Nuclear co-expression of p21 and p27 induced effective cell-cycle arrest in T24 cells treated with BCG.

A proposed mechanism underlying the effect of bacillus Calmette-Guérin (BCG) treatment for bladder cancer cells is as follows: BCG-induced crosslinking of cell-surface receptors results in the activation of signaling cascades, including cell-cycle regulators. However, the clinical significance of cell-cycle regulators such as p21 and p27 is controversial. Here we investigated the relationship between BCG exposure and p21 and p27.

Adjusting the 17β-Estradiol-to-Androgen Ratio Ameliorates Diabetic Nephropathy.

Diabetes is manifested predominantly in males in experimental models, and compelling evidence suggests that 17β-estradiol (E2) supplementation improves hyperglycemia in humans. We previously generated a severely diabetic transgenic (Tg) mouse model by β-cell–specific overexpression of inducible cAMP early repressor (ICER) and found that male but not female ICER-Tg mice exhibit sustained hyperglycemia and develop major clinical and pathologic features of human diabetic nephropathy (DN). Thus, we hypothesized that differences in circulating hormone levels have a key role in determining susceptibility to diabetes.

TYK2 Promoter Variant and Diabetes Mellitus in the Japanese.

Background: Recently, natural mutation of Tyrosine kinase 2 (Tyk2) gene has been shown to determine susceptibility to murine virus-induced diabetes. In addition, a previous human genome-wide study suggested the type 1 diabetes (T1D) susceptibility region to be 19p13, where the human TYK2 gene is located (19p13.2).

Reduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes.

Accumulating evidence suggests that viruses play an important role in the development of diabetes. Although the diabetogenic encephalomyocarditis strain D virus induces diabetes in restricted lines of inbred mice, the susceptibility genes to virus-induced diabetes have not been identified. We report here that novel Tyrosine kinase 2 (Tyk2) gene mutations are present in virus-induced diabetes-sensitive SJL and SWR mice.

Regulation of human autoimmune regulator (AIRE) gene translation by miR-220b.

Although mutations of autoimmune regulator (AIRE) gene are responsible for autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), presenting a wide spectrum of many characteristic and non-characteristic clinical features, some patients lack AIRE gene mutations. Therefore, something other than a mutation, such as dysregulation of AIRE gene, may be a causal factor for APECED or its related diseases. However, regulatory mechanisms for AIRE gene expression and/or translation have still remained elusive.

Liver-derived systemic factors drive β cell hyperplasia in insulin-resistant states.

Integrative organ crosstalk regulates key aspects of energy homeostasis, and its dysregulation may underlie metabolic disorders such as obesity and diabetes. To test the hypothesis that crosstalk between the liver and pancreatic islets modulates β cell growth in response to insulin resistance, we used the liver-specific insulin receptor knockout (LIRKO) mouse, a unique model that exhibits dramatic islet hyperplasia. Using complementary in vivo parabiosis and transplantation assays, as well as in vitro islet culture approaches, we demonstrate that humoral, nonneural, non-cell-autonomous factor(s) induces β cell proliferation in LIRKO mice.

Birth and death of human β-cells in pancreases from cadaver donors, autopsies, surgical specimens, and islets transplanted into mice.

There is great interest in the potential of the human endocrine pancreas for regeneration by β-cell replication or neogenesis. Our aim was to explore this potential in adult human pancreases and in both islet and exocrine tissue transplanted into mice. The design was to examine pancreases obtained from cadaver donors, autopsies, and fresh surgical specimens and compare these findings with those obtained from islet and duct tissue grafted into the kidney.

Subpopulations of GFP-marked mouse pancreatic β-cells differ in size, granularity, and insulin secretion.

There is growing information about the heterogeneity of pancreatic β-cells and how it relates to insulin secretion. This study used the approach of flow cytometry to sort and analyze β-cells from transgenic mice expressing green fluorescent protein (GFP) under the control of the mouse insulin I gene promoter. Three populations of β-cells with differing GFP brightness could be identified, which were classified as GFP-low, GFP-medium, and GFP-bright.

Protective unfolded protein response in human pancreatic beta cells transplanted into mice.

Background: There is great interest about the possible contribution of ER stress to the apoptosis of pancreatic beta cells in the diabetic state and with islet transplantation.

