placebo or Pro-CHO within 10 min after exercise for each day. Before and after training, PV at rest, heart rate (HR), and esophageal temperature (T(es)) during 30-min exercise at 65% of pretraining VO2peak in the same condition as training were determined. Also, the sensitivity of the chest sweat rate (ΔSR/ΔT(es)) and forearm vascular conductance (ΔFVC/ΔT(es)) in response to increased T(es) were determined. After training, PV and cardiac stroke volume (SV) at rest increased in both groups (P < 0.001) but the increases were twofold higher in Pro-CHO than CNT (P = 0.007 and P = 0.078, respectively). The increases in HR from 5 to 30 min and T(es) from 0 to 30 min of exercise were attenuated after training in both groups with greater attenuation in Pro-CHO than CNT (P = 0.002 and P = 0.072, respectively). ΔSR/ΔT(es) increased in CNT (P = 0.052) and Pro-CHO (P < 0.001) and the increases were higher in Pro-CHO than CNT (P = 0.018). ΔFVC/ΔT(es) increased in Pro-CHO (P < 0.001), whereas not in CNT (P = 0.16). Thus protein-CHO supplementation during 5-day training enhanced PV expansion and thermoregulatory adaptation and, thereby, the reduction in heat and cardiovascular strain in young men.

E6201, a novel kinase inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-1 and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase-1: in vivo effects on cutaneous inflammatory responses by topical administration.

E6201 [(3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,10-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione)] is a novel anti-inflammatory agent that has potent inhibitory effects on the production of proinflammatory cytokines from leukocytes and antiproliferative activity on keratinocytes. To characterize the in vivo pharmacological activity of E6201, topically administered E6201 was evaluated in several different animal models of dermatitis. E6201 formulated as an ointment or cream showed dose-dependent inhibition of croton oil-induced acute edema formation and neutrophil infiltration into mouse skin. In addition, E6201 cream inhibited the 1-fluoro-2,4-dinitrobenzene-induced contact hypersensitivity reaction mediated by T cells in mice. In this model, E6201 cream also suppressed the migration of neutrophils and lymphocytes into the inflammatory site. Pretreatment with E6201 cream attenuated phorbol-12 myristate 13-acetate-induced ornithine decarboxylase activity, a marker of proliferation in epidermis. Furthermore, E6201 ointment showed inhibitory effects on both mezerein-induced and interleukin (IL)-23-induced epidermal hyperplasia. E6201 also suppressed T cell receptor-stimulated IL-17 production from human T cells. These results indicate that topically administered E6201 may be a useful agent for the prevention and treatment of cutaneous inflammatory and hyperproliferative diseases such as psoriasis.

Protein and carbohydrate supplementation increases aerobic and thermoregulatory capacities.

The incidence of heat illness and heat stroke is greater in older than younger people. In this context, exercise training regimens to increase heat tolerance in older people may provide protection against heat illness. Acute increases in plasma volume (PV) improve thermoregulation during exercise in young subjects, but there is some evidence that changes in PV in response to acute exercise are blunted in older humans. We recently demonstrated that protein-carbohydrate (Pro-CHO) supplementation immediately after a bout of exercise increased PV and plasma albumin content (Alb(cont)) after 23 h in both young and older subjects. We also examined whether Pro-CHO supplementation during aerobic training enhanced thermoregulation by increasing PV and Alb(cont) in older subjects. Older men aged 68 years exercised at moderate intensity, 60 min day(1), 3 days week(1), for 8 weeks, at 19 degrees C, and took either placebo (CNT; 0.5 kcal, 0 g protein kg(1)) or Pro-CHO supplement (Pro-CHO; 3.2 kcal, 0.18 g protein kg(1)) immediately after exercise. After training, we found during exercise at 30 degrees C that increases in oesophageal temperature (T(es)) were attenuated more in Pro-CHO than CNT and associated with enhanced cutaneous vasodilatation and sweating. We also confirmed similar results in young subjects after 5 days of training. These results demonstrate that post-exercise protein and CHO consumption enhance thermoregulatory adaptations especially in older subjects and provide insight into potential strategies to improve cardiovascular and thermoregulatory adaptations to exercise in both older and younger subjects.