Biomedical subjects

F Furukawa

Publications and source records attributed to F Furukawa.

At least 145 records · Page 8Linked to original sources

PubMed1994

Effects of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) on N-nitrosobis(2-oxopropyl)amine (BOP)-initiated carcinogenesis in hamsters.

The effects of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) administration during the post-initiation phase of carcinogenesis were investigated in hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP). Female Syrian golden hamsters were given a single s.c. injection of BOP at a dose of 10 mg/kg and then administered 3 ppm (H) or 1 ppm (L) NNK in their drinking water for the following 87 weeks. Additional groups of animals received the BOP injection alone, or only the 3 or 1 ppm NNK treatments as BOP-negative controls. At week 88 of the experiment, all surviving animals were sacrificed and development of proliferative lesions was assessed histopathologically. The results showed no statistically significant influence on pancreatic adenocarcinomas or dysplastic lesions, although the incidence and the number of atypical hyperplasias in the pancreas head in the BOP/NNK (L) group was significantly increased as compared to BOP alone group values (P < 0.05). Similarly, the NNK treatments did not affect the incidences or multiplicities of neoplastic or hyperplastic lesions in the endocrine pancreas, lung, liver or kidney. Thus, the present experiment demonstrates that the tobacco-specific carcinogen NNK does not enhance BOP-induced hamster tumorigenesis when given in the promotion phase.

Animals↗

PubMed1994

Enhancing effects of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) on cell proliferation and lipid peroxidation in the rat gastric mucosa.

The influence of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone, a mutagen in chlorinated water, on cell proliferation and lipid peroxidation in the glandular stomach mucosa was investigated in male 4-week-old Wistar rats. Animals were given 50 p.p.m., 25 p.p.m., 12.5 p.p.m., 6.25 p.p.m. or 0 p.p.m. of MX solution in their drinking water for 5 weeks. At the end of this period, cell proliferation in the mucosal epithelia of the gastric fundus was increased in a dose-dependent manner up to 25 p.p.m., at which dose the induction was statistically significant as compared with the control value (P < 0.05). The MX treatment was also associated with increased lipid peroxidation levels in the gastric mucosa as well as in the urine, with loose dose-dependence, although not at 50 p.p.m. Mucosal lipid peroxidation was significantly increased in animals given 25 p.p.m. as compared with controls (P < 0.05). Similarly, the levels of urinary lipid peroxidation were significantly higher in rats given 25 p.p.m. or 12.5 p.p.m. than in the controls (P < 0.05). Histopathologically, gastric erosion was noted in rats receiving 25 p.p.m. or more of MX. There were no statistical differences between groups for serum biochemical data. The results thus suggest that MX may exert a gastric tumor-promoting action in rats, even at low doses which do not give rise to toxic effects, because of the clear dose-response relationship evident at low levels.

Animals↗

PubMed1994

Cell proliferation induced by laxatives and related compounds in the rat intestine.

Induction of cell proliferation by laxatives and related compounds in rat intestines was analysed by BrdU-labelling and compared with histopathological changes in the mucosa and findings for feces. Male F344 rats were fed a diet containing danthron, sennosid A, bisacodyl, 1-hydroxyanthraquinone (1-HAQ), magnesium sulfate (MgSO4), dextran sulfate sodium (DSS), pectin, carboxymethylcellulose sodium (CMC-Na) or sodium chloride (NaCl) for 7 days. The stimulant laxatives, danthron, sennosid A and bisacodyl, significantly induced cell proliferation in almost the entire intestinal epithelia in a clear dose-dependent manner. DSS also induced cell proliferation in some portions at high doses. Increase in BrdU-labelling indices was correlated well with the severity of inflammatory changes in the intestinal mucosa as well as with purging effects of stimulant laxatives and DSS. In contrast, the bulk-forming laxative CMC-Na did not consistently enhance cell proliferation nor cause apparent cytotoxicity in the intestine despite exerting remarkable purging effects. 1-HAQ and MgSO4 slightly induced cell proliferation in the cecum and the colorectum, although there was little or no intestinal cytotoxicity. Pectin and NaCl did not influence cell kinetics of the epithelia, nor cause any inflammatory changes in the mucosa. Our results thus indicate that diarrhea caused by laxatives is not necessarily correlated with induction of cell proliferation, as in the intestinal mucosa, and that inflammatory changes followed by regenerative process could be responsible for enhancing cell kinetics. Although the precise significance of cell proliferation in carcinogenesis remains unclear, it is crucial for setting doses of carcinogenicity testings that charges in cell kinetics caused by chemicals be taken into account.

