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Biomedical subjects

Takashi Nagase

Publications and source records attributed to Takashi Nagase.

At least 19 recordsLinked to original sources
PubMed2006

Enhanced aldosterone signaling in the early nephropathy of rats with metabolic syndrome: possible contribution of fat-derived factors.

Metabolic syndrome is an important risk factor for proteinuria and chronic kidney disease independent of diabetes and hypertension; however, the underlying mechanisms have not been elucidated. Aldosterone is implicated in target organ injury of obesity-related disorders. This study investigated the role of aldosterone in the early nephropathy of 17-wk-old SHR/NDmcr-cp, a rat model of metabolic syndrome. Proteinuria was prominent in SHR/NDmcr-cp compared with nonobese SHR, which was accompanied by podocyte injury as evidenced by foot process effacement, induction of desmin and attenuation of nephrin. Serum aldosterone level, renal and glomerular expressions of aldosterone effector kinase Sgk1, and oxidative stress markers all were elevated in SHR/NDmcr-cp. Mineralocorticoid receptors were expressed in glomerular podocytes. Eplerenone, a selective aldosterone blocker, effectively improved podocyte damage, proteinuria, Sgk1, and oxidant stress. An antioxidant tempol also alleviated podocyte impairment and proteinuria, along with inhibition of Sgk1. As for the mechanisms of aldosterone excess, visceral adipocytes that were isolated from SHR/NDmcr-cp secreted substances that stimulate aldosterone production in adrenocortical cells. The aldosterone-releasing activity of adipocytes was not inhibited by candesartan. Adipocytes from nonobese SHR did not show such activity. In conclusion, SHR/NDmcr-cp exhibit enhanced aldosterone signaling, podocyte injury, and proteinuria, which are ameliorated by eplerenone or tempol. The data also suggest that adipocyte-derived factors other than angiotensin II might contribute to the aldosterone excess of this model.

Adipocytes↗
PubMed2006

Podocyte injury underlies the glomerulopathy of Dahl salt-hypertensive rats and is reversed by aldosterone blocker.

Recent clinical studies implicate proteinuria as a key prognostic factor for renal and cardiovascular complications in hypertensives. The pathogenesis of proteinuria in hypertension is, however, poorly elucidated. Podocytes constitute the final filtration barrier in the glomerulus, and their dysfunction may play a pivotal role in proteinuria. In the present study, we examined the involvement of podocyte injury in Dahl salt-hypertensive rats, an animal model prone to hypertensive glomerulosclerosis, and explored the effects of inhibition of aldosterone. Four-week-old Dahl salt-resistant and salt-sensitive rats were fed a 0.3% or 8.0% NaCl diet. Some salt-loaded Dahl salt-sensitive rats were treated with a selective aldosterone blocker eplerenone (1.25 mg/g diet) or hydralazine (0.5 mmol/L). After 6 weeks, salt-loaded Dahl salt-sensitive rats developed severe hypertension, proteinuria, and glomerulosclerosis. Immunostaining for nephrin, a constituent of slit diaphragm, was attenuated, whereas expressions of damaged podocyte markers desmin and B7-1 were upregulated in the glomeruli of salt-loaded Dahl salt-sensitive rats. Electron microscopic analysis revealed podocyte foot process effacement. Podocytes were already impaired at as early as 2 weeks of salt loading in Dahl salt-sensitive rats, when proteinuria was modestly increased. Both eplerenone and hydralazine partially reduced systemic blood pressure as measured by indirect and direct methods in salt-loaded Dahl salt-sensitive rats, but only eplerenone dramatically improved podocyte damage and retarded the progression of proteinuria and glomerulosclerosis. Our findings suggest that podocyte injury underlies the glomerulopathy of Dahl salt-hypertensive rats and that inhibition of aldosterone by eplerenone is protective against podocyte damage, proteinuria, and glomerulosclerosis in this hypertensive model.

Animals↗
PubMed2006

Critical time window of hedgehog-dependent angiogenesis in murine yolk sac.

