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1.  Role of Fc Receptors as a Therapeutic Target 
It has been forty years since the discovery of Fc Receptors and their function. Fc Receptors include the IgG receptors (FcγR), high-affinity IgE receptor (FcεRI), IgA and IgA/IgM receptors, and neonatal Fc receptor for IgG (FcRn). In particular, the FcγRs have been well known to play an important role in many biologic processes including those associated with the response to infection and cancer as well as in the pathogenesis of immune-mediated diseases. Both positive and negative regulatory function has ascribed to Fc receptors and FcγRs in particular which serve to establish a threshold for immune cell activation. In other cases, Fc receptors such as FcRn possess a novel structure and function by playing a major role in the transport of IgG across polarized epithelial barriers at mucosal surfaces and in the regulation of IgG half-life. These diverse functions highlight the potential effectiveness of targeting Fc receptors for therapeutic purposes. This review summarizes new information available in the therapeutic applications of this biology.
PMCID: PMC3990358  PMID: 19275696
Fc receptors; FcRn; IgG; FcγR
2.  Intestinal and Hepatic Expression of Cytochrome P450s and mdr1a in Rats with Indomethacin-Induced Small Intestinal Ulcers 
Background: Non-steroidal anti-inflammatory drugs induce the serious side effect of small intestinal ulcerations (SIUs), but little information is available regarding the consequences to drug metabolism and absorption. Aim: We examined the existence of secondary hepatic inflammation in rats with indomethacin (INM)-induced SIUs and assessed its relationship to the cytochrome P450 (CYP) and P-glycoprotein (mdr1a), the major drug-metabolizing factors in the small intestine and the liver. Methods: Gene expression of the CYP family of enzymes and mdr1a was measured with quantitative real-time polymerase chain reaction (qPCR). Vancomycin (VCM), a poorly absorbed drug, was administered intraduodenally to rats with SIUs. Results: INM induced SIUs predominantly in the lower region of the small intestine with high expression of inflammatory markers. Liver dysfunction was also observed, which suggested a secondary inflammatory response in rats with SIUs. In the liver of rats with SIUs, the expression of CYP2C11, CYP2E1, and CYP3A1 was significantly decreased, and loss of CYP3A protein was observed. Although previous studies have shown a direct effect of INM on CYP3A activity, we could not confirm any change in hepatic CY3A4 expression (major isoform of human CYP3A) in vitro. The plasma VCM concentration was increased in rats with SIUs due to partial absorption from the mucosal injury, but not in normal mucosa. Conclusions: INM-induced SIUs had a subtle effect on intestinal CYP expression, but had an apparent action on hepatic CYP, which was influenced, at least in part, by the secondary inflammation. Furthermore, drug absorption was increased in rats with SIUs.
PMCID: PMC4196121  PMID: 25317066
indomethacin; cytochrome P450; P-glycoprotein; secondary inflammation; small intestine.
3.  THRB Genetic Polymorphisms Can Predict Severe Myelotoxicity after Definitive Chemoradiotherapy in Patients with Esophageal Squamous Cell Carcinoma 
Objective: Chemotherapy-related toxicities are difficult to predict before treatment. In this study, we investigated whether thyroid hormone receptor beta (THRB) genetic polymorphisms can serve as a potential biomarker in patients with esophageal squamous cell carcinoma (ESCC).
Methods: Forty-nine Japanese patients with ESCC who received a definitive chemoradiotherapy (CRT) with 5-fluorouracil and cisplatin in conjunction with concurrent irradiation were retrospectively analyzed. Severe acute toxicities, including leukopenia, stomatitis, and cheilitis, were evaluated according to 6 single nucleotide polymorphisms (SNPs) in the gene; the intronic SNPs of rs7635707 G/T, rs6787255 A/C, rs9812034 G/T, and rs9310738 C/T and the SNPs in the 3′-untranslated region (3′-UTR) of rs844107 C/T and rs1349265 G/A.
Results: Distribution of the 4 intronic SNPs, but not the 2 SNPs in the 3′-UTR, showed a significant difference between patients with and without severe acute leukopenia. Stomatitis and cheilitis were not associated with any of the 6 analyzed SNPs. Frequency of haplotype of the 4 intronic SNPs reached approximately 97% with the 2 major haplotypes G-A-G-C (73.4%) and T-C-T-T (23.5%).
Conclusions: THRB intronic SNPs can provide useful information on CRT-related severe myelotoxicity in patients with ESCC. Future studies will be needed to confirm these findings.
PMCID: PMC3491433  PMID: 23136537
esophageal squamous cell carcinoma; thyroid hormone receptor beta; chemoradiotherapy; severe acute toxicity; prognosis.
