Inhibitory Effects of Saururus chinensis Extract on Receptor for Advanced Glycation End-Products-Dependent Inflammation and Diabetes-Induced Dysregulation of Vasodilation.

Advanced glycation end-products (AGEs) and the receptor for AGEs (RAGE) are implicated in inflammatory reactions and vascular complications in diabetes. Signaling pathways downstream of RAGE are involved in NF-κB activation. In this study, we examined whether ethanol extracts of Saururus chinensis (Lour.) Baill. (SE) could affect RAGE signaling and vascular relaxation in streptozotocin (STZ)-induced diabetic rats. Treatment with SE inhibited AGEs-modified bovine serum albumin (AGEs-BSA)-elicited activation of NF-κB and could compete with AGEs-BSA binding to RAGE in a dose-dependent manner. Tumor necrosis factor-α (TNF-α) secretion induced by lipopolysaccharide (LPS)-a RAGE ligand-was also reduced by SE treatment in wild-type Ager+/+ mice as well as in cultured peritoneal macrophages from Ager+/+ mice but not in Ager-/- mice. SE administration significantly ameliorated diabetes-related dysregulation of acetylcholine-mediated vascular relaxation in STZ-induced diabetic rats. These results suggest that SE would inhibit RAGE signaling and would be useful for the improvement of vascular endothelial dysfunction in diabetes.

ω-3 Polyunsaturated fatty acids accelerate airway repair by activating FFA4 in club cells.

A G protein-coupled receptor (GPCR) named free fatty acid receptor 4 (FFA4, also known as GPR120) was found to act as a GPCR for ω-3 polyunsaturated fatty acids. Its expression has been reported in lung epithelial club cells. We investigated whether supplementation of the ω-3 fatty acids benefits lung health. Omacor (7.75 mg/kg), clinically prescribed preparation of ω-3 fatty acids, and FFA4-knockout mice were utilized in a naphthalene-induced mouse model of acute airway injury (1 injection of 30 mg/kg ip). Naphthalene injection induced complete destruction of bronchiolar epithelial cells within a day. Appearance of bronchiolar epithelial cells was observed after 21 days in control mice. It was found, however, that supplementation of Omacor accelerated the recovery. The appearance of bronchiolar epithelial cells was observed between 7 and 14 days after naphthalene injury in Omacor-treated mice. In isolated club cells, ω-3 fatty acids were found to stimulate cell proliferation and migration but to inhibit cell differentiation. With the use of pharmacological tools and FFA4-knockout mice, FFA4 was found to be responsible for ω-3 fatty acids-induced proliferation in vitro in club cells. Furthermore, accelerated recovery from naphthalene-induced airway injury in Omacor-treated mice was not observed in FFA4-knockout mice in vivo. Present findings indicate that ω-3 fatty acids-induced proliferation of bronchiole epithelial cells through FFA4 is responsible for Omacor-induced accelerated recovery from airway injury. Therefore, intermittent administration of Omacor needs to be tested for acute airway injury because ω-3 fatty acids stimulate proliferation but inhibit differentiation of club cells.

Risk factors for discontinuation of s-1 adjuvant chemotherapy for gastric cancer.

PURPOSE: The aim of this study was to clarify the risk factors for discontinuing tegafur/gimeracil/oteracil potassium (S-1) adjuvant chemotherapy following gastrectomy in patients with gastric cancer. METHODS: We retrospectively investigated patients with curatively-resected gastric cancer who received S-1 adjuvant chemotherapy. S-1 was administered orally at 80-120 mg/day, depending on body surface area, on days 1-28 every 6 weeks for 1 year. The dose and treatment schedule were modified at the clinicians' discretion, according to toxicity. RESULTS: Seventy-one patients were included in the study, 26 of whom discontinued S-1 therapy. The relapse-free survival rates in the S-1-completed and S-1-discontinuation groups at 5 years post-surgery were 88.1% and 55.8%, respectively. The overall survival rates in the S-1-completed and S-1-discontinuation groups at 5 years post-surgery were 89.4% and 59.8%, respectively. The hazard ratios for relapse and death were significantly lower in the S-1-completed group compared with those in the S-1-discontinuation group (0.18; p<0.001 and 0.19; p=0.002, respectively). Multivariate logistic regression analysis revealed that S-1 discontinuation was significantly associated with an initial overdose of S-1, having stage I cancer, creatinine clearance <66 mL/min, and a side effect of nausea. CONCLUSIONS: These results suggest that assessing renal function to avoid initial overdose of S-1, together with the early management of side effects, may support the continuation of S-1 adjuvant chemotherapy in patients with gastric cancer.