Hedgehog family was reported to be involved in murine yolk sac angiogenesis. However, it has not been clarified whether impaired angiogenesis under hedgehog signaling blockade is attributable to true defect in angiogenic process or just a sequel of earlier vasculogenic abnormalities. In the present study, we examined the effects of stage-specific inhibition of hedgehog cascade on vascular morphogenesis by applying cyclopamine or jervine to culture media of whole embryo culture system from embryonic days 8.0 until 9.5. Whole-mount immunostaining revealed that cyclopamine or jervine treatment in a narrow time window impaired angiogenic remodeling such as ramification into large and small branches and pericyte recruitment, although vasculogenesis was grossly normal. Molecular analyses suggest that indian hedgehog in the yolk sac endoderm regulates the induction of VEGF, Flk-1 and Notch-1. Our results indicate that hedgehog signaling is indispensable for mouse yolk sac angiogenesis, even when vasculogenesis is not perturbed.

Angiopoietin-1↗
PubMed2006

Characterization of freshly isolated and cultured cells derived from the fatty and fluid portions of liposuction aspirates.

Liposuction aspirates (primarily saline solution, blood, and adipose tissue fragments) separate into fatty and fluid portions. Cells isolated from the fatty portion are termed processed lipoaspirate (PLA) cells and contain adipose-derived adherent stromal cells (ASCs). Here we define cells isolated from the fluid portion of liposuction aspirates as liposuction aspirate fluid (LAF) cells. Stromal vascular fractions (SVF) were isolated separately from both portions and characterized under cultured and non-cultured conditions. A comparable number of LAF and PLA cells were freshly isolated, but fewer LAF cells were adherent. CD34+ CD45- cells from fresh LAF isolates were expanded by adherent culture, suggesting that LAF cells contain ASCs. Although freshly isolated PLA and LAF cells have distinct cell surface marker profiles, adherent PLA and LAF cells have quite similar characteristics with regard to growth kinetics, morphology, capacity for differentiation, and surface marker profiles. After plating, both PLA and LAF cells showed significant increased expression of CD29, CD44, CD49d, CD73, CD90, CD105, and CD151 and decreased expression of CD31 and CD45. Multicolor FACS analysis revealed that SVF are composed of heterogeneous cell populations including blood-derived cells (CD45+), ASCs (CD31- CD34+ CD45- CD90+ CD105- CD146-), endothelial (progenitor) cells (CD31+ CD34+ CD45- CD90+ CD105low CD146+), pericytes (CD31- CD34- CD45- CD90+ CD105- CD146+), and other cells. After plating, ASCs showed a dramatic increase in CD105 expression. Although some adherent ASCs lost CD34 expression with increasing culture time, our culture method maintained CD34 expression in ASCs for at least 10-20 weeks. These results suggest that liposuction-derived cells may be useful and valuable for cell-based therapies.

Adipocytes↗
PubMed2006

Defects in aortic fusion and craniofacial vasculature in the holoprosencephalic mouse embryo under inhibition of sonic hedgehog signaling.

Sonic hedgehog (Shh) is a well-known morphogen indispensable in facial and nervous development, and recently it has also garnered much attention as a potent angiogenic factor. We previously created an animal model of holoprosencephaly by administration of cyclopamine, a specific inhibitor of hedgehog signaling, to the mouse embryos cultured in vitro, and found several types of angiogenic defects. In this study, we focused on other angiogenic phenotypes in the same model. When cyclopamine was added for embryonic day (E) 8.0-9.5, a pair of immature dorsal aortae, which normally fuse to form the single aorta by E9.5, remained to be separated. Expressions of vascular endothelial growth factor and bone morphogenetic protein 4, putative mediators of aortic fusion, were also reduced around the aorta by blockade of Shh signaling. When cyclopamine was added for E8.5-10.5, vessels on the surface of craniofacial region (possibly external cardinal veins) were extended and malformed. These results suggest that Shh signaling is essential for some aspects of embryonic angiogenesis, and that pathophysiology of holoprosencephaly may involve, at least in part, the Shh-dependent angiogenesis.

