[From fatty liver to liver cancer--new development in non-alcoholic steatohepatitis (NASH) using animal models].
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Animals↗
Biomedical subjects
Sumio Watanabe
Publications and source records attributed to Sumio Watanabe.
Neuropathology of paraneoplastic neuropathy with anti-disialosyl antibody.
We report a paraneoplastic neuropathy with severe motor involvement following sensory-ataxic disturbance. Anti-disialosyl immunoglobulin M (IgM) antibody was detected in the course of malignant lymphoma of diffuse large B-cell type, which usually spares the motor system. Onset was subacute, with relapsing and remitting sensory ataxia, muscle weakness, bulbar palsy, respiratory paralysis, and ophthalmoplegia; only neck rotation was retained in the terminal stage. Autopsy showed no lymphoma cells infiltrating the nervous system. Motor neurons survived in the spinal cord, but mean diameter of the ventral spinal nerve roots was reduced considerably. The gracile fasciculus and the sural nerve were more markedly degenerated than proximal portions. Morphometric study showed that most of the proximal motor and sensory axons did not extend distally. This autopsy report provides further definition of a neuropathy associated with malignant lymphoma and IgM antibodies against disialosyl residues.
Aged↗
Gabexate mesilate, a synthetic protease inhibitor, attenuates carbon tetrachloride-induced liver injury in rats.
BACKGROUND: Gabexate mesilate, a synthetic protease inhibitor, is used to treat acute pancreatitis and disseminated intravascular coagulation because it inhibits various serine proteases; however, whether gabexate mesilate prevents acute liver failure has not yet been studied. The aim of the present study was to investigate the effect of gabexate mesilate in carbon tetrachloride (CCl4)-induced liver injury in rats. METHODS: Acute hepatic failure was induced by administration of CCl4 intragastrically to male Sprague-Dawley rats. The effects of gabexate mesilate were examined in terms of serum transaminase levels, liver histology, and the prognosis of rats. RESULTS: Gabexate mesilate treatment significantly decreased the elevation of serum transaminase levels and improved liver histology 24 h after the administration of CCl4 (0.2 ml/100 g rat weight). Plasma tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) decreased significantly in the gabexate mesilate-treated rats compared with saline-treated rats. Gabexate mesilate treatment also significantly improved survival rate after a lethal dose of CCl4 (0.5 ml/100 g rat weight) from 0% to 20%. CONCLUSIONS: Gabexate mesilate treatment attenuated CCl4-induced liver injury via a suppression of proinflammatory cytokine production. In addition, these investigations suggest that gabexate mesilate treatment may provide therapeutic strategies for human acute liver failure.
Animals↗
Ecabet sodium prevents the delay of wound repair in intestinal epithelial cells induced by hydrogen peroxide.
BACKGROUND: Recent studies showed that ecabet sodium (ES), a gastro-protective agent, also had a therapeutic effect on inflammation in ulcerative colitis. The aim of this study was to clarify the function of ES in wound repair in intestinal epithelial cells (IECs). METHODS: The activation of signal proteins (ERK1/2 mitogen-activated protein kinase MAPK, and IkappaB-alpha) in IEC-6 cells after stimulation with 2.5 mg/ml of ES was assessed by Western blot. The induction of transforming growth factor (TGF)-beta1, TGF-alpha, and cyclooxygenase-2 (COX-2) mRNAs after the stimulation of IEC-6 cells with ES was assessed by reverse transcription ploymerase chain reaction (RT-PCR). IEC-6 cells were wounded and cultured for 24 h with various concentrations of ES in the absence or presence of 20 microM H2O2. Epithelial migration or proliferation was assessed by counting migrated or bromodeoxyuridine (BrdU)-positive cells observed across the wound border. We also assessed apoptotic epithelial cells after the culture. RESULTS: ES clearly activated ERK1/2 MAPK and slightly activated IkappaB-alpha. ES also enhanced the expression of TGF-alpha and COX-2 mRNAs. This enhancement was suppressed by a MAPK/Erk kinase (MEK) inhibitor. ES did not enhance epithelial migration in the absence of H2O2. In contrast, ES significantly decreased the number of apoptotic cells and prevented the reduction of epithelial migration (51.1%; P < 0.01) and proliferation (56%; P < 0.01) induced by H2O2. The function of ES was suppressed by a cyclooxygenase-2 (COX-2) inhibitor and by the MEK inhibitor, and partly suppressed by a nuclear factor (NF)-kappaB inhibitor. CONCLUSIONS: ES prevents the delay of wound repair in IEC-6 cells induced by H2O2, probably through the activation of ERK1/2 MAPK and the induction of COX-2.
