A case of generalized hair follicle hamartoma associated with diffuse sclerosis of the face.
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Aged↗
Biomedical subjects
M Ichihashi
Publications and source records attributed to M Ichihashi.
Regulation of melanogenesis through phosphatidylinositol 3-kinase-Akt pathway in human G361 melanoma cells.
The involvement of the phosphatidylinositol 3-kinase pathway in the regulation of melanogenesis was examined using human G361 melanoma cells. In the cells treated with wortmannin, a potent inhibitor of phosphatidylinositol 3-kinase, the melanin content increased concomitant with the elevated protein level of tyrosinase, a key enzyme in melanogenesis. Northern blot analysis revealed that the mRNA level of tyrosinase increased transiently on treatment of the cells with the phosphatidylinositol 3-kinase inhibitor. When the cells were infected with the adenovirus vector encoding the mutant adapter subunit of phosphatidylinositol 3-kinase, which acts as a dominant negative of phosphatidylinositol 3-kinase, both the melanin content and the expression of tyrosinase increased. In cells infected with the adenovirus vector encoding the constitutively active mutant of the lipid kinase, a decrease in melanin content as well as reduced expression of tyrosinase was observed. In cells expressing the constitutively active mutant of the serine-threonine protein kinase Akt, one of the downstream targets of phosphatidylinositol 3-kinase, the melanin content decreased as in the cells overproducing the constitutively active mutant of phosphatidylinositol 3-kinase. These results indicate that phosphatidylinositol 3-kinase regulates melanogenesis by modulating the expression of tyrosinase, and that activation of Akt is sufficient for suppression of melanin production in G361 melanoma cells.
Androstadienes↗
Elimination of CD4(+) T cells enhances anti-tumor effect of locally secreted interleukin-12 on B16 mouse melanoma and induces vitiligo-like coat color alteration.
CD4(+) T cells have been reported to suppress immunity against cancer in certain animal models. In this study, we investigated the role of CD4(+) T cells in the anti-tumor immune response when interleukin-12-producing melanoma cells are inoculated in mice. We found that interleukin-12-transfected B16 melanoma showed retarded tumor growth in syngeneic mice; however, all the mice developed tumors eventually. In vivo depletion of CD4(+) T cells led to complete regression of B16/interleukin-12 tumors in 12 of 20 mice (60%). Immunohistochemical analyses revealed that a number of CD8(+) T cells accumulated in close proximity to the B16/interleukin-12 tumors in the CD4(+) T cell-depleted mice, whereas CD8(+) T cells were only scarcely observed at the periphery of the tumors in control immunocompetent mice. Furthermore, 10 of 20 mice treated with both B16/interleukin-12 inoculation and CD4(+) T cell depletion exhibited vitiligo-like coat color alteration. B16/interleukin-12 tumors completely regressed in all the mice with vitiligo. Histologic examination showed that CD8(+) lymphocytes accumulated around the hair bulbs of mice with vitiligo, but not in those without vitiligo. These results suggest that CD4(+) T cells have an inhibitory effect on tumor rejection by suppressing cytotoxic CD8(+) T cells in this melanoma loading model with local interleukin-12 secretion. To investigate the mechanism of enhanced anti-tumor effects by CD4(+) T cell depletion, we examined the T helper type 1/2 cytokine profile in the tumor draining lymph nodes of B16/interleukin-12-bearing mice with or without CD4(+) T cell depletion using the reverse transcription-polymerase chain reaction method. We found that CD4(+) T cell depletion eliminated T helper type 2 cells and resulted in a T helper type 1-dominant cytokine profile in tumor draining lymph nodes. We emphasize that this T helper type 1-dominant cytokine profile may generate further activated CD8(+) T cells against B16 melanoma cells, lead B16/interleukin-12 to regress, and result in the destruction of the melanocytes in hair bulbs due to cross-antigenicity between both cell types. This mouse model not only demonstrates the depletion of CD4(+) T cells as a useful strategy for cancer gene therapy with interleukin-12 but also provides a model for human melanoma-associated vitiligo.J Invest Dermatol 115:1059-1064 2000
Animals↗
Mercury-induced nummular dermatitis.