Animals↗
PubMed2006

Repeated treatment protocols for melasma and acquired dermal melanocytosis.

BACKGROUND AND OBJECTIVE: Melasma and acquired dermal melanocytosis (ADM; acquired bilateral nevus of Ota-like macules) are both seen most commonly symmetrically on the face of women with darker skin and are also known as difficult conditions to treat. METHODS: Our topical bleaching protocol with 0.1 to 0.4% tretinoin gel and 5% hydroquinone was performed repeatedly (1-3 times) for melasma (n=163), and a combination treatment with topical bleaching and Q-switched ruby (QSR) laser was performed repeatedly (1-3 times) for ADM (n=62). RESULTS: There is a significant correlation between clinical results (clearance of pigmentation) and the number of sessions in both melasma (p=.019) and ADM (p<.0001). CONCLUSION: The repeated treatment protocol for melasma and ADM showed successful clinical results compared with conventional ones, and they may be applied to other pigment conditions. It may be better that epidermal and dermal pigmentations are treated separately, especially in dark-skinned people who are more likely to suffer postinflammatory hyperpigmentation after inflammation-inducing therapies.

Adult↗
PubMed2006

Incontinence induces stratum corneum vulnerability and impairs the skin barrier function in the perianal region.

BACKGROUND: Incontinence leads to a reduced skin barrier function, while also increasing the risk of skin breakdown. AIM: To investigate the perianal skin barrier function of elderly patients with or without incontinence. METHODS: We compared the skin barrier function by investigating the skin hydration, the skin pH, the amount of ceramide and by making a dermatological skin inspection of the perianal region in patients with and without incontinence. RESULTS: Twenty-one incontinent patients (70.0%) showed a glossy skin, which indicates impairment of the skin barrier while none of the patients in the continence group did so. In the incontinence group, those who had a glossy skin showed a significantly greater skin pH and total amount of ceramide than those with a normal skin (p = 0.0099, p = 0.0179, respectively). CONCLUSIONS: These results demonstrate that a glossy skin may be a useful indicator of a reduced perianal skin barrier function.

Aged, 80 and over↗
PubMed2005

Nuclear translocation of the heterotrimeric CCAAT binding factor of Aspergillus oryzae is dependent on two redundant localising signals in a single subunit.

The CCAAT-binding complex in the Aspergillus species, also known as the Hap complex, consists of at least three subunits, namely HapB, HapC and HapE. Each Hap subunit contains an evolutionary conserved core domain. Recently, we have found that the HapC and HapE subunits do not carry a nuclear localisation signal. Furthermore, when in complex with HapB, they are transported into the nucleus via a 'piggy back mechanism' in A. nidulans. To extend our findings to other filamentous fungi, we examined the nuclear localisation of the A. oryzae Hap subunits by analysing several GFP fusion proteins with these Hap subunits in the hap deletion strains of A. nidulans. The nuclear translocation of the A. oryzae complex was found to be dependent on two redundant localising signals in HapB.

Amino Acid Sequence↗
PubMed2005

Expression and regulation of adrenomedullin in renal glomerular podocytes.

Adrenomedullin (AM) is postulated to exert organ-protective effects. It is expressed in the renal glomeruli, but its roles in the glomerular podocytes have been poorly elucidated. In the present study, we investigated the expression and regulation of AM in recently established conditionally immortalized mouse podocyte cell line in vitro and podocyte injury model in vivo. The cultured differentiated podocytes expressed AM mRNA and secreted measurable amount of AM. AM secretion from the podocytes was increased by H(2)O(2), hypoxia, puromycin aminonucleoside (PAN), albumin overload, and TNF-alpha. Real-time RT-PCR analysis revealed that AM mRNA expression in the podocytes was enhanced by PAN and TNF-alpha, both of which were suppressed by mitochondrial antioxidants. Furthermore, AM expression was upregulated in the glomerular podocytes of PAN nephrosis rats. These results indicated that AM expression in the podocytes was upregulated by stimuli or condition relevant to podocyte injury, suggesting its potential role in podocyte pathophysiology.

