Effects of a Citrus depressa Hayata (shiikuwasa) extract on obesity in high-fat diet-induced obese mice.

Citrus depressa Hayata (commonly known as shiikuwasa) is cultivated in the northern areas of Okinawa, Japan, and used as a juice. In this study, we examined the anti-obesity effects and mechanism of action of shiikuwasa peel extract (SE) using high-fat diet (HFD)-induced obese mice. Mice were fed a low-fat diet (LFD), HFD or HFD containing 1% or 1.5% (w/w) SE (HFD+1 SE and HFD+1.5 SE, respectively) for 5 weeks. The body weight gain and white adipose tissue weight were significantly decreased in the HFD+1.5 SE group compared with the HFD group. The plasma triglyceride and leptin levels were also significantly reduced in the HFD+1.5 SE group compared with the HFD group. Histological examinations showed that the sizes of the adipocytes were significantly smaller in the HFD+1.5 SE group than in the HFD group. The HFD+1.5 SE group also showed significantly lower mRNA levels of lipogenesis-related genes, such as activating protein 2, stearoyl-CoA desaturase 1, acetyl-CoA-carboxylase 1, fatty acid transport protein and diacylglycerol acyltransferase 1, than the HFD group. These results suggest that the anti-obesity effects of SE may be elicited by regulating the expressions of lipogenesis-related genes in white adipose tissue.

Nobiletin improves hyperglycemia and insulin resistance in obese diabetic ob/ob mice.

Nobiletin is a polymethoxylated flavone found in certain citrus fruits that exhibits various pharmacological effects including anti-inflammatory, antitumor and neuroprotective properties. The present study investigated the effects of nobiletin on insulin sensitivity in obese diabetic ob/ob mice, and the possible mechanisms involved. The ob/ob mice were treated with nobiletin (200mg/kg) for 5 weeks. Nobiletin significantly improved the plasma glucose levels, homeostasis model assessment index, glucose tolerance in an oral glucose tolerance test and plasma adiponectin levels. In white adipose tissue (WAT), nobiletin significantly decreased the mRNA expression levels of inflammatory adipokines such as interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1 and increased the mRNA expression levels of adiponectin, peroxisome proliferator-activated receptor (PPAR)-gamma and its target genes. At the same time, nobiletin increased the glucose transporter (Glut) 4 expression levels in the whole plasma membrane, and Glut1 and phospho-Akt expression in the whole cell lysates in WAT and muscle. Nobiletin also increased Glut4 protein expression level in the whole cell lysates of the muscle. Taken together, the present results suggest that nobiletin improved the hyperglycemia and insulin resistance in obese diabetic ob/ob mice by regulating expression of Glut1 and Glut4 in WAT and muscle, and expression of adipokines in WAT.

Enhanced expression of heat shock proteins in gradually dying cells and their release from necrotically dead cells.

Heat shock proteins (HSPs) have molecular chaperone functions in protein biogenesis as well as cytoprotective functions against deleterious environmental stresses, and they work mainly inside of the cells. HSPs are usually induced in living cells that have been exposed to mild stresses or have recovered from severe stresses. Here, we show the enhanced synthesis of HSPs in gradually and necrotically dying cells that were treated with a high concentration of acrylamide (10 mM). This treatment caused irreversible cell death. The synthesis of HSPs, which was enhanced before cell death, was mediated by the activation of heat shock transcription factor 1 (HSF1); that is, the treatment led to the phosphorylation of HSF1, formation of characteristic HSF1 granules in the nucleus, and acquisition of DNA binding ability of HSF1. The induction of HSPs by acrylamide treatment was dependent on the consensus sequence of heat shock element (HSE) as demonstrated by a reporter assay. Also, several HSPs (Hsp90, Hsc70, Hsp70, Hsp60, Hsp47, Hsp40, and Hsp27) were detected outside of the cells after the treatment with acrylamide, indicating that these HSPs are released from necrotically dead cells. These results suggest that when cells are slowly and irreversibly dying, they augment the expression of HSPs and release them outside of the cells as a danger signal or dying messages.

Antioxidant and immuno-enhancing effects of Echinacea purpurea.

We studied the protective effects of Echinacea purpurea against radiation by evaluating changes in the peripheral blood cell count and peripheral blood antioxidant activity. E. purpurea administration had a suppressive effect on radiation-induced leukopenia, especially on lymphocytes and monocytes, and resulted in a faster recovery of blood cell counts. Mouse peripheral blood antioxidant activity was increased by E. purpurea, and a relationship between the suppressive effect on radiation-induced leukopenia and the antioxidant effect was suggested. Furthermore, we reviewed the evidence of augmentation of found in this study humoral immunity. The effects of immune activation by E. purpurea were investigated by measuring total immunoglobulin (IgG, IgM). The radioprotective effects of immune activation by E. purpurea were investigated by measuring T lymphocyte subsets in the peripheral blood of mice following whole-body irradiation. E. purpurea activates macrophages to stimulate IFN-gamma production in association with the secondary activation of T lymphocytes, resulting in a decrease in IgG and IgM production. Cytokines released from macrophages in mouse peripheral blood after E. purpurea administration activated helper T cells to proliferate. In addition, it is reported that activated macrophages in association with the secondary T lymphocyte activation increases IFN-gamma production and stimulates proliferation of cytotoxic T cells and suppressor T cells. We think that CD 4 and CD 8 subsets were more immunologically enhanced by E. purpurea than helper T cells and suppressor T cell these results reflect activation. In addition, we think that these results reflect cell-mediated immune responses.

Paeoniflorin, a novel heat shock protein-inducing compound.

Heat shock proteins (HSPs) are induced by various physical, chemical, and biological stresses. HSPs are known to function as molecular chaperones, and they not only regulate various processes of protein biogenesis but also function as lifeguards against proteotoxic stresses. Because it is very useful to discover nontoxic chaperone-inducing compounds, we searched for them in herbal medicines. Some herbal medicines had positive effects on the induction of HSPs (Hsp70, Hsp40, and Hsp27) in cultured mammalian cells. We next examined 2 major constituents of these herbal medicines, glycyrrhizin and paeoniflorin, with previously defined chemical structures. Glycyrrhizin had an enhancing effect on the HSP induction by heat shock but could not induce HSPs by itself. In contrast, paeoniflorin had not only an enhancing effect but also an inducing effect by itself on HSP expression. Thus, paeoniflorin might be termed a chaperone inducer and glycyrrhizin a chaperone coinducer. Treatment of cells with paeoniflorin but not glycyrrhizin resulted in enhanced phosphorylation and acquisition of the deoxyribonucleic acid-binding ability of heat shock transcription factor 1 (HSF1), as well as the formation of characteristic HSF1 granules in the nucleus, suggesting that the induction of HSPs by paeoniflorin is mediated by the activation of HSF1. Also, thermotolerance was induced by treatment with paeoniflorin but not glycyrrhizin. Paeoniflorin had no toxic effect at concentrations as high as 80 microg/ mL (166.4 microM). To our knowledge, this is the first report on the induction of HSPs by herbal medicines.