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Biomedical subjects

Hiroshi Shinkai

Publications and source records attributed to Hiroshi Shinkai.

At least 19 recordsLinked to original sources
PubMed2006

Chronic pulmonary complications associated with toxic epidermal necrolysis: report of a severe case with anti-Ro/SS-A and a review of the published work.

Patients with toxic epidermal necrolysis (TEN) have been known to have various complications. Though pulmonary complications are often observed, they usually show an acute form; however, chronic complications are quite rare and little is known about either their incidences or clinical manifestations. We herein report a 33-year-old man who presented with chronic pulmonary complications after a recovery from TEN. At the onset of TEN, he had severe respiratory failure and artificial ventilation was instituted. Despite being extubated successfully, respiratory failure reappeared 1 month later. A diagnosis of chronic bronchitis with severe obstructive ventilatory impairment and bronchiectasis was made and he was treated with steroids, bronchodilators and antibiotics, however, he died 1.5 years after the onset of TEN. There have been 13 reported cases of chronic pulmonary complications with TEN or Stevens-Johnson syndrome (SJS) in the English published work. Such cases are usually classified into chronic bronchitis/bronchiolitis with obstructive change (including bronchiolitis obliterans and bronchiolitis obliterans organizing pneumonia), respiratory tract obstruction and bronchiectasis. Approximately 40% of all such patients die while the surviving continue to suffer from these complications because no curative therapy yet exists. As a result, the prognosis seems to be poor. The relationship between TEN and these chronic pulmonary complications remains to be elucidated. Interestingly, our patient was asymptomatically anti-Ro/SS-A positive at the onset of TEN. In addition, eccrine gland involvement and an extremely high level of serum salivary amylase were observed at the onset of TEN, furthermore, Sjögren-like symptoms occurred after recovery from TEN. These findings suggested that the Sjögren-like autoimmune abnormalities induced by anti-Ro/SS-A correlated with the development of chronic pulmonary complications in our patient.

Adult↗
PubMed2006

The role of dermatopontin in the stromal organization of the cornea.

PURPOSE: Dermatopontin (DPT) is an abundant component of the stromal extracellular matrix; however, its function in the cornea is poorly understood. This study was conducted to determine whether DPT has a direct role in corneal matrix organization by investigating the ultrastructure of Dpt-null (Dpt(-/-)) mouse corneas. METHODS: Conventional light microscopy was used to compare the corneal thickness of Dpt(-/-) mice with that of the wild type. Collagen fibril distribution was studied using transmission electron microscopy and the datasets analyzed using image analysis software to determine fibrillar volume, fibril diameter, and spacing. RESULTS: Light microscopy demonstrated that Dpt(-/-) corneas in 2-month-old mice showed a 24% reduction in average stromal thickness compared with wild type (P < 0.001). The epithelium and Descemet's membrane appeared normal. Examination of Dpt(-/-) stroma by transmission electron microscopy indicated significant disruption of fibril spacing within the posterior lamellae, whereas the mid and anterior regions appeared largely unaffected compared with wild type. The collagen fibrils in Dpt(-/-) stroma showed a lower fibril volume fraction and a pronounced change in posterior fibrillar organization. There was no apparent difference in fibril diameter between Dpt(-/-) and wild-type mice. CONCLUSIONS: Collectively, these data suggest that DPT plays a key role in collagen fibril organization. The defects in collagen organization in Dpt(-/-) cornea appear to be most severe in the posterior stroma. It is possible that DPT interacts with corneal proteoglycans and that this interaction is involved in the maintenance of stromal architecture.

Animals↗
PubMed2005

Laminin alpha3 LG4 module induces keratinocyte migration: involvement of matrix metalloproteinase-9.

Laminin alpha3 chain, a functionally key subunit of laminin-5, contains a large globular module (G module) which consists of a tandem repeat of five homologous LG modules (LG1-5). We previously demonstrated that the LG4 module of laminin alpha3 chain (alpha3 LG4) induces a matrix metalloproteinase-1 (MMP-1) expression through the interaction with syndecans leading to MAPK activation/IL-1beta expression signaling loop (Utani et al., J. Biol. Chem. 278, 34483-34490, 2003). Here, we show that a recombinant alpha3 LG4 and synthetic peptides containing syndecan binding motif induced a cell motility and a MMP-9 expression in ketarinocytes. The synthetic peptide (A3G756)-induced cell migration and MMP-9 upregulation were inhibited by each application of a heparin and an IL-1 receptor antagonist (IL-1RA), suggesting the involvement of syndecans and IL-1beta autocrine. Furthermore, the A3G756-induced cell motility was inhibited by an MMP-9 inhibitor and a neutralizing antibody of MMP-9, indicating induced cell motility was dependent on an MMP-9 activity. Taken these together, laminin-5 alpha3 LG4 module may play an important role in re-epithelialization at tissue remodeling.

