Epinephrine is an enhancer of rat intestinal absorption.

Some physiological substances, including acetylcholine and nitric oxide, are useful candidates for stimulation of intestinal absorption of drugs. In the present study, we elucidated the ability of epinephrine (Epi) to stimulate the intestinal absorption of drugs. We evaluated the ability of Epi to enhance absorption of macromolecules using dextran (Mw 4000 Da), which is poorly absorbed from the intestine, as a model compound in situ in a closed loop of the rat jejunum. Treatment of the jejunum with Epi resulted in significant increase in absorption of dextran in a dose-dependent fashion. The area under the curve (AUC) from 0 to 4 h in the Epi-treated jejunum was 13-fold higher than that in the vehicle-treated jejunum. The absorption-enhancing activity of Epi was 40-fold higher than that of caprate, a clinically used absorption-enhancer of drugs. In the experimental conditions used in this study, histological injury of the mucosa and perturbation of the mucosal membrane were not observed in the Epi-treated jejunum. Treatment with an antagonist of alpha-adrenergic receptors attenuated the stimulation of intestinal absorption by Epi, and treatment with an agonist of alpha-adrenergic receptors resulted in enhancement of intestinal absorption. While an antagonist of beta-adrenergic receptors enhanced the absorption-enhancing effect of Epi, an agonist of beta-adrenergic receptors stimulated intestinal absorption. These results indicate that stimulation of adrenergic receptors may be a novel strategy for intestinal absorption of drugs.     

Fidgetin-like 1 gene inhibited by basic fibroblast growth factor regulates the proliferation and differentiation of osteoblasts.

The FIGNL1 gene was proven to be a new subfamily member of ATPases associated with diverse cellular activities (AAA proteins). In this in vitro study, the AAA proteins inhibited osteoblast proliferation and stimulated osteoblast differentiation. We showed that FIGNL1 may play some regulatory role in osteoblastogenesis. INTRODUCTION: The fidgetin-like 1 (FIGNL1) gene encodes a new subfamily member of ATPases associated with diverse cellular activities (AAA proteins). Although the FIGNL1 protein localizes to both the nucleus and cytoplasm, the function of FIGNL1 remains unknown. In a previous study, we identified several genes that mediate the anabolic effects of basic fibroblast growth factor (bFGF) on bone by using microarray data. FIGNL1 was one of the genes that downregulated >2-fold in MC3T3-E1 cells after treatment with bFGF. Therefore, this study was aimed to identify and confirm the function of FIGNL1 on osteoblastogenesis. MATERIALS AND METHODS: We examined the effect of the FIGNL1 gene on proliferation, differentiation, and apoptosis in mouse osteoblast cells (MC3T3-E1 and mouse primary calvarial cells) using flow cytometry, RT-PCR, cell proliferation assay, and cell death assay. MC3T3-E1 cells and mouse calvarial cells were transfected with small interfering RNA (siRNA) directed against the FIGNL1 or nontargeting control siRNA and examined by cell proliferation and cell death assays. Also, FIGNL1 was fused to enhance green fluorescent protein (EGFP), and the EGFP-fused protein was transiently expressed in MC3T3-E1 cells. RESULTS: Reduced expression of FIGNL1 by bFGF and TGF-beta1 treatment was verified by RT-PCR analysis. Overexpression of FIGNL1 reduced the proliferation of MC3T3-E1 and calvarial cells, more than the mock transfected control cells did. In contrast, siFIGNL1 transfection significantly increased the proliferation of osteoblasts, whereas overexpression of FIGNL1 did not seem to alter apoptosis in osteoblasts. Meanwhile, overexpression of FIGNL1 enhanced the mRNA expression of alkaline phosphatase (ALP) and osteocalcin (OCN) in osteoblasts. In contrast, siFIGNL1 decreased the expression of ALP and OCN. A pEGFP-FIGNL1 transfected into MCT3-E1 cells had an initially ubiquitous distribution and rapidly translocated to the nucleus 1 h after bFGF treatment. CONCLUSIONS: From these results, we proposed that FIGNL1, a subfamily member of the AAA family of proteins, might play some regulatory role in osteoblast proliferation and differentiation. Further analyses of FIGNL1 will be needed to better delineate the mechanisms contributing to the inhibition of proliferation and stimulation of osteoblast differentiation.     

