Vascular endothelial growth factors C and D and lymphangiogenesis at the early stage of esophageal squamous cell carcinoma progression.

We conducted a detailed study of lymphangiogenesis and subsequent lymph node metastasis in early-stage esophageal squamous cell carcinoma (ESCC) using immunostaining for D2-40 and vascular endothelial growth factor (VEGF)-C and D. The study materials included 13 samples of normal squamous epithelium, 6 samples of low-grade intraepithelial neoplasia (LGIN), and 60 samples of superficial ESCC (M1 and M2 cancer 24; M3 or deeper cancer 36). We assessed lymphatic vessel density (LVD) using D2-40 and immunoreactivity for VEGF-C and D in relation to histological type, lymphatic invasion, and lymph node metastasis. LVD in M1 and M2 lesions and M3 or deeper lesions was significantly higher than in normal squamous epithelium (P < 0.001). High expression of VEGF-C and D was observed in M1 and M2 cancer and in M3 or deeper cancer, but not in normal squamous epithelium or LGIN. LVD in VEGF-C- and D-positive cases was significantly higher than in negative cases (P < 0.001). In M3 or deeper cancer, the correlation between VEGF-C or D status and lymphatic invasion or lymph node metastasis was not significant. LVD in cases with positive lymphatic invasion and those with lymph node metastasis was significantly higher than in cases lacking either (P = 0.02 and 0.03, respectively). ESCC cells produce VEGF-C and D from the very early stage of progression. VEGF-C and D activate lymphangiogenesis, and this increase of lymphatic vessels leads to lymphatic invasion and subsequent lymph node metastasis.

Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1.

Caloric restriction (CR) is known to retard aging and delay functional decline as well as the onset of diseases in most organisms. Ghrelin is secreted from the stomach in response to CR and regulates energy metabolism. We hypothesized that in CR ghrelin has a role in protecting aging-related diseases. We examined the physiological mechanisms underlying the ghrelin system during the aging process in three mouse strains with different genetic and biochemical backgrounds as animal models of accelerated or normal human aging. The elevated plasma ghrelin concentration was observed in both klotho-deficient and senescence-accelerated mouse prone/8 (SAMP8) mice. Ghrelin treatment failed to stimulate appetite and prolong survival in klotho-deficient mice, suggesting the existence of ghrelin resistance in the process of aging. However, ghrelin antagonist hastened death and ghrelin signaling potentiators rikkunshito and atractylodin ameliorated several age-related diseases with decreased microglial activation in the brain and prolonged survival in klotho-deficient, SAMP8 and aged ICR mice. In vitro experiments, the elevated sirtuin1 (SIRT1) activity and protein expression through the cAMP-CREB pathway was observed after ghrelin and ghrelin potentiator treatment in ghrelin receptor 1a-expressing cells and human umbilical vein endothelial cells. Furthermore, rikkunshito increased hypothalamic SIRT1 activity and SIRT1 protein expression of the heart in the all three mouse models of aging. Pericarditis, myocardial calcification and atrophy of myocardial and muscle fiber were improved by treatment with rikkunshito. Ghrelin signaling may represent one of the mechanisms activated by CR, and potentiating ghrelin signaling may be useful to extend health and lifespan.

RETRACTED: P444 Shared decision making for switching from oral mesalazine tablets to granules in low adherent inflammatory bowel disease patients.

BACKGROUND: Oral mesalazine effectively induces and maintains remission in inflammatory bowel diseases (IBD) patients. However, adherence to the drug regimen is low. Shared decision-making (SDM) is considered effective in promoting treatment adherence in IBD patients. We used SDM to switch non-adherent IBD patients from oral mesalazine tablets to granules and checked the new adherence rates. METHODS: The IRB of our hospital approved this observational study named 'Evaluation of improvement of adherence by changing oral mesalazine to Pentasa granule in low adherent inflammatory bowel disease patients, IMPACT-PG'. We used the Morisky Medication Adherence Scale (MMAS-8, where an MMAS-8 score of ≥6 indicates good adherence) to assess adherence to oral mesalazine. We met with low adherence patients and explained the benefits and characteristics of mesalazine granules and tablets; we then gave them a choice between continuing with the same pH-dependent mesalazine tablets (with a 20% weight/volume decrease) and switching to oral mesalazine granules (2 g in one stick, 2 g once or twice a day). Primary endpoint was adherence rate in IBD patients with granule or with tablet at 6 months, and secondary endpoint was adherence rate at 12 months. Contributing factors to good adherence to the oral regimen were also examined. The adherence rate was analysed using chi-square test, and contributing factors were determined by multivariate analysis using SPSS ver24. RESULTS: One hundred and eighty-three patients (126 UC and 57 Crohn's colitis patients) were enrolled and examined adherence by MMAS-8 score. Good adherence ratio was 42.6% (78 of 183). Both higher age and low frequency of medication were significantly more common in adherent patients than in non-adherent patients. Odds ratios of age and the frequency of daily medication were 1.057 (95% CI 1.029-1.086; p < 0.0001) and 0.407 (95% CI 0.218-0.759; p = 0.005), respectively. SDM was performed to the 105 low adherence patients. 67% of the low adherence patients (70 of 105) preferred mesalazine granules. Five patients were dropped out until 6 months, as well as 13 patients were dropped out until 12 months. Remission rates at 0, 6, and 24 months were not significantly different between granule and tablet groups. Adherence rates at 6 [67% (44/66) vs. 32% (11 of 34)] and at 12 [72% (43 of 60) vs. 44% (14 of 32)] months were significantly higher in the granule group than in the tablet group. CONCLUSIONS: SDM was effective for switching patients from a mesalazine tablet to a granule regimen, and adherence rates were improved in IBD patients.

