Intravital imaging of neutrophil recruitment in intestinal ischemia-reperfusion injury

Background

Neutrophils are known to be key players in innate immunity. Activated neutrophils induce local inflammation, which results in pathophysiologic changes during intestinal ischemia-reperfusion injury (IRI). However, most studies have been based on static assessments, and few have examined real-time intravital neutrophil recruitment. We herein report a method for imaging and evaluating dynamic changes in the neutrophil recruitment in intestinal IRI using two-photon laser scanning microscopy (TPLSM).

Sulfated Purine Alkaloid Glycosides from the Pupal Case Built by the Bruchid Beetle Bruchidius dorsalis Inside the Seed of Gleditsia japonica

Three new sulfated isoguanine alkaloid glycosides, designated as saikachinoside A monosulfate ( 1 ), saikachinoside A disulfate ( 2 ), and locustoside B disulfate ( 3 ), have been isolated from the pupal case of the wild bruchid seed beetle Bruchidius dorsalis (Chrysomelidae, Bruchinae) infesting the seed of Gleditsia japonica Miq . (Fabaceae). Their structures were determined by spectroscopic methods and the inhibitory activity of 2 and 3 against acid phosphatase was evaluated.     

Prostaglandin E2 aggravates gastric mucosal injury induced by histamine in rats through EP1 receptors

We demonstrated that prostaglandin (PG) E2 aggravates gastric mucosal injury caused by histamine in rats, and investigated using various EP agonists which EP receptor subtype is involved in this phenomenon. Rats were used after 18 hr fasting. Histamine (80 mg/kg) dissolved in 10% gelatin, was given s.c., either alone or in combination with i.v. administration of PGE2 or various EP agonists such as 17-phenyl PGE2 (EP1), butaprost (EP2), sulprostone (EP1/EP3), ONO-NT012 (EP3) and ONO-AE1-329 (EP4). The animals were killed 4 hr later, and the mucosa was examined for lesions. The mucosal permeability was determined using Evans blue (1%). Histamine alone induced few lesions in the gastric mucosa within 4 hr. PGE2 dose-dependently worsened the lesions induced by histamine, the response being inhibited by tripelennamine but not cimetidine. The effect of PGE2 was mimicked by 17-phenyl PGE2 and sulprostone, but not other EP agonists, including EP2, EP3, and EP3/EP4 agonists. The mucosal vascular permeability was slightly increased by histamine, and this response was markedly enhanced by co-administration of 17-phenyl PGE2 as well as PGE2. The mucosal ulcerogenic and vascular permeability responses induced by histamine plus PGE2 were both suppressed by pretreatment with ONO-AE829, the EP1 antagonist. These results suggest that PGE2 aggravates histamine-induced gastric mucosal injury in rats. This action of PGE2 is mediated by EP1 receptors and functionally associated with potentiation of the increased vascular permeability caused by histamine through stimulation of H1-receptors.     

Synthesis and biological activities of 1-pyridylisoquinoline and 1-pyridyldihydroisoquinoline derivatives as PDE4 inhibitors

A novel series of 1-pyridylisoquinoline and 1-pyridyldihydroisoquinoline derivatives has been prepared. These compounds showed potent PDE4 inhibitory activities and a broad margin between the K(i) value of the rolipram binding affinity and the IC(50) value of PDE4 inhibition. They also exhibited potent inhibitory activities toward LPS-induced TNF-alpha production in mice.     

Antagonistic indirect interactions between large and small conspecific prey via a heterospecific predator

Intrapopulation size variation strongly influences ecological interactions because individuals belonging to different size groups have distinct functions. Most demonstrations of the impacts of size variation in trophic systems have focused on size variation in predator species, and the consequences of size variation in prey species are less well understood. We investigated how prey size structure shapes intra‐ and interspecific interactions in experiments with a gape‐limited predator (larvae of the salamander Hynobius retardatus) and its heterospecific prey (frog tadpoles, Rana pirica). We found that large and small tadpole size groups each increased mortality in the other group by intensifying salamander predation; this type of indirect interactions is called apparent competition. The antagonistic impacts on the prey size groups were caused by different size‐specific mechanisms. By consuming small tadpoles, the salamanders grew large enough to consume large tadpoles. The activity of large tadpoles, by increasing the activity of the small tadpoles, may increase the number of encounters with the predator and thus small tadpole mortality. These results suggest that the magnitude of a predator's ecological role, such as whether a top–down trophic cascade is initiated, depends on size variation in its heterospecific prey.     

Histological Characterization of the Tumorigenic “Peri-Necrotic Niche” Harboring Quiescent Stem-Like Tumor Cells in Glioblastoma

Background

Characterization of the niches for stem-like tumor cells is important to understand and control the behavior of glioblastomas. Cell-cycle quiescence might be a common mechanism underlying the long-term maintenance of stem-cell function in normal and neoplastic stem cells, and our previous study demonstrated that quiescence induced by hypoxia-inducible factor (HIF)-1α is associated with a high long-term repopulation capacity of hematopoietic stem cells. Based on this, we examined human astrocytoma tissues for HIF-1α-regulated quiescent stem-like tumor cells as a candidate for long-term tumorigenic cells and characterized their niche histologically.

Methods

Multi-color immunohistochemistry was used to visualize HIF-1α-expressing (HIF-1α⁺) quiescent stem-like tumor cells and their niche in astrocytoma (WHO grade II–IV) tissues. This niche was modeled using spheroids of cultured glioblastoma cells and its contribution to tumorigenicity was evaluated by sphere formation assay.

Results

A small subpopulation of HIF-1α⁺ quiescent stem-like tumor cells was found in glioblastomas but not in lower-grade astrocytomas. These cells were concentrated in the zone between large ischemic necroses and blood vessels and were closer to the necrotic tissues than to the blood vessels, which suggested that a moderately hypoxic microenvironment is their niche. We successfully modeled this niche containing cells of HIF-1α⁺ quiescent stem-like phenotype by incubating glioblastoma cell spheroids under an appropriately hypoxic condition, and the emergence of HIF-1α⁺ quiescent stem-like cells was shown to be associated with an enhanced sphere-forming activity.

Conclusions

These data suggest that the “peri-necrotic niche” harboring HIF-1α⁺ quiescent stem-like cells confers a higher tumorigenic potential on glioblastoma cells and therefore may be a therapeutic target to control the behavior of glioblastomas.