Animals↗

PubMed1994

Analysis of proliferative activity in renal lesions induced by N-nitrosobis(2-oxopropyl)amine (BOP) in male Syrian golden hamsters.

Binding of a specific antibody to proliferating cell nuclear antigen (PCNA) and staining of argyrophilic proteins associated with nucleolar organizer regions (AgNORs) were investigated in proliferative lesions induced by N-nitrosobis(2-oxopropyl)amine (BOP) in the hamster kidney. Thirty male Syrian golden hamsters were given three weekly s.c. injections of BOP (10 mg/kg body wt.) and sacrificed for characterization of proliferative changes 30 weeks after the first BOP treatment. Morphologically, lesions of the tubular epithelia were classified either as tubular adenoma or dysplasia, the latter being further classified into small cluster, acidophilic cell, clear cell and cystic types. Immunohistochemistry for PCNA revealed significant increases of cell proliferation activity in adenomas and acidophilic cell types of dysplasia, along with significantly elevated mean numbers of AgNORs per nucleus. The results thus indicate that the acidophilic cell type of dysplasia may be of prime significance as the preneoplastic renal lesion induced by BOP.

Adenoma↗

PubMed1994

Keratinocyte differentiation is induced by cell-permeant ceramides and its proliferation is promoted by sphingosine.

Ceramide and sphingosine have been suggested to be intracellular modulators of cell growth and differentiation. The effects of these sphingolipids on the growth and differentiation of keratinocytes were examined using cultured human keratinocytes (the squamous cell carcinoma cell line, DJM-1). The synthetic short-chain cell-permeant analogues of ceramides, N-acetylsphingosine, N-hexanoylsphingosine and N-octanoylsphingosine, significantly promoted differentiation as confirmed by upregulation of cornified envelope formation, synthesis of involucrin and increased transglutaminase activity, and inhibited proliferation as shown by a reduction in cell numbers, DNA amount and thymidine incorporation. Generally, these activities were greater the longer the N-acyl carbon chain. On the other hand, sphingosine at an appropriate concentration modestly stimulated the proliferation of cultured cells. Our results suggest the possibility that the growth and differentiation of keratinocytes are at least partially regulated by ceramide and sphingosine.

Carcinoma, Squamous Cell↗

PubMed1994

Promoting effects of ethinyl estradiol on development of renal proliferative lesions induced by N-nitrosobis (2-oxopropyl)amine in female Syrian golden hamsters.

The modulating effects of female sex hormones, ethinylestradiol and levonorgestrel, on the development of renal proliferative lesions after initiation with N-nitrosobis(2-oxopropyl)amine (BOP) were investigated. Three groups of female Syrian golden hamsters, each comprising 30 animals, were given four weekly s.c. injections of BOP (10 mg/kg body weight) and then fed diet containing 1 ppm ethinylestradiol (group 1: BOP/EE), diet containing 10 ppm levonorgestrel (group 2) or basal diet (group 3) for the next 27 weeks. As hormone controls, two groups of 20 female hamsters each received diet containing 1 ppm ethynylestradiol (group 4) and 10 ppm levonorgestrel (group 5) from week 3 for 27 weeks without the prior initiation treatment. The severity of diffuse anisokarya, characterized by varied nuclear size and the incidence of dysplasias of the proximal tubular epithelia induced by BOP, were significantly increased in the BOP/EE group, indicating the promoting effects of the hormone. In the renal dysplastic lesions (small-cluster, cystic, clear-cell and acidophilic cell types), adenomas and nephroblastomas, increases in the numbers of argyrophilic proteins associated with nucleolar organizer regions (NOR) in the nucleus, suggesting a high proliferative activity, were seen in dysplasia of acidophilic cell types and adenomas. In addition, the number of bizarre NOR per nucleus was significantly higher in adenomas than in dysplasias and highest in nephroblastomas. This morphological change in NOR should therefore be a useful parameter for the diagnosis of malignancy of renal tumors.