We report 2 cases of relapsing nummular dermatitis according to mercury sensitivity, which was confirmed by patch testing. Removal of the amalgam from dental metal alloys markedly improved their skin eruptions. One of the patients, a dentist, experienced exacerbation of the eruptions on his lower legs after handling dental amalgam. Hypersensitivity to haptens such as metals is possibly involved in, at least in some patients, the pathogenesis of nummular dermatitis.
Adult↗
Linear lichen planopilaris of the face treated with low-dose cyclosporin A.
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Cyclosporine↗
Involvement of an SHP-2-Rho small G protein pathway in hepatocyte growth factor/scatter factor-induced cell scattering.
Hepatocyte growth factor/scatter factor (HGF/SF) induces cell scattering through the tyrosine kinase-type HGF/SF receptor c-Met. We have previously shown that Rho small G protein (Rho) is involved in the HGF/SF-induced scattering of Madin-Darby canine kidney (MDCK) cells by regulating at least the assembly and disassembly of stress fibers and focal adhesions, but it remains unknown how c-Met regulates Rho activity. We have found here a novel signaling pathway of c-Met consisting of SHP-2-Rho that regulates the assembly and disassembly of stress fibers and focal adhesions in MDCK cells. SHP-2 is a protein-tyrosine phosphatase that contains src homology-2 domains. Expression of a dominant negative mutant of SHP-2 (SHP-2-C/S) markedly increased the formation of stress fibers and focal adhesions in MDCK cells and inhibited their scattering. C3, a Clostridium botulinum ADP-ribosyltransferase, and Y-27632, a specific inhibitor for ROCK, reversed the stimulatory effect of SHP-2-C/S on stress fiber formation and the inhibitory effect on cell scattering. Vav2 is a GDP/GTP exchange protein for Rho. Expression of a dominant negative mutant of Vav2 blocked the stimulatory effect of SHP-2-C/S on stress fiber formation. Conversely, expression of mutants of Vav2 that increased stress fiber formation inhibited HGF/SF-induced cell scattering. These results indicate that SHP-2 physiologically modulates the activity of Rho to form stress fibers and focal adhesions and thereby regulates HGF/SF-induced cell scattering. In addition, Vav2 may be involved in the SHP-2-Rho pathway.
ADP Ribose Transferases↗
Protective effect of topically applied olive oil against photocarcinogenesis following UVB exposure of mice.
Reactive oxygen species have been shown to play a role in ultraviolet light (UV)-induced skin carcinogenesis. Vitamin E and green tea polyphenols reduce experimental skin cancers in mice mainly because of their antioxidant properties. Since olive oil has also been reported to be a potent antioxidant, we examined its effect on UVB-induced skin carcinogenesis in hairless mice. Extra-virgin olive oil was applied topically before or after repeated exposure of mice to UVB. The onset of UVB-induced skin tumors was delayed in mice painted with olive oil compared with UVB control mice. However, with increasing numbers of UVB exposures, differences in the mean number of tumors between UVB control mice and mice pretreated with olive oil before UVB exposure (pre-UVB group) were lost. In contrast, mice that received olive oil after UVB exposure (post-UVB group) showed significantly lower numbers of tumors per mouse than those in the UVB control group throughout the experimental period. The mean number of tumors per mouse in the UVB control, pre-UVB and post-UVB groups was 7.33, 6.69 and 2.64, respectively, in the first experiment, and 8.53, 9.53 and 3.36 in the second experiment. Camellia oil was also applied, using the same experimental protocol, but did not have a suppressive effect. Immunohistochemical analysis of DNA damage in the form of cyclobutane pyrimidine dimers (CPD), (6-4) photoproducts and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in samples taken 30 min after a single exposure of UVB showed no significant difference between UVB-irradiated control mice and the pre-UVB group. In the post-UVB group, there were lower levels of 8-OHdG in epidermal nuclei, but the formation of CPD and (6-4) photoproducts did not differ. Exposure of olive oil to UVB before application abrogated the protective effect on 8-OHdG formation. These results indicate that olive oil topically applied after UVB exposure can effectively reduce UVB-induced murine skin tumors, possibly via its antioxidant effects in reducing DNA damage by reactive oxygen species, and that the effective component may be labile to UVB.
8-Hydroxy-2'-Deoxyguanosine↗
Depigmenting effect of alpha-tocopheryl ferulate on normal human melanocytes.
