PubMed Health⌕ Search

Biomedical subjects

Seijiro Mori

Publications and source records attributed to Seijiro Mori.

17 recordsLinked to original sources
PubMed2006

Postprandial reactive hypoglycemia in an oldest-old patient effectively treated with low-dose acarbose.

We recently encountered a 96-year-old Japanese woman who suffered from frequent hypoglycemia. Endocrinological and imaging data eliminated the possibility of insulinoma, whereas oral glucose tolerance testing revealed impaired glucose tolerance and subsequent reactive hypoglycemia. The patterns between insulin or C-peptide secretions and glucose excursions demonstrated that the discrepancy occurred in the late postprandial stage. Administration of small doses of alpha-glucosidase inhibitor (alpha-GI) dramatically inhibited the rapid rise and subsequent precipitous fall of plasma glucose. Reactive hypoglycemia may be one of the important cause of hypoglycemia in the elderly, and alpha-GI could effectively and safely prevent such hypoglycemic attacks in those patients.

Acarbose↗
PubMed2006

A case of type 2 diabetes mellitus in an elderly patient with rapid attenuation of insulin secretion that resembled fulminant type 1 DM but with incomplete beta cell damage.

We recently encountered a 66-year-old Japanese man who had suffered from acute hyperglycemia following flu-like symptoms during treatment of type 2 diabetes. Despite significantly increased plasma glucose levels, HbA1c was only slightly elevated. The possibility of autoimmune type 1 diabetes was excluded because of negative islet-related autoantibodies. Serum levels of pancreatic exocrine enzymes, amylase, lipase, and elastase-l were elevated. However, the insulin-secreting function of his islets was not severely damaged. This case is particularly notable for two reasons. First, it showed a fulminant type 1 diabetes-like clinical onset, but his beta cell function was fairly preserved. Second, it developed during the treatment of type 2 diabetes in an elderly patient.

Aged↗
PubMed2005

Targeted disruption of TGF-beta-Smad3 signaling leads to enhanced neointimal hyperplasia with diminished matrix deposition in response to vascular injury.

The role of transforming growth factor (TGF)-beta and its signal in atherogenesis is not fully understood. Here, we examined mice lacking Smad3, a major downstream mediator of TGF-beta, to clarify the precise role of Smad3-dependent signaling in vascular response to injury. Femoral arteries were injured in wild-type and Smad3-null (null) male mice on C57Bl/6 background. Histopathological evaluation of the arteries 1 to 3 weeks after the injury revealed significant enhancement of neointimal hyperplasia in null compared with wild-type mice. Transplantation of null bone marrow to wild-type mice did not enhance neointimal thickening, suggesting that vascular cells in situ play a major role in the response. Null intima contained more proliferating smooth muscle cells (SMC) with less amount of collagen compared with wild-type intima. TGF-beta caused significant inhibition of cellular proliferation in wild-type aortic SMC, whereas the growth of null SMC was only weakly inhibited by TGF-beta in vitro, indicating a crucial role of Smad3 in the growth inhibitory function. On the other hand, Smad3-deficiency did not attenuate chemotaxis of SMC toward TGF-beta. TGF-beta increased transcript level of alpha2 type I collagen and tissue inhibitor of metalloproteinases-1, and suppressed expression and activity of matrix metalloproteinases in wild-type SMC. However, these effects of TGF-beta were diminished in null SMC. Our findings altogether show that the loss of Smad3 pathway causes enhanced neointimal hyperplasia on injury through modulation of growth and matrix regulation in vascular SMC. These results indicate a vasculoprotective role of endogenous Smad3 in response to injury.

Animals↗
PubMed2005

[A case of an elderly type 2 diabetes who had severe diabetic nephropathy without retinopathy].

We encountered a man who developed severe diabetic nephropathy without progression of diabetic retinopathy. He had a 14-year history of diabetes, and had been treated with sulfonylurea, and his HbA1c remained around 6.5%. He was admitted because of systemic edema and dyspnea on effort Laboratory data revealed renal failure and nephrotic syndrome, whereas there was no symptom of diabetic retinopathy. Since diabetic nephropathy usually progresses in parallel with retinopathy, it is atypical to develop severe nephropathy without retinopathy. In this case, longstanding hypertension and his genetic background including angiotensin converting enzyme D/I polymorphism might have played an important role in development of diabetic nephropathy.