Abietanes↗
Selective A2A adenosine agonist ATL-146e attenuates acute lethal liver injury in mice.
BACKGROUND: D-Galactosamine (GalN)/lipopolysaccharide (LPS)-induced liver injury is an experimental model of fulminant hepatic failure in which tumor necrosis factor-alpha (TNF-alpha) plays a pivotal role. We examined the effects of a highly selective adenosine A2A receptor agonist (ATL-146e) on GalN/LPS-induced fulminant hepatic failure. METHODS: Mice were given an intraperitoneal dose of GalN (800 mg/g body weight)/LPS (100 ng/g body weight) with and without ATL-146e (0.01 microg/kg) treatment. Liver injury was assessed biochemically and histologically. Also, TNF-alpha levels in the serum were determined. RESULTS: The serum liver enzyme (ALT) level in vehicle-treated mice was 20 960 +/- 2800 IU/ml and was reduced by 63% to 7800 +/- 1670 IU/ml by treatment with 0.01 microg/kg per minute ATL146e, P < 0.05. Treatment with ATL-146e significantly reduced serum TNF-alpha and greatly reduced inflammation assessed by histopathologic examination compared with control mice treated with GalN/LPS. ATL-146e also reduced lethality at 12 h from 65% to 13%. CONCLUSION: The present findings suggest that the highly selective adenosine A2A receptor agonist (ATL-146e) prevents endotoxin-induced lethal liver injury by suppression of TNF-alpha secretion.
Adenosine A2 Receptor Agonists↗
Relationship between IL-1beta gene polymorphism and gastric mucosal IL-1beta levels in patients with Helicobacter pylori infection.
BACKGROUND: Interkeukin-1 (IL-1) gene cluster polymorphisms that are thought to enhance the production of IL-1beta are associated with an increased risk of gastric cancer. To determine the role of host genetic factors in Helicobacter pylori infection, we examined the relationship between gastric mucosal IL-1beta levels and IL-1B polymorphisms in patients with H. pylori infection. METHODS: Biopsy tissues obtained from 99 patients were homogenized and gastric mucosal IL-1beta levels were measured by enzyme-linked immunosorbent assay (ELISA). Single-base polymorphisms at positions -511 and -31 in IL-1B were analyzed. RESULTS: The IL-1beta level in the antrum was significantly higher in genotype IL-1B-511C/C than in H. pylori-negative patients (P < 0.05). The IL-1B polymorphism did not influence the degree of gastric neutrophil and mononuclear cell infiltration, or gastric atrophy. IL-1beta levels in the corpus, but not those in the antrum, correlated to the severity of gastric atrophy. CONCLUSIONS: These findings indicate that IL-1B polymorphisms enhance IL-1beta production in the antrum; however, other factors might regulate the production of IL-1beta in the corpus of the stomach, regardless of IL-1B polymorphisms, and high IL-1beta production may be associated with the grade of gastric atrophy in the corpus mucosa in patients with H. pylori infection.
Adult↗
Rolipram, a specific type IV phosphodiesterase inhibitor, ameliorates aspirin-induced gastric mucosal injury in rats.
Inhibition of type IV phosphodiesterase (PDE IV) activity reduces the production of various proinflammatory cytokine and suppresses neutrophil activation. Nonsteroidal anti-inflammatory drugs such as aspirin induce gastric mucosal lesions. In the pathogenesis of aspirin-induced gastric mucosal lesion, the contributions, of activated inflammatory cells and proinflammatory cytokine production are critical. The specific PDE IV inhibitor rolipram is known to be a potent inhibitor of inflammation by increasing intracellular cyclic AMP in leukocytes. The aim of the present study was to determine whether rolipram can ameliorate aspirin-induced gastric mucosal lesions in rats and whether the agent can inhibit the inrease in neutrophil accumulation and the production of proinflammatory cytokines. Gastric lesions were produced by administration of aspirin (200 mg/kg) and HCI (0.15 N; 8.0 ml/kg). Rolipram was injected 30 min before aspirin administration. The tissue myeloperoxidase concentration in gastric mucosa was measured as an indicat or of neutrophil infiltration. The gastric mucosal concentrations of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were determined by ELISA. The intragastric administration of aspirin induced multiple hemorrhagic erosions in rat gastric mucosa. Gastric mucosal lesions induced by aspirin were significantly inhibited by treatment with rolipram. The mucosal myeloperoxidase concentration was also suppressed by rolipram. Increases in the gastric content of TNF-alpha and IL-1beta after aspirin administration were inhibited by pretreatment with rolipram. We demonstrated that the specific type IV PDE inhibitor, rolipram, could have a potent antiulcer effect, presumably mediated by its anti-inflammatory properties.
