Shigeto Mizuno

Helicobacter pylori Infection and Gastric Cancer A Nested Case± Control Study in a Rural Area of Japan

We conducted a seroepidemiological nested case-control study to determine the association of gastriccancer with Helicobacter pylori infection and atrophicgastritis. A cohort of 2858 participants in an annual multiphasic health check-up werefollowed for eight years. Data for 45 gastric cancercases and 225 sex-, age-, and address-matched controlsubjects were analyzed. Helicobacter pylori infectionwas determined by IgG antibodies, and atrophicgastritis was diagnosed by both serum pepsinogen I level(≤70 ng/ml) and the pepsinogen I/II ratio (≤3.0).Univariate analysis showed that Helicobacter pylori and atrophic gastritis were significantlyassociated with gastric cancer. In a multivariateanalysis, atrophic gastritis was associated withsignificantly increased risk of cancer (odds ratio,3.38; 95% confidence interval, 1.54-7.42); however,Helicobacter pylori was not associated with cancer (oddsratio, 1.84; 95% confidence interval, 0.59-5.72). Theseresults suggest that Helicobacter pylori infection alone is not directly associated with gastriccarcinogenesis but has an indirect relation to gastriccancer through the development of atrophicgastritis.

Resolvin E1, an endogenous lipid mediator derived from eicosapentaenoic acid, prevents dextran sulfate sodium-induced colitis

Background: Resolvin E1 (RvE1), an endogenous lipid mediator derived from eicosapentaenoic acid, 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 pathogenesis and tissue damage. Methods: The RvE1 receptor ChemR23 was expressed in mouse peritoneal macrophages as defined by flow cytometry. Peritoneal macrophages were pretreated with RvE1, followed by lipopolysaccharide stimulation, whereupon transcriptional levels of proinflammatory cytokines were analyzed. Results: RvE1 treatment led to inhibition of proinflammatory cytokines including TNF‐&agr; and IL‐12p40. In HEK293 cells, pretreatment with RvE1 inhibited TNF‐&agr;‐induced nuclear translocation of NF‐&kgr;B in a ChemR23‐dependent manner. These results suggested that RvE1 could regulate proinflammatory responses of macrophages expressing ChemR23. Therefore, we investigated the beneficial effects of RvE1 in dextran sulfate sodium–induced colitis. RvE1 treatment led to amelioration of colonic inflammation. Conclusions: These results indicate that RvE1 suppresses proinflammatory responses of macrophages. RvE1 and its receptor may therefore be useful as therapeutic targets in the treatment of human inflammatory bowel disease and other inflammatory disorders. Inflamm Bowel Dis 2010

Maitake β-glucan enhances therapeutic effect and reduces myelosupression and nephrotoxicity of cisplatin in mice

Cisplatin is broadly used clinically as an anticancer drug. Despite its significant anticancer activity, cisplatin-induced nephrotoxicity and myelosuppression limit its use. MD-Fraction is glucan purified from maitake (Grifola frondosa), which has beta-1, 6-main chain with beta-1, 3-branches, has been reported to exhibit antitumor and antimetastatic activities by enhancing the immune system. In this study, we demonstrate that MD-Fraction in combination with cisplatin significantly enhanced antitumor and antimetastatic activity compared to cisplatin alone. MD-Fraction reduced decreases in body weight, spleen weight and the number of immunocompetent cells such as macrophages, DCs and NK cells in cisplatin-treated mice. MD-Fraction also induced IL-12p70 production by splenocytes, resulting in increased NK cell activity in cisplatin-treated mice. MD-Fraction significantly increased the mRNA expression of GM-CSF, G-CSF, M-CSF, IFN-gamma, IL-12 p40 in splenocytes and reduced the decrease in the number of CFU-GM colonies in cisplatin-treated bone marrow. These facts suggest that MD-Fraction can reduce cisplatin-induced myelosuppression. Moreover, treatment with MD-Fraction significantly reduced cisplatin-induced nephrotoxicity accompanied by increases in serum creatinine level, necrosis and apoptosis of renal tubular cells. These results suggest that MD-Fraction in combination with cisplatin cannot only enhance antitumor and antimentastatic acitivity, but also reduce cisplatin-induced myelotoxicity and nephrotoxicity.

