Anti-stress effects of rosemary (Rosmarinus officinalis L.) leaf extract on intestinal goblet cells and immobility of forced-swimming test in BALB/c mice.

We investigated the anti-stress effect of rosemary (Rosmarinus officinalis L.) leaf extract (RLE) on restraint-stressed mice and found that RLE alleviated decreases in the number of intestinal goblet cells and amount of hepatic triglycerides. It also decreased the immobility time in the forced-swimming test and activation of microglia in the brain, suggesting that RLE has beneficial effects on stress-induced dysfunctions.

Efficacy of Long-Term Feeding of α-Glycerophosphocholine for Aging-Related Phenomena in Old Mice.

α-Glycerophosphocholine (GPC) is a natural source of choline. It reportedly prevents aging-related decline in cognitive function, but the underlying mechanism remains unclear. Although it is understood that aging influences taste sensitivity and energy regulation, whether GPC exerts antiaging effects on such phenomena requires further elucidation. Here, we used old C57BL/6J mice that were fed a GPC-containing diet, to investigate the molecular mechanisms underlying the prevention of a decline in cognitive function associated with aging and examine the beneficial effects of GPC intake on aging-related phenomena, such as taste sensitivity and energy regulation. We confirmed that GPC intake reduces the aging-related decline in the expression levels of genes related to long-term potentiation. Although we did not observe an improvement in aging-related decline in taste sensitivity, there was a notable improvement in the expression levels of ß-oxidation-associated genes in old mice. Our results suggest that the prevention of aging-related decline in cognitive function by GPC intake may be associated with the improvement of gene expression levels of long-term potentiation. Furthermore, GPC intake may positively influence lipid metabolism.

Anti-Angiogenic Activity of Rotenoids from the Stems of Derris trifoliata.

The plants in the genus Derris have proven to be a rich source of rotenoids, of which cytotoxic effect against cancer cells seem to be pronounced. However, their effect on angiogenesis playing a crucial role in both cancer growth and metastasis has been seldom investigated. This study aimed at investigating the effect of the eight rotenoids (1: -8: ) isolated from Derris trifoliata stems on three cancer cells and angiogenesis. Among them, 12a-hydroxyrotenone (2: ) exhibited potent inhibition on both cell growth and migration of HCT116 colon cancer cells. Further, anti-angiogenic assay in an ex vivo model was carried out to determine the effect of the isolated rotenoids on angiogenesis. Results revealed that 12a-hydroxyrotenone (2: ) displayed the most potent suppression of microvessel sprouting. The in vitro assay on human umbilical vein endothelial cells was performed to determine whether compound 2: elicits anti-angiogenic effect and its effect was found to occur via suppression of endothelial cells proliferation and tube formation, but not endothelial cells migration. This study provides the first evidence that compound 2: could potently inhibit HCT116 cancer migration and anti-angiogenic activity, demonstrating that 2: might be a potential agent or a lead compound for cancer therapy.

The delaying effect of alpha-glycerophosphocholine on senescence, transthyretin deposition, and osteoarthritis in senescence-accelerated mouse prone 8 mice.

Administration of alpha-glycerophosphocholine (GPC), a choline compound in food, is expected to contribute to human health. In this study, we evaluated its effect on aging in senescence-accelerated mouse prone 8 (SAMP8) mice. Male SAMP8 mice had free access to a commercial stock diet and drinking water with or without GPC (0.07 mg/ml). Mice in the GPC group had significantly lower total senescence grading score than that of the control group at 36 weeks of age. Administration of GPC decreased the deposition of transthyretin (TTR), an amyloidogenic protein, in the brain. Aggregated TTR activated microglia and led to neuroinflammation. Thus, GPC would protect the brain by reducing TTR deposition and preventing neuroinflammation. In a histological study of knee joints, it was found that SAMP8 mice administered GPC showed decreased joint degeneration. These results suggest that GPC delays the aging process and may be a useful compound in anti-aging functional food development.