Ghrelin enhancer, rikkunshito, improves postprandial gastric motor dysfunction in an experimental stress model.

BACKGROUND: Functional dyspepsia (FD) is one of the most common disorders of gastrointestinal (GI) diseases. However, no curable treatment is available for FD because the detailed mechanism of GI dysfunction in stressed conditions remains unclear. We aimed to clarify the association between endogenous acylated ghrelin signaling and gastric motor dysfunction and explore the possibility of a drug with ghrelin signal-enhancing action for FD treatment. METHODS: Solid gastric emptying (GE) and plasma acylated ghrelin levels were evaluated in an urocortin1 (UCN1) -induced stress model. To clarify the role of acylated ghrelin on GI dysfunction in the model, exogenous acylated ghrelin, an endogenous ghrelin enhancer, rikkunshito, or an α2 -adrenergic receptor (AR) antagonist was administered. Postprandial motor function was investigated using a strain gauge force transducer in a free-moving condition. KEY RESULTS: Exogenous acylated ghrelin supplementation restored UCN1-induced delayed GE. Alpha2 -AR antagonist and rikkunshito inhibited the reduction in plasma acylated ghrelin and GE in the stress model. The action of rikkunshito on delayed GE was blocked by co-administration of the ghrelin receptor antagonist. UCN1 decreased the amplitude of contraction in the antrum while increasing it in the duodenum. The motility index of the antrum but not the duodenum was significantly reduced by UCN1 treatment, which was improved by acylated ghrelin or rikkunshito. CONCLUSIONS & INFERENCES: The UCN1-induced gastric motility dysfunction was mediated by abnormal acylated ghrelin dynamics. Supplementation of exogenous acylated ghrelin or enhancement of endogenous acylated ghrelin secretion by rikkunshito may be effective in treating functional GI disorders.

[Acute gastroduodenal mucosal lesion].

AGML (acute gastric mucosal lesion) is now recognized as one of the important causal disease for gastrointestinal bleeding. If patients have sudden onsets of epigastralgia, epigastric discomfort, vomiting, hematemesis and melena following probable causes, it seems quite reasonable to make diagnosis of AGML by endoscopy with findings of gastric erosion, hemorrhagic gastritis and gastric ulcer. There are a variety of causes for AGML such as psychological and physical stress, drugs (NSAIDs, antibiotics, adrenal corticoid steroid, anti cancer drug), alcohol, serious organ failure of liver, kidney, heart, anisakiasis and etc. There are aslso a variety of endoscopic findings of AGML such as redness, edema, erosion, ulcer, bleeding which vary quickly in a short time. In this article we describe the definition, the cause, the clinical course, the location, the diagnosis, the endoscopic findings, our cases, the treatment of AGML.

[Bleeding in chronic refractory peptic ulcer].

The authors reviewed the clinical problems of the bleeding in refractory ulcers. Incidence of refractory and easily-relapsing ulcers are about 40% of all chronic ulcers and their bleeding rate seemed to be more than 10% of them. We discussed the relationship between bleeding and risk factors such as age, NSAID use, H. pylori infection, etc. The consideration to them is very important in the present time, being difficult to predict ulcer bleeding.

[The role and significance of acid suppressive drugs in the eradication of H. pylori].

