This paper is focused on the role of reactive oxygen species (ROS), nitric oxide (NO), and carbon monoxide (CO) in inflammatory bowel disease. ROS and NO production as well as the expression of inducible NO synthase (iNOS) appears to be enhanced in the intestinal mucosa with active inflammation. Treatment of superoxide dismutase (SOD) or the potent iNOS inhibitor, ONO-1714, ameliorated colonic mucosal injury and NO production in mice administered with dextran sulfate sodium (DSS) in mice. The expression of heme oxygenase (HO)-1 is markedly induced in inflamed colonic tissue, and co-administration with an HO inhibitor enhanced inflammation and the disease activity index in mice. These results suggest that gaseous mediators may play a role in regulating the inflammatory response in the intestinal mucosa.

View full abstract

Blood vessel formation consists of two processes, such as vasculogenesis and angiogenesis. A lot of ligandreceptor system, adhesion molecules, matrix generation and degradation system involves in these processes. Hematopoiesis and blood vessel formation are closely relating, because there are common progenitors termed hemangioblasts those can differentiate into hematopoietic cells and endothelial cells and endothelial cells can support hematopoiesis. Therefore, we have been trying to examine the interaction between hematopoietic cells and endothelial cells especially focusing on the function of hematopoietic cells in promoting angiogenesis. So far, we found that hematopoietic stem cells promote angiogenesis by producing angiopoietin-1, a ligand for TIE2 expressed on endothelial cells and neuropilin-1 expressed on various lineages of hematopoietic cells promotes proliferation of endothelial cells strongly. Moreover, other groups showed that macrophages and mast cells produce various kinds of pro-angiogenic cytokine, chemokine, and matrix metalloproteinase and regulate angiogenesis. Those function of hematopoietic cells are utilized physiologic and pathologic situation where angiogenesis is taking place and we recently found that hematopoietic cells regulate tumor angiogenesis very strongly. On the other hand, cell therapy for revascularization in ischemic region have performed using bone marrow cells. There might be contribution of endothelial progenitors for new vessel formation, however, we have to consider that hematopoietic cells in bone marrow regulate angiogenesis in such ischemic region.

View full abstract

Hearing and balance disorders are included in most common disabilities, and the majority is incurable because of the low capability for regeneration of the inner ear. New therapeutic approaches including cell transplantation are therefore subjected to overcome degenerative diseases of inner ears. Firstly, transplantation of neural stem cells (NSCs) into inner ears has been attempted as well as the retina. Grafted NSCs can survive and migrate into inner ear tissues including sensory epithelia after transplantation into inner ears of newborn rats. Histological analysis following transplantation of NSCs into injured, matured inner ears of mice demonstrates the potential of NSCs for replacement of inner ear hair cells or primary neurons. In vitro analysis also support the hypothesis that NSCs can differentiate into inner ear hair cells. In addition, NSC-derived cells have the potential for producing several neurotrophins in the inner ear, suggesting the potential of NSC transplantation for protection of inner ear tissues from degeneration.

View full abstract

Studies of chemokines and their cognate receptors have shed light on the detailed molecular mechanisms of leukocyte trafficking and activation in various inflammatory diseases including renal ones. Chemokine receptors expressed on renal resident cells might be involved in proliferation, proteinuria and fibrogenesis. Novel biological functions of chemokines would expand their universe beyond chemotaxis and activation of inflammatory cells in renal diseases. Importantly, MCP-1 and its cognate receptor CCR2 are now considered to contribute to progressive renal fibrosis, which is a hallmark of progressive renal diseases despite their etiologies, including diabetic nephropathy. The selective intervention of MCP-1-CCR2 via the administration of anti-MCP-1 neutralizing antibodies, CCR2 antagonists and the MCP-1 mutant ameliorated progressive renal fibrosis by resulting in decrease in the deposit of type I collagen and in reduced expression of TGF-β. This MCP-1-CCR2-dependent loop for progressive renal fibrosis was confirmed in CCR2 gene targeted mice. These findings suggest that the therapeutic strategy of blocking MCP-1-CCR2 may prove beneficial for progressive renal fibrosis.

View full abstract

Members of the TGF-β/BMP family such as BMP-4 and TGFβ-1,2 are involved in the control of hair follicle morphogenesis. This prompted us to explore the role of TGF-β/BMP family member activin and its antagonist follistatin in pelage hair follicle development. Here, we show that during hair follicle development, follistatin mRNA is prominently expressed by hair matrix and outer root sheath keratinocytes as well as by interfollicular epidermis, whereas activin βA-mRNA is mainly expressed in dermal papilla cells. Compared to age-matched wild-type controls, both follistatin knockout mice and activin βA transgenic mice show a significant retardation of hair follicle morphogenesis. Treatment of wild-type, embryonic skin explants with follistatin protein stimulates hair follicle development. This effect is inhibited by the addition of recombinant activinA protein. These observations suggest that follistatin and activin interaction plays an important role both in hair follicle development and may be exploited as a regenerative treatment for patients with alopecia.

View full abstract

Matrix metalloproteinase-9 has been suggested to play many roles in the inflammation including bullous disease, tumor invasion and metastasis, ultraviolet (UV) B-irradiated dermatosis, and dyskeratosis. We previously showed the upregulation of MMP-9 transcripts due to KRE-M9 element in the MMP-9 promoter in the differentiation of keratinocytes.
Recently, much attention has been paid to leptomycin B (LMB), a modulator for trafficking a variety of transcription-related proteins from nucleus to cytoplasm.
By the addition of LMB for kertinocytes in culture, MMP-9 secretions were reduced in comparison with MMP-2, even in the up-regulations of MMP-9 expression in high calcium or in the addition of transforming growth factor-β, both of which cause the differentiation of keratinocytes, and in the additions of tumor necrosis factor-α or interleukin-1α, inflammatory and apoptotic cytokines. In addition, KRE-M9 as well as other elements including 12-o-tetradecanoyl-o-phorbol-13-acetate responsive element was shown to be responsible for the reduced MMP-9 transcription by LMB.
Topical applications of LMB on the murine skin after UVB irradiation prevented the skin from the dyskeratosis and from the infiltrates of inflammatory cells.
These results indicate that the applications of LMB and of its derivatives could be a useful remedy for many pathological conditions in which MMP-9 are involved.

View full abstract