Expression of cysLT1 and cysLT2 Receptor in Chronic Hyperplastic Eosinophilic Sinusitis

Elevated production of cysteinyl leukotrienes (cysLTs) from sinus tissues and abundant sinus eosinophils are characteristic features of chronic hyperplastic eosinophilic sinusitis (CHS). CysLTs exert their action through G-protein-coupled receptors named cysLTs receptor type I (cysLT1R) and type II (cysLT2R). These expressions of cysLT receptors in the sinus mucosa have yet to be clarified and the relationship between eosinophilia and the expression of these receptors remains obscure. We compared the expressions of cysLT1R and cysLT2R in the sinus mucosa in patients with CHS, non-eosinophilic chronic sinusitis (NECS), and control sinus tissues; and analyzed the correlation between the expression of CysLTRs and the presence of sinus eosinophils by immunohistochemistry and real-time PCR. A significantly higher percentage of eosinophils expressing cysLT2R protein was observed in patients with CHS compared with NECS and controls. In addition, cysLT2R mRNA expression in CHS was significantly higher than in NECS and controls. Furthermore, a positive correlation was observed between cysLT2R mRNA expression and the number of infiltrated eosinophils. In contrast, the cysLT1R mRNA expression did not differ significantly among these groups. The effect of cysLTs on sinus eosinophils may be mediated through the cysLT2R in patients with CHS. These results may suggest the therapeutic benefit of cysLT2R antagonists in CHS

Differential impact of Ink4a and Arf on hematopoietic stem cells and their bone marrow microenvironment in Bmi1-deficient mice

The polycomb group (PcG) protein Bmi1 plays an essential role in the self-renewal of hematopoietic and neural stem cells. Derepression of the Ink4a/Arf gene locus has been largely attributed to Bmi1-deficient phenotypes in the nervous system. However, its role in hematopoietic stem cell (HSC) self-renewal remained undetermined. In this study, we show that derepressed p16Ink4a and p19Arf in Bmi1-deficient mice were tightly associated with a loss of self-renewing HSCs. The deletion of both Ink4a and Arf genes substantially restored the self-renewal capacity of Bmi1−/− HSCs. Thus, Bmi1 regulates HSCs by acting as a critical failsafe against the p16Ink4a- and p19Arf-dependent premature loss of HSCs. We further identified a novel role for Bmi1 in the organization of a functional bone marrow (BM) microenvironment. The BM microenvironment in Bmi1−/− mice appeared severely defective in supporting hematopoiesis. The deletion of both Ink4a and Arf genes did not considerably restore the impaired BM microenvironment, leading to a sustained postnatal HSC depletion in Bmi1−/−Ink4a-Arf−/− mice. Our findings unveil a differential role of derepressed Ink4a and Arf on HSCs and their BM microenvironment in Bmi1-deficient mice. Collectively, Bmi1 regulates self-renewing HSCs in both cell-autonomous and nonautonomous manners

Association of IL28B gene polymorphism with development of hepatocellular carcinoma in Japanese patients with chronic hepatitis C virus infection

IL28B single nucleotide polymorphisms (SNPs) are associated with spontaneous and treatment-induced elimination of hepatitis C virus (HCV). To assess whether the IL28B rs8099917 SNP also affects the progression of chronic HCV infection, we genotyped 511 Japanese HCV patients, including 69 with hepatocellular carcinoma (HCC). The T/T genotype of rs8099917 was not associated with the development of HCC (p = 0.623), although stepwise logistic regression analysis showed that liver cirrhosis, age greater than 68 years, and serum albumin <4.2 mg/dl were associated with HCC onset. It appears that the IL28B SNP does not directly influence hepatocarcinogenesis in chronic HCV infection.ArticleHUMAN IMMUNOLOGY. 73(3):298-300 (2012)journal articl

Kidney transplantation recovers the reduction level of serum sulfatide in ESRD patients via processes correlated to oxidative stress and platelet count