Animals↗
Oncogenic potential of MEK1 in rat intestinal epithelial cells is mediated via cyclooxygenase-2.
BACKGROUND & AIMS: The mitogen-activated protein kinase/extracellular signal-regulated protein kinase kinase (MEK) pathway plays an important role in the regulation of cell growth and differentiation. Constitutively active components of the MEK signaling cascade can induce oncogenic transformation in many cell systems. Downstream MEK signaling also plays an important role in the regulation of cyclooxygenase-2 (COX-2), which is known to be involved in colorectal cancer. Therefore, we determined the role of COX-2 on the oncogenic potential of MEK1 in nontransformed rat intestinal epithelial cells. METHODS: Constitutively active MEK1 (CA-MEK) mutant transfected rat intestinal epithelial cells were established and tested for their ability to grow in soft agar and form tumors in vivo. The effect of CA-MEK on sodium butyrate (NaB)-induced apoptosis was evaluated by the Annexin V assay. The transcriptional activity and posttranscriptional stability of the COX-2 gene was determined by transient transfection with COX-2 reporter variants and by Northern analysis. To address the role of COX-2 in tumor growth in vivo, xenografted mice were treated with celecoxib (100 mg/kg) or vehicle. RESULTS: CA-MEK transfected RIE-1 and IEC-6 cells formed colonies in soft agar and tumors in nude mice. These cells showed resistance to NaB-induced apoptosis and cell cycle arrest. MEK activation led to increased expression of COX-2, Bcl-X(L), Mcl-1, and phosphorylated Bad and decreased expression of Bak. Along with elevated COX-2 levels, PGI(2) and PGE(2) levels were also increased. Pharmacologic inhibition of COX-2 inhibited MEK-induced tumor growth in vivo through enhanced apoptosis. CONCLUSIONS: COX-2 and its bioactive lipid products may play an important role in MEK-induced transformation.
Animals↗
Stochastic complexities of reduced rank regression in Bayesian estimation.
Reduced rank regression extracts an essential information from examples of input-output pairs. It is understood as a three-layer neural network with linear hidden units. However, reduced rank approximation is a non-regular statistical model which has a degenerate Fisher information matrix. Its generalization error had been left unknown even in statistics. In this paper, we give the exact asymptotic form of its generalization error in Bayesian estimation, based on resolution of learning machine singularities. For this purpose, the maximum pole of the zeta function for the learning theory is calculated. We propose a new method of recursive blowing-ups which yields the complete desingularization of the reduced rank approximation.
Artificial Intelligence↗
Development of lupus nephritis in a patient with human T-cell lymphotropic virus type I-associated myelopathy.
A 77-year-old Japanese man with a 14-year history of human T-cell lymphotropic virus type I-associated myelopathy developed pancytopenia, proteinuria, renal dysfunction, and hypocomplementemia. Antinuclear antibody and anti-double-stranded DNA antibody test results were positive, and circulating immune complexes were detected. A renal biopsy showed diffuse and global mesangiocapillary proliferation with extensive subendothelial deposits. Immunofluorescence microscopy showed strong granular staining for immunoglobulins and complements in the mesangium and along capillary walls. Electron microscopy showed numerous mesangial and subendothelial electron-dense deposits. From these findings, systemic lupus erythematosus and diffuse global lupus nephritis were diagnosed. This is a rare case of a patient developing lupus nephritis during the long-term course of human T-cell lymphotropic virus type I-associated myelopathy.
Aged↗
Activation of A2A adenosine receptor attenuates intestinal inflammation in animal models of inflammatory bowel disease.
