Identification of cembratriene-4,6-diol as antitumor-promoting agent from cigarette smoke condensate

Cigarette smoke condensate (CSC) was separated into severalfractions and each was tested for an inhibitory effect on theearly antigen (EA) of Epstein-Barr virus (EBV) which can beinduced by 12-0-tetradecanoylphorbol-13-acetate (TPA) in Rajicells. Two diastereoisomers of 2,7,11-cembratriene-4,6-diol(- and ß-CBT) were isolated from the neutral fractionsof CSC and these showed potent inhibitory effects on the inductionof EBV-EA by TPA. The doses of - and ß-CBT requiredfor 50% inhibition of EBV-EA induction by TPA were 7.7 and 6.7µg/ml, respectively, which are comparable with those ofretinoic acid, a potent inhibitor of induction of epideral ornithinedecarboxylase (ODC) activity and tumor promotion by TPA in mice.Application of - and ß-CBT to mouse skin prior totreatment with TPA inhibited TPA-induced ODC activity. The degreeof inhibition was dependent on the dose and application of 16.5µmol/mouse of - and ß-CBT resulted in a 50 and40% reduction, respectively, of the maximum of the ODC activityinduced as a result of treatment with TPA. In initiation-promotionexperiments, -CBT markedly inhibited the promoting effect ofTPA on skin tumor formation in mice which were initiated with7,12-dimethylbenz[a]anthracene, but ß-CBT was foundto be less effective. Application of 3.3 µmol of -CBT40 min prior to treatment with TPA (1 µg) resulted ina 53% reduction in the number of papillomas per mouse. Our presentdata suggest that EBV-EA inhibition assay using Raji cells iseffective for the first screening of inhibitors of tumor promotion,and provide evidence that CSC contains antitumor-promoting agentsin addition to carcinogenic and tumor-promoting agents alreadyreported.     

Acute Low-Intensity Treadmill Running Upregulates the Expression of Intestinal Glucose Transporters via GLP-2 in Mice

The effects of exercise on nutrient digestion and absorption in the intestinal tract are not well understood. A few studies have reported that exercise training increases the expression of molecules involved in carbohydrate digestion and absorption. Exercise was also shown to increase the blood concentration of glucagon-like peptide-2 (GLP-2), which regulates carbohydrate digestion and absorption in the small intestine. Therefore, we investigated the effects of exercise on the expression of molecules involved in intestinal digestion and absorption, including GLP-2. Six-week-old male mice were divided into a sedentary (SED) and low-intensity exercise (LEx) group. LEx mice were required to run on a treadmill (12.5 m/min, 1 h), whereas SED mice rested. All mice were euthanized 1 h after exercise or rest, and plasma, jejunum, ileum, and colon samples were collected, followed by analysis via IHC, EIA, and immunoblotting. The levels of plasma GLP-2 and the jejunum expression of the GLP-2 receptor, sucrase-isomaltase (SI), and glucose transporter 2 (GLUT2) were higher in LEx mice. Thus, we showed that acute low-intensity exercise affects the expression of molecules involved in intestinal carbohydrate digestion and absorption via GLP-2. Our results suggest that exercise might be beneficial for small intestine function in individuals with intestinal frailty.     

Effect of neutral endopeptidase inhibition on substance-P-induced increase in short-circuit current of canine cultured tracheal epithelium.

We studied the effect of substance P (SP) on the electric properties of cultured canine tracheal epithelium and its possible modulation by neutral endopeptidase (NEP) by Ussing's short-circuited technique in vitro. Addition of SP (5 x 10(-6) M) to the mucosal side increased short-circuit current (SCC) from 5.1 +/- 0.9 to 10.3 +/- 2.2 microA/cm2 (mean +/- SE; p less than 0.01), which was accompanied by increases in transepithelial potential difference and conductance. The effect of the mucosal SP on SCC was dose-dependent, with the maximal increase from the baseline value being 5.8 +/- 1.0 microA/cm2 observed at 5 x 10(-5) M. The NEP inhibitor phosphoramidon (10(-5) M) did not affect these responses. On the other hand, SCC was not altered by the addition of SP to the submucosal side. However, it was increased dose-dependently in the presence of phosphoramidon (10(-5) M) but not in the presence of captopril, bestatin or leupeptin. This stimulatory effect of submucosal SP was abolished by furosemide, diphenylamine-2-carboxylate and Cl-free medium, but not by amiloride. These results suggest that SP may selectively stimulate Cl secretion across the airway epithelium and that this effect may be modulated by submucosal NEP.     

The significance of preoperative chemotherapy for early gastric carcinoma

In order to achieve a complete prognosis for early gastric carcinoma, a greater effort must be made to improve its present treatment, considering the small percentage of patients who still die from recurrence despite the prompt initiation of surgery. Over the past 9 years, 26 patients with early gastric carcinoma have undergone surgical resection after receiving preoperative chemotherapy in the form of oral 5-FU or 5-DFUR in our institute. The effectiveness of preoperative chemotherapy was evaluated by histopathological examination of the resected stomachs. Of a total of 24 patients with depressed type gastric cancer, 19 were histologically found to have a cancerless area within the cancerous lesion, 8 of whom were classified as being over Grade 1b. Gross changes were observed in 13 of these 24 patients. The frequency of multiple early gastric cancer occurring in patients who had not received chemotherapy was 11.6%, whereas in those who had received chemotherapy it was 3.8%. The findings of this study thus indicate that preoperative chemotherapy is useful for reducing minute cancer foci and microscopic metastatic lesions.     