Recently a new triple therapy with PPI and two antimicrobials is widely accepted instead of classical triple therapy. PPI has direct and indirect effects on H. pylori. Practically a single use of PPI is almost noneffective for eradication of H. pylori. In the combination therapy PPI is supposed to contribute to successful eradication through the inhibition of acid secretion. Because a raise of pH in stomach protects antimicrobials from the degradation by acidic environment. The decrease in the volume of gastric juice also contributes to concentrate antibiotics. Recently interaction between PPI and clarithromycin on metabolic enzyme in liver was reported that explains the synergistic effects of these drugs. The heterogeneity of genotype of metabolic enzyme was also elucidated which might be responsible for the difference in the effect of PPI between the patients. To accomplish successful eradication, full inhibition of acid secretion has to be done. To consider the interactions between PPI and antimicrobials and the heterogeneity of genotype of metabolic enzyme may improve eradication therapy of H. pylori.

Pretreatment with mild irritant enhances prostaglandin E2 release from isolated canine gastric mucosal mast cells.

Endogenous prostaglandin E2 has been indicated to have an important role in preventing gastric mucosal damage from noxious agents (i.e., in adaptive cytoprotection). However, the response of endogenous prostaglandin E2 to a mild irritant is controversial. In this study, we attempted to determine whether pretreatment with a low concentration of ethanol could induce endogenous prostaglandin E2 production by isolated canine fundic mucosal cells and to identify cells that are responsible for an increase of prostaglandin E2 production. Canine fundic mucosa was digested by collagenase, dispase, and EDTA. The cells were separated into five fractions with an elutriator rotor. Pretreatment with 5% ethanol induced a significant increase of prostagladin E2 release only from the secondary small-sized cell fraction, which was rich in mast cells and endocrine cells, and not from the other four fractions. Further cell separation by density gradient centrifugation revealed that the mast cell-enriched fraction (54%) was responsible for the increase of prostaglandin E2 release induced by the pretreatment with 5% ethanol. The results suggest that mast cells of the gastric mucosa play an important role in the production of endogenous prostaglandin E2 in adaptive cytoprotection.

Interleukin-8 enhances tetragastrin-stimulated acid secretion in vivo.

Recent studies have demonstrated a relationship between cytokines and gastric acid secretion. However, details of the mechanism underlying that relationship have not been elucidated. For this study, an in vivo experiment was undertaken to investigate the possibility that IL-8 would be involved in the mechanism of gastric acid secretion. Gastric lumen-perfused rats were prepared and the stomachs were perfused with a saline solution. The effluent was collected at 15-min intervals and assayed for titratable acid against 0.01 M NaOH. IL-8 (200 ng/rat) given intravenously did not influence basal acid output in rats. However, when IL-8 was administered by injection during continuous tetragastrin infusion (4 microg/kg/hr) acid output increased significantly (P < 0.01). The acid output during the first hour following IL-8 injection was 43.6% higher than prior to the injection. Acid output during the second hour was lower than during the first hour. However, successive injection of IL-8 again increased tetragastrin-stimulated acid output by 23.4% (P < 0.05). IL-8 injection did not change histamine-stimulated acid output. The results indicate that IL-8 has the effect of enhancing gastrin-stimulated acid secretion and might have an important role in the pathophysiology of gastric acid secretion in vivo.

Oesophageal involvement in pemphigus vulgaris.

Oesophageal involvement of pemphigus vulgaris had been considered an exceptional event. However, our endoscopic study found oesophageal lesions in seven of eight (87.5%) patients with pemphigus vulgaris.

Effect of 2'-carboxymethoxy-4,4'-bis(3-methyl-2-butenyloxy)chalcone (SU-88) on gastric local blood flow.

Effect of 2'-carboxymethoxy-4,4'-bis(3-methyl-2-butenyloxy)chalcone (SU-88), a new anti-ulcer drug, on gastric tissue blood flow was investigated by using an inhaled hydrogen gas clearance method in rats. As a result, following the intravenous infusions of 10,20 and 30 mg/kg/h of SU-88, the gastric blood flow increased with an increase rate of 38.1, 70.5 and 61.7% as compared with the control value, respectively. Following the intraperitoneal administrations of 50 and 100 mg/kg of SU-88, the gastric blood flow increased by 59.8 and 51.2%, respectively, immediately after the administration.

Water extract of Helicobacter pylori stimulates interleukin-8 secretion by a human gastric epithelial cell line (JR-St) through protein tyrosine phosphorylation.