Adrenomedullin↗
PubMed2005

Treatment of lymphedema with lymphaticovenular anastomoses.

Although lymphedema in the extremities is a troublesome adverse effect following radical resection of various cancers, conventional therapies for lymphedema are not always satisfactory, and new breakthroughs are anticipated. With the introduction of supermicrosurgical techniques for the anastomosis of blood or lymphatic vessels less than 0.8 mm in diameter, we have developed a novel method of lymphaticovenular anastomosis for the treatment of primary as well as secondary lymphedema in the extremities. Here, we review the pathophysiological aspects of lymphedema, emphasizing the importance of smooth-muscle cell function in the affected lymphatic walls. We then describe the theoretical basis and detailed operative techniques of our lymphaticovenular anastomoses. Although technically demanding, especially for beginners, we believe that this method will become a new clinical standard for the treatment of lymphedema in the near future.

Anastomosis, Surgical↗
PubMed2005

Simultaneous reconstruction of breast and well-projected nipple after expansion of mammary skin.

The problem of postoperative reduction of projecting reconstructed nipples remains to be resolved. To this end we did a clinical study of reconstructing the nipple at the same time as the breast. A tissue-expander was placed under the skin of the breast at the first operation, and then the breast and nipple were reconstructed at the second. A nipple was reconstructed using a dermal-fat flap harvested from the myocutaneous flaps used for reconstruction of the breast. A small hole was made in the corresponding site of the skin of the breast, and the reconstructed nipple was projected through the hole. This method was used in 8 cases. This method is useful in reconstructing a breast without a pad of skin and a projected nipple simultaneously. Its disadvantages are the relatively weak blood supply of the flaps, and difficulty in calculating the position of the nipple. The procedure may be beneficial for selected cases.

Adult↗
PubMed2005

Craniofacial anomalies of the cultured mouse embryo induced by inhibition of sonic hedgehog signaling: an animal model of holoprosencephaly.

The pathogenesis of holoprosencephaly is multifactorial, and blockage of Sonic hedgehog signaling is one of the most important causative factors in animal models and human cases. In this study, the authors analyzed facial anomalies of mouse embryos, which were cultured in vitro and exposed to cyclopamine, an alkaloid blocker of Sonic hedgehog signaling. When cultured with cyclopamine for embryonic day 8.5 to 10.5, the whole body size was smaller than normal, and the distance and angle between the nasal placodes were remarkably reduced. Extension of the cranial surface vessels also was noted. No cyclopia was observed. Migration of the cranial neural crest cells seemed to be intact. Expressions of Patched-1 and Gli-1, downstream genes of Sonic hedgehog signaling, also were down-regulated in in situ hybridization and real-time reverse transcriptase-polymerase chain reaction analyses. The authors consider that these facial anomalies represent milder phenotypes of holoprosencephaly.

Animals↗
PubMed2005

Angle-splitting ostectomy followed by face lift for elderly patients with prominent mandibular angles.

A prominent mandibular angle is a relatively common aesthetic problem among Asians, and the reduction angle-splitting ostectomy is now becoming a very popular procedure in Asian countries. Although this operation is usually performed on young patients, the same aesthetic demands are also seen in the elderly. In this report, the authors describe their experience with angle-splitting ostectomies followed by face lifts in three patients older than 50 years. The angle-splitting procedure was the same as that performed in young patients, and clinical results were assessed with photographs and three-dimensional computed tomographic scans. The facial contours after angle-splitting ostectomy were satisfactory, but the patients showed postoperative redundancy of the skin, especially along the jaw line, because of the loss of bony protrusion laterally. Therefore, the patients underwent subsequent superficial musculoaponeurotic system cheek lifts. The final aesthetic results were satisfactory in all cases. When surgeons want to perform the angle-splitting ostectomy safely and effectively on the elderly, they should be aware of the risks and indications specific for elderly patients, and a multidisciplinary support system should be available. Subsequent face lifts can improve skin redundancy and lead to better cosmetic results.