Adenoma↗

PubMed1994

High calcium induces heat shock proteins 72 and 60 in cultured human keratinocytes: comparative study with heat shock and sunlamp light irradiation.

Expression/induction of the 72 and 60 kDa heat shock proteins (HSPS 72 and 60) in cultured human keratinocytes by high calcium was studied with immunofluorescent staining and the flow cytometric method. Normal human keratinocytes cultured in serum free, low calcium medium (Ca2+, 0.1 mM) at 3-passage weakly expressed HSP 60, but not HSP 72, as fine granules in the cytoplasm. HSP 72 was induced in the perinuclear cytosomal area and then in the nucleus after transferring the cells in high calcium medium (Ca2+, 1.8 mM). Whereas the nuclear accumulation began to decrease 24 h after the treatment, the perinuclear cytosomal staining continued. High calcium also augmented the expression of HSP 60 as coarse granules in the cytoplasm. Flow cytometric analyses quantitatively revealed the induction of HSP 72 and the upregulation of HSP 60 by high calcium treatment. Our results clearly demonstrated that extracellular calcium concentration modifies the level of expression of HSP 72 and 60 in normal human keratinocytes, indicating the importance of the careful attention to medium condition in evaluating the expression of HSPS 72 and 60 in cultured keratinocytes.

Calcium↗

PubMed1994

Soluble intercellular adhesion molecule-1 (sICAM-1) in atopic dermatitis.

The serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) were determined by enzyme-linked immunosorbent assay, in 88 patients with atopic dermatitis (AD), 29 patients with eczematous dermatitis (ED) and in 33 healthy controls. The sICAM-1 levels were significantly higher in both AD and ED patients than in normal individuals. The longitudinal study of patients with AD revealed a significant decrease in the levels of sICAM-1 (P < 0.05) with improvements in disease activity. In AD patients, the sICAM-1 level correlated significantly with the total numbers of leukocytes and lymphocytes (P < 0.01 and P < 0.05, respectively), whereas no such correlation was found in patients with ED. Our studies show that the levels of sICAM-1 may be a useful immunologic parameter for monitoring disease activity in some of the individuals with AD.

Dermatitis, Atopic↗

PubMed1994

Elevated serum levels of IgE-binding factor/soluble CD23 in bullous pemphigoid.

IgE-related abnormalities and impaired B cell function have been reported in patients with bullous pemphigoid (BP). CD23 is a low affinity Fc epsilon RII on haematopoietic cells and its soluble form (sCD23) is involved in B cell growth and differentiation. In order to determine the role of CD23 in the pathomechanisms of BP, the present study assayed the level of sCD23 in sera of BP patients using an ELISA method. Levels of sCD23 were elevated in BP patients compared with mean levels in the sera of normal control. Furthermore, the increase in sCD23 levels correlated with the degree of disease activity. A significant correlation was found between sCD23 and serum IgE levels in BP sera, but not in normal control sera. These results suggest that sCD23 is an important index for monitoring BP with respect to IgE-related abnormalities and impaired B cell function.

Animals↗

PubMed1994

Dose-dependent promoting effects of sodium chloride (NaCl) on rat glandular stomach carcinogenesis initiated with N-methyl-N'-nitro-N-nitrosoguanidine.