BACKGROUND: Infection by Helicobacter pylori induces cytokine production in gastric mucosal cells. Production of interleukin-8 (IL-8) is known to be markedly increased and is believed to play an important role in gastric mucosal inflammation. The aim of this study was to elucidate the effects of soluble factors of H. pylori on IL-8 production in a gastric epithelial cell line, JR-St. METHODS: JR-St cells were cocultured with a H. pylori water extract, live H. pylori or culture medium supernatant for 24 h, then the IL-8 secreted into the culture medium was assayed. The effects of three different inhibitors; (i) an inhibitor of protein kinase C (PKC); (ii) an inhibitor of PKC and protein kinase A (PKA); and (iii) an inhibitor of protein tyrosine kinase (PTK) were also compared. Specific induction of IL-8 mRNA was also examined. RESULTS: Water extract of H. pylori increased IL-8 secretion 7.72-fold, more than the control. The increase was concentration dependent. Live bacteria, supernatant and water extract significantly stimulated IL-8 secretion. Addition of live bacteria increased IL-8 secretion most strongly, while the effect of water extract was small (22% that of live bacteria). Secretion was not inhibited by the PKC inhibitor staurosporine or the inhibitors of PKA and PKC H7. However, secretion was significantly reduced by the PTK inhibitor herbimycin in a dose-dependent manner. Furthermore, 24 h exposure to water extract increased IL-8 mRNA expression, suggesting water extract increased production of IL-8. CONCLUSIONS: Some soluble factors of H. pylori can stimulate IL-8 production by JR-St cells. Stimulation was not dependent on PKA or PKC but was, at least partially, dependent on protein tyrosine phosphorylation. This suggests that soluble factors of H. pylori can play an important role in mediating the inflammatory response of H. pylori gastritis.

Mechanisms for contractile effect of Dai-kenchu-to in isolated guinea pig ileum.

The mechanisms by which Dai-kenchu-to (TJ-100), a kampo medicine, enhances gastrointestinal motility was investigated using isolated guinea pig ileum. TJ-100 induced contractions accompanied by autonomous contraction at a concentration of more than 3 x 10(-4) g/ml in a dose-related manner. The TJ-100-induced ileal contraction was suppressed by atropine and tetrodotoxin, but not by hexamethonium. This effect was partially suppressed in the presence of high concentrations of ICS 205-930, a serotonin 4 (5-HT4) receptor antagonist. In addition, TJ-100 showed an acetylcholine (ACh)-releasing action in the smooth muscle tissues of ileum. These results suggest that contractile response induced by TJ-100 is partially mediated by ACh released from the cholinergic nerve endings and that 5-HT4 receptors would be involved in the effect of TJ-100.

Mechanism of atropine-resistant contraction induced by Dai-kenchu-to in guinea pig ileum.

To clarify the contractile mechanism of Dai-kenchu-to, the effects of hydroxy beta-sanshool (an ingredient of Zanthoxylum fruit), Zanthoxylum fruit (a constituent herb of Dai-kenchu-to) and Dai-kenchu-to were studied in mucosa-free longitudinal muscle of guinea pig ileum. Hydroxy beta-sanshool at 10(-7)-10(-5) g/ml induced dose-related contractions accompanied by autonomous contraction and produced an initial contraction at a concentration of 10(-4) g/ml or more. The contraction induced by hydroxy beta-sanshool (10(-5) g/ml) was significantly inhibited by tetrodotoxin or the capsaicin-receptor antagonist capsazepine. Although atropine or the substance P antagonist spantide tended to inhibit the contraction, a combination of atropine and spantide almost abolished the contraction by hydroxy beta-sanshool. The P2-purinoceptor antagonist pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid did not affect hydroxy beta-sanshool-induced contraction in the presence or absence of spantide. The tonic contractions by Zanthoxylum fruit (2 x 10(-4) g/ml) and Dai-kenchu-to (10(-3) g/ml) were significantly inhibited or tended to be inhibited by atropine, spantide, tetrodotoxin or capsazepine and were remarkably suppressed by the combination of atropine and spantide. These results suggested that acetylcholine release from intrinsic cholinergic nerves and tachykinins from sensory neurons are involved in the contractions induced by hydroxy beta-sanshool and that tachykinins may be involved in the atropine-resistant contraction by Dai-kenchu-to.

Modulatory effect of aliphatic acid amides from Zanthoxylum piperitum on isolated gastrointestinal tract.

beta-Sanshool and gamma-sanshool, unsaturated aliphatic acid amides isolated from the pericarpium of Zanthoxylum piperitum De Candolle (Rutaceae), relax the circular muscle of the gastric body, as well as contract the longitudinal muscle of the ileum and distal colon in an experimental system using the gastrointestinal tract isolated from a guinea pig.