Interleukin-1β-induced, nitric oxide-dependent and -independent inhibition of vascular smooth muscle contraction

Stimulation of vascular smooth muscle by bacterial lipopolysaccharide has been shown to produce interleukin-1β and to induce vasodilation in septic shock. To understand the mechanisms of interleukin-1β-induced relaxation, we examined the effects of interleukin-1β on contractility and cyclic GMP contents of vascular smooth muscle. After treatment of the rat aorta with interleukin-1β (20 ng/ml) for 6 h, the cyclic GMP content increased and the contraction induced by phenylephrine (1 μM) was partially inhibited. An inhibitor of nitric oxide (NO) synthase, N^G-monomethyl-

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-arginine (

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-NMMA, 100 μM), prevented the inhibitory effect of interleukin-1β. After treatment with interleukin-1β for 24 h, the phenylephrine-induced contraction was inhibited more strongly. Neither

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-NMMA (100 μM) nor aminoguanidine (100 μM) reversed the inhibition, whereas methylene blue (10 μM) partially reversed the inhibition. After treatment with interleukin-1β for 12 or 24 h, the cyclic GMP content increased but to a level lower than that obtained with a 6-h treatment. The effects of sodium nitroprusside (1 μM) to inhibit the phenylephrine-induced contraction and to increase the cyclic GMP content were markedly suppressed by the 24-h interleukin-1β treatment. In contrast, the 24-h interleukin-1β treatment did not change the ability of 8-bromo-cGMP to relax the phenylephrine-stimulated aorta. Addition of

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-NMMA (1 mM) during the 24 h treatment prevented NO production and preserved the sodium nitroprusside-induced cGMP generation by interleukin-1β. The 24 h interleukin-1β treatment increased the threshold concentration of KCl needed to induce contraction without changing the maximum contraction. In the presence of 25.4 mM KCl or the non-selective K⁺ channel inhibitor, tetraethylammonium, the inhibitory effect of the 24-h interleukin-1β treatment on phenylephrine-induced contraction was restored. These results suggest that interleukin-1β inhibits vascular smooth muscle contraction by a time-dependent, dual mechanism. After a 6-h treatment with interleukin-1β, the NO/cyclic GMP system is activated. After a 24-h interleukin-1β treatment, in contrast, the NO/cyclic GMP system may be desensitized and the contraction of vascular smooth muscle is inhibited by another mechanism, possibly membrane hyperpolarization.     

A new mass screening method for methylmercury poisoning using mercury-volatilizing bacteria from Minamata Bay.

A simplified mass screening method for methylmercury exposure was developed using methylmercury-volatilizing bacteria from Minamata Bay. Some bacteria can transform methylmercury into mercury vapor. Most mercury in the hair is methylmercury, which is readily extracted with HCl solution. Black spots are formed on X-ray film due to the reduction of Ag(+) emulsion with mercury vapor produced by methylmercury-volatilizing bacteria. By exploiting these characteristics, a screening method was developed, whereby the fur of rats injected with methylmercury chloride formed clear black spots on X-ray film, whereas the fur of rats injected with saline did not. Subsequently, 50 human hair samples were examined using this mass screening method. The method identified people who had high mercury concentration, over 20 microg/g. A few thousand hair samples may be screened in a day using this method because it is rapid, simple, and economical. This method, therefore, enables screening of persons with methylmercury poisoning in mercury-polluted areas.     

Spectral analysis of cerebrospinal fluid pulse wave

The change of the cerebrospinal pressure wave from during the continuous monitoring of intracranial pressure is often experienced. We supposed that this phenomenon would be the result of the change of transmission of spinal fluid pulse through the cerebrospinal fluid (CSF) system. Our study was performed to determine the change of auto power spectrum of CSF pulse when CSF pressure was increased by the slow infusion of lactate linger solution. The spectrum of CSF pulse was found to be composed of four main waves; wave derived from the respiratory movement, fundamental wave of cardiac origin and its 2nd and 3rd harmonic waves. The power of waves derived from the cardiac beats were increased when CSF pressure was elevated by the slow infusion, but the degree of increment was larger in the fundamental wave than harmonic waves. Elevation of CSF pressure caused relative attenuation of the harmonic waves included in CSF pulse. From the result of this study we found that CSF system would have the function of "high-cut filter" and its cut-off frequency was lowered by the slow infusion of lactate linger solution.     

Surgical treatments for 7 pituitary adenomas in multiple endocrine neoplasia type 1

We analyzed 7 pituitary adenomas in patients with multiple endocrine neoplasia type 1 (MEN1). Their incidence was 1.6% among 450 patients with pituitary adenomas which had been treated surgically in our department between 1978 and 1999. The age, gender, symptoms, type of hormone secretion, pathological and operative findings in the MEN1 patients were not apparently different from those in the non-MEN1 patients. Incidence of non-functioning pituitary adenomas, however, was more frequently encountered in our series than that in previous reports among Caucasian people. One patient who had 5 previous operations for the MEN tumors died following postoperative subarachnoid hemorrhage. Four of the seven patients presented initial symptoms related to pituitary adenomas and increased serum Ca level was retrospectively recognized in three of the four at the time of treatment for the pituitary adenomas.     

Pharmacological evidence that tetraethylammonium-sensitive,iberiotoxin-insensitive K+ channels function as a negative feedback element for sympathetic neurotransmission by suppressing ω-conotoxin-GVIA-insensitive Ca2+ channels in the relaxation of rabbit facial vein

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