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Biomedical subjects

S Noji

Publications and source records attributed to S Noji.

At least 55 records · Page 3Linked to original sources
PubMed1997

Induction of osteogenic differentiation by hedgehog proteins.

In this study we asked whether members of the hedgehog gene family are involved in osteogenesis. C3H10T1/2 cells and MC3T3-E1 cells expressed the putative hedgehog receptor patched (Ptc) gene. Medium conditioned by chicken embryo fibroblast cultures expressing either Indian hedgehog or Sonic hedgehog stimulated alkaline phosphatase (APase) activity in cultures of the mouse mesenchymal cell line C3H10T1/2 and the osteoblastic cell line MC3T3-E1. These stimulatory effects were synergistically enhanced by bone morphogenetic protein-2 (BMP-2). Treatment with the amino-terminal portion of recombinant Sonic hedgehog proteins (rShh-N) up-regulated the expression of the Ptc gene within 12 h and increased production of APase in C3H10T1/2. rShh-N and BMP-2 also synergistically stimulated APase activity. rShh-N treatment did not affect the expression levels of Bmp-2, -4, -5, -6 and -7 genes. These findings indicate that hedgehog proteins directly act on osteogenic precursor cells and osteoblasts and stimulate osteogenic differentiation of these cells in co-operation with BMPs.

3T3 Cells↗
PubMed1997

Identification of alpha-fodrin as a candidate autoantigen in primary Sjögren's syndrome.

It is unclear whether organ-specific autoantigens are critical for the development of primary Sjögren's syndrome (SS). A 120-kilodalton organ-specific autoantigen was purified from salivary gland tissues of an NFS/sld mouse model of human SS. The amino-terminal residues were identical to those of the human cytoskeletal protein alpha-fodrin. The purified antigen induced proliferative T cell responses and production of interleukin-2 and interferon-gamma in vitro. Neonatal immunization with the 120-kilodalton antigen prevented the disease in mice. Sera from patients with SS reacted positively with purified antigen and recombinant human alpha-fodrin protein, whereas those from patients with systemic lupus erythematosus and rheumatoid arthritis did not. Thus, the immune response to 120-kilodalton alpha-fodrin could be important in the initial development of primary SS.

Amino Acid Sequence↗
PubMed1997

Fibroblasts expressing Sonic hedgehog induce osteoblast differentiation and ectopic bone formation.

We investigated the role of Sonic hedgehog (SHH) in osteoblast differentiation and bone formation. The numbers of ALP-positive cells in the mouse fibroblastic cell line C3H10T1/2 and the mouse osteoblastic cell line MC3T3-E1 were increased by co-culture with chicken fibroblasts transfected with chicken Shh cDNA encoding amino-terminal peptide (Shh-N). The conditioned medium of Shh-N-RCAS-transfected chicken fibroblast cultures also significantly increased ALP activity in both C3H10T1/2 and MC3T3-E1 cells. Intramuscular transplantation of Shh-N-RCAS-transfected chicken fibroblasts into athymic mice induced ectopic bone formation. These results indicate that SHH induces osteoblast differentiation and ectopic bone formation.

3T3 Cells↗
PubMed1997

Induction of additional limb at the dorsal-ventral boundary of a chick embryo.

In the early chick embryo, an apical ectodermal ridge (AER) is formed from the overlying ectoderm of the presumptive limb bud region at the dorsal-ventral (DV) boundary. We report here that the ectopic DV boundary formed in the presumptive wing, flank, and leg fields induces an ectopic AER structure. Dorsal tissue (ectoderm and mesoderm) from the presumptive wing field of stage 10 to 17 embryos was inserted into a slit in the somatopleure of the future ventral side of host embryos. The same method was used to implant ventral tissue into the future dorsal side of host embryos. After the implantation, ectopic AER was induced and an additional limb or limb-like structure developed. In related experiments, ectoderm-free presumptive wing tissue was implanted, which resulted in a considerably decreased frequency of ectopic AER formation. Further analysis of chick and quail chimeras suggests that the ectopic AER was formed from the ectodermal cells overlying the boundary of host and graft mesodermal cells. These results indicate that the DV boundary organizes the AER structure in the limb bud field of early-stage chick embryos and that the ectoderm of the grafted tissues plays an important role in this process.