Amino Acid Sequence↗
PubMed2005

Leptomycin B reduces matrix metalloproteinase-9 expression and suppresses cutaneous inflammation.

Matrix metalloproteinase-9 (MMP-9), a type of gelatinase, plays many roles in tissue metabolism, especially in inflammation, and many regulatory elements have been reported in the promoter region of its encoding gene. Leptomycin B, which regulates the nucleo-cytoplasmic trafficking of proteins, including transcription-factor-related ones, has the potential to exert important biological effects. The addition of leptomycin B to keratinocytes in culture had no effect on matrix metalloproteinase-2 (another gelatinase) but caused the selective down-regulation of MMP-9 during the stimulation of differentiation with high Ca(2+) or transforming growth factor-beta, as well as during the stimulation of inflammation by tumor necrosis factor-alpha or interleukin-1alpha. This down-regulation depended on multiple regulatory elements in the promoter of MMP-9 including KRE-M9 (which we have recently identified), and a classical 12-o-tetradecanoyl-phorbol-13-acetate-responsive element. The topical application of leptomycin B to murine skin also effectively suppressed inflammation, including MMP-9 expression, after ultraviolet B irradiation. These results suggest that the application of leptomycin B and/or its derivatives could be useful for treating many inflammatory conditions.

Animals↗
PubMed2005

Elastin gene expression in blepharochalasis.

Blepharochalasis is a rare condition characterized by recurrent episodes of eyelid edema lead to an atrophic eyelid skin with fine wrinkles and peculiar bronze discoloration. A 32-year-old female presented with loose and redundant skin of the bilateral eyelids. We diagnosed her disease as blepharochalasis by clinical features and by disappearance of elastic fibers from the dermis in the biopsied specimen. Because elastic fibers diminish in the late phase of blepharochalasis, we performed RT-PCR to analyze the mRNA expression of elastin, a major component of elastic fiber. Elastin mRNA expression in the patient's cultured fibroblasts had not decreased compared with that in the control fibroblasts. This result suggests that environmental factors or other matrix components of elastic fibers may be involved in the loss of elastic fiber.

Adult↗
PubMed2005

Primary localized cutaneous nodular amyloidosis in a patient with Sjögren's syndrome: a review of the literature.

We report a 53-year-old Japanese woman with multiple, red, and elastic soft nodules on the left waist, left thigh, and right lower leg. She had had polyclonal hyperglobulinemia for one year, rheumatoid arthritis for 13 years, and Sjögren's syndrome (SjS) for 18 years. Histochemical examination of the nodule on the left thigh revealed a deposition of amyloid by Congo red staining. It was also positively stained with both anti-kappa and -lambda light chain antibodies. Moreover, the cytoplasm of the infiltrating plasma cells also positively reacted to both antibodies. The major amyloid proteins of primary localized cutaneous nodular amyloidosis (PLCNA) generally consist of monoclonal immunoglobulin light chains. A review of literature demonstrates 13 cases of PLCNA with SjS, in which immunoglobulin light chains were demonstrated in the amyloid in 5 cases. Amyloid in the 3 cases was composed of a single class immunoglobulin light chain and that in the 2 cases was composed of both kappa and lambda light chains. Polyclonal immunoglobulin amyloid has been reported only in PLCNA with SjS, which may be related to the fact that a certain population of SjS develops polyclonal B cell proliferation and hyperglobulinemia.

Amyloidosis↗
PubMed2005

Malignant melanoma and acquired dermal melanocytosis on congenital nevus spilus.

We reported a case of malignant melanoma and acquired dermal melanocytosis that appeared on congenital nevus spilus; this is the first report from Japan. An 85-year-old woman had had a nevus spilus on the right lower leg since birth. A black-brown nodule developed on the nevus three years before treatment. Blue-gray patches were found within the nevus on inspection. Histopathological analysis of these lesions revealed superficial spreading melanoma and acquired dermal melanocytosis, respectively. There have been 19 previous case reports of malignant melanoma on nevus spilus, and there have only been 4 cases of dermal melanocytosis (plaque-type blue nevus) on nevus spilus. We reviewed the reported cases in the literature and discussed the risk factors of nevus spilus.

Aged↗
PubMed2005

Primary anetoderma: a case report and its modified classification.