Prevalence and patient's consciousness of tinea pedis and onychomycosis]

Epidemiological studies on tinea pedis and onychomycosis have been performed across Europe and East Asia. The prevalence of these conditions was 20%, respectively, and it increased with advancing age, more men than women had fungal infection of the feet. The prevalent predisposing factors were sports participation, average temperature, and family history of tinea pedis. The predisposing diseases were hypercholesterolemia, cardiovascular disease, diabetes mellitus, and osteoarticular disease. We conducted an epidemiological investigation to determine the prevalence and circumstances of untreated and unsuspected tinea pedis and onychomycosis. The results showed that the prevalence of occult athlete's foot was 25%, and that 59% of those cases were complicated by tinea unguium. The characteristics of patients with occult athlete's foot included a higher proportion of men and a tendency toward a low clinical score together with a high severity score. In the patient background, a strong correlation was observed between a positive KOH test result and characteristics such as past history of tinea pedis and/or onychomycosis, age, disposition of toes, and predisposing disease, as well as the type of shoes worn daily. We suspected that a patient's local and systemic conditions affected each other, creating good conditions for tinea pedis and onychomycosis so that the prevalence has increased. More understanding of occult athlete's foot will lead to prevention and improvement in treatment and diagnosis.     

Intrahepatic Delivery of Glutathione by Conjugation to Dextran

Glutathione was covalently attached to dextran (T-40) by the CNBr activation method. The compound obtained was a water-soluble powder containing 10 (w/w%) glutathione, which was gradually released from the conjugate in aqueous media. Mice depleted of glutathione by treatment with buthionine sulfoximine, a potent inhibitor of -glutamylcysteine synthetase, exhibited a significant increase in hepatic glutathione level after intravenous injection of the conjugate. In mice given a lethal dose of acetaminophen, the survival rate increased progressively with coadministration of the conjugate, whereas little improvement was found when free glutathione was given. The conjugate maintained the serum transaminase activities at lower level after acetaminophen administration. These findings suggest that the dextran conjugate of glutathione is transported into hepatic cells and is intracellulary hydrolyzed to free form, which protects mice from hepatotoxicity due to acetaminophen.     

Effects of lumbar skin warming on gastric motility and blood pressure in humans

We examined the possibility that lumbar skin warming can increase gastrointestinal motility by investigating the electrogastrogram (EGG), blood pressure, and heart rate with psychometric ratings in healthy humans. Scores of mood state profiles showed that lumbar skin warming (42 degrees C, 20 min) decreased tension-anxiety, depression, anger-hostility, fatigue, and confusion of the participants. A multiple bandpass filter analysis of EGGs showed that a postural transition from orthostatic to supine for measurement caused an increase in dominant frequency of 25-29% towards the frequencies of the normal interdigestive migrating motor complex (IMC). The spectral power of the IMC band, 2.55-3.05 cycles/min, was increased by 20 min-warming, reflecting the increase in gastric contractility. No increase in the spectral power was observed in the time-matched control group without skin warming. Therefore, an increase in contractility is a characteristic of lumbar skin warming. The systolic blood pressure increased by 15% during warm stimulation. Interbeat intervals were not influenced by warm stimulation. An analysis of interbeat intervals by a fast Fourier transform method showed that the cardiac sympathetic and parasympathetic nerves did not play a major role in raising the blood pressure. Vasoconstriction of the mesenteric artery was therefore considered to cause a blood pressure increase during warming. It is hypothesized that vasoconstriction of the visceral arteries by lumbar skin warming increases the blood pressure and gastrointestinal contractility.     