Methods And Findings: Expression of genes involved in ER stress were examined in beta cell enriched tissue obtained with laser capture microdissection (LCM) from frozen sections of pancreases obtained from non-diabetic subjects at surgery and from human islets transplanted into ICR-SCID mice for 4 wk. Because mice have higher glucose levels than humans, the transplanted beta cells were exposed to mild hyperglycemia and the abnormal environment of the transplant site.

Adult mouse intrahepatic biliary epithelial cells induced in vitro to become insulin-producing cells.

Transdifferentiation of cells from a patient's own liver into pancreatic beta-cells could be useful for beta-cell replacement. We hypothesized that intrahepatic biliary epithelial cells (IHBECs) could become a new source of insulin-producing cells. IHBECs isolated from adult mice were expanded using our novel culture method termed, collagen-embedded floating culture method (CEFCM).

Carbonic anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth.

The regenerative process in the pancreas is of particular interest because diabetes results from an inadequate number of insulin-producing beta cells and pancreatic cancer may arise from the uncontrolled growth of progenitor/stem cells. Continued and substantial growth of islet tissue occurs after birth in rodents and humans, with additional compensatory growth in response to increased demand. In rodents there is clear evidence of pancreatic regeneration after some types of injury, with proliferation of preexisting differentiated cell types accounting for some replacement.

Adverse effects of obesity on β-cell function in Japanese subjects with normal glucose tolerance.

The purpose of the present study was to elucidate the role of obesity in both early- and late-phase insulin secretion during an oral glucose tolerance test (OGTT) performed with 75 g glucose in Japanese subjects. This was performed using indices of β-cell function adjusted for insulin sensitivity. Of 155 subjects assessed, 68 had normal glucose tolerance (NGT) and 87 had impaired glucose tolerance (IGT).

The significance of T cells, B cells, antibodies and macrophages against encephalomyocarditis (EMC)-D virus-induced diabetes in mice.

In order to clarify the significance of protective mechanisms against encephalomyocarditis (EMC) virus-induced diabetes in mice, we studied the relative importance of T cells, B cells, antibodies and macrophages in the prevention of virus-induced diabetes. Neither T cell-deficient athymic nude mice nor B cell-deficient microMT/microMT mice showed an enhanced clinical course of EMC-D virus-induced diabetes, indicating that neither T cells nor B cells played a major role in the protection against EMC-D-virus-induced diabetes. Transfer of a large amount of antiserum to EMC-D-virus-infected mice protected the development of diabetes only when transferred within 36 h of infection, the timing of which was earlier than that for the production of natural neutralizing antibodied.

Patients with dilated cardiomyopathy possess insulin resistance independently of cardiac dysfunction or serum tumor necrosis factor-alpha.

It has recently been reported that insulin resistance is prevalent in patients with dilated cardiomyopathy (DCM); however, it remains unclear whether insulin resistance is directly induced by DCM or if it is caused by congestive heart failure associated with DCM. We evaluated homeostasis model assessment insulin resistance (HOMA-R) in 14 patients with DCM in comparison with 9 patients with valvular heart diseases (VHD). We also measured the level of serum tumor necrosis factor (TNF)-alpha as a possible causative factor for inducing insulin resistance.

Autoimmune regulator (AIRE) gene is expressed in human activated CD4+ T-cells and regulated by mitogen-activated protein kinase pathway.

The autoimmune regulator (AIRE) gene is a gene responsible for autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Here we show that AIRE is expressed in human peripheral CD4-positive T-cells, and most highly in antigen-and interleukin 2-stimulated T (IL-2T) cells. Mitogen-activated protein kinases (MAPKs), including MAPK kinase (MEK) 1/2 and p38 MAPK, were phosphorylated in IL-2T cells and the expression of the AIRE gene was inhibited by a specific p38 MAPK inhibitor (SB203580), thereby indicating that AIRE gene expression is controlled by the MAPK pathway in IL-2T cells.

[A case of metabolic syndrome with coronary artery disease advanced over 13 years. Case report].

A 61-year-old man was diagnosed with obesity, diabetes mellitus, and hyperlipidemia associated with insulin resistance in 1988. His condition was complicated with asymptomatic coronary artery disease in 1992. His coronary artery disease gradually progressed during the subsequent 13 years of observation, and he underwent percutaneous coronary intervention four times and also received a coronary artery bypass graft.

cDNA microarray analysis after laser microdissection in proliferating islets of partially pancreatectomized mice.

