Atsuhiro Ogawa

CYP1A1 CYP2E1 and GSTM1 polymorphisms are not associated with susceptibility to squamous-cell carcinoma of the esophagus

We investigated the genetic polymorphisms of CYPIAI, CYP2EI and GSTMI in Japanese esophageal cancer patients (n = 53) with a histological diagnosis of squamous‐cell carcinoma, to determine whether susceptibility to esophageal cancer is associated with these polymorphisms. There were no significant differences in the frequency distribution of any one of the 3 polymorphisms between esophageal cancer patients and 132 healthy Japanese controls. The genotype distributions in tobacco smokers or alcohol drinkers were also quite similar for male patients and male controls. The age at onset of esophageal cancer was also similar for patients with any genotype of the 3 polymorphisms. We conclude that the 3 polymorphisms are unlikely to be associated with esophageal cancer susceptibility. Int. J. Cancer 71:192–195, 1997.

Association between genetic polymorphisms of glutathione S‐transferase P1 and N‐acetyltransferase 2 and susceptibility to squamous‐cell carcinoma of the esophagus

We examined the effect of genetic polymorphisms of phase‐II enzymes, glutathione S‐transferase P1 (GSTP1) and N‐acetyltransferase2 (NAT2) on susceptibility to esophageal squamous‐cell carcinoma. To determine the genotypes of the 2 polymorphisms, PCR‐based analysis was performed on samples from 66 Japanese patients who had been histologically diagnosed as having esophageal squamous‐cell carcinoma, and 164 healthy Japanese controls. The frequency of the AA genotype of GSTP1 was significantly higher in esophageal‐cancer patients than in the controls according to logistic‐regression analysis (92% of the patients and 68% of the controls; odds ratio (OR), 8.0; p = 0.0013). Also, more patients had the slow and intermediate acetylator genotypes of NAT2 than the controls (15% and 38% vs. 10% and 32% respectively; OR of the slow acetylator genotype, 4.2; p = 0.032; OR of the slow plus intermediate acetylator genotypes, 2.9; p = 0.015). Polymorphisms of GSTP1 and NAT2 may serve as genetic biomarkers for predicting susceptibility to esophageal squamous‐cell carcinoma. Int. J. Cancer (Pred. Oncol.) 79:517–520, 1998.© 1998 Wiley‐Liss, Inc.

Shear stress down‐regulates gene transcription and production of adrenomedullin in human aortic endothelial cells

Vascular endothelial cells are potent modulators of vascular tone in response to shear stress. Levels of vasoactive peptides such as adrenomedullin (AM), endothelin‐1 (ET‐1), C‐type natriuretic peptide (CNP), and nitric oxide (NO) are affected by fluid shear stress. AM, a potent vasodilator and suppressor of smooth muscle cell proliferation, contains the shear stress responsive element (SSRE) “GAGACC” in its promoter region. To examine the role of AM in the shear stress response, cultured human aortic endothelial cells (HAoECs) were exposed to fluid shear stresses of 12 and 24 dynes/cm2 in a cone‐plate shear stress loading apparatus for various time periods, and the levels of AM gene expression and peptide secretion from HAoECs were measured by Northern blotting analysis and radioimmunoassay (RIA), respectively. Both AM gene transcription and AM peptide levels were down‐regulated by fluid shear stress in a time‐ and magnitude‐dependent manner. Our results demonstrate that the normal level of arterial shear stress down‐regulates AM expression in HAoECs, suggesting that AM participates in the modulation of vascular tone by fluid shear stress. J. Cell. Biochem. 71:109–115, 1998.