Oral vitamin E supplementation has been reported to improve facial hyperpigmentation. alpha-Tocopheryl ferulate (alpha-TF) is a compound of alpha-tocopherol (alpha-T) and ferulic acid connected by an ester bond. Ferulic acid is also an antioxidant, and could scavenge free radicals induced by ultraviolet (UV) radiation, and thus maintain the long-lasting antioxidative effect of alpha-T. Previously we have reported that alpha-TF inhibited melanogenesis in human melanoma cells. To know whether alpha-TF might be useful as a whitening agent to improve and prevent facial hyperpigmentation, the depigmenting effect of alpha-TF in normal human melanocytes was examined in this study. The results showed that 30 microg/ml of alpha-TF dissolved in 150 microg/ml of lecithin inhibited melanization significantly without inhibiting cell growth. This phenotypic change was associated with the inhibition of tyrosinase and the degree of inhibition was dose dependent. No significant effect on DOPAchrome tautomerase (DT) activity was observed. These results suggest that alpha-TF is a candidate for an efficient whitening agent which suppresses melanogenesis. In this paper, the role of alpha-T and alpha-TF in inhibiting biological reactions induced by reactive oxygen species (ROS) is also discussed.
Adult↗
A case of classic Kaposi's sarcoma in a Japanese man: detection of human herpes virus 8 (HHV-8) infection by means of polymerase chain reaction and immunofluorescence assay.
The recently discovered human herpes virus 8 (HHV-8) has been implicated in the pathogenesis of Kaposi's sarcoma (KS). Because classic KS in Japan is rare and the detection of HHV-8 DNA by polymerase chain reaction (PCR) has been successful only in limited cases, the frequency and role of HHV-8 infection in KS in Japan remain unclear. Herein we report a case of classic KS in a Japanese man whose HHV-8 infection was confirmed by the detection of lesional viral DNA and serum antibodies against lytic antigen.
Aged↗
Heterozygous HPS1 mutations in a case of Hermansky-Pudlak syndrome with giant melanosomes.
We report a Japanese man with Hermansky-Pudlak syndrome, having oculocutaneous albinism with a bleeding diathesis. Gene analysis of the patient's peripheral blood cells revealed that he was a compound heterozygote for HPS1 gene mutations. One of the mutations was a novel frameshift mutation at codon 321 (a G insertion) in exon 11 ( approximately 962-963insG), and the other was a 5' splice-junction mutation of IVS5 (IVS5 + 5G-->A). The content of eumelanin in the patient's hairs was significantly reduced. Histological analysis using light and electron microscopy revealed that melanocytes in the patient's epidermis contained an appreciable number of giant melanosomes. Cultured melanocytes from the patient's skin also contained giant melanosomes. Our finding of mutations in the HPS1 gene in relation to abnormalities in melanosome morphology and melanin production shed light on the role and function of the HPS1 gene product in the synthesis of melanosomes and melanin pigment.
Adult↗
Antitumor effects on mouse melanoma elicited by local secretion of interleukin-12 and their enhancement by treatment with interleukin-18.
To investigate the mechanism of the antitumor effect of locally secreted interleukin-12 (IL-12), we introduced the IL-12 p35 and p40 cDNAs into mouse B16 melanoma cells. IL-12 gene-transfected B16 melanoma (B16/IL12) showed marked retardation of tumor growth when implanted subcutaneously into syngeneic mice. In these mice, depletion of not only Natural Killer (NK) cells but also CD8+ T cells diminished the antitumor effect of locally secreted IL-12. Immunohistochemical analysis showed that NK cells and macrophages accumulated more densely at the center and periphery of B16/IL12 tumors than that of parental B16 tumors, whereas CD4+ T cells and CD8+ T cells accumulated sparsely only at the periphery of both transfected and untransfected tumors. Systemic treatment with interleukin-18 (IL-18) markedly inhibited the growth of B16/IL12 but did not influence the tumor growth of parental B16 cells in vivo. These results suggest that local IL-12 secretion can retard the growth of B16 melanoma mediated primarily by NK cells and indirectly by CD8+ T cells and that its antitumor effect is augmented by systemic treatment with the novel cytokine IL-18.
Animals↗
Correlation of the expression of human telomerase subunits with telomerase activity in normal skin and skin tumors.