Animals↗
PubMed1997

Acarbose controls postprandial hyperproinsulinemia in non-insulin dependent diabetes mellitus.

We investigated how fasting or postprandial insulin levels were altered by treatment with acarbose or sulfonylureas. Plasma glucose and serum insulin, C-peptide, and proinsulin levels were measured before as well as 1 and 2 h after breakfast in 23 patients with non-insulin-dependent diabetes mellitus and 17 patients with impaired glucose tolerance. In the diabetic patients, 12 weeks of acarbose therapy decreased the postprandial levels of glucose (1 h: -60.0%; 2 h: -67.6%), insulin (1 h: -67.5%; 2 h: -72.2%) and proinsulin (1 h: -55.2%; 2 h: -46.7%), and proinsulin (1 h: -20.9%; 2 h: -57.5%). In contrast, sulfonylurea treatment increased postprandial insulin and proinsulin levels. Since increased in the serum insulin or proinsulin levels are associated with a higher risk of cardiovascular disease, the present findings suggest that the acarbose-induced reduction of the postprandial serum insulin or proinsulin responses to food intake might be useful for preventing vascular complications in patients with diabetes.

Acarbose↗
PubMed1997

A chick wingless mutation causes abnormality in maintenance of Fgf8 expression in the wing apical ridge, resulting in loss of the dorsoventral boundary.

We analyzed a Japanese chick wingless mutant (Jwg) to know a molecular mechanism underlying wing development. We observed expression patterns of eleven marker genes to characterize the mutant. Expressions of dorsoventral (DV) and mesenchymal marker genes were intact in nascent Jwg limb buds. However, expression of Fgf8, a marker gene for the apical ectodermal ridge (AER), was delayed and shortly disappeared in the wing regressing AER. Later on, ventral expression of dorsal marker genes of Wnt7a and Lmx1 indicated that the wing bud without the AER became bi-dorsal. In addition, the posterior mesoderm became defective, as deduced from the impaired expression patterns of Sonic hedgehog (Shh), Msx1, and Prx1. We attempted to rescue a wing by implanting Fgf8-expressing cells into the Jwg wing bud. We found that FGF8 can rescue outgrowth of the wing bud by maintaining Shh expression. Thus, the Jwg gene seems to be involved in maintenance of the Fgf8 expression in the wing bud. Further, it is suggested that the AER is required for maintenance of the DV boundary and the polarizing activity of the established wing bud.

Animals↗
PubMed1997

The mesenchymal factor, FGF10, initiates and maintains the outgrowth of the chick limb bud through interaction with FGF8, an apical ectodermal factor.

Vertebrate limb formation has been known to be initiated by a factor(s) secreted from the lateral plate mesoderm. In this report, we provide evidence that a member of the fibroblast growth factor (FGF) family, FGF10, emanates from the prospective limb mesoderm to serve as an endogenous initiator for limb bud formation. Fgf10 expression in the prospective limb mesenchyme precedes Fgf8 expression in the nascent apical ectoderm. Ectopic application of FGF10 to the chick embryonic flank can induce Fgf8 expression in the adjacent ectoderm, resulting in the formation of an additional complete limb. Expression of Fgf10 persists in the mesenchyme of the established limb bud and appears to interact with Fgf8 in the apical ectoderm and Sonic hedgehog in the zone of polarizing activity. These results suggest that FGF10 is a key mesenchymal factor involved in the initial budding as well as the continuous outgrowth of vertebrate limbs.

Amino Acid Sequence↗
PubMed1997

Pax-6 is involved in the specification of hindbrain motor neuron subtype.