Aged↗
PubMed2003

High glucose-induced upregulation of osteopontin is mediated via Rho/Rho kinase pathway in cultured rat aortic smooth muscle cells.

OBJECTIVE: Osteopontin is upregulated in the diabetic vascular wall and in vascular smooth muscle cells cultured under high glucose concentration. In the present study, we analyzed the mechanism of high glucose-induced upregulation of osteopontin in cultured rat aortic smooth muscle cells. METHODS AND RESULTS: We found that an inhibitor of Rho-associated protein kinase, Y-27632, suppressed osteopontin mRNA expression under high glucose concentration. Transfection of cells with a constitutive active Rho mutant, pSRalpha-myc-RhoDA, enhanced osteopontin mRNA expression. Furthermore, incubation of cells under high glucose concentration activated Rho, indicating that Rho/Rho kinase pathway mediates high-glucose-stimulated osteopontin expression. Treatment of cells with an inhibitor of protein kinase C, GF109203X, and azaserine, an inhibitor of the hexosamine pathway, suppressed high glucose-induced Rho activation. Glucosamine treatment was shown to activate Rho. Treatment of cells with an inhibitor of MEK1, PD98059, suppressed osteopontin mRNA expression under high glucose concentration. Incubation of cells under high glucose concentration activated ERK. Finally, transfection of cells with pSRalpha-myc-RhoDA also activated ERK. CONCLUSIONS: In conclusion, our present findings support a notion that Rho/Rho kinase pathway functions downstream of protein kinase C and the hexosamine pathways and upstream of ERK in mediating high-glucose-induced upregulation of osteopontin expression.

Amides↗
PubMed2003

Mice lacking Smad3 are protected against streptozotocin-induced diabetic glomerulopathy.

Transforming growth factor-beta (TGF-beta) has been implicated in the development of diabetic glomerulopathy. In order to evaluate a role of Smad3, one of the major signaling molecules downstream of TGF-beta, in the pathogenesis of diabetic glomerulopathy, Smad3-null mice were made diabetic with streptozotocin injection and analyzed 4 weeks after induction of diabetes. Electron microscopy revealed that the thickness of glomerular basement membrane (GBM) in wild-type diabetic mice was significantly higher than that in non-diabetic mice, whereas no appreciable GBM thickening was found in Smad3-null diabetic mice. Urinary albumin excretion was dramatically increased in wild-type diabetic mice, whereas Smad3-null diabetic mice did not show any overt albuminuria. Northern blotting revealed that mRNA levels of fibronectin and alpha 3 chain of type IV collagen (alpha 3Col4) in renal cortex of wild-type diabetic mice were approximately twice as much as those of non-diabetic mice, whereas their mRNA levels were not increased in Smad3-null diabetic mice. Real-time polymerase chain reaction (PCR) also confirmed diabetes-induced upregulation of fibronectin and alpha 3Col4 in glomeruli of wild-type mice. Glomerular expression of TGF-beta 1, as assessed by real-time PCR, was enhanced to a similar degree in wild-type and smad3-null diabetic mice, indicating that the observed differences between wild-type and Smad3-null mice are not attributable to difference in the expression of TGF-beta 1. These data clearly demonstrate a critical role of Smad3 in the early phase of diabetic glomerulopathy. This may be due at least partly to the present findings that diabetes-induced upregulation of fibronectin and alpha 3Col4 is dependent on Smad3 function.

Albuminuria↗
PubMed2003

[A report of a case with Werner's syndrome suffering from end-stage renal failure].

A 54-year-old man was found to have hypertension at age 32, and a diagnosis of Werner's Syndrome was made at age 36 when he was examined for hyperlipidemia. Diabetes mellitus was found at age 42. Proteinuria appeared at age 49, and microscopic hematuria was seen at age 50. At age 51, serum creatinin level began to rise and atrophy of bilateral kidneys was observed by abdominal CT. There after, the renal function gradually worsened. At age 53, the serum creatinin level rose to 8.3 mg/dl, and systemic edema as well as loss of appetite appeared, resulting in the initiation of hemodialysis. In Werner's syndrome, though arteriosclerosis arises frequently, case reports with chronic renal failure are extremely rare. To investigate the cause of the renal dysfunction, renal biopsy was performed and the samples were histologically examined, revealing the presence of hypertensive glomerular changes. It is, thus, conceivable that hypertension had played a major role in the progression of renal failure in this case.

Humans↗
PubMed2003

Bone marrow-derived vascular cells in response to injury.