BACKGROUND: Telomerase activation is thought to be crucial for the continued growth or progression of cancer cells. Three major subunits of human telomerase, human telomerase RNA (hTR), telomerase-associated protein (TP1), and human telomerase catalytic subunit (hTERT) have been identified recently. In the current study, the expression of these telomerase subunits was examined in various human skin tumors and in normal skin samples, and the correlation of their expression with telomerase activity was evaluated. METHODS: Forty-five skin tumors, including benign, premalignant, and malignant tumors, and 19 samples of normal skin were analyzed by reverse transcriptase-polymerase chain reaction for the expression of telomerase subunits and by telomeric repeat amplification protocol assay for telomerase activity. RESULTS: TP1 expression was found in 43 of 45 skin tumors (95.6%) and in all normal skin samples analyzed. hTR expression was found in 42 of 45 skin tumors (93.3%) and in 18 of 19 normal skin samples (94.7%). In contrast, hTERT expression was detected in 33 of 45 skin tumors (73.3%) and in only 3 of 19 normal skin samples (15.8%). Telomerase activity was positive in 33 of 45 skin tumors (73.3%) and in 3 of 19 normal skin samples (15.8%). All together, 53 of 64 cases (82.8%) were concordant for both results (P < 0.001), i.e., telomerase activity positive and hTERT positive, or telomerase activity negative and hTERT negative. CONCLUSIONS: Activation of telomerase activity in skin tumors is strongly correlated with hTERT expression.
Catalytic Domain↗
UV light and MSH receptors.
Ultraviolet B (UVB) radiation in the skin induces pigmentation that protects cells from further UVB damage and reduces photocarcinogenesis. Although the mechanisms are not well understood, our laboratory has shown that UVB radiation causes increased MSH receptor activity by redistributing MSH receptors from internal pools to the external surface, with a resultant increase in cellular responsiveness to MSH. By this means, UVB and MSH act synergistically to increase melanin content in the skin of mice and guinea pigs. In humans, MSH causes increased skin pigmentation, predominantly in sun-exposed areas. We have shown recently that UVB irradiation and exposure to MSH or to dbcAMP, stimulates production of mRNAs for both alpha MSH receptors and POMC in human melanocytes and keratinocytes. This indicates that at least one action of UVB on the pigmentary system is mediated through increased MSH receptor production, as well as through the production of the signal peptides, MSH and ACTH, that can further activate MSH receptors. The results add support to the hypothesis that the effects of UVB on cutaneous melanogenesis are mediated through a series of coordinated events in which MSH receptors and POMC-derived peptides play a central role.
Animals↗
Expression of corticotropin releasing hormone in malignant melanoma.
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Animals↗
Effect of stress on atopic dermatitis: investigation in patients after the great hanshin earthquake.
BACKGROUND: Although a variety of factors are responsible for atopic dermatitis (AD), very little is known about the effect of stress caused by a natural disaster on AD symptoms. OBJECTIVE: This study was conducted to assess the effect of stress or trauma on the symptoms of AD. METHODS: One thousand four hundred fifty-seven patients with AD (745 males and 712 females), diagnosed by using the criteria of the Japanese Dermatology Association, were enrolled in the study. The data were obtained from a self-administered questionnaire given to patients with AD after experiencing the Great Hanshin Earthquake. The data were analyzed by multivariate logistic regression analysis. Patients were divided into 3 groups: area A, severe damage to buildings and houses; area B, mild damage; and control area, no damage. RESULTS: Exacerbation of skin symptoms was found in 38% and 34% of patients in areas A and B, respectively, whereas similar exacerbation was seen in 7% of control patients. Nine percent and 5% of the patients in areas A and B, respectively, showed improvement in their symptoms compared with 1% in the control group. The earthquake caused stress in 63% and 48% of the patients in areas A and B, respectively, but fewer patients felt stress in undamaged areas (19%). Multiple logistic regression analysis revealed that of the factors examined here, subjective distress is the factor that is most responsible for the exacerbation of skin symptoms (odds ratio, 2.98; 95% confidence interval, 2.25-3.96). CONCLUSION: The results presented here strongly suggest that stress caused by a natural disaster influences AD symptoms.
Adolescent↗
Skin cancer screening in Okinawa, Japan.