A fifty-nine-year-old healthy male presented with fifteen round pouches around his bilateral shoulders and proximal thighs, at which elasticity was lost on palpation. Histopathological examinations demonstrated that the lesional dermis was thinner than normal skin and there was loss of elastic fibers and mild inflammatory cell infiltration. Because there was no preceding inflammatory skin lesion or associated diseases, the patient was diagnosed with primary anetoderma. This is a rare case of primary anetoderma that showed loss of elastic fibers and the thinner dermis. In addition, a modified classification is proposed considering associated diseases with a review of literature.

Antibodies, Antiphospholipid↗
PubMed2004

Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.

Splice site mutations in the COL1A2 gene of type I collagen can give rise to forms of Ehlers-Danlos syndrome (EDS) because of partial or complete skipping of exon 6, as well as to mild, moderate, or lethal forms of osteogenesis imperfecta as a consequence of skipping of other exons. We identified three unrelated individuals with a rare recessively inherited form of EDS (characterized by joint hypermobility, skin hyperextensibility, and cardiac valvular defects); in two of them, COL1A2 messenger RNA (mRNA) instability results from compound heterozygosity for splice site mutations in the COL1A2 gene, and, in the third, it results from homozygosity for a nonsense codon. The splice site mutations led to use of cryptic splice donor sites, creation of a downstream premature termination codon, and extremely unstable mRNA. In the wild-type allele, the two introns (IVS11 and IVS24) in which these mutations occurred were usually spliced slowly in relation to their respective immediate upstream introns. In the mutant alleles, the upstream intron was removed, so that exon skipping could not occur. In the context of the mutation in IVS24, computer-generated folding of a short stretch of mRNA surrounding the mutation site demonstrated realignment of the relationships between the donor and acceptor sites that could facilitate use of a cryptic donor site. These findings suggest that the order of intron removal is an important variable in prediction of mutation outcome at splice sites and that folding of the nascent mRNA could be one element that contributes to determination of order of splicing. The complete absence of pro alpha 2(I) chains has the surprising effect of producing cardiac valvular disease without bone involvement.

Adult↗
PubMed2004

Matrix metalloproteinase 9 expression is coordinately modulated by the KRE-M9 and 12-O-tetradecanoyl-phorbol-13-acetate responsive elements.

To investigate the pathophysiologic role of matrix metalloproteinase 9 (MMP-9), we analyzed the mechanism of its transcriptional regulation in keratinocytes and in HT1080 fibrosarcoma cells in culture. The KRE-M9 element, which is located between the 12-O-tetradecanoyl-phorbol-13-acetate responsive element (TRE) and the transcription initiation site in the MMP-9 promoter, is essential for MMP-9 transcription in the absence of the TRE. The KRE-M9 binding protein, however, is shown to be a repressor of transcription rather than an activator; we found several times higher transcriptional activity when the KRE-M9 element was mutated. In contrast, activator protein 1 proteins (AP-1) are shown to activate transcription of MMP-9 by binding to the TRE, which is located adjacent to the KRE-M9 element. Moreover, we found that the KRE-M9 binding protein could serve as a differentiation repressing factor 1 (DRF-1) as shown by the decrease in levels of this protein with differentiation. In addition, the TRE binding protein is able to bind to the KRE-M9 to some extent. These results indicate that the coordinated modulation of MMP-9 transcription via the TRE and the KRE-M9 elements is important in epidermal and mesenchymal tissues. Our findings could facilitate consideration of the molecular mechanism in a variety of pathophysiologic conditions with which MMP-9 is involved.

Carcinogens↗
PubMed2004

Localization of the laminin alpha4 chain in the skin and identification of a heparin-dependent cell adhesion site within the laminin alpha4 chain C-terminal LG4 module.