Pax-6 is a member of the vertebrate Pax gene family, which is structurally related to the Drosophila pair-rule gene, paired. In mammals, Pax-6 is expressed in several discrete domains of the developing CNS and has been implicated in neural development, although its precise role remains elusive. We found a novel Small eye rat strain (rSey2) with phenotypes similar to mouse and rat Small eye. Analyses of the Pax-6 gene revealed one base (C) insertion in an exon encoding the region downstream of the paired box of the Pax-6 gene, resulting in generation of truncated protein due to the frame shift. To explore the roles of Pax-6 in neural development, we searched for abnormalities in the nervous system in rSey2 homozygous embryos. rSey2/rSey2 exhibited abnormal development of motor neurons in the hindbrain. The Islet-1-positive motor neurons were generated just ventral to the Pax-6-expressing domain both in the wild-type and mutant embryos. However, two somatic motor (SM) nerves, the abducent and hypoglossal nerves, were missing in homozygous embryos. By retrograde and anterograde labeling, we found no SM-type axonogenesis (ventrally growing) in the mutant postotic hindbrain, though branchiomotor and visceral motor (BM/VM)-type axons (dorsally growing) were observed within the neural tube. To discover whether the identity of these motor neuron subtypes was changed in the mutant, we examined expression of LIM homeobox genes, Islet-1, Islet-2 and Lim-3. At the postotic levels of the hindbrain, SM neurons expressed all the three LIM genes, whereas BM/VM-type neurons were marked by Islet-1 only. In the Pax-6 mutant hindbrain, Islet-2 expression was specifically missing, which resulted in the loss of the cells harboring the postotic hindbrain SM-type LIM code (Islet-1 + Islet-2 + Lim-3). Furthermore, we found that expression of Wnt-7b, which overlapped with Pax-6 in the ventrolateral domain of the neural tube, was also specifically missing in the mutant hindbrain, while it remained intact in the dorsal non-overlapping domain. These results strongly suggest that Pax-6 is involved in the specification of subtypes of hindbrain motor neurons, presumably through the regulation of Islet-2 and Wnt-7b expression.

Animals↗
PubMed1997

Essential roles of the winged helix transcription factor MFH-1 in aortic arch patterning and skeletogenesis.

Mesenchyme Fork Head-1 (MFH-1) is a forkhead (also called winged helix) transcription factor defined by a common 100-amino acid DNA-binding domain. MFH-1 is expressed in non-notochordal mesoderm in the prospective trunk region and in cephalic neural-crest and cephalic mesoderm-derived mesenchymal cells in the prechordal region of early embryos. Subsequently, strong expression is localized in developing cartilaginous tissues, kidney and dorsal aortas. To investigate the developmental roles of MFH-1 during embryogenesis, mice lacking the MFH-1 locus were generated by targeted mutagenesis. MFH-1-deficient mice died embryonically and perinatally, and exhibited interrupted aortic arch and skeletal defects in the neurocranium and the vertebral column. Interruption of the aortic arch seen in the mutant mice was the same as in human congenital anomalies. These results suggest that MFH-1 has indispensable roles during the extensive remodeling of the aortic arch in neural-crest-derived cells and in skeletogenesis in cells derived from the neural crest and the mesoderm.

Animals↗
PubMed1996

Sonic hedgehog is expressed in epithelial cells during development of whisker, hair, and tooth.

Sonic hedgehog (Shh) is a vertebrate gene homologous to a Drosophila segment polarity gene, hedgehog, and functions as a secreted signaling molecule in limb pattern formation, differentiation of motor neurons, and sclerotome induction. We found that Shh is also expressed in epithelia of the developing whisker, hair, tooth, rugae, and thyroid primordium of mouse embryos. In whisker and hair development, Shh is expressed in epithelial cells before condensation of the underlying mesenchymal cells and then in the placode. The expression of Shh continues in the hair bulb surrounding the dermal papilla. Shh is also expressed in epithelial cells of the tooth bud, then localized to the enamel knot. The Shh expression continues in developing ameloblasts. These results suggest that SHH is an essential epithelial signaling molecule in epithelio-mesenchymal interactions for the terminal differentiation.

Animals↗
PubMed1996

Polarizing activity, Sonic hedgehog, and tooth development in embryonic and postnatal mouse.

