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Papers by Kazuhiko Okumura

Japanese Journal of Oral & Maxillofacial Surgery, 1990

Japanese Journal of Oral and Maxillofacial Surgery, 1990

Diabetic patients often have ulcers on their lower-limbs that are infected by multiple biofilmfor... more Diabetic patients often have ulcers on their lower-limbs that are infected by multiple biofilmforming genera of bacteria, and the elimination of the biofilm has proven highly successful in resolving such wounds in patients.To that end, antimicrobial peptides have shown potential as a new anti-biofilm approach.The single human cathelicidin peptide LL-37 has been shown to have antimicrobial and anti-biofilm activity against multiple Gram-positive and Gramnegative human pathogens, and have wound-healing effects on the host. The combination of the anti-biofilm effect and wound-healing properties of LL-37 may make it highly effective in resolving polymicrobially infected wounds when topically applied. Such a peptide or its derivatives could be a platform from which to develop new therapeutic strategies to treat biofilm-mediated infections of wounds. This review summarizes known mechanisms that regulate the endogenous levels of LL-37 and discusses the anti-biofilm, antibacterial, and immunological effects of deficient vs. excessive concentrations of LL-37 within the wound environment. Here, we review recent advances in understanding the therapeutic potential of this peptide and other clinically advanced peptides as a potential topical treatment for polymicrobial infected wounds.

Journal of Oral Biosciences, 2005

ABSTRACT

Journal of Radiation Research, 2005

We investigated the role of the caspase activation cascade in apoptosis induced by ionizing radia... more We investigated the role of the caspase activation cascade in apoptosis induced by ionizing radiation or hydrogen peroxide (H(2)O(2)) in human leukemia HL60 cells. Electron paramagnetic resonance (EPR) spectra revealed that hydroxyl and hydrogen radicals were generated in the culture medium after exposure to radiation or H(2)O(2). Initial accumulation of DNA fragments at 2 h after exposure was delayed in irradiated cells compared with H(2)O(2)-treated cells, although formation of abasic sites immediately after exposure was significantly higher in irradiated cells and similar quantities of hydroxyl radicals were produced under both conditions. Activity assay of caspases revealed that caspase-3, -8 and -9 were activated 2 h after exposure to H(2)O(2), whereas in irradiated cells caspase-3 and -9 activation occurred 4 h after exposure but increased caspase-8 activation was not observed. Release of cytochrome c into cytosol was seen at 2 h after radiation and H(2)O(2) treatment. Radiation did not affect proapoptotic proteins (Bax and Bid), whereas H (2)O(2) increased accumulation of Bax in the mitochondrial membrane 2 h to 6 h after treatment, independently of the truncation of Bid by activated caspase-8. Moreover, treatment with the caspase-8 inhibitor Z-IETD-FMK increased cell survival and prevented accumulation of DNA fragments in H(2)O(2)-treated cells, but not in irradiated cells. These results suggest that, unlike the caspase cascade of H(2)O(2)-induced apoptosis, cytochrome c and caspase-9 are important for the intrinsic pathway of radiation-induced apoptosis, independent of caspase-8.

Journal of Radiation Research, 2007

We examined effects of local and whole body irradiation before tooth extraction on appearance and... more We examined effects of local and whole body irradiation before tooth extraction on appearance and differentiation of osteoclasts in the alveolar bone of rat maxillary first molars. Wistar rats weighting 100 g were divided into three groups: non-irradiation group, local irradiation group, and whole body irradiation group. In the local irradiation group, a field made with lead blocks was placed over the maxillary left first molar tooth. In the whole body irradiation group, the animals were irradiated in cages. Both groups were irradiated at 8 Gy. The number of osteoclasts around the interradicular alveolar bone showed chronological changes common to non-irradiated and irradiated animals. Several osteoclasts appeared one day after tooth extraction, and the maximal peak was observed 3 days after extraction. Local irradiation had no difference from non-irradiated controls. In animals receiving whole body irradiation, tooth extraction one day after irradiation caused smaller number of osteoclasts than that 7 day after irradiation during the experimental period. Whole body-irradiated rats had small osteoclasts with only a few nuclei and narrow resorption lacunae, indicating deficiency of radioresistant osteoclast precursor cells. Injection of intact bone marrow cells to whole body-irradiated animals immediately after tooth extraction recovered to some content the number of osteoclasts. These findings suggest that bone resorption in the wound healing of alveolar socket requires radioresistant, postmitotic osteoclast precursor cells from hematopoietic organs, but not from local sources around the alveolar socket, at the initial phase of wound healing.

