Antifatigue properties of tanshinone IIA in mice subjected to the forced swimming test.

CONTEXT: Tanshinone IIA (Tan IIA) is a constituent of Danshen Salvia miltiorrhiza Bunge (Lamiaceae); however, its antifatigue activity remains unclear. OBJECTIVE: To study the antifatigue properties of Tan IIA and its underlying mechanisms. MATERIALS AND METHODS: In program I, three mouse groups were separately subjected to three gavages with 0, 1 and 6 mg/kg Tan IIA and forced swimming test (FST) weekly for 8 weeks; in program II, one gavage with 0, 2 and 10 mg/kg Tan IIA was administered plus FST weekly for 4 weeks. Serum glucose, lactate, superoxide dismutase (SOD), malondialdehyde (MDA) and blood urea nitrogen (BUN) were determined after final FST. RESULTS: Tan IIA significantly prolonged swimming durations in program I but not in program II. Swimming times were 3208 ± 1054 and 2443 ± 1054 s for the 1 and 6 mg/kg treatments and 856 ± 292 s for the vehicle control. The two doses significantly reduced serum glucose levels (40.3 ± 8.5 and 60.0 1 ± 11.8 mg/kg) and lactate levels (61.3 ± 27.5 and 68.8 ± 8.5 mg/kg) in treated mice compared with those in control mice (137.5 ± 38.6 mg/kg and 122.7 ± 18.2 mg/kg, respectively). However, no significant differences were observed regarding SOD, MDA or BUN levels. DISCUSSION AND CONCLUSIONS: Tan IIA has antifatigue activity and is associated with reductions in serum glucose and lactate levels. Further studies should assess muscle hypertrophy and efficient aerobic glycolysis caused by Tan IIA. Tan IIA has potential as a pharmacological agent for fatigue resistance.

Opportunistic gill infection is associated with TiO2 nanoparticle-induced mortality in zebrafish.

The large amounts of engineered titanium dioxide nanoparticles (TiO2NPs) that have been manufactured have inevitably been released into the ecosystem. Reports have suggested that TiO2 is a relatively inert material that has low toxicity to animals. However, as various types of NPs increasingly accumulate in the ocean, their effects on aquatic life-forms remain unclear. In this study, a zebrafish model was used to investigate TiO2NP-induced injury and mortality. We found that the treatment dosages of TiO2NP are positively associated with increased motility of zebrafish and the bacterial counts in the water. Notably, gill but not dorsal fin and caudal fin of the zebrafish displayed considerably increased bacterial load. Metagenomic analysis further revealed that gut microflora, such as phyla Proteobacteria, Bacteroidetes, and Actinobacteria, involving more than 95% of total bacteria counts in the NP-injured zebrafish gill samples. These results collectively suggest that opportunistic bacterial infections are associated with TiO2NP-induced mortality in zebrafish. Infections secondary to TiO2NP-induced injury could be a neglected factor determining the detrimental effects of TiO2NPs on wild fish.

Soluble P-selectin rescues mice from anthrax lethal toxin-induced mortality through PSGL-1 pathway-mediated correction of hemostasis.

As one of the virulence factors of Bacillus anthracis, lethal toxin (LT) induces various pathogenic responses including the suppression of the coagulation system. In this study, we observed that LT markedly increased the circulating soluble P-selectin (sP-sel) levels and microparticle (MP) count in wild-type but not P-selectin (P-sel, Selp-/-) or P-sel ligand-1 (PSGL-1, Selplg-/-) knockout mice. Because sP-sel induces a hypercoagulable state through PSGL-1 pathway to generate tissue factor-positive MPs, we hypothesized that the increase in plasma sP-sel levels can be a self-rescue response in hosts against the LT-mediated suppression of the coagulation system. In agreement with our hypothesis, our results indicated that compared with wild-type mice, Selp-/- and Selplg-/- mice were more sensitive to LT. In addition, the recombinant sP-sel treatment markedly ameliorated LT-mediated pathogenesis and reduced mortality. As a result, elicitation of circulating sP-sel is potentially a self-rescue response, which is beneficial to host recovery from an LT-induced hypocoagulation state. These results suggest that the administration of sP-sel is likely to be useful in the development of a new strategy to treat anthrax.

