Flavones induce neutrophil apoptosis by down-regulation of Mcl-1 via a proteasomal-dependent pathway

Neutrophil apoptosis and subsequent nonphlogistic clearance by surrounding phagocytes are key to the successful resolution of neutrophilic inflammation, with dysregulated apoptosis reported in multiple human inflammatory diseases. Enhancing neutrophil apoptosis has proresolution and anti-inflammatory effects in preclinical models of inflammation. Here we investigate the ability of the flavones apigenin, luteolin, and wogonin to induce neutrophil apoptosis in vitro and resolve neutrophilic inflammation in vivo. Human neutrophil apoptosis was assessed morphologically and by flow cytometry following incubation with apigenin, luteolin, and wogonin. All three flavones induced time- and concentration-dependent neutrophil apoptosis (apigenin, EC(50)=12.2 μM; luteolin, EC(50)=14.6 μM; and wogonin, EC(50)=28.9 μM). Induction of apoptosis was caspase dependent, as it was blocked by the broad-spectrum caspase inhibitor Q-VD-OPh and was associated with both caspase-3 and caspase-9 activation. Flavone-induced apoptosis was preceded by down-regulation of the prosurvival protein Mcl-1, with proteasomal inhibition preventing flavone-induced Mcl-1 down-regulation and apoptosis. The flavones abrogated the survival effects of mediators that prolong neutrophil life span, including lipoteichoic acid, peptidoglycan, dexamethasone, and granulocyte-macrophage colony stimulating factor, by driving apoptosis. Furthermore, wogonin enhanced resolution of established neutrophilic inflammation in a zebrafish model of sterile tissue injury. Wogonin-induced resolution was dependent on apoptosis in vivo as it was blocked by caspase inhibition. Our data show that the flavones induce neutrophil apoptosis and have potential as neutrophil apoptosis-inducing anti-inflammatory, proresolution agents.—Lucas, C. D., Allen, K. C., Dorward, D. A., Hoodless, L. J., Melrose, L. A., Marwick, J. A., Tucker, C. S., Haslett, C., Duffin, R., Rossi, A. G. Flavones induce neutrophil apoptosis by down-regulation of Mcl-1 via a proteasomal-dependent pathway

Heavy Ion Carcinogenesis and Human Space Exploration

Prior to the human exploration of Mars or long duration stays on the Earth s moon, the risk of cancer and other diseases from space radiation must be accurately estimated and mitigated. Space radiation, comprised of energetic protons and heavy nuclei, has been show to produce distinct biological damage compared to radiation on Earth, leading to large uncertainties in the projection of cancer and other health risks, while obscuring evaluation of the effectiveness of possible countermeasures. Here, we describe how research in cancer radiobiology can support human missions to Mars and other planets

Reduced PU.1 expression causes myeloid progenitor expansion and increased leukemia penetrance in mice expressing PML-RARα

PU.1 is a member of the ETS family of transcription factors that is known to be important for hematopoietic development. Recently, haploinsufficiency for PU.1 has been shown to cause a shift in myelomonocytic progenitor fate toward the myeloid lineage. We have previously shown that transgenic mice expressing PML-RARα (PR) and RARα-PML frequently develop acute promyelocytic leukemia (APL) in association with a large (>20 Mb) interstitial deletion of chromosome 2 that includes PU.1. To directly assess the relevance of levels of expression of PU.1 for leukemia progression, we bred hCG-PR mice with PU.1(+/-) mice and assessed their phenotype. Young, nonleukemic hCG-PR × PU.1(+/-) mice developed splenomegaly because of the abnormal expansion of myeloid cells in their spleens. hCG-PR × PU.1(+/-) mice developed a typical APL syndrome after a long latent period, but the penetrance of disease was 84%, compared with 7% in hCG-PR × PU.1(+/+) mice (P < 0.0001). The residual PU.1 allele in hCG-PR × PU.1(+/-) APL cells was expressed, and complete exonic resequencing revealed no detectable mutations in nine of nine samples. However, PR expression in U937 myelomonocytic cells and primary murine myeloid bone marrow cells caused a reduction in PU.1 mRNA levels. Therefore, the loss of one copy of PU.1 through a deletional mechanism, plus down-regulation of the residual allele caused by PR expression, may synergize to expand the pool of myeloid progenitors that are susceptible to transformation, increasing the penetrance of APL

How Will the Hematopoietic System Deal with Space Radiation on the Way to Mars?

Traveling through deep space raises challenges to biological systems that have not been fully appreciated or addressed. In addition to the lack of gravity, the space environment includes exposure to charged remnants of supernova explosions beyond our solar system that travels with enormous velocities and energies, called HZE (high atomic number Z and energy E) particles and have the potential to disrupt chemical bonds within the human body though ionization. As a process, the collision of charged particles with matter is not new to physicists and biologists on Earth, and we have extensive data on low-linear energy transfer (LET) ionizing radiation from both accidental and deliberate exposures, dating back to the discovery of radioactive isotopes by Madame Curie. One of the primary morbidities associated with radiation exposure is the challenge to the hematopoietic system. The purpose of the current review is to discuss some of the basic tenants of hierarchical tissue systems by elaborating the effects of radiation damage to the hematopoietic stem cell and how terrestrial radiation and space radiation differ.The last few decades of research in the field of space radiation, which consists of high-LET ions of 4He, 12C, 16O, 28Si, 48Ti, and 56Fe, and low-LET protons, have shown that there is a significantly more deleterious impact on the hematopoietic system by the high-LET ions compared to protons, X-rays, and γ-rays. Ground-based high-LET radiation experiments have shown not only in vitro and in vivo adverse effects on hematopoietic stem cells, but also that human leukemia can be induced in humanized mouse models.High-LET space radiation is more lethal to hematopoietic stem cells compared to low-LET radiation, but further research is required in order to understand the impact of high-LET radiation on hematopoietic malignancies. Most of the ground-based studies, because of technical difficulties and cost issues, have been carried out at high dose rates with only one ion species at a time. What remains to be clearly described, however, is the potential damage to the hematopoietic system from exposure to the more complex types of radiation at low dose rates that will occur during space travel and how space agencies can sufficiently protect our astronauts