Junichi Nagakawa

Involvement of tumor necrosis factor-α in the pathogenesis of activated macrophage-mediated hepatitis in mice

The possible involvement of tumor necrosis factor-alpha in the pathogenesis of an experimentally induced hepatitis was investigated. Balb/c mice were primed with Propionibacterium acnes to induce the infiltration of mononuclear cells into the liver. Immunohistochemical study showed that most of the accumulated mononuclear cells at 7 days were Mac-2 positive, suggesting that they were activated macrophages. An injection of lipopolysaccharide resulted in massive hepatic necrosis and high mortality in the mice within 24 hours. Plasma tumor necrosis factor-alpha activity initially rose sharply and then declined over 3 hours. The increase in plasma aminotransferase activity correlated well with the elevation of plasma tumor necrosis factor-alpha activity. Pretreatment with dexamethasone or 16,16-dimethyl-prostaglandin E2 attenuated not only the elevation of plasma tumor necrosis factor-alpha activity but also the increase in plasma aminotransferase activity and improved the survival rate. Passive immunization against tumor necrosis factor-alpha showed protective effects. These findings suggest that tumor necrosis factor-alpha released from activated macrophages may play a crucial role in the pathogenesis of this murine hepatitis.

Suppressive effects of E3330, a novel quinone derivative, on tumor necrosis factor-α generation from monocytes and macrophages

E3330 {(2E)-3-[5-(2,3-dimethoxy-6-methyl-1,4-benzoquinoyl)]-2-nonly-2-propenoic acid}, a novel synthesized hepatoprotective compound, has suppressive effects on tumor necrosis factor-α (TNF-α) generation from monocytes/macrophagesin vitro. E3330 (1–100 μM) reduced lipopolysaccharide (LPS, 10 mg/ml or 1μg/ml)-induced TNF-α generation from rat resident andPropionibacterium acnes (P. acnes)-elicited peritoneal macrophages, rat and human monocytes, rat Kupffer cells, and splenic mononuclear cells in a concentration-dependent manner. E3330 also (1–100 μM) suppressed TNF-α generation stimulated with egg-albumin immune complex in ratP. acnes-elicited peritoneal macrophages. Northern blot analysis showed that LPS-induced expression of TNF-α messenger RNA (mRNA) in human blood monocytes was suppressed by E3330. These findings indicate that E3330 has a suppressive effect on TNF-α generation from monocytes/macrophages, regardless of origin or species, and this effect is based in part on the suppression of TNF-α mRNA expression.

Protective effects of E3330, a novel quinone derivative, on galactosamine/tumor necrosis factor-α-induced hepatitis in mice

Oral pretreatment with E3330, a novel quinone derivative, attenuated liver injury induced with tumor necrosis factor-alpha in galactosamine-sensitized mice. Tumor necrosis factor-alpha is known to induce inflammatory mediators such as leukotrienes and prostanoids. An in vitro study showed that E3330 inhibited the generation of leukotriene B4 and thromboxane B2, but enhanced prostaglandin E2 generation from rat peritoneal exudate cells stimulated with the Ca(2+)-ionophore, A23187. These findings suggest that the protective effect of E3330 on galactosamine/tumor necrosis factor-alpha hepatitis is due at least in part to its inhibition of the generation of leukotrienes. The inhibition of thromboxane B2 generation or the enhancement of prostaglandin E2 generation by E3330 may also contribute to its hepatoprotective effect.

E3710, a new proton pump inhibitor, with a long lasting inhibitory effect on gastric acid secretion