Gene expression profiling: cell cycle deregulation and aneuploidy do not cause breast cancer formation in WAP-SVT/t transgenic animals.

Microarray studies revealed that as a first hit the SV40 T/t antigen causes deregulation of 462 genes in mammary gland cells (ME cells) of WAP-SVT/t transgenic animals. The majority of deregulated genes are cell proliferation specific and Rb-E2F dependent, causing ME cell proliferation and gland hyperplasia but not breast cancer formation. In the breast tumor cells a further 207 genes are differentially expressed, most of them belonging to the cell communication category. In tissue culture breast tumor cells frequently switch off WAP-SVT/t transgene expression and regain the morphology and growth characteristics of normal ME cells, although the tumor-revertant cells are aneuploid and only 114 genes regain the expression level of normal ME cells. The profile of retransformants shows that only 38 deregulated genes are tumor-specific, and that none of them is considered to be a typical breast cancer gene.

HBX causes cyclin D1 overexpression and development of breast cancer in transgenic animals that are heterozygous for p53.

Transgenic mice, which selectively express the WAP-HBX transgene in mammary gland epithelial cells (ME-cells), were established in order to elucidate the consequences of HBX gene expression on organ differentiation, cell death program and tumor development. Transgene expression was demonstrable by RT-PCR, Northern and Western blot analysis during pregnancy, lactation and after weaning. HBX synthesis neither affect mammary gland differentiation nor apoptosis in ME-cells. Although breast cancer formation was rare in WAP-HBX animals (<1%), WAP-HBX*p53+/- hybrid animals developed breast tumors at an increased rate (12/85) after a latency period of 8-18 months. We also show here for the first time that HBX can immortalize ME-cells generated from mammary gland tissue segments in a p53-independent fashion. HBX causes cyclin D1 gene overexpression during early pregnancy, and this is maintained in ME-cells isolated either from mammary gland or from breast tumors. Intranuclear cyclin D1 accumulation also occurs in the absence of external growth factors and the BrdU incorporation rate remains high under serum starvation conditions. Finally, both cyclin D1 induction and HBX mitotic activity are dependent on p38 and c-Jun N-terminal kinase, but not on MEK-1 kinase activity.

Synergistic combinations of tanshinone IIA and trans-resveratrol toward cisplatin-comparable cytotoxicity in HepG2 human hepatocellular carcinoma cells.

AIM: To determine the combinative effects of tanshinone IIA (Tan IIA) and trans-resveratrol (Resv) on cytotoxicity, apoptosis, cell-cycle arrest and DNA fragmentation in HepG2 human liver cancer cells. MATERIALS AND METHODS: Cytotoxicity was detected by the cell proliferation and cytotoxicity WST-1 assay. Cell-cycle arrest and apoptosis were determined using flow cytometry analysis. DNA fragments were separated by gel electrophoresis. RESULTS: Tan IIA and Resv at mixture ratios of 1/2:1/2 and 1/3:2/3 exerted synergistic cytotoxicity comparable to that of cisplatin. Elevated proportions of sub-G1 and apoptotic cells were respectively found in the combinative treatments in comparison with hypothetic values of additive effects. Moreover, a more intensive pattern of apoptotic DNA fragmentation was visualized in combined treatments than in individual ones. CONCLUSION: Combining Tan IIA and Resv causes synergistic cisplatin-comparable, cytotoxicity and robustly induces apoptosis, sub-G1 cell cycle arrest and DNA fragmentation. This study provides evidence supporting further pre-clinical investigations of the combinational synergism.