With islet transplantation having grown in popularity since the introduction of the Edmonton protocol, how to secure an unlimited source of islets has become an urgent problem. To resolve this problem, techniques to induce or proliferate islets are urgently required. To achieve this goal, gene expression analysis using a cDNA microarray in islets of partially pancreatectomized mice, in which the remaining islets regenerate and proliferate with insulin secretion and glucose responsiveness, provides us with valuable information.

[B cells as key contributors in determining the level of immune responses -B-cell-targeted therapy in patients with autoimmune diseases].

The levels and types of immune responses are determined dependent on the extent of pathogen invasion, reactions to antigens mediated by macrophage-dendritic cells, T cells and antibodies. Recently, accumulating evidence suggests that B cells also play an important role in the regulation of immune responses. Here we have made a review to present a role of B cells in determining the level of immune responses and discussed about the clinical significance of B cell-targeted therapy in patients with autoimmune diseases.

Mitogen-activated protein kinase pathway controls autoimmune regulator (AIRE) gene expression in granulo-monocyte colony stimulating factor (GM-CSF)-stimulated myelomonocytic leukemia OTC-4 cells.

Autoimmune regulator (AIRE) gene is a responsible gene for the rare autosomal recessive autoimmune disease: autoimmune-polyendocrinopathy-candidiasis ectodermal dystrophy (APECED). Although it has been reported that AIRE is expressed in the thymic epithelial cells and monocyte-dendritic cell lineage, the regulatory mechanisms of AIRE gene expression have as yet been poorly understood. Here we show that the expression of AIRE gene was induced in granulo-monocyte colony stimulating factor (GM-CSF)-stimulated myelomonocytic leukemia OTC-4 cells.

A delayed type hypersensitivity (DTH) skin reaction to hepatitis B surface antigen (HBsAg) and intradermal hepatitis B vaccination.

The significance of a delayed type hypersensitivity skin reaction to hepatitis B surface antigen (HBsAg) (HBs-DTH) in type B viral hepatitis (VHB) and in intradermal hepatitis B (HB) vaccination is reviewed. HBs-DTH could be developed by the intradermal injection of HB vaccine in anti-HBs positive people and also in persons immunized with HB vaccine. Thus, HBs-DTH could serve as a useful marker for the acquisition of an active Th1 type immunoreactivity to HBsAg.

Acceptance of islet allografts in the liver of mice by blockade of an inducible costimulator.

Background: An inducible costimulator (ICOS) has been found to be a novel costimulator for T-cell activation, although its precise role in transplant immunobiology remains unclear. This study determined whether ICOS plays an essential role in rejection of intrahepatic islet allografts in streptozotocin-induced diabetic mice.

Methods: Mononuclear cells in the liver of mice were isolated and examined by flow cytometry with respect to expression of ICOS in association with rejection, and the effects of in vivo treatment with an anti-ICOS antibody on survival of intrahepatic islet allografts were determined.

Distinct clinical phenotype and immunoreactivity in Japanese siblings with autoimmune polyglandular syndrome type 1 (APS-1) associated with compound heterozygous novel AIRE gene mutations.

We herein report on two Japanese siblings with autoimmune polyglandular syndrome type 1 (APS-1). The brother, who expressed a characteristic phenotype of APS-1, had developed severe mucocutaneous candidiasis in early infancy and thereafter developed hypoparathyroidism and Addison's disease, along with a severe deterioration of his immunologic function. In contrast, the 44-year-old sister, who showed a noncharacteristic phenotype of APS-1, developed insulin-dependent diabetes with high anti-glutamic acid decarboxylase antibody, mild nail candidiasis, and autoimmune hepatitis with intact immunoreactivity.

Expression of AIRE gene in peripheral monocyte/dendritic cell lineage.

The responsible gene for autoimmune polyglandular syndrome type 1, known as autoimmune regulator (AIRE), was identified by positional cloning. The AIRE gene was reported to be expressed in the thymus medulla and lymph nodes. However, an expression of the AIRE gene in peripheral blood cells has not yet been reported.