Apoptosis-inducing effect of a new bisphosphonate,YM529, on various hematopoietic tumor cell lines

In recent years, it has been reported that bisphosphonates inhibited the cell cycle of myeloma cells to inhibit cell proliferation directly, and it was also reported that bisphosphonates induced apoptosis of myeloma cells in vitro. Recently, YM529 was developed as a new third-generation bisphosphonate. In our experiment, we investigated whether YM529 showed an antitumor effect on hematopoietic tumor cell lines other than myeloma, and we compared YM529 with YM175, which had a relatively more potent antitumor effect than that of existing bisphosphonates. We found that YM529 inhibited cell proliferation in various hematopoietic tumor cell lines (acute promyelocytic leukemia cell line HL-60, chronic myeloid leukemia cell line K562, histiocytic lymphoma cell line U937, lymphoblastic leukemia T cell line Jurkat, acute lymphoblastic leukemia T cell line MOLT-4, lymphoblastic leukemia B cell line CCRF-SB) including myeloma (myeloma cell line HS-Sultan) dose-dependently and time-dependently to a degree equivalent or superior to that in myeloma, and induced apoptosis at a lower concentration as compared with YM175. We confirmed many dead cells as well as apoptosis based on the detection of the nuclei with separate globular structure, the activation of caspase-3, and the decrease in mitochondrial transmembrane potential. Therefore, it is concluded that further utilization of YM529 can be expected against hematopoietic tumor cells in the future.     

DIF-1, an anti-tumor substance found in Dictyostelium discoideum,inhibits progesterone-induced oocyte maturation in Xenopus laevis

Differentiation-inducing factor-1 (DIF-1; 1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl)hexan-1-one) is a putative morphogen that induces stalk-cell formation in the cellular slime mold Dictyostelium discoideum. DIF-1 has previously been shown to suppress cell growth in mammalian cells. In this study, we examined the effects of DIF-1 on the progesterone-induced germinal vesicle breakdown in Xenopus laevis, which is thought to be mediated by a decrease in intracellular cAMP and the subsequent activation of mitogen-activated protein kinase (MAPK) and maturation-promoting factor, a complex of cdc2 and cyclin B, which regulates germinal vesicle breakdown. DIF-1 at 10–40 μM inhibited progesterone-induced germinal vesicle breakdown in de-folliculated oocytes in a dose-dependent manner. Progesterone-induced cdc2 activation, MAPK activation, and c-Mos accumulation were inhibited by DIF-1. Furthermore, DIF-1 was found to inhibit the progesterone-induced cAMP decrease in the oocytes. These results indicate that DIF-1 inhibits progesterone-induced germinal vesicle breakdown possibly by blocking the progesterone-induced decrease in [cAMP]_i and the subsequent events in Xenopus oocytes.     

Place-specific constructs of social capital and their possible associations to health: a Japanese case study

The story of Roseto, Pennsylvania, USA, is one of the most widely cited studies of the putative influence of community social cohesion on population health. However, few contemporary studies of community-based "social capital" on health have addressed "communities" as unique places with unique histories outside of a Western context. In the present study, we focus on a specific region of Japan (which we call the M-region to preserve anonymity). Using survey data and qualitative interviews, we discuss the historical and contextual origins of the high social capital in the M-region that could account for its relatively good health profile. The analysis of survey data suggested that the residents of M-region have higher norms of reciprocity and participate more in horizontal organizations (including volunteer group, citizen or consumer group, sports group or club, and hobby group), and it also indicated better health status and behaviors in some outcomes among the residents of M-region. Based on qualitative interviews, the origins of social capital in the M-region appeared to be rooted in the strong sense of solidarity fostered by the fact that many of the residents were recruited into the region by the same local employer (a steel manufacturing company). Our study points to the need to ground studies of community-based "social capital" and health on detailed knowledge of the historical context of specific places.     

Antipruritic effects of 1,4-naphthoquinones and related compounds

The antipruritic effects of orally administered 1,4-naphthoquinone derivatives and related compounds on compound 48/80-induced scratching behavior in mice were studied. 2-Hydroxy-3-(2-hydroxyethyl)-1,4-naphthoquinone, ferulic acid, 2,2'-methylenebis(3-hydroxy-1,4-naphthoquinone), and 2,2'-ethylidenebis(3-hydroxy-1,4-naphthoquinone) (impatienol) all exhibited significant antipruritic activity. However, 2-methoxy-3-(2-hydroxyethyl)-1,4-naphthoquinone (balsaquinone), which was isolated from a natural source for the first time, did not show any activity. The present results indicate that these compounds are promising for treating allergic diseases with chronic and severe pruritus.     

Effects of conjugated linoleic acid on anaphylaxis and allergic pruritus

The effects of conjugated linoleic acid (CLA) against anaphylaxis and allergic pruritus were investigated using a in vivo assay. Inhibitory effects of CLA were observed on the immediate (type 1) hypersensitivity reaction, with CLA significantly suppressing the decrease in blood pressure (BP) and blood flow (BF) induced by the hen egg-white lysozyme (HEL)-anaphylactic reaction in ddY mice. After oral administration, CLA showed antipruritic activity, with significant inhibition of scratching behavior induced by compound 48/80 (COM), a histamine-release agent. When painted onto the skin, CLA also inhibited COM, platelet-activating factor, and protease-induced scratching behavior, and COM-induced vasodilation of the skin. CLA offers promise as a drug for the treatment of allergic and inflammatory pruritus not only as an oral but also a topical agent. The present findings demonstrate that CLA can be effective for the prevention and treatment of allergic disease with severe pruritus.     