Carnosic acid protects starvation-induced SH-SY5Y cell death through Erk1/2 and Akt pathways, autophagy, and FoxO3a.

Carnosic acid (CA) is recognized as a unique neuroprotective compound in the herb rosemary, since it induces expression of antioxidant enzymes including heme oxygenase-1 (HO-1), γ-glutamylcysteine synthase (γ-GCS), and glutathione S-transferase (GST) via activation of nuclear factor erythroid 2-related factor 2 (Nrf2), which is a nuclear transcription factor. In this study, we examined the cytoprotective effects of CA against starvation. We found that CA protected starvation-induced SH-SY5Y cell death by activating Akt and extracellular signal-regulated kinase 1/2 (Erk1/2). Interestingly, CA induced moderate autophagy and dephosphorylation of a transcriptional factor, the forkhead box protein O3a (FoxO3a). These effects of CA play an important role in cytoprotection.

Antiangiogenetic effects of anthranoids from Alternaria sp., an endophytic fungus in a Thai medicinal plant Erythrina variegata.

Endophytic fungi are known as a prolific source for the discovery of structurally interesting and biologically active secondary metabolites, some of which are promising candidates for drug development. In the present study, three anthranoids were isolated from an Alternaria sp. endophytic fungus and evaluated for their antiangiogenic activity in a rat aortic sprouting assay, an ex vivo model of angiogenesis. Of these three compounds, altersolanol (2) was further characterized and found to show a promising activity in ex vivo, in vitro and in vivo angiogenesis asssays. Using human umbilical vein endothelial cells as an in vitro model, the angiogenic effect of 2 was found to occur via suppression of all three main functions of endothelial cells, namely proliferation, tube formation and migration.

Cytotoxic and anti-angiogenic properties of minor 3,4-seco-cycloartanes from Gardenia sootepensis exudate.

Gardenia plants have long been used as traditional medicines in various countries including Thailand. In this study, two new 3,4-seco-cycloartane triterpenes, sootependial (1) and sootepenoic acid (2), were isolated from bud exudate of G. sootepensis, together with five known compounds. Their structures were elucidated on the basis of spectroscopic data. Sootependial (1) showed potent cytotoxicity selective to Hep-G2 cell lines and anti-angiogenic activity in ex vivo model (a rat aortic ring sprouting) assay. Furthermore, its angiogenic effect was found to occur mainly by suppressing endothelial cell proliferation and tubule formation, suggesting the potential of 1 as a lead compound for cancer treatment.

Antiangiogenic effect of carnosic acid and carnosol, neuroprotective compounds in rosemary leaves.

Carnosic acid, a diterpene in rosemary, is considered to be beneficial in the prevention of chronic neurodegenerative diseases. Recently, it has been found that drugs with antiangiogenic activity lower the risk of neurodegenerative diseases. Thus it is of interest whether carnosic acid has antiangiogenic activity. In this study, carnosic acid suppressed microvessel outgrowth on ex vivo angiogenesis assay using a rat aortic ring at higher than 10 µM. The antiangiogenic effect of carnosic acid was found in angiogenesis models using human umbilical vein endothelial cells with regard to tube formation on reconstituted basement membrane, chemotaxis and proliferation. Although the carnosol in rosemary also suppressed angiogenesis, its effect was not more potent than that of carnosic acid in the ex vivo model. These results suggest that carnosic acid and rosemary extract can be useful in the prevention of disorders due to angiogenesis, and that their antiangiogenic effect can contribute to a neuroprotective effect.

Antiangiogenic activity of 3,4-seco-cycloartane triterpenes from Thai Gardenia spp. and their semi-synthetic analogs.

Twelve naturally occurring 3,4-seco-cycloartane triterpenes (1-12) isolated from Gardenia sootepensis and Gardenia obtusifolia, and eight semi-synthetic derivatives (13-20) were evaluated for their antiangiogenic activity on a rat aortic sprouting assay, an ex vivo model of angiogenesis. Among these compounds, sootepin B (1) displayed the most potent activity in terms of the inhibition of microvessel sprouting from rat aortic rings in a dose-dependent manner with IC(50) value of 4.46 µM. Its angiogenic effect was found to occur via suppression of endothelial cell proliferation and tubular formation, and was likely mediated by regulation (inhibition) of the Erk1/2 signaling pathway.