The laminin alpha4 chain, a component of laminin-8/9, is expressed in basement membranes of endothelial cells, the peripheral nerves, and muscle fibers. The localization and functions of laminin alpha4 chain in the skin have not been elucidated. By immunostaining with specific antibodies, we demonstrate here that the alpha4 chain is located in the basement membrane zones of blood vessels and is also associated with fibroblast-like cells in the dermis. Western blot showed that cultured fibroblasts secreted a laminin trimer containing the alpha4 chain. We have also focused on the cell adhesion activities of the human laminin alpha4 LG4 module since the corresponding LG4 module of laminin alpha3 was previously identified as active for cell adhesion. Recombinant human alpha4 LG4 was active for heparin-dependent fibroblast adhesion. Screening assays with 19 synthetic peptides covering the entire alpha4 LG4 module identified three peptides (HA4G82: TLFLAHGRLVYM; HA4G83: LVYMFNVGHKKL; and HA4G90: TEATWKIKGPIYL) as active sites for heparin- and heparan sulfate-dependent cell adhesion. Serine-substituted peptides demonstrated that two basic residues, His and Arg, within HA4G82 were essential for cell adhesion activity. The cell surface heparan sulfate proteoglycans (HSPGs), syndecan-2, -4, and glypican-1, were stably expressed in 293T cells to estimate whether they function as cell adhesion receptors. 293T cells overexpressing syndecan-2 or -4 bound to recombinant alpha4 LG4 and to HA4G82, but parental or glypican-1-overexpressing 293T cells did not. Therefore, syndecan-2 and -4 could mediate cell adhesion to the laminin alpha4 LG4 module. Our study suggests that the laminin alpha4 LG4 module may play an important role in cell adhesion and/or vessel wall formation in the skin by interacting with syndecan-2 and/or -4.

Binding Sites↗
PubMed2004

Type II collagen accumulation in overlying dermo-epidermal junction of pilomatricoma is mediated by bone morphogenetic protein 2 and 4.

Pilomatricoma consists of the cells differentiating towards hair matrix cells. Immunohistochemical study revealed the deposition of type II collagen in the overlying dermo-epidermal junction (DEJ) of this benign tumor. Proalpha(1)(II) mRNA was detected by RT-PCR in the overlying epidermal layer but not in the dermal layer prepared from the lesional skin of pilomatricoma. The neutral salt-soluble proteins extracted from the tumor of pilomatricoma induced proalpha(1)(II) mRNA in the cultured human keratinocytes but not in the cultured dermal fibroblasts. Bone morphogenetic protein 2 or 4 (BMP2 or 4) was immunohistochemically detected in some shadow cells of pilomatricoma. Recombinant BMP2 and BMP4 were found to induce proalpha(1)(II) mRNA concentration dependently in the cultured human keratinocytes but not in the cultured fibroblasts. Proalpha(1)(II) mRNA induced by BMP2 and in cultured keratinocytes contained exon 2, indicating that the mRNA species is non-chondrogenic type IIA form. The results strongly suggest that BMP2 or 4 expressed in pilomatricoma is responsible for the induction of proalpha(1)(II) collagen mRNA in the overlying epidermal cells resulting in the deposition of type II collagen in the DEJ. When human keratinocytes were cultured on type II collagen substratum in vitro, the cell proliferation was accelerated at the early period of culture but was inhibited at the late period of culture, whereas the cell proliferation was persistently accelerated by type I or IV collagen substratum. Type II collagen deposition in the DEJ may potentially exert profound effects on keratinocyte proliferation and differentiation.

Adolescent↗
PubMed2004

Prurigo pigmentosa in a patient with primary biliary cirrhosis and Sjögren syndrome.

A 44-year-old Japanese woman suddenly developed severely pruritic erythematous papules on her trunk in a symmetrical distribution. Biopsy specimens showed the typical histopathological findings of prurigo pigmentosa. She had had recurrent episodes of high fever spikes for several years, and lost 10 kg in the last year. She was diagnosed as primary biliary cirrhosis (PBC) associated with subclinical Sjögren syndrome (SjS). Predonisolone (60 mg/day) for two weeks was effective for the PBC and fever, but not for the prurigo pigmentosa. PBC may be involved in the pathogenesis of this rare skin disease.

Administration, Oral↗
PubMed2004

Plexiform neurofibromas express the transcription factor Gli1.

BACKGROUND: Plexiform neurofibromas occur commonly in individuals with neurofibromatosis type 1 (NF1) and consist of neurofibromatous change in multiple nerve fascicles. Previously, we had observed that both plexiform neurofibromas and normal cutaneous nerves expressed Hedgehogs (Hhs), which are intercellular signaling molecules and regulate growth and patterning during embryonic development, and their receptors. In the present study, we examined the expression of Gli1, a transcription factor which mediates Hh signaling to investigate the activation of Hh signaling in plexiform neurofibromas and normal cutaneous nerves. METHODS: An antihuman Gli1 antibody was used with a standard immunoperoxidase technique to determine Gli1 expression in 5 specimens of plexiform neurofibromas and 5 specimens of normal cutaneous nerves. RESULTS: Our results showed Gli1 expression in S-100-positive tumor cells within the involved nerve fascicles in plexiform neurofibromas but not in control normal skins. CONCLUSIONS: Our findings indicate that the Hh signaling pathway is activated in plexiform neurofibromas.