Intimal hyperplasia is a key lesion for various vascular disorders such as atherosclerosis, postangioplasty restenosis and transplant arteriopathy. It has widely been accepted that intimal smooth muscle cells (SMC) originate from the medial layer in the same artery. However, recent studies suggest that bone marrow can also provide circulating progenitors for vascular SMC. Bone marrow-derived SMC participate in neointimal formation in animal models of allotransplantation, severe mechanical injury and hyperlipidemia-induced atherosclerosis. In human, transplantation arteriopathy also seems to involve circulating SMC, but their role in atherosclerosis and restenosis remains to be elucidated. Mobilization, differentiation and proliferation steps of SMC progenitors will provide promising targets for novel therapeutic approaches against proliferative vascular diseases.

Animals↗
PubMed2002

Role of SRC homology 2-containing tyrosine phosphatase 2 on proliferation of rat smooth muscle cells.

OBJECTIVE: Src homology 2-containing phosphotyrosine phosphatase 2 (SHP2) is ubiquitously expressed and believed to function as part of a positive signaling pathway mediating growth factor-induced protein tyrosine phosphorylation. Proliferation of aortic vascular smooth muscle cells (SMCs) is an important contributor to atherosclerosis. We examined the effect of SHP2 expression on SMC proliferative activity. METHODS AND RESULTS: SHP2 was abundant in cultured aortic SMCs, and SHP2 staining was markedly increased in the thickened aortic intima in rats with balloon-induced injury. We obtained several SMC clones by using geneticin screening. Endogenous SHP2 expression varied among individual clones. Significant positive relationships were observed between SHP2 expression and bromodeoxyuridine uptake in SMCs stimulated by FBS, platelet-derived growth factor, or insulin-like growth factor-1. In SMCs transiently transfected with SHP2, FBS stimulation significantly increased bromodeoxyuridine uptake beyond the uptake by control SMCs. CONCLUSIONS: Increased SHP2 expression in SMCs may accelerate aortic atherosclerosis by increasing cell growth.

Animals↗
PubMed2002

Functional analysis of aortic endothelial cells expressing mutant PDGF receptors with respect to expression of matrix metalloproteinase-3.

Platelet-derived growth factor (PDGF) stimulates expression of matrix metalloproteinases (MMPs), including stromelysin-1 (MMP-3). Induction of these expressions is known to occur during the course of atherosclerosis, tumor invasion, and metastasis. We investigated PDGF-alpha receptor (alphaR)- and beta receptor (betaR)-mediated signaling pathways for the expression of MMP-3 and invasion activity using porcine aortic endothelial (PAE) cells with stable expression of normal or mutated PDGF receptors. RT-PCR and Western blot analyses revealed that PDGF-BB induces MMP-3 expression in PAE cells that exclusively express either the PDGF-alphaR or the -betaR, but not in non-transfected control cells. To identify the signals necessary for PDGF receptor-mediated induction of MMP-3 expression, several lines of PAE cells expressing mutant PDGF receptors were further analyzed. Cells expressing mutant PDGF receptors unable to associate with Src or PLCgamma, retained the ability to induce MMP-3 expression as a result of PDGF-BB stimulation. However, incubation with PDGF-BB did not induce MMP-3 expression in cells expressing a mutant PDGF-betaR unable to associate with phosphatidylinositol 3(')-kinase (PI3K). LY294002, a PI3K inhibitor, reduced PDGF-BB-stimulated MMP-3 expression in PAE cells expressing wild-type PDGF receptors. In contrast, PDGF-BB induced MMP-3 expression in the presence of U-73122, a PLCgamma inhibitor. Moreover, PDGF-BB enhanced the invasiveness of cells expressing wild type PDGF-beta receptors, but not of cells expressing mutant PDGF-betaRs impaired in their ability to associate with PI3K. In light of these results, it appears that PDGF-BB is capable of inducing MMP-3 expression through both the PDGF-alphaR and the -betaR, and the effects are contributed by the PI3K-mediated transduction pathways.

Animals↗
PubMed2002

[Pleiotropic effects of statins].

The advent of statin therapy has revolutionized the ability of the clinician to manage patients at risk for the development of an ischemic event due to dyslipidemia. Large-scale clinical trials involving thousands of patients in both primary and secondary prevention have clearly demonstrated that statin therapy will reduce cardiovascular mortality across a broad spectrum of patient subgroups. However, the precise mechanism underlying the benefit of statin therapy has been controversial due to the multiplicity of potential benefits that statins have demonstrated in addition to pure lipid lowering. Recent experimental evidence supports the premise that clinical benefits are related primarily to pleiotropic effects of statins (endothelial function, inflammation, coagulation and plaque vulnerability).