Tumor local chemohyperthermia using docetaxel-embedded magnetoliposomes: Interaction of chemotherapy and hyperthermia.

BACKGROUND AND AIM: We have studied and reported the usefulness of tumor local chemohyperthermia at a low-grade temperature below 43°C with docetaxel-embedded magnetoliposome (DML) and an applied alternating current magnetic field. However, the mechanisms of this treatment and the dynamics of the injected docetaxel were not investigated in our previous study. Thus, we investigated the interaction of chemotherapy and hyperthermia in the treated tumor. METHODS: Human MKN45 gastric cancer cells were implanted in the hind limbs of Balb-c/nu/nu mice. DML, magnetite-loaded liposome, and docetaxel were injected into the tumors with or without being exposed to an alternating current magnetic field. Docetaxel and tumor necrosis factor-α concentrations, the cell cycle, and cell death rates in the tumor were examined. RESULTS: Docetaxel concentrations were significantly higher in the DML-injected group than in the docetaxel-injected group 3 days after injection. A G2/M peak was observed 1 day after treatment in the DML-injected and exposed group and the docetaxel-injected group, while it was observed 3 days after treatment in the DML-injected without heating group and the magnetite-loaded liposome group. The tumor cell death rate gradually increased in the DML-injected group, with or without being exposed, while it gradually decreased after its peak in other groups. The tumor necrosis factor-α concentration in the tumor treated with DML with heating remained at a high level on the 7th day after treatment, while it decreased after its peak in other groups. CONCLUSION: The antitumor effect of this treatment derives from a combination of hyperthermia and chemotherapy locally in the tumor.

Major factors of homologous blood transfusion in valvular heart operation with intraoperative autologous blood predonation in cases with difficulty in preoperative predonation.

Intraoperative autologous blood predonation is reported to be useful for the prevention of homologous blood transfusion in cardiac operations, especially in on-pump coronary artery bypass grafting (CABG). However, CABG is now performed more often off-pump than on-pump. We analyzed the major factors of homologous blood transfusion in 25 consecutive cases of valvular heart operation with intraoperative autologous blood predonation except those with preoperative autologous blood donation. Homologous blood was not transfused in 18 cases, but was in 7 cases only after cardiopulmonary bypass (CPB). The homologous transfusion was not correlated with body weight, CPB dilution or duration, or preoperative hematocrit level, but was found to correlate with age (r2=0.289, p=0.0413), bleeding output (r2=0.197, p=0.0485), and predonation blood volume (r2=0.436, p=0.0152). In conclusion, suitable intraoperative predonation may reduce the necessity for homologous blood transfusion in valvular heart operations.

Feasibility of chemohyperthermia with docetaxel-embedded magnetoliposomes as minimally invasive local treatment for cancer.