The influence of different doses of sodium chloride (NaCl) on glandular stomach carcinogenesis was examined in male outbred Wistar rats after initiation with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Rats were given 100 p.p.m. MNNG in their drinking water for 8 weeks and then fed a diet supplemented with NaCl at doses of 10, 5, 2.5 or 0% for the next 82 weeks. The administration of 10% and 5% NaCl significantly enhanced the development of gastric adenocarcinomas and adenomas in a dose-dependent manner. Similar but non-significant tendencies for increase were also seen in the group given 2.5% NaCl compared to the MNNG-alone group values. Clear linear correlations between incidences of adenocarcinomas and/or adenomas and the concentration of supplemented NaCl were found. Mesenchymal tumors were also induced in the stomach of rats given MNNG, although the incidence was not statistically different between groups. Independent of the MNNG treatment, urinary lipid peroxidation levels were significantly increased in the NaCl-treated groups as compared to the control values. Thus, the results in the present study indicate that NaCl exerts dose-dependent tumor promoting activity on gastric carcinogenesis in rats, even at doses as low as 2.5%, when given after MNNG initiation.

Adenocarcinoma↗

PubMed1994

Blocking effects of synthetic trypsin inhibitor (camostat) on pancreatic carcinogenesis in hamsters initiated with N-nitrosobis(2-oxopropyl)amine.

The effects of concomitant administration of a synthetic trypsin inhibitor (camostat) on pancreatic carcinogenesis in hamsters treated with N-nitrosobis(2-oxopropyl)amine (BOP) were investigated. Thirty-two female Syrian golden hamsters were given weekly 10 mg/kg s.c. injections of BOP for 5 weeks while simultaneously receiving a 500 ppm camostat diet (BOP + camostat group). Additional groups of 30 animals received either the s.c. injections of BOP (BOP group), or the 500 ppm camostat diet (camostat group) during the same 5-week period. Thirty weeks after the first BOP administration, the incidence of pancreatic adenocarcinomas in the BOP + camostat group was significantly lower than in the group administered BOP only (p < 0.05). Similarly, the total numbers of pancreatic adenocarcinomas or dysplastic lesions were significantly decreased in the BOP + camostat group as compared with the BOP group (p < 0.01). None of the animals receiving camostat alone developed any adenocarcinomas or dysplastic lesions of the pancreas. The results of the present experiments clearly show that camostat can inhibit induction of hamster pancreatic ductal neoplasms when administered simultaneously with BOP.

Adenocarcinoma↗

PubMed1994

Correlation between nucleolar organizer regions and cell proliferation in pancreatic acinar cell proliferative lesions in rats.

The numbers of nucleolar organizer regions (NORs) stained by the one-step silver (Ag) colloid method were measured in rat pancreatic basophilic foci, eosinophilic foci, and acinar cell adenomas induced by 4-hydroxyaminoquinoline 1-oxide (HAQO) followed by crude soybean trypsin inhibitor (SBTI) treatments and compared with values for bromodeoxyuridine (BrdU)-incorporating cells and nuclear DNA contents. Both numbers of AgNORs and BrdU-labeling indices showed stepwise increases from normal pancreatic acinar cells through eosinophilic foci to adenomas, and a good correlation was found between cell proliferation and mean numbers of AgNORs. Microspectrometry of nuclear DNA contents revealed a wide range of values in basophilic and eosinophilic foci and acinar cell adenomas as compared with normal acinar cells, but there was no significant difference in the profile of DNA content among these three proliferative lesions. The present results suggest that mean numbers of AgNORs may reflect cellular kinetics in rat pancreatic acinar cell lesions.

4-Hydroxyaminoquinoline-1-oxide↗

PubMed1994

Epitope mapping for epidermolysis bullosa acquisita autoantibody by molecularly cloned cDNA for type VII collagen.