Tooth development involves reciprocal epithelial-mesenchymal interactions, polarized growth, mesenchyme condensation, and complex morphogenetic events. Because these processes bear similarities to those occurring in the developing limb, we asked whether morphogenetic signals found in the limb also occur in the developing tooth. We grafted mouse embryo tooth germs to the anterior margin of host chick embryo wing buds and determined whether the dental tissues had polarizing activity. Indeed, the grafts induced supernumerary digits. Activity of both molar and incisor tooth germs increased from bud to cap stages and was maximal at late bell stage in newborn. With further development the polarizing activity began to decrease, became undetectable in adult molar mesenchyme but persisted in incisor mesenchyme, correlating with the fact that incisors grow throughout postnatal life while molars do not. When different portions of neonatal incisors were assayed, a clear proximo-distal gradient of activity was apparent, with maximal activity restricted to the most proximal portion where undifferentiated mesenchyme and enamel organ reside. In situ hybridizations demonstrated that prior to induction of supernumerary digits, the tooth germ grafts induced expression in host tissue of Hoxd-12 and Hoxd-13. In addition, whole-mount in situ hybridizations and immunohistochemistry showed that developing tooth germs express Sonic hedgehog (Shh). Shh expression was first detected in bud stage tooth germs; at later stages Shh transcripts were prominent in enamel knot and differentiating ameloblasts at the cuspal region. We concluded that tooth germs possess polarizing activity and produce polarizing factors such as Shh. As in the limb, these factor(s) and activity probably play key roles in establishing polarity and regulating morphogenesis during early tooth development. Given its subsequent association with differentiating ameloblasts, Shh probably participates also in cytogenetic events during odontogenesis.

Aging↗
PubMed1996

Early chick limb cartilaginous elements possess polarizing activity and express hedgehog-related morphogenetic factors.

Skeletal patterning and morphogenesis in the developing limb are thought to be regulated by instructive factors and cues from the zone of polarizing activity (ZPA), the apical ectodermal ridge (AER), and the dorsal ectoderm. However, the activities of the ZPA and AER dwindle early in embryogenesis and soon after ceases, when in fact the proximal skeletal elements are still rudimentary in structure and the more distal ones are yet to become recognizable. Thus, we asked whether the chondrocytes emerging within each mesenchymal condensation may themselves start expressing properties similar to those of ZPA and/or AER and, in so doing, may bring skeletal development to completion. Indeed, we found that the cartilaginous, but not precartilaginous, tissues in early chick limbs possess ZPA-like properties. They expressed an endogenous factor related to Sonic hedgehog (Shh), most likely Indian hedgehog (Ihh), and when fragments were grafted to the anterior margin of host stage 16-20 chick wing buds, they induced supernumerary skeletal elements (polarizing activity). The acquisition of polarizing activity by the cartilaginous structures followed clear proximo-to-distal and posterior-to-anterior routes. Thus, (1) stage 25 cartilaginous humerus had polarizing activity while stage 25 prospective radius did not, (2) posteriorly-located stage 29 ulna had stronger activity than anteriorly-located stage 29 radius, and (3) ulna's diaphysis had stronger activity at stage 29 than 31 while radius's diaphysis was stronger at stage 31 than 29. Prior to inducing extra digit formation, the cartilaginous grafts induced Hoxd-12 and Hoxd-13 gene expression in adjacent competent mesenchymal tissue. Strikingly, the cartilaginous grafts activity also expression of Shh and polarizing activity in adjacent mesenchyme, which ZPA grafts cannot do; thus, the cartilaginous structures displayed activities "upstream" of those of the ZPA. The results support our hypothesis that chondrocytes may themselves direct skeletal morphogenesis. In so doing and as a result of their inductive activities, the cells may also have an important role in the completion of limb patterning and morphogenesis.

Animals↗
PubMed1996

The critical role of intercellular adhesion molecule-1 in Masugi nephritis in rats.

Intercellular adhesion molecule-1 (ICAM-1, CD54), an adhesion molecule of the immunoglobulin superfamily, is an endothelial cell surface ligand for such leukocyte integrins as lymphocyte-function-associated molecule 1 (LFA-1, CD11a/CD18), Mac-1 (CD11b/CD18) and CD43. These molecules mediate adhesive interactions between leukocytes and endothelial cells and are critically involved in infiltration of leukocytes into inflammatory lesions. We examined the expression of ICAM-1 in renal tissues of Masugi nephritis rats and directly examined the role of ICAM-1 by administration of neutralizing monoclonal antibodies (MAbs) to rat ICAM-1, LFA-1 alpha-subunit (LFA-1 alpha), beta-subunit (LFA-1 beta) and Mac-1 alpha-subunit (Mac-1 alpha). Within 3 h after injection of nephrotoxic serum, increased expression of ICAM-1 was detected in the glomeruli by in situ hybridization and an immunofluorescence study. Proteinuria was significantly suppressed by the MAbs against ICAM-1, Mac-1 alpha and LFA-1 beta. Neutrophil infiltration into the glomeruli was significantly prevented by injection of the MAbs against ICAM-1, LFA-1 alpha and LFA-1 beta. These results indicate that both ICAM-1/LFA-1 and ICAM-1/Mac-1 pathways are involved in neutrophil infiltration into the glomeruli. On the other hand, monocytic infiltration was prevented by the MAbs against ICAM-1, LFA-1 alpha and LFA-1 beta but not by anti-Mac-1 alpha MAb. Due to these results, ICAM-1 is considered to be a critical molecule involved in the pathogenesis of the leukocyte infiltration into the glomeruli in the heterologous phase of Masugi nephritis. Anti-ICAM-1 antibody may be beneficial in the treatment of leukocyte-mediated glomerular diseases.