Hyperthermia is a minimally invasive approach to cancer treatment, but it is difficult to heat only the tumor without damaging surrounding tissue. To solve this problem, we studied the effectiveness of chemohyperthermia with docetaxel-embedded magnetoliposomes (DMLs) and an applied alternating current (AC) magnetic field. Human MKN45 gastric cancer cells were implanted in the hind limb of Balb-c/nu/nu mice. Various concentrations of docetaxel-embedded DMLs were injected into the tumors and exposed to an AC magnetic field (n = 6, each). For comparison with hyperthermia alone, magnetite-loaded liposome (ML)-injected tumors were exposed to an AC magnetic field. Furthermore, the results of DML without AC treatment and docetaxel diluted into PBS with AC treatment were also compared (n = 10, each). Tumor surface temperature was maintained between 42 and 43 degrees C. Tumor volume was reduced in the DML group with a docetaxel concentration > 56.8 microg/ml, while a docetaxel concentration > 568.5 microg/ml was required for tumor reduction without hyperthermia. Statistically significant differences in tumor volume and survival rate were observed between the DML group exposed to the magnetic field and the other groups. The tumor disappeared in 3 mice in the DML group exposed to the magnetic field; 2 mice survived over 6 months after treatment, whereas all mice of the other groups died by 15 weeks. Histologically, hyperthermia with DML damaged tumor cells and DML diffused homogeneously. To the best of our knowledge, this is the first report to show that hyperthermia using chemotherapeutic agent-embedded magnetoliposomes has an anticancer effect.

Novel tumor-ablation device for liver tumors utilizing heat energy generated under an alternating magnetic field.

BACKGROUND AND AIMS: We have developed a novel tumor-ablation device for liver tumors utilizing heat energy induced by magnesium ferrite (MgFe(2)O(4)) particles under an alternating magnetic field (AMF) produced by electric currents. This novel device can repeatedly heat liver tumors at lower temperature than usual heating devices, such as radiofrequency ablation therapy, with slight infliction of pain. This study assesses its heating effect on rat liver tumors as local therapy. METHOD: The small needle was manufactured from MgFe(2)O(4) particles by sintering at 1100 degrees C. After a MgFe(2)O(4) needle was inserted into liver tumors comprising of dRLh-84 cells, the tumors were heated for 30 min under an AMF. We examined cellular activity by using nicotinamide adenine dinucleotide (NADH) diaphorase staining and terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling (TUNEL) staining, and evaluated the effect of suppressing tumor growth by sequentially comparing the tumor diameter with that of the control group. RESULTS: The mean temperature of the heated tumors was 60.2 +/- 1.8 degrees C. The tumor cells were constricted, and chromatin of nuclei had shrunk immediately after heating. The heat-injury area that contained the tumors was negative for NADH diaphorase activity. After 3 days, the tumor cells in the heat-injury area became positive for TUNEL staining, which detects cell death. At 7 days, the mean tumor diameters were significantly smaller in the heating group than in the control group (6.15 +/- 0.47 mm vs 16.89 +/- 2.69 mm; P < 0.05). CONCLUSION: This device, utilizing heat energy induced by ferromagnetic metal under an AMF, appears useful as local thermotherapy for human liver cancer.

PET study of brain acetylcholinesterase in cerebellar degenerative disorders.

To elucidate characteristic changes of brain acetylcholinesterase (AChE) in cerebellar degenerative disorders. Eight patients with the cerebellar variant of multiple system atrophy (MSA-C), 7 patients with spinocerebellar ataxia type-3 (SCA-3), 3 patients with SCA-6, and 13 healthy age-matched volunteers participated in this study. Brain AChE activity was measured by [(11)C] N-methylpiperidin-4-yl propionate PET in all subjects. Brain AChE activities were significantly decreased in the thalamus (-27%) and the posterior lobe of cerebellar cortex (-36%) in patients with MSA-C and in the thalamus (-23%) in patients with SCA-3 compared with healthy controls (P < 0.01). Thalamic AChE activities of SCA-3 patients were negatively correlated with the unified Parkinson's disease rating scale motor subscore (P < 0.001). AChE activities were not significantly altered in the cerebral cortex in any disease group. Reduction of AChE activities in the thalamus and cerebellum in MSA and in the thalamus in SCA-3 suggest that cholinergic modulating drugs may have a role in the treatment of ataxia and other symptoms in these disorders.