Soluble β-glucan from Grifola frondosa induces proliferation and Dectin-1/Syk signaling in resident macrophages via the GM-CSF autocrine pathway

MD‐Fraction, a highly purified, soluble β‐(1,3) (1,6)‐glucan obtained from Grifola frondosa (an oriental edible mushroom), has been reported to inhibit tumor growth by modulating host immunity. β‐Glucan, a major component of the fungal cell wall, is generally recognized by PRRs expressed on macrophages and DCs, such as Dectin‐1, and the ability of β‐glucans to modulate host immunity is influenced by their structure and purity. Most cellular studies have used particulate β‐glucans, such as yeast zymosan (crude β‐glucan) and curdlan (purified β‐glucan). However, little is known about the cellular mechanism of soluble β‐glucans, including MD‐Fraction, despite significant therapeutic implications. In this study, we investigated the cellular mechanism of MD‐Fraction in murine resident macrophages and compared it with two well‐known β‐glucan particles. MD‐Fraction induced GM‐CSF production rapidly through Dectin‐1‐independent ERK and p38 MAPK activation. Subsequently, MD‐Fraction‐induced GM‐CSF enhanced proliferation and Dectin‐1 expression, which permitted Dectin‐1‐mediated TNF‐α induction through the Syk pathway. Curdlan induced not only the proliferation and activation of Dectin‐1/Syk signaling in a manner similar to MD‐Fraction but also the uncontrolled, proinflammatory cytokine response. Contrastingly, zymosan reduced proliferation and Dectin‐1 expression significantly, indicating that the mechanism of macrophage activation by MD‐Fraction differs from that of zymosan. This is the first study to demonstrate that purified β‐glucans, such as MD‐Fraction and curdlan, induce GM‐CSF production directly, resulting in Dectin‐1/Syk activation in resident macrophages. In conclusion, we demonstrated that MD‐Fraction induces cell proliferation and cytokine production without excessive inflammation in resident macrophages, supporting its immunotherapeutic potential.

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.

Validation of the pepsinogen test method for gastric cancer screening using a follow-up study

BackgroundSerum pepsinogen (PG) measurement has been used for gastric cancer screening since the 1990s. However, there are no reports comparing the screening validity of the PG test method with that of conventional X-ray examination directly in the same population, using a follow-up study.MethodsFrom April 2000 to March 2001, 12 120 residents of Osaka Prefecture, who underwent opportunistic screening at a medical checkup organization in Osaka city (hereafter, “the organization”), were enrolled. They received both a barium meal examination and PG test simultaneously. All the participants were followed up for a 1-year period after the screening. For the participants advised to undergo endoscopic examination, the results of those who were examined at the organization were tallied. The other participants were checked using the Osaka Cancer Registry (hereafter, “the registry”).ResultsOf the 12 120 participants, 493 (4.1%) were positive with the PG method and 728 (6.0%) were positive with the X-ray method. Fifty-four (0.4%) were positive for both methods. Thirteen gastric cancer cases were diagnosed by successive esophagogastroduodenoscopies at the organization. Six additional gastric cancer cases were identified by record linkage with the registry. The sensitivity, specificity, and positive predictive values of the PG method with a PGI cutoff level of ≤30 ng/ml and PGI/PGII ratio of ≤2.0 were 36.8%, 96.0%, and 1.4%, respectively. These values for the direct X-ray examination were 68.4%, 94.1%, and 1.8%, respectively.ConclusionThe PG test method alone with a PGI cutoff level of ≤30 ng/ml and PGI/PGII ≤ 2.0 is not appropriate for gastric cancer screening.

Synergistic effect of HLA class II loci and cytokine gene polymorphisms on the risk of gastric cancer in Japanese patients with Helicobacter pylori infection

