Resveratrol inhibits inflammation induced by heat-killed Listeria monocytogenes.

Resveratrol is a polyphenolic compound in red wine that has antioxidant and cardioprotective effects in animal models. Listeria monocytogenes is a pathogen that mainly affects immunocompromised individuals and is initially detected at the cell surface or in phagosomes by toll-like receptor 2. Many antioxidants also exert anti-inflammatory activities; therefore, we evaluated the anti-inflammatory properties of resveratrol by studying the various inflammatory responses induced by heat-killed L. monocytogenes (HKLM). Resveratrol strongly blocked HKLM-induced NADPH oxidase-1 mRNA and reactive oxygen species production by macrophages. Resveratrol also suppressed monocyte chemotactic protein-1 expression, cyclooxygenase-2 expression, prostaglandin production, inducible nitric oxide (NO) synthase expression, and NO production induced by HKLM. We investigated the signaling pathway involved in the resveratrol effect. HKLM stimulated glycogen synthase kinase 3ß (GSK3ß) and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. The involvement of GSK3ß and ERK1/2 was tested using inhibitors. While the GSK3ß inhibitor LiCl potentiated the effect of HKLM, the MEK inhibitor U0126 blocked these responses. Additionally, pretreatment with resveratrol blocked phosphorylation of both kinases induced by HKLM. These results suggest that HKLM is strong inducer of inflammatory mediators, and that the inhibitory effect of resveratrol may be mediated by the GSK3ß and ERK1/2 pathways.

Twenty-eight-day oral toxicity, genotoxicity, and gender-related tissue distribution of silver nanoparticles in Sprague-Dawley rats.

The antibacterial effect of silver nanoparticles has resulted in their extensive application in health, electronic, and home products. However, while the population exposed to silver nanoparticles continues to increase with ever new applications, silver nanoparticles remain a controversial research area as regards their toxicity to biological systems. In particular, the oral toxicity of silver nanoparticles is of particular concern to ensure public and consumer health. Accordingly, this study tested the oral toxicity of silver nanoparticles (60 nm) over a period of 28 days in Sprague-Dawley rats following Organization for Economic Cooperation and Development (OECD) test guideline 407 with Good Laboratory Practice (GLP) application. Eight-week-old rats, weighing about 283 g for the males and 192 g for the females, were divided into four 4 groups (10 rats in each group): vehicle control, low-dose group (30 mg/kg), middle-dose group (300 mg/kg), and high-dose group (1000 mg/kg). After 28 days of exposure, the blood biochemistry and hematology were investigated, along with a histopathological examination and silver distribution study. The male and female rats did not show any significant changes in body weight relative to the doses of silver nanoparticles during the 28-day experiment. However, some significant dose-dependent changes were found in the alkaline phsophatase and cholesterol values in either the male or female rats, seeming to indicate that exposure to over more than 300 mg of silver nanoparticles may result in slight liver damage. There were no statistically significant differences in the micronucleated polychromatic erythrocytes (MN PCEs) or ratio of polychromatic erythrocytes among the total erythrocytes after silver nanoparticle exposure when compared with the control. Therefore, the present results suggest that silver nanoparticles do not induce genetic toxicity in male and female rat bone marrow in vivo. Nonetheless, the tissue distribution of silver nanopaticles did show a dose-dependent accumulation of silver content in all the tissues examined. In particular, a gender-related difference in the accumulation of silver was noted in the kidneys, with a twofold increase in the female kidneys when compared with the male kidneys.

Enhancement of radiation response with combined Ganoderma lucidum and Duchesnea chrysantha extracts in human leukemia HL-60 cells.

We previously demonstrated that combined treatment with extracts of the medicinal mushroom Ganoderma lucidum and the herb Duchesnea chrysantha (GDE) significantly suppresses cell growth and selectively induces apoptosis in human leukemia HL-60 cells, but not in normal cells. GDE?s mechanism of action and its activity against HL-60 cells suggest that it could be suitable for the combined-modality treatment of hematological malignancies. In the present study, we examined whether treatment with a combination of GDE and ionizing radiation enhances the therapeutic effect. We demonstrated that, when used in combination with radiation at a clinically relevant dose of 2 Gy, GDE further suppressed cell proliferation and induced apoptosis as well as micronuclei formation in HL-60 cells, leading to increased cell death. Furthermore, GDE pretreatment not only reduced radiation-induced G2/M-phase arrest, but also induced G1-phase arrest. These events are associated with the inhibition of cyclin-dependent kinase 1 (CDK1) phosphorylation and the dephosphorylation of retinoblastoma protein (pRB). Collectively, these data show that combined treatment with GDE and radiation enhances radiation-induced apoptosis and overall cell death. These findings may be clinically relevant and suggest a novel therapeutic strategy for increasing the efficacy of radiotherapy.

Enhanced induction of mitochondrial damage and apoptosis in human leukemia HL-60 cells by the Ganoderma lucidum and Duchesnea chrysantha extracts.

Combined treatment with the medicinal mushroom Ganoderma lucidum and the herb Duchesnea chrysantha extracts (GDE) causes a synergistic induction of mitochondrial damage and apoptosis in HL-60 cells. GDE treatment is selectively toxic to HL-60 leukemia cells whereas no cytotoxic effect is observed in normal peripheral blood mononuclear cells. GDE-induced apoptosis is associated with Bcl-2 down-regulation, Bax translocation, mitochondrial cytochrome c release and caspase-3 activation, suggesting that apoptosis by this combination occurs through the mitochondria-dependent pathway. The present findings suggest that this combination merits further investigation as a potential therapeutic agent for the treatment of cancer.

Effects of Tiron, 4,5-dihydroxy-1,3-benzene disulfonic acid, on human promyelotic HL-60 leukemia cell differentiation and death.

Tiron, 4,5-dihydroxy-1,3-benzene disulfonic acid, has been known to be a widely used antioxidant to rescue ROS-evoked cell death and a non-toxic chelator to alleviate an acute metal overload. In this study, we showed that Tiron is a potent inducer of cell differentiation and apoptotic cell death in human promyelotic HL-60 leukemia cell. At a low level of concentration (<0.5mM), Tiron caused HL-60 cells to induce differentiation-related alterations such as the increase of CD11b and CD14 expression or chromatin condensation. Hypoxia inducible factor-1alpha (HIF-1alpha) was also increased at mRNA and protein level, and thus the CCAAT/enhancer-binding protein alpha, which is a downstream target of HIF-1alpha and acts as a critical factor for granulocytic differentiation was increased. High dose of Tiron (>0.5mM) induced severe DNA damage in HL-60 cells, as measured by the cytokinesis-block micronucleus test and the comet assay. Consequently, high dose of Tiron led to apoptotic cell death, which showed the DNA fragmentation, the caspase activation and the unbalance between antiapoptotic (Bcl-2) and proapoptotic proteins (Bax). However, an exogenous supplement of iron (FeCl(3)) reversed all of these effects, the cell differentiation and the apoptotic cell death. Therefore, these results suggest that Tiron-mediated differentiation and cell death result from the disturbance of iron metabolism.