Feasibility of new heating method of hepatic parenchyma using a sintered MgFe2O4 needle under an alternating magnetic field.

BACKGROUND: Magnetic metal particles such as magnesium ferrite (MgFe2O4) induce heat energy under an alternating magnetic field that was produced by electric current. We have developed a new heating device using a sintered MgFe2O4 needle under an alternating magnetic field. This device can repeatedly heat target tissue at lower temperatures than that for radiofrequency ablation therapy. This study aims to assess whether the new heating device has the ability to heat rat liver tissue. METHOD: A small needle made from MgFe2O4 particles was prepared by sintering at 1100 degrees C and inserted into rat liver tissue. The rat liver was then heated under an alternating magnetic field, 4 kA/m, for 30 min. We measured the temperature of rat tissue during the heat treatment, and sequentially evaluated histological changes and hepatocyte cellular activity after heat stimulus by using nicotinamide adenine dinucleotide diaphorase staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining. RESULTS: The mean temperature of the liver tissue during heating was 60.7 +/- 1.1 degrees C. Immediately after heating, nuclei of the hepatocytes were hyper-chromatin, with hepatocytes negative for nicotinamide adenine dinucleotide diaphorase activity in the heat-injury area. The injury area spread progressively until 3 d after heating, when the area was surrounded by fibroblasts, with hepatocytes positive for terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining. CONCLUSIONS: This is the first time that a ferromagnetic metal heating device under an alternating magnetic field has achieved a temperature beyond 60 degrees C and led hepatocytes to complete cell death. This device would be of future use as a local heat-treatment for human liver cancer.

Effect of nifedipine on C-reactive protein levels in the coronary sinus and on coronary blood flow in response to acetylcholine in patients with stable angina pectoris having percutaneous coronary intervention.

The effects of nifedipine on inflammation and endothelial function in the coronary circulation were studied in patients who had angina pectoris (n = 17). Long-term treatment with nifedipine (nifedipine CR, 20 mg/day for 4 months) decreased levels of C-reactive protein in the coronary sinus (from 0.35 +/- 0.09 mg/dl to 0.07 +/- 0.01 mg/dl, mean +/- SEM, p <0.05) and enhanced acetylcholine-induced increases in coronary blood flow. Thus, nifedipine is effective in decreasing inflammation and incresing endothelial function in the coronary circulation.

Antihypertensive effects of long-acting calcium channel blockers on hemodialysis days--a randomized crossover trial between benidipine and nifedipine CR.

BACKGROUND/AIMS: Since antihypertensive effects of most calcium channel blockers largely depend on their plasma concentrations, a rapid increase in blood pressure may occur as circulating levels of such blockers decrease after hemodialysis. Thus, the effects of benidipine and nifedipine CR (extended-release coated tablets, Adalat CR), which are long-acting calcium channel blockers, on post-hemodialytic blood pressures were investigated. METHODS: A randomized crossover trial was carried out with 10 hypertensive patients on chronic maintenance hemodialysis. Patients were assigned to receive benidipine (4-8 mg/day) or nifedipine CR (20-40 mg/day), and after 4 weeks, 24-hour ambulatory blood pressure monitoring was performed on the day of hemodialysis and blood samples were obtained before and after hemodialysis to measure plasma concentrations of the blockers. The calcium channel blockers were then exchanged in each patient and the same protocol was repeated. RESULTS: The pattern of fluctuation of blood pressure differed markedly between the treatment with benidipine and nifedipine CR. Under treatment with nifedipine CR, rapid increase in blood pressure was observed after hemodialysis, while blood pressure remained at favorable levels with benidipine. Plasma concentrations of the blockers were significantly decreased by hemodialysis. CONCLUSION: Benidipine exerts more sustained antihypertensive effects than expected from its disposition in plasma. The stable depressor effects of benidipine even after hemodialysis may contribute to favorable control of blood pressure in this population.