Oral intake of beet extract provides protection against skin barrier impairment in hairless mice.

The epidermis acts as a functional barrier against the external environment. Disturbances in the function of this barrier cause water loss and increase the chances of penetration by various irritable stimuli, leading to skin diseases such as dry skin, atopic dermatitis, and psoriasis. Ceramides are a critical natural element of the protective epidermal barrier. The aim of this study was to evaluate whether the oral intake of beet (Beta vulgaris) extract, a natural product rich in glucosylceramide (GlcCer), may prevent disturbance in skin barrier function. When HR-1 hairless mice were fed a special diet (HR-AD), transepidermal water loss (TEWL) from the dorsal skin increased, with a compensatory increase in water intake after 5 weeks. Mice fed with HR-AD had dry skin with erythema and showed increased scratching behaviour. Histological examinations revealed a remarkable increase in the thickness of the skin at 8 weeks. Supplemental addition of beet extract, which contained GlcCer at a final concentration of 0.1%, significantly prevented an increase TEWL, water intake, cumulative scratching time, and epidermal thickness at 8 weeks. These results indicate that oral intake of beet extract shows potential for preventing skin diseases associated with impaired skin barrier function.

Orally active benzoxazole derivative as 5-HT3 receptor partial agonist for treatment of diarrhea-predominant irritable bowel syndrome.

During our search for therapeutic agents to treat diarrhea-predominant IBS, we found that 2-substituted benzoxazole derivatives have a characteristic 5-HT(3) receptor partial agonist activity with high affinity. Some of these compounds showed high in vitro metabolical stability, and 6g showed marked antidiarrhetic activity with little side effect of constipation in in vivo tests. Our results indicate that 5-HT(3) receptor partial agonists might be superior as therapeutic agents to the drugs currently used for IBS treatment.

5-HT3-receptor antagonist inhibits visceral pain differently in chemical and mechanical stimuli in rats.

The present study was designed to compare the effects of a selective 5-HT(3)-receptor antagonist, alosetron, on the glycerol-and colorectal distention (CRD)-induced visceral nociception as measured by changes in EMG of the external oblique muscle in conscious rats. Both glycerol and CRD evoked the EMG response, and these amplified EMG were attenuated by morphine, indicating that these responses might reflect visceral nociceptive responses. In the present study, we showed that alosetron significantly attenuated the glycerol-induced visceral pain, but not that of CRD. These results suggest that the mechanism of glycerol-induced visceral nociception are apparently different from that of CRD.

A novel guinea pig model with cyclic flow reductions following thrombotic cerebral ischemia.

Cyclic flow reductions (CFRs), a phenomenon indicated with repeating rethrombosis following thrombolysis in clotted vessel has been observed in coronal, carotid and popliteal arteries in various species when they were occluded with vessel damage, suggesting the presence of CFRs in the acute phase of stroke in man. Although much effort has been directed toward rethrombosis or ischemia-reperfusion injuries in acute strokes, a therapy for CFRs in strokes has not been established because of the lack of ideal animal models. We have established a novel guinea pig model with CFRs in the middle cerebral artery (MCA) using a photothrombotic technique, in which the MCA was spontaneously recanalized within 20 min after the first occlusion with subsequent CFRs. We also investigated the effects of antiplatelet agents and the anticoagulant heparin using this model. All tested antiplatelet agents inhibited CFRs, whereas an anticoagulant did not. These results show that this model is unique with respect to its development of MCA cyclic flow reductions, and may be suitable for investigating mechanisms and therapeutic reagents of CFRs in the MCA.

Klotho gene polymorphisms associated with bone density of aged postmenopausal women.

Because mice deficient in klotho gene expression exhibit multiple aging phenotypes including osteopenia, we explored the possibility that the klotho gene may contribute to age-related bone loss in humans by examining the association between klotho gene polymorphisms and bone density in two genetically distinct racial populations: the white and the Japanese. Screening of single-nucleotide polymorphisms (SNPs) in the human klotho gene identified 11 polymorphisms, and three of them were common in both populations. Associations of the common SNPs with bone density were investigated in populations of 1187 white women and of 215 Japanese postmenopausal women. In the white population, one in the promoter region (G-395A, p = 0.001) and one in exon 4 (C1818T, p = 0.010) and their haplotypes (p < 0.0001) were significantly associated with bone density in aged postmenopausal women (> or = 65 years), but not in premenopausal or younger postmenopausal women. These associations were also seen in Japanese postmenopausal women. An electrophoretic mobility shift analysis revealed that the G-A substitution in the promoter region affected DNA-protein interaction in cultured human kidney 293 cells. These results indicate that the klotho gene may be involved in the pathophysiology of bone loss with aging in humans.

A novel MCA occlusion model of photothrombotic ischemia with cyclic flow reductions: development of cerebral hemorrhage induced by heparin.

Intracerebral hemorrhage is the major complication associated with antithrombotic and thrombolytic therapy. Despite efforts directed toward achieving hemorrhagic infarction, an ideal animal model of cerebral hemorrhage has not yet to be established. Using the photothrombotic technique in rabbits, we developed a model of cerebral hemorrhage by inducing cyclic flow reductions in the middle cerebral artery (MCA). Furthermore, the hemorrhage increased 4-fold after infusion of heparin at a dose prolonging activated partial thromboplastin time by about three times that of control animals. The photothrombotic occlusion of the MCA is based on a thrombosis induced by endothelial injury through singlet oxygen produced by Rose Bengal injection and green light irradiation (Acta Neuropathol. 72 (1987) 315; Acta Neuropathol. 72 (1987) 326; J. Pharmacol. Toxicol. Methods. 29 (1993) 165). Using a pulse Doppler flowmeter, spontaneous reperfusion of the MCA after the thrombotic occlusion following cyclic flow reductions was observed within 2 h in the majority of animals. This model is unusual with respect to the development of clinical stroke, because of the MCA cyclic flow reductions. Thus it is different from permanent or ischemia/reperfusion MCA occlusion in rodents and may be suitable for studying hemorrhagic risks associated with the use of antithrombotic agents.