Obesity, diabetes, hyperlipidemia and hypertension, which are caused by hypernutrition and lack of exercise, are often found in the same person. These symptoms used to be called "the deadly quartet," "Syndrome X" or "insulin resistance syndrome," but these names have recently been collectively replaced with "metabolic syndrome (MS)," since the presence of visceral fat accumulation-type obesity has been recognized as the major disease base. It should be noted that progression of MS increases the risk of future onset of ischemic cardiac diseases and cerebrovascular diseases, and the importance of "prevention" and "early therapy" of MS is emphasized.Gardeniae fructus, the fruit of Gardenia jasminoides ELLIS, is widely used in Asian countries as a natural colorant, and it is also used as a Japanese and Chinese traditional medicine since it has a homeostatic effect, an antiphlogistic effect, an analgesic effect, an antipyretic effect, a hepatoprotective effect and a hypolipidaemic effect.1,2) Geniposide, an iridoid glycoside contained in Gardeniae fructus, is reported to have a hepatoprotective effect, an antioxidant effect, a hypoglycemic effect, a vascular endothelial cell adhesion-suppressing effect, an anti-lipopolysaccharide (LPS) effect, a neuroprotective effect, and an anti-inflammatory effect. [3][4][5][6][7][8][9] In addition, genipin, which is the aglycone portion of geniposide and is formed as a metabolite, is also reported to have an anti-inflammatory effect, a bile secretion-enhancing effect, and an anti-thrombotic effect. [10][11][12] Geniposide is promising as a seed compound for developing therapeutic medicines for metabolic diseases. However, no publication has reported the effect of geniposide on various metabolic disease symptoms based on visceral fat accumulation. TSOD mice are model animals showing spontaneously multifactorial genetic Type 2 diabetes based on visceral fat accumulation. [13][14][15][16][17][18] Since the cause of onset and the symptoms are very similar to those of human MS, this model is regarded as promising for the study of MS. In the present study, we investigated the effect of geniposide on various metabolic disease symptoms based on visceral fat accumulation using TSOD mice. In addition, a fatty liver model was prepared by adding a free fatty acid to human liver cancer cells (HepG2 cells), 19) and the direct effect of genipin on the liver was investigated. MATERIALS AND METHODSReagents Geniposide and genipin (Fig. 1) were supplied by Tsumura and Co. (Ibaraki, Japan). Palmitic acid powder was purchased from Sigma-Aldrich (MO, U.S.A.). The other reagents used were of the highest grade available.Animal Experiments Experimental Animals: Male TSOD mice and corresponding control animals (TSNO mice) were purchased from the Institute for Animal Reproduction (Ibaraki) at the age of 3 weeks. They were acclimated under controlled circumstances (temperature: 23Ϯ1°C, humidity: 55Ϯ5%, lighting hours: 12 h) for one week. During the acclimation period, the animals were given ordinary powder ...

Dysthymia is a depressive mood disorder characterized by chronic and persistent but mild depression. It is often difficult to be distinguished from major depression, specifically in its partially remitted state because “loss of interest” or “apathy” tends to prevail both in dysthymia, and remitted depression. Apathy may also occur in various psychiatric and neurological disorders, including schizophrenia, stroke, Parkinson's disease, progressive supranuclear palsy, Huntington's disease, and dementias such as Alzheimer's disease, vascular dementia, and frontotemporal dementia. It is symptomatologically important that apathy is related to, but different from, major depression from the viewpoint of its causes and treatment. Antidepressants, especially noradrenergic agents, are useful for depression-related apathy. However, selective serotonin reuptake inhibitors (SSRIs) may be less effective for apathy in depressed elderly patients and have even been reported to worsen apathy. Dopaminergic agonists seem to be effective for apathy. Acetylcholine esterase inhibitors, methylphenidate, atypical antipsychotics, nicergoline, and cilostazol are another choice. Medication choice should be determined according to the background and underlying etiology of the targeting disease.

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Remarkable improvements in rCBF in the left dorsolateral PFC to precentral regions are consistent with the hypothesis that neuronetworks including the left frontal cortex may be functionally and reversibly involved in late-life unipolar major depression (state-dependent). In contrast, neural circuits including bilateral medial, dorsolateral, and parietal areas may reflect underlying and continuous pathognomonic brain dysfunction of depression (trait-dependent).

Hard tissues, such as bone and teeth, consist of hydroxyapatite (HAP), collagenous proteins and noncollagenous proteins. Osteopontin and bone sialoprotein are two major noncollagenous proteins in bone and have many L-Asp and L-Glu repetitive sequences, respectively, as possible hydroxyapatite (HAP)binding sites. Fluorescence-labeled acidic amino acid (L-Asp or L-Glu) homopeptides containing six or more residues bound strongly to HAP and were selectively delivered to and retained in bone after systemic administration. This result stimulated the development of bone-targeting drugs by tagging with acidic oligopeptides. Three model drugs, estradiol, quinolone antibiotics and tissue-nonspecific alkaline phosphatase (TNSALP), tagged with aspartic acid hexapeptide were examined the clinical feasibility of the acidic oligopeptide strategy for selective drug delivery to bone. In vivo experiments confirmed the long acting effects of L-Asp hexapeptide-tagged estradiol and levofloxacin on animal models of osteoporosis and osteomyelitis, respectively, although there was loss of in vitro bioactivity, suggesting that the acidic hexapeptide was removed by hydrolysis in the body after delivery to bone. The adverse effect of estradiol on the uterus was greatly reduced by conjugation to the hexapeptide. The L-Asp hexapeptide-tagged TNSALP has the enzyme activity similar to untagged enzyme and was selectively delivered to bone and retained for long time in comparison with the untagged enzyme. These results support the usefulness of acidic oligopeptides as bone-targeting carriers for therapeutic agents.

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The photodegradation products of the anticancer drug, dacarbazine, cause adverse reactions including local venous pain when injected intravenously. In this study, we attempted to identify which of these products is responsible. We synthesized or purchased five photodegradation products of dacarbazine (dimethylamine, 5-diazoimidazole-4-carboxamide (Diazo-IC), 4-carbamoylimidazolium-5-olate, 5-carbamoyl-2-(4-carbamoylimidazol-5-ylazo)imidazolium-5-olate and 2-azahypoxanthine) and examined the pain reaction induced by their intraperitoneal administration in mice using an abdominal stretching or constriction assay. Only Diazo-IC clearly induced pain reaction in mice in a dose-dependent manner, the other products caused no pain reaction. The threshold concentration for pain reaction in mice was estimated to be about 0.1 mg mL-1. While diclofenac sodium significantly reduced acetic-acid-induced pain reaction in mice, it did not influence those induced by Diazo-IC. This result suggests that the mechanism of Diazo-IC-induced pain is different from that of acetic-acid-induced inflammatory pain. Dacarbazine itself produced marked relaxation of rat thoracic aorta strips in a concentration-dependent manner, but there was no difference between the activity of dacarbazine and its photo-exposed solution, so constriction or relaxation of blood vessels is unlikely to be a factor in the pain reaction. In conclusion, Diazo-IC generated by photodegradation of dacarbazine solution causes the side-effect of venous pain. Dacarbazine solution that has turned pink should not be used, because Diazo-IC is an intermediate in the formation of the reddish product, 5-carbamoyl-2-(4-carbamoylimidazol-5-ylazo)imidazolium-5-olate. Drip infusion preparations of dacarbazine should be shielded from light.