The effect of alphaMSH analogues on rat bones

Melanocortin is the downstream mediator of leptin signaling and absence of leptin signaling in ob/ob and db/db mice revealed the enhancement of bone formation through the central regulation. While alpha-melanocyte-stimulating hormone (alphaMSH) inhibits the secretion of interleukin-1alpha and tumor necrosis factor-alpha from the inflammatory cells, alphaMSH can also enhance clonal expansion of pro B cells linked to stimulation of osteoclastogenesis. Therefore, we tested the effect of melanocortin on bones. alphaMSH analogues [(6)His]alphaMSH-ND and [(6)Asn]alphaMSH-ND were synthesized and the radio-ligand receptor binding- and cyclic AMP generating activity were analyzed in China Hamster Ovary cell line over- expressing melanocortin receptors. The EC(50) of [(6)His]alphaMSH-ND measured from melanocortin-1, 3, 4 and 5 receptors were 0.008 +/- 0.0045, 1.523 +/- 0.707, 0.780 +/- 0.405, and 250.320 +/- 42.234 nM, respectively, and the EC(50) of [(6)Asn]alphaMSH-ND were 16.8 +/- 6.94, 271.8 +/- 21.95, 8.0 +/- 1.21, and 1132.5 +/- 635.46 nM, respectively. Four weeks after the subcutaneous injection of the analogues, the body weights in the [(6)His]alphaMSH-ND and the [(6)Asn]alphaMSH-ND treated groups (346.0 +/- 20.63 g vs. 350.0 +/- 13.57 g) were lower than that of the vehicle treated group (375.8 +/- 17.31 g, p < 0.05). There was no difference in the total femoral BMD measured by dual x-ray absorptiometry among the three groups. Among the three groups, there were no differences in the total numbers of crystal violet positive- or alkaline phosphatase positive colonies, in the expression of Receptor Activator of Nuclear Factor Kappa-B ligand on the tibia and the total number of multinucleated osteoclast-like cells differentiated from primary cultured bone marrow cells. From the above results, no evidence of bone gain or loss was found after treatment of the alphaMSH analogues peripherally.     

Purification of merozoites ofTheileria sergenti from infected bovine erythrocytes

A simple and rapid method for purifying merozoites ofTheileria sergenti from infected bovine erythrocytes was developed. Infected erythrocytes were lysed by the use of a cytolytic toxin produced byAeromonas hydrophila and the lysate was subjected to ultracentrifugation in a Percoll discontinuous density gradient. Pure and morphologically intact merozoites free of erythrocyte membrane were recovered from a band formed at the interface of 40% and 60% (by vol.) Percoll solutions. In this merozoite fraction, contamination of erythrocyte membrane proteins was not detected as examined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis.     

ULTRASTRUCTURAL ASPECTS OF THE ROLE OF THE MEDIA-SMOOTH MUSCLE CELLS IN ARTERIOSCLEROSIS OF MAN AND ANIMALS

In various arterial lesions including atherosclerotic lesions, the main morphological change involves smooth muscle cells. The potential sensitivity is different among the arterial smooth muscle cells, venous smooth muscle cells and smooth muscle cells of other organs. The modified smooth muscle cells characterized by the increase of rough endoplasmic reticula are considered to express their latent ability to synthesize collagen fibers, elastic fibers and other ground substances.
The foam cells noted in atherosclerosis and fatty streak consist of lipid accumulated smooth muscle cells and hematogenous macrophages. Lipid metabolism and synthesis in the latter differ from those in the former. The ratio of the two kinds of foam cells in atheroma or fatty streak varies by the stage of the lesion.
It is possible to suppose that there exists a factor which would selectively attack the media smooth muscle cells of small arteries or arterioles. This is observed electron microscopically as focal cytoplasmic necrosis (cytoplasmolysis) of smooth muscle cells and plays an important role in the histogenesis of fibrinoid necrosis.
In case of experimental periarteritis nodosa the early stage begins with cytoplasmolysis of smooth muscle cells and marked increase of rough endoplasmic reticula in adjacent smooth muscle cells.     

Immunoreactivity and receptor expression of insulinlike growth factor I and insulin in human adrenal tumors. An immunohistochemical study of 94 cases.

Using immunoperoxidase methods, 94 human adrenal tumors were examined for evidence of immunoreactivity and receptor expression of insulinlike growth factor I (IGF-I) and insulin. The frequency of IGF-I in adrenocortical carcinomas was significantly higher than that in adenomas of the adrenal glands. The adrenocortical carcinomas showed strong intensity of staining for IGF-I, IGF-I receptors, and insulin receptors. A significant correlation between immunoreactivity and receptor expression of both IGF-I and insulin was found only in the adrenocortical carcinomas. The adrenocortical adenomas with Cushing's syndrome and pheochromocytomas, more than adrenocortical adenomas with Conn's syndrome, also stained strongly for insulin receptors. Thus the IGF-I and insulin probably play a role in the growth of adrenocortical carcinoma tissues, possibly through autocrine mechanisms. The expression of insulin receptors in adrenocortical adenomas in the presence of Cushing's syndrome and pheochromocytomas may be associated with functions.