Aged↗
PubMed2005

Changes in angiogenic gene expression in a case of expanded capillary malformation: does an expanded capillary malformation grow?

We examined a 59-year-old woman with a capillary malformation (CM) in her thigh, which was serially excised. Interestingly, the remnant CM after the first excision was enlarged at the time of the second excision. To investigate whether this phenomenon was caused by mere passive expansion or regrowth, the CM specimens of the first operation (nonexpanded) and the second operation (expanded) were examined. Expressions of angiogenic genes Tie2 and Angiopoietin-1 were up-regulated within the expanded CM compared with the nonexpanded lesion, suggesting angiogenesis in the expanded CM. Expression pattern of the endothelial marker von Willebrand factor and the capillary densities were unchanged after the excision, suggesting that angiogenesis seen in the expanded CM resulted in reorganization of vascular networks. We consider that our data support a hypothesis that the expanded lesion in this case was caused by regrowth, not a passive expansion, of the CM.

Angiopoietin-1↗
PubMed2005

Gene expression changes of sonic hedgehog signaling cascade in a mouse embryonic model of fetal alcohol syndrome.

Fetal alcohol syndrome (FAS) is a congenital anomaly attributable to prenatal maternal excessive intake of ethanol. The authors made a mammalian model of FAS by culturing mouse embryos with high ethanol for embryonic day 7.8 to 9.5 in the whole embryo culture system. The embryos exposed to high ethanol were smaller and less advanced in development than were the embryos in the control group and showed craniofacial abnormalities, such as a fusion defect of the neural tube. The expression patterns of CRABP-I and AP-2 as markers of the neural crest cells were mostly unchanged in the in situ hybridization. However, the density and area of the expression were decreased, possibly because of the death of the neural crest cells. The expression patterns of the Sonic hedgehog signaling cascade genes (Shh, Ptc-1 and Gli-1) were mostly unchanged in the in situ hybridization, but the quantitative expressions of Ptc-1 and Gli-1 were increased in real-time reverse transcriptase-polymerase chain reaction analyses, quite contrary to the findings of a previous study using chick embryos. These findings suggest Shh signaling also is involved in the pathogenesis of FAS in mammalian embryo, but in a mode different from that in the chick embryo.

Animals↗
PubMed2005

Angiogenesis within the developing mouse neural tube is dependent on sonic hedgehog signaling: possible roles of motor neurons.

Embryonic morphogenesis of vascular and nervous systems is tightly coordinated, and recent studies revealed that some neurogenetic factors such as Sonic hedgehog (Shh) also exhibit angiogenetic potential. Vascularization within the developing mouse neural tube depends on vessel sprouting from the surrounding vascular plexus. Previous studies implicated possible roles of VEGF/Flk-1 and Angiopoietin-1(Ang-1)/Tie-2 signaling as candidate molecules functioning in this process. Examining gene expressions of these factors at embryonic day (E) 9.5 and 10.5, we unexpectedly found that both VEGF and Ang-1 were expressed in the motor neurons in the ventral neural tube. The motor neurons were indeed located in the close vicinity of the infiltrating vessels, suggesting involvement of motor neurons in the sprouting. To substantiate this possibility, we inhibited induction of the motor neurons in the cultured mouse embryos by cyclopamine, a Shh signaling blocker. The vessel sprouting was dramatically impaired by inhibition of Shh signaling, together with nearly complete loss of the motor neurons. Expression of Ang-1, but not VEGF, within the neural tube was remarkably reduced in the cyclopamine treated embryos. These results suggest that the neural tube angiogenesis is dependent on Shh signaling, and mediated, at least in part, by the Ang-1 positive motor neurons.

Angiopoietin-1↗