We have investigated the pharmacology of sodium (R)-2-[4-(2,2-dimethyl-1,3-dioxan-5-yl) methoxy-3,5-dimethylpyridin-2-yl]methylsulfinyl-1H-benzimidazol (E3710), a new proton pump inhibitor (PPI), and its effect on gastric acid secretion. E3710 irreversibly inhibited H+,K+-ATPase activity in pig gastric vesicles with an acidic internal environment with an IC50 of 0.28 μM. Administration of E3710 (0.1, 0.2, 0.4, and 0.8 mg/kg; n = 6) intraduodenally in a gastric fistula model in dogs inhibited histamine-stimulated gastric acid secretion at 0 to 2 and 24 to 26 h after administration with ED50 values of 0.18 and 0.22 mg/kg, respectively. The inhibition by E3710 was 2.3 times more potent than that of another representative PPI, esomeprazole (0.2, 0.4, 0.8, and 1.6 mg/kg; n = 6) at 0 to 2 h after administration (ED50 = 0.40 mg/kg) and 2.8 times more potent at 24 to 26 h (ED50 = 0.71 mg/kg). In the gastric fistula dogs, the intragastric pH was ≥4 for 17% (n = 27) of a 24-h period with vehicle alone, but when E3710 was administered, at 0.2 (n = 4), 0.4 (n = 8), and 0.8 mg/kg (n = 5), the pH was ≥4 for 40, 79, and 88% of a day, respectively. The corresponding values for esomeprazole at 0.8 (n = 4) and 1.6 mg/kg (n = 8) were 55 and 59%, respectively. In a crossover study with vehicle, E3710 at 0.4 mg/kg and esomeprazole at 1.6 mg/kg (n = 6), E3710 increased the intragastric pH to >4 for 82% of a day compared with 61% of a day with esomeprazole. These results show that E3710 is a long-acting inhibitor of gastric acid secretion and a promising novel therapy for acid-related diseases, such as gastroesophageal reflux disease.

Ago-allosteric modulators of human glucagon-like peptide 2 receptor

Glucagon-like peptide 2 (GLP-2) is an intestinotropic peptide that binds to GLP-2 receptor (GLP-2R), a class-B G protein-coupled receptor (GPCR). Few synthetic agonists have been reported so far for class-B GPCRs. Here, we report the first scaffold compounds of ago-allosteric modulators for human GLP-2R, derived from methyl 2-{[(2Z)-2-(2,5-dichlorothiophen-3-yl)-2-(hydroxyimino)ethyl]sulfanyl}benzoate (compound 1).

Interleukin-Lα Enhances Hepatotoxicity of Tumor Necrosis Factor-α in Galactosamine-Sensitized Mice

AbstractThe possible involvement of interleukin-lα (IL-lα) in the pathogenesis of murine hepatitis model induced with galactosamine and lipopolysaccharide (LPS) was investigated. the injection of 10 ng/mouse of LPS in combination with 10 mg/mouse of galactosamine into mice induced hepatic damage at 24 hours. Treatment with anti-mouse IL-1α antiserum 30 min before galactosamine/LPS injection showed a tendency to reduce the liver injury, while pretreatment with anti-mouse tumor necrosis factor-α (TNF) antiserum significantly protected mice from liver injury. the use of recombinant murine TNF, instead of LPS, in combination with galactosamine could elicit hepatic damage, whereas recombinant murine IL-lα could not substitute for LPS. However, recombinant murine IL-lα enhanced the hepatotoxic effect of recombinant murine TNF in galactosamine-sensitized mice. These results suggest that TNF plays a major role in the pathogenesis of galactosamine/LPS hepatitis in mice and that IL-lα acts synergistically with TNF ...

E3710, Long-Acting PPI as New Approach for the Treatment of Unmet Medical Needs for GERD

Gastroesophageal reflux disease (GERD) is a spectrum of multifunctional disorder caused by the failure of the normal antireflux mechanism with frequent acid reflux. Patients with GERD experience primary symptoms of heartburn and/or acid regurgitation. The patients with GERD have erosive esophagitis, peptic strictures, Barrett esophagus or evidence of extraesophageal diseases such as chest pain, pulmonary symptoms or symptoms in ear, nose and throat symptoms, while others have no apparent mucosal injury by endoscopic diagnosis (non-erosive GERD) [Armstrong, 2005]. GERD is a chronic, relapsing disorder requiring long term management. The pathophysiological mechanism of GERD is complicated. The decreased lower esophageal sphincter pressure, night time reflux, impaired mucosal defense factors, bile reflex, delayed gastric emptying, visceral hypersensitivity, hiatal hernia, insufficient esophageal clearance, physiological comorbidity and concomitant functional bowl diseases are implicated in the refractory mechanism of GERD [Castell et al., 2004; Fass and Sifrim, 2009].