Effects of Nucleosides and a Nucleotide Mixture on Gut Mucosal Barrier Function on Parenteral Nutrition in Rats

BACKGROUND We have previously reported that the addition of nucleosides and a nucleotide mixture (OG-VI) to total parenteral nutrition (TPN) prevents TPN-induced intestinal mucosal atrophy and results in increased intestinal cathepsin activities under TPN. The aims of the present study are to examine the effects of OG-VI on mucosal barrier functions and to clarify whether the intestinal cathepsins can be used as a new marker of mucosal barrier function. METHODS Male Wistar rats were divided into three groups: FED (food ad libitum), TPN (a standard TPN solution), and OG (OG-VI in addition to the TPN solution). Mucosal barrier functions were analyzed by the lactulose/mannitol (L/M) test, mucosal ZO-1 messenger RNA level, and electron micrographs in the gut. Intestinal cathepsin B, H, and L activities were also measured. RESULTS The L/M ratio for TPN was much higher than that for FED. Only lactulose excretion was significantly reduced by OG-VI. The intercellular spaces of the mucosal cells for TPN were significantly wider than those for FED, but were reduced in size by the addition of OG-VI. All cathepsin activities of the ileum were higher for TPN than for FED, whereas OG showed no increase. CONCLUSION OG-VI contributes to the improvement of gut mucosal barrier function. Intestinal cathepsin activities can be used as a new marker of mucosal barrier function.

Modulation of circadian expression of D‐site binding protein by the schedule of parenteral nutrition in rat liver

The aim of this study was to investigate the changes in the circadian rhythm of the expression of liver‐specific genes caused by different schedules of parenteral nutrition (PN). Rats received PN continuously throughout the day or intermittently during the night or day for 7 days. They were examined for gene expression of D‐site binding protein (DBP), albumin, and cytochrome P450 cholesterol 7α‐hydroxylase (CYP7) in the liver. The nocturnal PN group showed circadian expression of DBP messenger RNA (mRNA) and protein with a peak at 10 PM, in the same manner as the control rats receiving normal chow feeding. However, the diurnal PN group showed inverted expression of DBP mRNA and protein with a peak at 10 AM. CYP7 mRNA levels exhibited good synchronization with the levels of DBP mRNA in all groups, whereas albumin mRNA levels did not show such synchronization. Gel mobility‐shift assay disclosed that the binding activity of the nuclear extracts to the CYP7 gene promoter was changed by the PN schedule in accordance with the expression of CYP7 mRNA. The PN schedule modulates the circadian rhythm of DBP expression and may have an effect on hepatic bile acid formation through transcriptional regulation of the CYP7 gene.

Increased Urinary Excretion of Bilirubin Metabolites in Association with Hyperbilirubinemia After Esophagectomy

This study was conducted to investigate the rationale for postoperative hyperbilirubinemia after major surgery. The serum bilirubin values and urinary excretion of bilirubin metabolites (BM) were monitored in 11 patients who underwent esophagectomy via right thoracotomy for esophageal cancer. Both the serum bilirubin values and the urinary excretion of BM increased postoperatively in all patients. The maximum serum bilirubin level in four patients with septic complications, two of whom developed pneumonia and two, anastomotic leakage (group A), was significantly higher at 5.25+/-4.16 mg/dl than in the remaining patients without septic complications (group B), at 2.11+/-0.07 mg/dl. The peak value of urinary BM was 99.5+/-88.2 micromol/day in group A and 23.5 +/-26.7 micromol/day in group B. The correlation between the level of serum bilirubin and urinary BM excretion was found to be significant. Thus, the metabolism of bilirubin was increased by extensive surgical stress and septic insult.

Effect of parenteral and enteral nutrition on hepatic albumin synthesis in rats

The route of nutrient delivery may alter the production of albumin and induce changes at the molecular level. Donryu rats (n = 75) were divided into the following three groups. The oral feeding (OR) group received a non-purified solid diet ad libitum, the parenteral nutrition (PN) group received a total parenteral nutrition (TPN) solution intravenously, and the enteral nutrition (EN) group received intragastric infusions of the TPN solution for 7 d. Serum albumin and glucocorticoid levels were measured and messenger RNA (mRNA) levels of albumin and hepatic specific transcription factors in the liver were analyzed. Serum albumin and albumin mRNA levels in the PN group became significantly decreased compared to those in the OR group, whereas the EN group did not show a significant difference compared to the OR group. mRNA levels of DBP, D-site binding transcription factor for the albumin gene, showed a circadian rhythm in the OR and EN groups, but not in the PN group, as indicated by a DBP mRNA level at 2200 h in the PN group that was significantly lower than that in the OR group. mRNA levels of C/EBP alpha, CCAAT-enhancer binding protein alpha, were highest in the OR group and lowest in the PN group. In contrast, mRNA levels of C/EBP beta were highest in the PN group and lowest in the OR group. Serum glucocorticoid level showed a circadian rhythm in the OR group, highest at 2200 h and lowest at 1000 h, whereas such a rhythm was not found in either the PN or the EN group. Albumin synthesis was down-regulated in PN in association with changes in transcription factors. A loss of circadian rhythm reflected in changes of DBP mRNA and serum glucocorticoid level may play a role. Down-regulation of albumin was improved by enteral feeding, indicating that EN is more advantageous for albumin synthesis than PN.