BACKGROUND & AIMS: Adenosine has been implicated as an important regulator of the inflammatory response. Four subtypes of adenosine receptors (A 1 , A 2A , A 2B , and A 3 ) have been described, of which A 2A potentially inhibits inflammation. The aim of this study was to investigate the role of A 2A in mucosal inflammation by administering a selective A 2A agonist (ATL-146e) to experimental models of inflammatory bowel disease. METHODS: The anti-inflammatory effects of ATL-146e were studied in the acute and chronic rabbit formalin-immune complex models of colitis and the SAMP1/YitFc mouse model of spontaneous ileitis. RESULTS: ATL-146e significantly reduced the acute inflammatory index and tissue necrosis compared with vehicle ( P < .01) in the acute model of rabbit immune colitis. In the chronic rabbit immune colitis model, ATL-146e significantly suppressed inflammatory cell infiltration into the colonic mucosa ( P < .05) and prevented mortality. The administration of ATL-146e significantly decreased the chronic inflammatory index ( P < .01) and villus distortion index ( P < .01) in the ileum of SAMP1/YitFc mice, and ameliorated adoptively transferred ileitis in severe combined immunodeficient mice injected with CD4 + T cells from SAMP1/Yit mice ( P < .05). Tumor necrosis factor, interferon gamma, and interleukin 4 concentrations were significantly suppressed by ATL-146e treatment in supernatants from cultures of mesenteric lymph node cells of SAMP1/YitFc mice ( P < .05 vs vehicle-treated mice). CONCLUSIONS: A 2A adenosine receptor activation by ATL-146e significantly reduced inflammation in the intestinal mucosa. This effect was associated with decreased leukocyte infiltration and inhibition of proinflammatory cytokines. Activation of A 2A by selective agonism may therefore serve as a novel therapy for the treatment of inflammatory bowel disease.
Acute Disease↗
Specific type IV phosphodiesterase inhibitor ameliorates thioacetamide-induced liver injury in rats.
BACKGROUND AND AIMS: Rolipram is a specific type IV phosphodiesterase inhibitor that suppresses the activity of immune cells and the production of pro-inflammatory cytokines. In this study, we assessed the effect of rolipram on acute liver injury using thioacetamide (TAA)-induced liver injury in rats as a model. METHODS: Rats were treated with rolipram (0.5-5 mg/kg, intraperitoneally) or vehicle and injected 30 min later with TAA (100 mg/kg, subcutaneously). Serum transaminase concentrations and tumor necrosis factor-alpha (TNF-alpha), interleukin 1beta (IL-1beta) and growth related oncogene/cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1) levels were measured and livers were examined for microscopic changes. Dose-dependent protection against TAA liver injury was based on transaminase levels and inflammatory cytokine production, and was measured 9 h after TAA when the peak release of cytokines occurred. RESULT: Rolipram suppressed liver injury based on serum aspartate transaminase (AST), alanine transaminase (ALT) and histology and reduced TNF-alpha, IL-1beta and GRO/CINC-1 levels. Rolipram, at doses of 0.5-5 mg/kg, suppressed serum transaminase and TNF-alpha production in a dose-dependent manner, and these effects were significant at doses of 2.5 and 5 mg/kg. CONCLUSION: In our rodent model of acute liver injury, rolipram clearly reduced liver damage and inhibited pro-inflammatory cytokine production. These results suggest that specific type IV phosphodiesterase inhibitors, such as rolipram, have potent hepatoprotective effects that are associated with suppressing inflammatory cytokine production.
Animals↗
Selective adenosine A receptor agonist, ATL-146e, attenuates stress-induced gastric lesions in rats.
BACKGROUND: Activation of adenosine A(2A) receptors reduces the production of various pro-inflammatory cytokines and suppresses neutrophil activation. Water-immersion restraint is well known to cause gastric mucosal lesions due to stress. The pathogenesis of stress-induced gastric mucosal lesions is characterized by activation of inflammatory cells and production of inflammatory cytokines. Agonists of adenosine A(2A) receptors are known to be anti-inflammatory, but the effects of these compounds on the development of gastric mucosal lesions has not been reported. In the present study, the effect of a potent and selective adenosine A(2A) receptor agonist, ATL-146e, on water-immersion stress-induced gastric mucosal lesions was studied. METHODS: Rats were subjected to water-immersion stress with or without pretreatment with a single intraperitoneal injection of a potent and selective agonist of the adenosine A(2A) receptor. The gastric concentrations of myeloperoxidase (MPO), as an index of neutrophil accumulation, and the pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), were measured. RESULTS: The total length of gastric erosions (ulcer index) in control rats was 21.6 +/- 3.23 mm and was reduced by 86% to 3.1 +/- 0.83 mm by pretreatment with 5.0 microg/kg ATL146e (P < 0.001). The gastric content of MPO, TNF-alpha and IL-1beta were all increased after water-immersion stress and reduced to near normal levels by ATL-146e. CONCLUSION: A specific adenosine A(2A) agonist inhibits stress-induced gastric inflammation and damage. A(2A) agonist compounds may be useful for preventing ulcers and appear to act by blocking gastric inflammation.
Adenosine A2 Receptor Agonists↗
Distribution and isoforms of epimorphin in carbon tetrachloride-induced acute liver injury in mice.