Sulfatide is a major component of glycosphingolipids in lipoproteins. Recently, we reported that a low serum level of sulfatide in hemodialysis patients might be related to the high incidence of cardiovascular diseases. However, the serum kinetics of sulfatide in kidney disease patients and the function of endogenous serum sulfatide are still unclear. To obtain novel knowledge concerning these issues, we investigated the serum kinetics of sulfatide in 5 adult kidney transplant recipients. We also analyzed the correlated factors influencing the serum sulfatide level, using multiple regression analysis. Kidney transplantation caused a dramatic increase of serum sulfatide without an alteration of its composition in all recipients in a time-dependent manner; however, the recovery speed was slower than that of the improvement of kidney function and the serum sulfatide reached a nearly normal level after 1 year. Multiple regression analysis showed that the significant correlated factor influencing the serum sulfatide level was log duration (time parameter) throughout the observation period, and the correlated factors detected in the stable phase were the decrease of serum concentration of malondialdehyde (an oxidative stress marker) as well as the elevation of platelet count. The current study results demonstrated the gradual but reliable recovery of the serum sulfatide level in kidney transplant recipients for the first time, suggesting a close correlation between serum sulfatide and kidney function. The recovery of serum sulfatide might derive from the attenuation of systemic oxidative stress. The normal level of serum sulfatide in kidney transplant recipients might affect platelet function, and contribute to the reduction of cardiovascular disease incidence.ArticleGLYCOCONJUGATE JOURNAL. 28(3-4):125-135 (2011)journal articl

Acute kidney injury induced by protein-overload nephropathy down-regulates gene expression of hepatic cerebroside sulfotransferase in mice, resulting in reduction of liver and serum sulfatides

Sulfatides, possible antithrombotic factors belonging to sphingoglycolipids, are widely distributed in mammalian tissues and serum. We recently found that the level of serum sulfatides was significantly lower in hemodialysis patients than that in normal subjects, and that the m serum level closely correlated to the incidence of cardiovascular disease. These findings suggest a relationship between the level of serum sulfatides and kidney function; however, the molecular mechanism underlying this relationship remains unclear. In the present study, the influence of kidney dysfunction on the metabolism of sulfatides was examined using an established murine model of acute kidney injury, protein-overload nephropathy in mice. Protein-overload treatment caused severe proximal tubular injuries within 4 days, and this treatment obviously decreased both serum and hepatic sulfatide levels. The sphingoid composition of serum sulfatides was very similar to that of hepatic ones at each time point, suggesting that the serum sulfatide level is dependent on the hepatic secretory ability of sulfatides. The treatment also decreased hepatic expression of cerebroside sulfotransferase (CST), a key enzyme in sulfatide metabolism, while it scarcely influenced the expression of the other sulfatide-metabolizing enzymes, including arylsulfatase A, ceramide galactosyltransferase, and galactosylceramidase. Pro-inflammatory responses were not detected in the liver of these mice: however, potential oxidative stress was increased. These results suggest that down-regulation of hepatic CST expression, probably affected by oxidative stress from kidney injury, causes reduction in liver and serum sulfatide levels. This novel mechanism, indicating the crosstalk between kidney injury and specific liver function, may prove useful for helping to understand the situation where human hemodialysis patients have low levels of serum sulfatides.ArticleBIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS. 390(4):1382-1388 (2009)journal articl

Peroxisome proliferator-activated receptor alpha mediates enhancement of gene expression of cerebroside sulfotransferase in several murine organs

Sulfatides, 3-O-sulfogalactosylceramides, are known to have multifunctional properties. These molecules are distributed in various tissues of mammals, where they are synthesized from galactosylceramides by sulfation at C3 of the galactosyl residue. Although this reaction is specifically catalyzed by cerebroside sulfotransferase (CST), the mechanisms underlying the transcriptional regulation of this enzyme are not understood. With respect to this issue, we previously found potential sequences of peroxisome proliferator-activated receptor (PPAR) response element on upstream regions of the mouse CST gene and presumed the possible regulation by the nuclear receptor PPAR alpha. To confirm this hypothesis, we treated wild-type and Ppara-null mice with the specific PPAR alpha agonist fenofibrate and examined the amounts of sulfatides and CST gene expression in various tissues. Fenofibrate treatment increased sulfatides and CST mRNA levels in the kidney, heart, liver, and small intestine in a PPAR alpha-dependent manner. However, these effects of fenofibrate were absent in the brain or colon. Fenofibrate treatment did not affect the mRNA level of arylsulfatase A, which is the key enzyme for catalyzing desulfation of sulfatides, in any of these six tissues. Analyses of the DNA-binding activity and conventional gene expression targets of PPAR alpha has demonstrated that fenofibrate treatment activated PPAR alpha in the kidney, heart, liver, and small intestine but did not affect the brain or colon. These findings suggest that PPAR alpha activation induces CST gene expression and enhances sulfatide synthesis in mice, which suggests that PPAR alpha is a possible transcriptional regulator for the mouse CST gene.ArticleGLYCOCONJUGATE JOURNAL. 30(6):553-560 (2013)journal articl