Consumption of vitamin B6 reduces colonic damage and protein expression of HSP70 and HO-1, the anti-tumor targets, in rats exposed to 1,2-dimethylhydrazine.

Mounting evidence indicates that vitamin B6 is a protective factor for colon cancer. Elevations in colonic damage, cell proliferation and heat shock proteins (HSPs, molecular chaperones) have been suggested to be associated with colon carcinogenesis. This study was performed to examine the effect of dietary levels of vitamin B6 (1, 7 or 35 mg pyridoxine HCl/kg diet) for 22 weeks on colon damage, epithelial cell proliferation and expression of HSPs in rats exposed to 1,2-dimethylhydrazine (DMH). Supplemental vitamin B6 with a low vitamin B6 diet (1 mg pyridoxine HCl/kg diet) significantly reduced fecal activity of intestinal alkaline phosphatase (an index of intestinal damage) and the colonic epithelium PCNA labeling index (a marker of cell proliferation). Analysis using ELISA indicated that supplemental vitamin B6 significantly lowered protein levels of colonic HSP70 and heme oxygenase-1, HSP32 (HO-1). However, real-time RT-PCR analysis revealed that the mRNA levels of these HSPs were not decreased by supplemental vitamin B6, suggesting that the lowering effect of vitamin B6 on the colon protein expression of the HSPs is mediated by mechanisms not involving altered gene expression. This study provided evidence that dietary supplemental vitamin B6 suppresses colon damage, epithelial cell proliferation and protein expression of HSP70 and HO-1, the targets for anti-tumor agents, in rats exposed to DMH.

Anti-angiogenic effect of siphonaxanthin from green alga, Codium fragile.

Since anti-angiogenic therapy has becoming a promising approach in the prevention of cancer and related diseases, the present study was aimed to examine the anti-angiogenic effect of siphonaxanthin from green alga (Codium fragile) in cell culture model systems and ex vivo approaches using human umbilical vein endothelial cells (HUVECs) and rat aortic ring, respectively. Siphonaxanthin significantly suppressed HUVEC proliferation (p<0.05) at the concentration of 2.5 µM (50% as compared with control) and above, while the effect on chemotaxis was not significant. Siphonaxanthin exhibited strong inhibitory effect on HUVEC tube formation. It suppressed the formation of tube length by 44% at the concentration of 10 µM, while no tube formation was observed at 25 µM, suggesting that it could be due to the suppression of angiogenic mediators. The ex vivo angiogenesis assay exhibited reduced microvessel outgrowth in a dose dependent manner and the reduction was significant at more than 2.5 µM. Our results imply a new insight on the novel function of siphonaxanthin in preventing angiogenesis related diseases.

Inhibitory effect of glycolipids from spinach on in vitro and ex vivo angiogenesis.

Anti-cancer activity of some glycolipids from animals and plants has been demonstrated, although it was unknown whether the glycolipids had anti-angiogenic activity. The effects of the purified three glycolipids, monogalactosyl diacylglycerol (MGDG), digalactosyl diacylglycerol (DGDG), and sulfoquinovosyl diacylglycerol (SQDG) from the green vegetable spinach (Spinacia oleracea L.) were examined on in vitro and ex vivo angiogenesis models. MGDG and SQDG suppressed microvessel growth in an ex vivo angiogenesis model using a rat aortic ring. The glycolipids inhibited human umbilical vein endothelial cell (HVUEC) tube formation on a reconstituted basement membrane and HUVEC proliferation. These results demonstrate that glycolipids from spinach would suppress tumor growth by suppressing angiogenesis and might be candidates for anti-cancer or anti-angiogenic materials.