Changes of liver-enriched nuclear transcription factors for albumin gene in starvation in rats.

The regulatory mechanism of albumin gene transcription was examined using male Donryu rats (7 wk old) starved for 1 or 3 d. At the designated times, the rats were sacrificed to harvest the liver and to measure the serum albumin level. Neither the serum albumin nor the albumin messenger RNA (mRNA) level showed a significant change for these starvation periods. Among nuclear factors binding to the D site of albumin gene promoter, the CCAAT/enhancer binding protein alpha (C/EBP alpha) mRNA level showed a decrease and the D site binding protein (DBP) mRNA level tended to decrease after 3 d of starvation. In contrast, the C/EBP beta mRNA level showed a significant increase at day 1. As a B site binding nuclear factor, the hepatocyte nuclear factor 1 (HNF-1) mRNA level significantly increased at day 1. Gel mobility-shift analysis combined with Western immunoblotting confirmed the presence of D site binding proteins composed of DBP and C/EBP alpha and beta in both groups subjected to oral feeding and to 3-d starvation, though quantitative analysis could not be done. In conclusion, the nuclear transcription factors binding to the albumin gene promoter undergo regulatory changes during 3 d of starvation, whereas there is no significant decrease in the albumin mRNA level.

Regulation of albumin mRNA and its promoter-binding nuclear factors under different perioperative nutritional methods in hepatectomized rats.

BACKGROUND Regulation of perioperative albumin synthesis under parenteral (PN) and enteral (EN) nutrition was investigated. METHODS Rats were divided into PN and EN groups. Both groups received the same regimen of artificial nutrition for 7 days and then underwent 70% hepatectomy. Serum albumin and mRNA levels of albumin and its promoter-binding nuclear factors (C/EBPalpha, beta, and DBP) were measured. RESULTS Serum albumin and albumin mRNA in the PN group were significantly lower than those in the EN group at 72 hours after hepatectomy. Preoperative and postoperative DBP and C/EBPalpha mRNA levels in the EN group were significantly higher than those in the PN group. CONCLUSION Serum albumin was well maintained by EN after hepatectomy owing to an early recovery of albumin mRNA level and its nuclear factor mRNA levels (C/EBPalpha and DBP). Compared with PN, EN is a more advantageous from of perioperative nutrition as pertains to albumin synthesis.

Benefits of using a self-expandable metallic stent as a bridge to surgery for right- and left-sided obstructive colorectal cancers

PurposeTo assess the benefit of placing a self-expandable metallic stent (SEMS) as a bridge to surgery for obstructive colorectal cancer (OCRC) according to the tumor site.MethodsThe subjects of this retrospective multicenter cohort study were 201 patients with OCRC, but without initial bowel perforation, who were treated either with a self-expandable metallic stent (SEMS) as a bridge to surgery (n = 109) or with primary surgery (PS; n = 92) between 2014 and 2016. The cohort consisted of 68 patients with right-sided and 133 left-sided OCRC. We evaluated the short-term surgical outcomes for each side.ResultsThe SEMS group of patients with left-sided OCRC had significantly higher rates of primary resection, primary resection with anastomosis, stoma-free surgery, and laparoscopic surgery than the PS group of patients with left-sided OCRC. In contrast, the SEMS group of patients with right-sided OCRC had only a significantly higher rate of laparoscopic surgery than the PS group of patients with right-sided OCRC, but they had a longer overall hospital stay. There were no significant differences between the two treatment groups in the rates of morbidity or mortality, for either right-sided or left-sided OCRC.ConclusionThe benefit of a SEMS as a bridge to surgery may be less for right-sided than for left-sided obstructions in colon cancer patients.