Epidermolysis bullosa acquisita is a subepidermal blistering disease in which patients have autoantibodies against the non-collagenous domain of type VII collagen. Starting with previously isolated 1-kilobase pair (Kb) cDNA for this autoantigen, we isolated overlapping cDNAs with a combined open reading frame of approximately 3.2 Kb, encoding most (approximately 115 kilodaltons [KDa]) of the N-terminal non-collagenous domain of type VII collagen. To localize immunogenic domains, we produced maltose-binding fusion proteins with cDNA encoding different portions of this autoantigen. These cDNA fragments scan from 5' to 3' of this non-collagenous domain and overlap each other. An immunoblot analysis of these fusion proteins with eight epidermolysis bullosa acquisita patient sera demonstrated that each patient serum binds to different regions of this molecule and that epitopes for these patient sera locate throughout this autoantigen. These data suggest that multiple epitopes on the N-terminal non-collagenous domain of type VII collagen are recognized by circulating autoantibodies in patients with epidermolysis bullosa acquisita.

Autoantibodies↗

PubMed1994

Cadherins in cutaneous biology.

The role of cadherins in cutaneous biology has focused mainly on the classical cadherins, E- and P-cadherin. In this review, roles for cadherins in skin morphogenesis, keratinocyte differentiation, and cancer metastasis are discussed. E-cadherin is expressed on the surfaces of whole epidermal layer cells, and P-cadherin is expressed only on the surfaces of basal cells. Ultrastructural studies have shown that E-cadherin is distributed on the cytoplasmic membranes of keratinocytes with a condensation in the intercellular space of the desmosomes. During human skin development, P-cadherin expression is spatiotemporally controlled and closely related to the segregation of basal layers as well as to the arrangement of epidermal cells into eccrine ducts. In human skin diseases, E-cadherin expression is markedly reduced on the acantholytic cells of tissues in pemphigus and also in Darier's disease. Keratinocytes cultured in high calcium produce a much more intense immunofluorescence of intercellular E- and P-cadherin than do cells grown in low calcium. Ultrastructural studies show that E-cadherin on the cytoplasmic membrane of the keratinocytes is shifted to desmosomes under physiological conditions and therein expresses an adhesion function is association with other desmosomal cadherins. Cell adhesion molecules are now considered to play significant roles in the cellular connections of cancers and metastatic cells. Reduced expression of E-cadherin on invasive neoplastic cells has been demonstrated for cancers of the stomach, liver, breast, and several other organs. This reduced expression of E-cadherin is observed in squamous cell carcinoma and Paget's disease. Soluble E-cadherins in sera are elevated in various skin diseases, including bullous pemphigoid, pemphigus vulgaris and psoriasis, but not in patients with burns. Markedly high levels in soluble E-cadherin are demonstrated in patients with metastatic cancers.

Cadherins↗

PubMed1994

Evaluation of the Japanese-Chinese herbal medicine, kampo, for the treatment of lupus dermatoses in autoimmune prone MRL/Mp-lpr/lpr mice.

Kampo, a Japanese-Chinese traditional herbal medicine, has been used for the treatment of various diseases for about 3,000 years in China. Among herbal medicines, Sairei-to is well known for improving the symptoms of rheumatoid arthritis (RA) and other collagen diseases. However, its immunosuppressive effects on autoimmune cutaneous phenomena are not completely understood. We investigated the effects of Sairei-to on the development of lupus dermatoses in autoimmune-prone MRL/Mp-lpr/lpr (MRL/lpr) mice, an animal model which spontaneously develops skin lesions similar to those seen in human lupus erythematosus. Virgin female MRL/lpr mice at 1 month of age, which were treated orally with Sairei-to, had reduced amounts of IgG deposition at the dermoepidermal junction, titers of anti-DNA antibodies and rheumatoid factor, and lymphoproliferation. These results support the use of traditional herbal medicines in patients with human RA and systemic lupus erythematosus.

Animals↗

PubMed1994

Effects of cigarette smoke on N-nitrosobis(2-oxopropyl)amine-induced pancreatic and respiratory tumorigenesis in hamsters.