Biomarkers, Tumor↗
PubMed2003

Laminin alpha 3 LG4 module induces matrix metalloproteinase-1 through mitogen-activated protein kinase signaling.

The LG4 module of the laminin alpha 3 chain (alpha 3 LG4), a component of epithelial-specific laminin-5, has cell attachment activity and binds syndecan (Utani, A., Nomizu, M., Matsuura, H., Kato, K., Kobayashi, T., Takeda, U., Aota, S., Nielsen, P. K., and Shinkai, H. (2001) J. Biol. Chem. 276, 28779-28788). Here, we show that recombinant alpha 3 LG4 and a 19-mer synthetic peptide (A3G756) within alpha 3 LG4 active for syndecan binding increased the expression of matrix metalloproteinase-1 (MMP-1) in keratinocytes and fibroblasts. This induction was inhibited by heparin and required de novo synthesis of proteins. In keratinocytes, A3G756 up-regulated interleukin (IL)-1 beta and MMP-1 expression and an IL-1 receptor antagonist thoroughly inhibited A3G756-mediated induction of MMP-1. A3G756 also activated p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-related kinase (Erk). Studies with specific inhibitors of MAPKs showed that p38 MAPK activation was necessary for both IL-1 beta and MMP-1 induction, but Erk activation was required only for MMP-1 induction. In fibroblasts, IL-1 receptor antagonist did not block A3G756-mediated induction of MMP-1. These results indicated that induction of MMP-1 by alpha 3 LG4 is mediated through the IL-1 beta autocrine loop in keratinocytes but the mechanism of the induction in fibroblasts is different. Our study suggests that the laminin alpha 3 LG4 module may play an important role in tissue remodeling by inducing MMP-1 expression during wound healing.

Animals↗
PubMed2003

The KDEL receptor modulates the endoplasmic reticulum stress response through mitogen-activated protein kinase signaling cascades.

The accumulation of misfolded proteins in the endoplasmic reticulum (ER) evokes the ER stress response. The resultant outcomes are cytoprotective but also proapoptotic. ER chaperones and misfolded proteins exit to the secretory pathway and are retrieved to the ER, during which process the KDEL receptor plays a significant role. Using an expression of a mutant KDEL receptor that lacks the ability for ligand recognition, we show that the impairment of retrieval by the KDEL receptor led to a mis-sorting of the immunoglobulin-binding protein BiP, an ER chaperone that has a retrieval signal from the early secretory pathway, which induced intense ER stress response and an increase in susceptibility to ER stress in HeLa cells. Furthermore, we show that the ER stress response accompanied the activation of p38 mitogen-activated protein (MAP) kinases and c-Jun amino-terminal kinases (JNKs) and that the expression of the mutant KDEL receptor suppressed the activation of p38 and JNK1 but not JNK2. The effect of the expression of the mutant KDEL receptor was consistent with the effect of a specific inhibitor for p38 MAP kinases, because the inhibitor sensitized HeLa cells to ER stress. We also found that activation of the KDEL receptor by the ligand induced the phosphorylation of p38 MAP kinases. These results indicate that the KDEL receptor participates in the ER stress response not only by its retrieval ability but also by modulating MAP kinase signaling, which may affect the outcomes of the mammalian ER stress response.

Carrier Proteins↗
PubMed2003

Activation of p38 MAPK suppresses matrix metalloproteinase-1 gene expression induced by platelet-derived growth factor.

p38 mitogen-activated protein kinase (MAPK) regulates matrix metalloproteinase-1 (MMP-1) gene expression bidirectionally depending on the induction. We sought to determine whether cytokines related to the regulation of extracellular matrix could activate p38 MAPK in dermal fibroblasts. We determined p38 MAPK phosphorylation/activation in dermal fibroblasts stimulated with platelet-derived growth factor-BB (PDGF-BB), transforming growth factor-beta or interleukin-4. Induction of MMP-1 mRNA by PDGF-BB was enhanced in the presence of a specific inhibitor of p38 MAPK, suggesting that p38 MAPK would function as a negative regulator of the MMP-1 mRNA level. We then determined which isoforms of p38 MAPK expressed in dermal fibroblasts were responsible for the downregulation of the MMP-1 mRNA level. Overexpression of p38beta2, but not of p38alpha, significantly decreased PDGF-BB-induced MMP-1 promoter activity, although PDGF-BB activated signaling pathways to both p38alpha and p38beta2. Taken together, the results of this study indicate that p38beta2 can function as a negative regulator of MMP-1 induced by PDGF-BB in vitro, suggesting that activation of p38beta2 might contribute to the pathogenesis of cutaneous fibrosis.

Animals↗