Depletion of the ozone layer has been observed on a global scale. Ozone depletion increases the amount of biologically harmful solar ultraviolet radiation (UV) that reaches the surface of the Earth, leading to an increased incidence of skin cancer. We previously reported the prevalence and incidence of actinic keratosis (AK) in Kasai City, which is located almost at the center of Japan. To evaluate the effects of different ambient annual UV doses on the prevalence and incidence of non-melanoma skin cancer and AK in Japan, we screened for skin cancer on Ie Island in Okinawa at the southern end of Japan, where the annual cumulative dose of UV is assumed to be the highest in Japan. The island had a population of 5562 in 1993. A prospective 4-year population-based study on the prevalence and incidence of cutaneous neoplasms was conducted by examining the sun-exposed skin of people over 40 years of age living on Ie Island. In 1993 1996, 86 cases of AK, nine of basal cell carcinoma (BCC), and two of squamous cell carcinoma were identified. The annual prevalence of AK on Ie Island was 1159.4 in 1993, 572.8 in 1994, 1014.3 in 1995 and 988.9 per 100000 Japanese in 1996. These values were significantly higher than those in Kasai City. The annual age-adjusted odds ratios for AK of Ie Island to Kasai City were 2.79, 1.38, 2.45 and 2.39, respectively. The incidences of AK on Ie Island per 100,000 were 637.0 in 1995 and 625.5 in 1996, which were also significantly higher than those in Kasai City (223.6 in 1993 and 171.2 in 1994). The prevalence of BCC was 123.6 and the incidence was 26.1. Together with our previous reports, the present results show a possible inverse relationship between the prevalence and incidence of AK and latitude among Japanese people.
Adult↗
Induced expression of p16 and p21 proteins in UVB-irradiated human epidermis and cultured keratinocytes.
It has been suggested that p16INK4a, the product of the cyclin-dependent kinase inhibitor 2 or multiple tumor suppressor 1 gene, prevents phosphorylation of the retinoblastoma gene product, and thus acts as a negative cell cycle regulator. To elucidate an effect of ultraviolet B (UVB) radiation on p16 expression and its relation to p21, and proliferating cell nuclear antigen (PCNA), immunohistochemical and western blot analyses were performed on UVB-irradiated normal human epidermis and cultured keratinocytes, respectively. Little p16 protein was seen in the control epidermis or keratinocytes. Increases in the levels of p16 protein in both UVB-irradiated epidermis and keratinocytes occurred in a similar manner, in which p16 was induced at 24-48 h and peaked at 72-120 h after irradiation. The induced expression of p21 was observed relatively earlier than that of p16, with peaked expression at 24-48 h and a return to control level by 168 h. PCNA expression was increased slightly until 48 h but significantly increased during 48-168 h of post-irradiation with peak expression at 72 h. These results indicate that together with p21, p16 protein may play an important role for protective or adaptive response to UVB exposure of human skin.
Adult↗
Expression of proopiomelanocortin, corticotropin-releasing hormone (CRH), and CRH receptor in melanoma cells, nevus cells, and normal human melanocytes.
Proopiomelanocortin (POMC) is a 31 kDa prohormone that is processed to various bioactive peptides, including adrenocorticotropin (ACTH), melanotropins (alpha, beta, gamma-MSH), lipotropins, and endorphins. POMC is expressed not only in the pituitary gland but also in a variety of nonpituitary organs and tumors, including melanomas. We previously showed that normal human melanocytes produce and secrete alpha-MSH and ACTH, and furthermore, that advanced melanoma cells generally produce higher amounts of POMC peptides that correlate with tumor progression. To elucidate the mechanism of this upregulation, the expression of genes encoding corticotropin-releasing hormone (CRH) and its receptor, CRH-R, as well as POMC and the MSH receptor (MC1-R), was evaluated by reverse transcriptase-polymerase chain reaction using cultured human melanoma cells, nevus cells, and normal melanocytes. Our results show that all melanocytic cells express CRH, CRH-R, POMC, and MC1-R, with highest intensities in melanoma cells. Furthermore, immunohistochemistry shows that CRH as well as POMC is strongly expressed in advanced melanomas, such as vertically growing lesions of acral lentiginous, nodular and metastatic melanomas, in contrast to negative expression in nevus cells. These results indicate that tumor progression accentuates CRH, CRH-R, and POMC expression by melanoma cells.
Corticotropin-Releasing Hormone↗