4.  Inhibitory Effects of Glycyrrhetinic Acid on DNA Polymerase and Inflammatory Activities 
We investigated the inhibitory effect of three glycyrrhizin derivatives, such as Glycyrrhizin (compound 1), dipotassium glycyrrhizate (compound 2) and glycyrrhetinic acid (compound 3), on the activity of mammalian pols. Among these derivatives, compound 3 was the strongest inhibitor of mammalian pols α, β, κ, and λ, which belong to the B, A, Y, and X families of pols, respectively, whereas compounds 1 and 2 showed moderate inhibition. Among the these derivatives tested, compound 3 displayed strongest suppression of the production of tumor necrosis factor-α (TNF-α) induced by lipopolysaccharide (LPS) in a cell-culture system using mouse macrophages RAW264.7 and peritoneal macrophages derived from mice. Moreover, compound 3 was found to inhibit the action of nuclear factor-κB (NF-κB) in engineered human embryonic kidney (HEK) 293 cells. In addition, compound 3 caused greater reduction of 12-O-tetradecanoylphorbol-13-acetate-(TPA-) induced acute inflammation in mouse ear than compounds 1 and 2. In conclusion, this study has identified compound 3, which is the aglycone of compounds 1 and 2, as a promising anti-inflammatory candidate based on mammalian pol inhibition.
PMCID: PMC3138047  PMID: 21785649
5.  Resolvin E1, an endogenous lipid mediator derived from eicosapentaenoic acid, prevents dextran sulfate sodium induced colitis 
Inflammatory bowel diseases  2010;16(1):87-95.
Resolvin E1 (RvE1), an endogenous lipid mediator derived from eicosapentaenoic acid (EPA), has been identified in local inflammation during the healing stage. RvE1 reduces inflammation in several types of animal models including peritonitis and retinopathy, and blocks human neutrophil transendothelial cell migration. The RvE1 receptor ChemR23 is expressed on myeloid cells such as macrophages and dendritic cells. The aim of this study was to determine whether RvE1 regulates colonic inflammation when the innate immune response of macrophages plays a key role in the pathogenesis and tissue damage.
RvE1 receptor, ChemR23, was expressed in mouse peritoneal macrophages as defined by flow cytometry. Peritoneal macrophages were pretreated with RvE1, followed by lipopolysaccharide (LPS) stimulation whereupon of the transcriptional levels of proinflammatory cytokines were analyzed. RvE1 treatment led to the inhibition of proinflammatory cytokines including TNF-α and IL-12p40. In HEK293 cells, pretreatment with RvE1 inhibited TNF-α-induced nuclear translocation of NF-κB in a ChemR23 dependent manner. These results suggested that RvE1 could regulate pro-inflammatory responses of macrophages expressing ChemR23. Therefore, we investigated the beneficial effects of RvE1 in dextran sulfate sodium (DSS) induced colitis. RvE1 treatment led to amelioration of colonic inflammation.
These results indicate that RvE1 suppresses pro-inflammatory responses of macrophages. RvE1 and its receptor may therefore be useful as therapeutic targets in the treatment of human inflammatory bowel disease (IBD) and other inflammatory disorders.
PMCID: PMC3070396  PMID: 19572372
Resolvin E1; macrophage; NF-κB; DSS-induced colitis
6.  Fcγ Receptor Regulation of Citrobacter rodentium Infection▿  
Infection and Immunity  2008;76(4):1728-1737.
Citrobacter rodentium, a murine model pathogen for enteropathogenic Escherichia coli, colonizes the colon utilizing attaching and effacing lesions to adhere specifically to the surfaces of intestinal epithelial cells and cause mucosal inflammation. CD4+ T cells, B cells, and immunoglobulin G (IgG), but not secretory IgA or IgM, play a critical role in eradicating this pathogen. Consistent with the importance of IgG in C. rodentium eradication, IgG transport by the neonatal Fc receptor for IgG within the intestinal epithelium also has a critical role in the regulation of C. rodentium infection. It remains to be determined, however, whether Fcγ receptors (FcγRs), the receptors for the Fc portion of IgG, regulate this bacterial infection within mucosal tissues. Therefore, we investigated the roles of FcγRs during C. rodentium infection. Fc receptor common gamma chain (FcRγ)-deficient mice were more susceptible to C. rodentium-induced colitis. This occurred through decreased efficiency of FcR-mediated endocytosis and maturation of dendritic cells and consequently T-cell activation of antigen-specific T cells. Moreover, in the absence of FcγRs, phagocytosis by macrophages was significantly diminished. Therefore, activating FcγRs play an important role in defending against C. rodentium infection, indicating that the critical role played by IgG in this infection is not mediated by IgG alone but is dependent upon this class of receptors.
PMCID: PMC2292883  PMID: 18227164

Results 1-6 (6)