BACKGROUND AND AIM: Epimorphin, a morphoregulatory factor essential to organ development, is believed to direct normal morphogenesis in tissue repair. We examined the dynamics and the roles of epimorphin, a cell surface-associated molecule detected on mesenchymal cells, in hepatic tissue repair from acute liver injury. METHODS: After acute liver injury was induced by carbon tetrachloride in Balb/c mice, the distribution of epimorphin-expressing cells was studied immunohistochemically. To clarify interactions between epimorphin expression and hepatocyte behavior, epimorphin-expressing cells and proliferating hepatocytes were counted. Then, epimorphin quantity and isoforms were assessed by western blotting. To better understand effects of epimorphin, we cultured rat hepatocytes in its presence. RESULTS: Epimorphin was distributed in relation to sinusoids, portal veins, central veins and granulomas, expressed in stellate cells and myofibroblasts. In the periportal zone, the expression in sinusoids was decreased at 24 h but increased on day 7 after carbon tetrachloride administration. Numbers of epimorphin-expressing cells and proliferating hepatocytes changed in an inverse manner as time progressed. In the pericentral zone, reactivity for epimorphin was markedly enhanced concurrently with appearance of granulomas. Quantities of 34-kDa isoform paralleled epimorphin-staining intensity. In vitro, epimorphin induced spherical hepatocyte aggregates and maintained differentiated hepatocyte function. CONCLUSIONS: Epimorphin is involved in tissue repair following a single injection of carbon tetrachloride, in which distribution and the quantity of epimorphin expression are important, particularly in maintaining hepatocyte function.
Acute Disease↗
[A case of encephalitis-type encephalopathy related to Pleurocybella porrigens (Sugihiratake)].
A 65-year-old man who had been on hemodialysis for chronic renal failure was well until 7 days after ingestion of Pleurocybella porrigens (Sugihiratake) when he developed a loss of consciousness and status epilepticus of generalized tonic and clonic seizures. High fever and high CRP were followed and cerebrospinal fluids showed marked pleocytosis with polynuclear cell predominance. Brain MRI showed diffuse lesions in the basal ganglia and multiple ringed lesions in cerebral cortex. Glucocorticoid therapy was effective for clinical improvement. This case showed the presence of encephalitis-type of encephalopathy related to Pleurocybella porrigens (Sugihiratake).
Aged↗
[Tumor suppressor gene PTEN and non-alcoholic steatohepatitis (NASH)].
Although hepatic steatosis had been considered to be a benign condition that does not deteriorate to either liver cirrhosis or hepatocellular carcinoma (HCC). Non-alcoholic steatohepatitis (NASH) is notable disease that has similar pathological features to alcoholic liver injury and progresses to liver cirrhosis and HCC. But the molecular mechanism for the onset of NASH, and for the transformation from steatosis to carcinogenesis are still unclear. Hepatocyte-specific PTEN deficient mice, we generated, have similar histological features to the patients of human NASH. These hepatocytes showed enhanced lipid accumulation, inflammatory change, and hyperoxidation. Moreover, they developed into HCC. Thus, impairment of PI3K/PTEN signaling may possibly be involved in a part of NASH/HCC cases in human.
Animals↗
[A case of gangrenous ischemic colitis complicated with sigmoid-ileal fistula].
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Aged↗
Targeted gene delivery to sinusoidal endothelial cells: DNA nanoassociate bearing hyaluronan-glycocalyx.
Liver sinusoidal endothelial cells (SECs) possess unique receptors that recognize and internalize hyaluronic acid (HA). To develop a system for targeting foreign DNA to SECs, comb-type polycations having HA side chains were prepared by coupling HA to poly(L-lysine) (PLL). The HA-grafted-PLL copolymer (PLL-g-HA) thus formed was mixed with DNA in 154 mM NaCl to form soluble nanoassociates bearing hydrated hyaluronate shells. Agarose gel retardation assays revealed selective interaction of the PLL backbone with DNA despite the presence of polyanionic HA side chains. To determine whether the PLL-g-HA/DNA complexes were recognized by SEC HA receptors in vivo, we injected Wistar rats i.v. via the tail vein with PLL-g-HA complexed to a beta-galactosidase expression plasmid (pSV beta-Gal) labeled with 32P. One hour postinjection, >90% of the injected radioactivity remained in the liver. Administration of the PLL-g-HA complexed to an FITC-labeled DNA revealed that the carrier-DNA complex was distributed exclusively in SECs. A large number of SECs expressing beta-galactosidase was detected along the sinusoidal lining after transfection with PLL-g-HA/pSV beta-Gal. Moreover, PLL-g-HA effectively stabilized DNA triplex formation. In conclusion, the new PLL-g-HA/DNA carrier system permits targeted transfer of exogenous genes selectively to the SECs.
Animals↗