Japanese Journal of Pharmacology, 1989

Journal of Cancer Research and Clinical Oncology, 1996

Distant-organ metastasis and regional lymph node metastasis are still the major cause of mortalit... more Distant-organ metastasis and regional lymph node metastasis are still the major cause of mortality of oral-cavity squamous-cell cancer (SCC). However, only a few studies have been undertaken to elucidate the mechanism of invasion and metastasis of oral SCC. In this study, we attempted to establish human oral SCC clones with different invasiveness, defined by endothelial cell monolayer assay, which can be used for the study of invasion and metastasis of oral SCC. We established five clones from the human oral SCC cell line SAS by a limiting-dilution method. Two distinct clones, SAS-L1 with very low invasive potential and SAS-H1 with very high invasive potential, were picked out by rat lung endothelial cell monolayer assay. The number of SAS-H1 that penetrated the rat lung endothelial cell monolayer was six fold higher than the number of SAS-L1. There were no differences of metalloproteinase production and cell adhesiveness to Matrigel of SAS-L1 and SAS-H1. However, SAS-H1 exhibited a higher migration ability than SAS-L1. This pair of clones would be a useful experimental model to help in the study of the invasiveness of human oral SCC.

Cancer Letters, 2004

Mammalian myeloid and epithelial cells express many antimicrobiotic peptides that contribute to i... more Mammalian myeloid and epithelial cells express many antimicrobiotic peptides that contribute to innate host defense against invading microbes. In the present study, a 27-mer peptide of the C-terminal domain (hCAP18(109-135)) and analogs of the antimicrobial peptide human cathelicidin LL-37/human cationic antimicrobial protein 18 (hCAP18) were examined for tumoricidal activity. In vitro results showed that hCAP18(109-135) induced apoptosis in human oral squamous cell carcinoma (OSCC), SAS-H1 cells. The hCAP18(109-135) induced mitochondrial depolarization and apoptosis in SAS-H1 cells, but not in healthy human gingival fibroblasts (HGF) and human keratinocyte line HaCaT cells. Caspases were not activated during hCAP18(109-135)-induced apoptosis in SAS-H1 cells. The results indicate that hCAP18(109-135) may induce caspase-independent apoptosis in OSCC but not in normal cells. hCAP18(109-135) can therefore be a useful anti-tumor therapeutic agent in the treatment of OSCC.

Tumor Biology, 1996

In order to ascertain the effects of epidermal growth factor (EGF) on human cancer invasion abili... more In order to ascertain the effects of epidermal growth factor (EGF) on human cancer invasion abilities, three cell lines of human oral squamous cell carcinoma were studied using a phagokinetic track assay and zymography. EGF (1-100 ng/ml) was found to inhibit the growth but enhance the random motility of all three cell lines in a concentration-dependent fashion. Exposure to EGF, dose-dependently, led to an increased production of urokinase-type plasminogen activator and M(r) 92 kD matrix metalloproteinase by the same cells. These results strongly suggest that EGF may promote human squamous cell carcinoma invasion and metastasis.

Pathology International, 1998

Two cases of basalold-squamous cell carcinoma (BSC) of the oral mucosa are described. The first c... more Two cases of basalold-squamous cell carcinoma (BSC) of the oral mucosa are described. The first case occurred at the floor of the mouth in a 58-year-old man, and the second case occurred at the mandibular gingiva in a 79-year-old woman. The laboratory data of the first case showed a positive response to hepatitis C virus antibody. in the first case, the tumor mass measured 4 times 4 cm in size, and was i-texl at the lingual side of the median mandible beside the sublingual gland. In the second case, the tumor mass measured 25 times 15 mm In size, and was located in the alveolar mucosa of the right mandible. Histologically, both tumors showed a neoplastic epithelium arranged in a solid pattern with evidence of peripheral palisading, central necrosis, and some squamous differentiation. The pro-ilferathfe activities of the BSC were compared with conventional squamous cell carcinomas (SCC) in the oral floor and gingiva, respectively, by employing a sensitive argy-rophillc nuclear organizer region (AgNOR) staining method. The number of AgNOR per nucleus of the BSC was higher than that of any other SCC cases. The results support the opinion that BSC of the oral mucosa has a worse prognosis than conventional SCC.

Archives of Oral Biology, 2003

Chemokines are a large superfamily of chemotactic cytokines involved in a variety of immunoregula... more Chemokines are a large superfamily of chemotactic cytokines involved in a variety of immunoregulatory and proinflammatory responses. MIP-3a, also called the liver-and activation-regulated chemokine (LARC) 1 or EXODUS 2 and recently listed as CCL20 in the systematic classification of chemokine ligands, 3 is a member of the CC chemokine subfamily. Initially, MIP-3a was noted to be expressed in human liver, lung, appendix, and tonsillar crypts. 1,2,4 Recently, MIP-3a has been detected in skin epidermal cells, suggesting that the epidermis may produce MIP-3a. The skin contains a population Archives of Oral Biology (2003) 48, 171-175 KEYWORDS MIP-3a/LARC/EXODUS/ CCL20; Squamous cell carcinoma; Quantitative RT-PCR; Bacterial infection; Cytokine