Animals↗
PubMedDate not supplied

Influence of C-peptide on early glomerular changes in diabetic mice.

BACKGROUND: C-peptide has been shown to ameliorate diabetes-induced functional and structural renal changes in animal models as well as in patients with type 1 diabetes. This study aims to examine the molecular effects of C-peptide on early glomerular changes in a mouse model of type 1 diabetes. METHODS: Fourteen days after induction of diabetes by streptozotocin (STZ), the animals received rat C-peptide for either 24 h or 7 days. Urinary albumin excretion was measured by ELISA. Glomerular mRNA expression of the transforming growth factor (TGF)-beta(1) and type IV collagen was quantified by real-time PCR. The effect of C-peptide on type IV collagen gene expression in cultured murine podocytes was also examined. RESULTS: C-peptide decreased urinary albumin excretion from 0.29 to 0.18 microg/min (-40.7%, P < 0.01). The transcript level of (alpha3)IV collagen in glomeruli was up-regulated 2.2-fold in diabetic mice and was inhibited by 45-70% (P < 0.05) upon C-peptide treatment. C-peptide suppressed glomerular expression of TGF-beta(1) by 36.6% after 7 days (P < 0.05) but not 24 h after injection. In vitro studies using cultured podocytes revealed that C-peptide dose-dependently inhibited TGF-beta-induced up-regulation of type IV collagen. Moreover, both pertussis toxin (PTX) and a specific inhibitor for extracellular signal-regulated kinase (ERK) pathway reversed the inhibitory effect of C-peptide on TGF-beta. Finally, C-peptide was shown to up-regulate the activity of ERK in podocytes. CONCLUSIONS: These findings indicate that C-peptide suppresses specific aspects of early glomerular changes in a mouse model of diabetes and that the effect is at least in part mediated via interaction with the TGF-beta signal in glomerular podocytes.

Albuminuria↗
PubMedDate not supplied

Hyperglycemia-induced alteration of vascular smooth muscle phenotype.

We have previously reported that high glucose stimulates osteopontin (OPN) expression through protein kinase C-dependent pathway, as well as the hexosamine pathway, in cultured rat aortic smooth muscle cells (SMC). The finding prompted us to study in vivo expression of OPN in diabetes mellitus. In the present study, we found by immunohistochemistry that medial layers of the carotid arteries of streptozotocin (STZ)-induced diabetic rats, as well as the forearm arteries of diabetic patients, stained positive with OPN antibodies, whereas the staining of control rats, as well as nondiabetic patients, was negative. We also found that OPN stimulated migration and enhanced platelet-derived growth factor (PDGF)-mediated DNA synthesis of cultured rat aortic SMC. OPN and PDGF synergistically activated focal adhesion kinase (FAK), as well as extracellular signal-regulated kinase (ERK), which seems to be a reason for OPN-induced enhancement of PDGF-mediated DNA synthesis. Taken together, our present results raise a possibility that OPN plays a role in the development of diabetic vascular complications.

Animals↗
PubMedDate not supplied

Identification and characterization of high glucose and glucosamine responsive element in the rat osteopontin promoter.

We have previously reported that high glucose stimulates osteopontin (OPN) expression via a protein kinase C-dependent pathway and a hexosamine pathway in cultured rat aortic smooth muscle cells (SMCs) [Biochem. Biophys. Res. Commun. 258 (1999) 722.]. In the present study, we carried out functional OPN promoter assays using the luciferase expression vector system in cultured rat aortic SMCs to determine a high glucose/glucosamine responsive element. An extensive deletion analysis of the 5'-flanking region of the rat OPN gene revealed that an element involved in high glucose and glucosamine responses was present within a region between -112 and -62 bp of the OPN promoter. This region is highly conserved in the rat, mouse, and human promoters and contains a number of consensus regions, including an E-box and a GC-rich region. Mutation of the E-box or the GC-rich region resulted in a significant loss of both high glucose and glucosamine responses. These results suggest that two cis-acting elements, the E-box and the GC-rich region, are involved at least partly in high glucose/glucosamine-stimulated transcription of the rat OPN gene.

Animals↗