Animals↗
PubMed1996

BMP signaling during bone pattern determination in the developing limb.

To examine the role of BMP signaling during limb pattern formation, we isolated chicken cDNAs encoding type I (BRK-1 and BRK-2) and type II (BRK-3) receptors for bone morphogenetic proteins. BRK-2 and BRK-3, which constitute dual-affinity signaling receptor complexes for BMPs, are co-expressed in condensing precartilaginous cells, while BRK-1 is weakly expressed in the limb mesenchyme. BRK-3 is also expressed in the apical ectodermal ridge and interdigital limb mesenchyme. BRK-2 is intensely expressed in the posterior-distal region of the limb bud. During digit duplication by implanting Sonic hedgehog-producing cells, BRK-2 expression is induced anteriorly in the new digit forming region as observed for BMP-2 and BMP-7 expression in the limb bud. Dominant-negative effects on BMP signaling were obtained by over-expressing kinase domain-deficient forms of the receptors. Chondrogenesis of limb mesenchymal cells is markedly inhibited by dominant-negative BRK-2 and BRK-3, but not by BRK-1. Although the bone pattern was not disturbed by expressing individual dominant-negative BRK independently, preferential distal and posterior limb truncations resulted from co-expressing the dominant-negative forms of BRK-2 and BRK-3 in the whole limb bud, thus providing evidence that BMPs are essential morphogenetic signals for limb bone patterning.

Amino Acid Sequence↗
PubMed1996

[Relationship between postoperative prognosis and preoperative immunological factors in aortitis syndrome].

Valve detachment or pseudoaneurysm is a well known complication of surgical treatment for cardiovascular disease due to aortitis syndrome. Although the preoperative management of inflammation by steroid therapy is very important, occasionally, the operation in active phase might be recommended because of progressive heart failure or impending rupture of aortic aneurysm. The pathology of aortitis syndrome is related to immunological abnormality, but there has been little information concerning the immunological factors. In order to evaluate the relationship between immunological factors and surgical results in patients with aortitis syndrome, immunological examination was obtained before surgery in 12 patients. Cardiovascular lesions due to aortitis syndrome were aortic regurgitation in 6 patients, annuloaortic ectasia in 1 patient, aortic arch aneurysm in 1 patient, mitral regurgitation in 2 patients, and coronary artery disease in 2 patients. Hospital mortality including initial operative death was not found. However, 6 late death (50%) occurred at late time with the mean of 23.8 months because of severe complications such as valve detachement or pseudoaneurysm after operation. In a comparison of the preoperative immunological values between survival group and late death group, immunoglobulins such as IgG, IgA, C3 and C4 were significantly higher in late death group. According to the recurrence of inflammation, the patients were divided into three groups. Group A included 3 patients who remains in active phase after initial operation in active phase. Group B included 3 patients who changed to active phase after initial operation in inactive phase. Group C included 6 patients who remains in inactive phase after initial operation. In a comparison among 3 groups, IgG and C4 showed no significant difference. However, IgA and C3 of group C were significantly lowest among three groups. This outcome is considered to be related to existence of latent inflammation. At operation, insertion of rigid prosthesis to fragile position due to latent inflammation may stimulate immunological reactions. We conclude that the preoperative values of the immunological factors, especially IgA and C3, are reliable predictors in postoperative prognosis.

Adult↗