Influences of cigarette smoke on N-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic duct and respiratory tract tumorigenesis were investigated using a hamster two-stage carcinogenesis model. Male 5-week-old hamsters were divided into 5 groups. Group 1 was s.c. injected with BOP at a dose of 10 mg/kg once a week for 3 weeks as an initiation treatment together with cigarette smoke exposure over the same 4-week period. Group 2 was exposed to cigarette smoke for 26 weeks after the BOP-initiation. Groups 3 and 4 were respectively given the BOP-initiation alone and the 26-week cigarette smoke exposure without initiation. Group 5 served as a sham-smoked negative control. The experiment was terminated 30 weeks after the first BOP injection. The incidence of pancreatic adenocarcinomas was significantly decreased in Group 1 as compared to the Group 3 value (P < 0.01) while the Group 2 value did not show any change. In contrast, the incidence of laryngeal and tracheal proliferative lesions (hyperplasias and papillomas) was significantly increased in Group 2 over Group 3 (P < 0.01). The incidence of pulmonary hyperplasias was also increased in Group 2 over Group 3 (P < 0.05), although that of pulmonary adenomas or adenocarcinomas was decreased in Group 2 as compared to the Group 3 value (P < 0.01). Cigarette smoke exposure in the BOP-initiation phase (Group 1) did not affect the development of respiratory proliferative lesions. No animals in Groups 4 and 5 developed any tumors in the pancreas or respiratory tract. Our results thus indicate that cigarette smoke exposure inhibits pancreatic carcinogenesis when given in the initiation phase, whereas it modulates (enhances or suppresses) the development of proliferative lesions in the respiratory tract if applied during the promotion stage to hamsters pretreated with BOP.

Animals↗

PubMed1994

The epitope for anti-type VII collagen monoclonal antibody (LH7:2) locates at the central region of the N-terminal non-collagenous domain of type VII collagen.

The monoclonal antibody LH7:2, which recognizes type VII collagen, is now used in the diagnosis and prenatal diagnosis of epidermolysis bullosa dystrophica. We constructed the expression vector which contains the cDNA fragment of type VII collagen. Western blot with LH7:2 was carried out with the resultant fusion proteins which overlap each other, and we found that reactivity is located in the central region of the N-terminal non-collagenous domain of type VII collagen, at a position 81 kDa upstream from the collagenous domain. This epitope mapping for LH7:2 may be useful in studying the role of type VII collagen in epidermolysis bullosa dystrophica.

Antibodies, Monoclonal↗

PubMed1994

Accessory cell ability of Langerhans cells for superantigen is resistant to ultraviolet-B light.

We examined the effects of ultraviolet-B (UVB) irradiation on the accessory cell ability of Langerhans cells (LC) to induce a T-cell response to a superantigen, staphylococcal enterotoxin B (SEB). The ability of LC-enriched epidermal cells (LC-EC) to evoke a T-cell response to SEB was retained at the doses of UVB (up to 40 mJ/cm2) that profoundly affected the antigen-presenting function of LC-EC for a hapten, trinitrophenyl (TNP), and a protein antigen, conalbumin. Thus, the LC accessory function for superantigens is more resistant to UVB irradiation than that for ordinary antigens. This UVB resistance is presumably due to no requirement of antigen processing for superantigens as chemically fixed or chloroquine-treated LC-EC still retained their ability to induce T-cell responses to SEB. Higher doses of UVB (more than 60 mJ/cm2) reduced the accessory cell ability of LC-EC for SEB up to 50% of control. The addition of monoclonal antibodies against adhesion molecules between LC and T cells to the culture resulted in a substantial suppression of the T-cell response to SEB induced by nonirradiated LC-EC, while the UVB-irradiated LC-EC-induced T-cell response was not significantly blocked with these monoclonal antibodies. This suggested that the reduction of LC ability for superantigen by high doses of UVB is at least partly due to the impairment of adhesion molecules on LC by UVB irradiation.

Animals↗