Effect of eviprostat on bladder overactivity in an experimental cystitis rat model

Objective:   The purpose of this study was to investigate the effects of eviprostat, a phytotherapeutic drug, on bladder overactivity and inflammation in a cyclophosphamide (CYP)-induced cystitis rat model.
Methods:   Female Sprague-Dawley rats received a single intraperitoneal injection of CYP (200 mg/kg) or saline. After the CYP injection, eviprostat (9, 18 or 54 mg/kg per day) or a vehicle was orally given twice each day. Four days after the CYP injection, bladder function was evaluated by cystometrograms under urethane anesthesia. In a separate group, bladder inflammation was compared between the eviprostat- or vehicle-treated animals. Furthermore, the effects of eviprostat on carbachol-induced muscle contraction were evaluated by an in vitro experiment.
Results:   The intercontraction interval (ICI) significantly decreased in the CYP-injected rats in comparison to the saline-injected rats. In the CYP-injected group, 18 and 54 mg/kg per day of eviprostat treatment significantly increased the ICI, but did not change the maximum voiding pressure in comparison to the vehicle treatment. In the saline-injected group, no significant changes of any parameters in the cystometrograms were observed between the eviprostat- and vehicle-treated groups. CYP-induced bladder inflammation tended to be lower in the eviprostat-treated group in comparison to the vehicle-treated group. An in vitro experiment revealed that eviprostat failed to inhibit carbachol-induced muscle contraction.
Conclusion:   The oral administration of eviprostat suppressed CYP-induced bladder overactivity. The effects of eviprostat on the micturition reflex may be irrespective of antimuscarinic action. The present findings raise the possibility that eviprostat could be an effective treatment for bladder overactivity associated with inflammation.     

L-methionine enhances the contractile response to norepinephrine of rat vas deferens

Under Ca-depleted conditions, the contractile responses of rat vas deferens in the presence of norepinephrine were not elicited until the addition of CaCl2. L-Methionine enhanced the contractile response of vas deferens in the presence of methylation blockers under these conditions. The enhancing effect of L-methionine on some other smooth muscles could not be determined because under Ca-depleted conditions, these muscles showed 60-80% of the maximal contractile response on addition of CaCl2 alone. These findings suggested that L-methionine has an enhancing effect on contraction of the rat vas deferens as it does on rat uterine muscle.     

Dysgenesis of corpus callosum with conjunctival malignant melanoma and iris nevus

A 32-year-old man had dysgenesis of the corpus callosum associated with iris nevi and conjunctival malignant melanoma. Iris lesions revealed intrastromal proliferation of melanocytes accompanied by surface plaque. Epithelioid and spindle cells with pigmentation, positive for the melanoma marker HMB-45 and S-100 protein, were observed in the conjunctival lesion by histologic examination. These findings may suggest an underlying neoplastic potential of melanocytes. The authors have stated that they do not have a significant financial interest or other relationship with any product manufacturer or provider of services discussed in this article.     

Biological Safety of LipoFullerene composed of Squalane and Fullerene‐C60 upon Mutagenesis,Photocytotoxicity, and Permeability into the Human Skin Tissue

Abstract: Fullerene‐C60 (C60) is mainly applied in the aqueous phase by wrapping with water‐soluble polymer or by water‐solublizing chemical‐modification, whereas C60 dissolved in oil is scarcely applied; still less explicable is its toxicity. We dissolved C60 in squalane at near‐saturated or higher concentrations (220–500 ppm), named LipoFullerene (LF‐SQ), and examined its biological safety. LF‐SQ was administered at doses of 0.49–1000 µg/ml to fibroblast cells Balb/3T3, and showed that cell viability was almost equal to that of the control regardless of the UVA‐ or sham‐irradiation, indicating no phototoxicity. Reverse mutation by LF‐SQ was examined on four histidine‐demanding strains of Salmonella typhimurium and a tryptophan‐demanding strain of Escherichia coli. As for the dosages of LF‐SQ (313–5000 µg/plate), the dose‐dependency of the number of reverse mutation colonies of each strain did not show a marked difference when compared with the negative control, regardless of the metabolic activation, in contrast to twice or more differences for five positive controls (sodium azide, N‐ethyl‐N′‐nitro‐N‐nitrosoguanidine, 2‐nitrofluorene, 9‐aminoacridine, and 2‐aminoanthracene). In human skin biopsy built in a diffusion chamber, C60 permeated into the epidermis at 33.6 nmol/g tissue (24.2 ppm), on administration with LF‐SQ containing 223 ppm of C60, but not detected in the dermis even after 24 hrs, as analysed by HPLC. It is presumed that LF‐SQ can permeate into the epidermis via the corneum but can not penetrate the basement membrane, and so can not reach into the dermis, suggesting no necessity for considering a toxicity of C60 due to systemic circulation via dermal veins. Thus, C60 dissolved in squalane may not give any significant biological toxic effects such as photocytotoxicity, bacterial reverse mutagenicity, and permeability into the human skin.