It has been reported that polymorphisms of human leukocyte antigen (HLA) genes and several cytokine genes are associated with an increased risk of developing gastric cancer (GC). However, the results of studies from different geographic regions, ethnic groups and study groups are inconsistent. The aim of this study was to evaluate the influence of H. pylori infection and host genetic factors on GC susceptibility in Japanese patients with GC. We analyzed genotypes for HLA class I and II, tumor necrosis factor α, interleukin (IL)‐1β, IL‐1 receptor, IL‐4, IL‐4Rα and IL‐10 in 330 H. pylori‐infected noncardia patients with GC and 190 H. pylori‐infected nonulcer dyspeptic controls. Haplotype analyses indicated that the frequencies of the HLA DRB1*0405 and DQB1*0401 alleles were increased in the patients with intestinal‐type GC when compared with controls (both DRB1*0405 and DQB1*0401: p = 0.015, OR = 1.57, 95% CI = 1.09–2.26), but the changes were not statistically significant after correction for multiple comparisons. None of the cytokine gene polymorphisms were associated with GC susceptibility, whether patients with GC were analyzed as a group according to the histological subtype. Of interest was the comparison of controls and patients with intestinal‐type GC. The frequency of an IL‐10‐592AA homozygote showing concomitant carriage of the HLA DRB1*0405‐DQB1*0401 haplotype was significantly higher in patients with intestinal‐type GC (χ2 = 6.369, p = 0.0116, pc = 0.0464, OR = 2.43, 95% CI = 1.21–4.48). Our results suggest that the HLA class II and IL‐10‐592A/C polymorphisms synergistically affect the susceptibility to GC development of H. pylori‐infected individuals in the Japanese population.

Helicobacter pylori infection and atrophic gastritis : A case-control study in a rural town of Japan

We enrolled five hundred twenty-one patients with atrophic gastritis and 769 controls in a case-control study of atrophic gastritis and Helicobacter pylori infection and lifestyle factors. The participants had no history of upper gastrointestinal surgery. They were selected from 1,395 adult (35 years or older) residents of a rural town in Kyoto prefecture who participated in an annual health examination in 1987. Atrophic gastritis was diagnosed on the basis of serum pepsinogen levels: pepsinogen I levels (< or = 70 ng/ml) and pepsinogen I/pepsinogen II ratios (< or = 3.0). The presence of immunoglobulin G antibodies to H. pylori indicated H. pylori infection. At the time of the health examination, participants were interviewed about daily lifestyle habits such as use of cigarettes and alcoholic beverages and consumption of green-yellow vegetables. Unconditional logistic regression analysis indicated that H. pylori infection was associated with a significantly increased risk for atrophic gastritis for all participants (odds ratio, 8.17; 95% confidence interval, 5.63-11.84); for men (odds ratio, 10.91; 95% CI, 5.25-22.67); and for women (odds ratio, 7.28; 95% CI, 4.72-11.22). We found no statistically significant relations between lifestyle factors and atrophic gastritis.

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 (FcgammaR), high-affinity IgE receptor (FcepsilonRI), IgA and IgA/IgM receptors, and neonatal Fc receptor for IgG (FcRn). In particular, the FcgammaRs 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 FcgammaRs 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.

Vitamin K3 attenuates lipopolysaccharide-induced acute lung injury through inhibition of nuclear factor-κB activation

Vitamin K is a family of fat‐soluble compounds including phylloquinone (vitamin K1), menaquinone (vitamin K2) and menadione (vitamin K3). Recently, it was reported that vitamin K, especially vitamins K1 and K2, exerts a variety of biological effects, and these compounds are expected to be candidates for therapeutic agents against various diseases. In this study, we investigated the anti‐inflammatory effects of vitamin K3 in in vitro cultured cell experiments and in vivo animal experiments. In human embryonic kidney (HEK)293 cells, vitamin K3 inhibited the tumour necrosis factor (TNF)‐α‐evoked translocation of nuclear factor (NF)‐κB into the nucleus, although vitamins K1 and K2 did not. Vitamin K3 also suppressed the lipopolysaccharide (LPS)‐induced nuclear translocation of NF‐κB and production of TNF‐α in mouse macrophage RAW264·7 cells. Moreover, the addition of vitamin K3 before and after LPS administration attenuated the severity of lung injury in an animal model of acute lung injury/acute respiratory distress syndrome (ARDS), which occurs in the setting of acute severe illness complicated by systemic inflammation. In the ARDS model, vitamin K3 also suppressed the LPS‐induced increase in the serum TNF‐α level and inhibited the LPS‐evoked nuclear translocation of NF‐κB in lung tissue. Despite marked efforts, little therapeutic progress has been made, and the mortality rate of ARDS remains high. Vitamin K3 may be an effective therapeutic strategy against acute lung injury including ARDS.