[The role of calcineurin in the regulation of transcription factors].
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Animals↗
Biomedical subjects
N Omori
Publications and source records attributed to N Omori.
Expression of alpha-fetoprotein and stem cell factor/c-kit system in bile duct ligated young rats.
The existence of a facultative hepatic stem cell compartment in bile ductules that participates in the renewal process of epithelial cell populations in the liver is well documented. The present study was undertaken to determine whether the immature bile epithelium responds differently to growth stimulus induced by bile stasis to that seen in the adult animal. In addition, the possible involvement of the growth factor/receptor systems associated with early activation of hepatic stem cells in bile duct proliferation was also examined. Bile duct ligation was used to induce the proliferation of bile epithelial cells. The expression of full-length alpha-fetoprotein (AFP) was used as an indicator for activation of the stem cell compartment. AFP was highly and selectively expressed in small bile ducts 7 days after bile duct ligation in immature rats up to 5 weeks of age. Although no significant increase in the expression of stem cell factor (SCF) c-kit, hepatocyte growth factor (HGF), and transforming growth factor-alpha (TGF-alpha) was observed 7 days after bile duct ligation in adult rats, the expression of all these growth factors was increased in bile duct ligated rats up to 5 weeks of age. These results suggest that the bile ductular epithelium in the young rats responds to bile stasis in a fashion that is phenotypically similar to that seen during early activation of hepatic stem cells in adult liver.
Age Factors↗
Partial cloning of rat CD34 cDNA and expression during stem cell-dependent liver regeneration in the adult rat.
The sialomucin CD34 is expressed on human and mouse hematopoietic stem cells and is used as an important marker for isolating the hematopoietic stem/progenitor cells. The involvement of hepatic stem cells in liver regeneration under certain conditions in adult rats is now well supported. The objective of the present research was to explore the idea that CD34 might also be expressed on hepatic stem cell progeny. Polymerase chain reaction (PCR)-based cloning of rat CD34 was partially accomplished. During the hepatic stem cell activation (2-acetylaminofluorene/partial hepatectomy [AAF/PH] model), the CD34 transcripts were increased and reached the peak level between 9 and 12 days after partial hepatectomy when the progenitor cells (e.g., oval cells, early hepatocytes in basophilic foci, and intestinal type of cells) are most abundant. Both in situ hybridization and immunohistochemistry, using anti-mouse CD34 antibody, which recognizes the cytoplasmic domain, clearly showed the expression of CD34 on oval cells as well as on endothelial cells of large hepatic vessels. In addition, bile ductular epithelial (BDE) cells both in the AAF/PH model and in normal liver expressed CD34, suggesting a close relationship between BDE cells and the hepatic stem-cell compartment. Taken together, the data indicate that CD34 would, similar to its role in the hematopoietic system, be an important probe for characterizing the cellular biology of the hepatic stem-cell compartment.
2-Acetylaminofluorene↗
Coexpression of flt-3 ligand/flt-3 and SCF/c-kit signal transduction system in bile-duct-ligated SI and W mice.
Stem cell factor (SCF) and its receptor c-kit constitute an important signal transduction system regulating cell growth and differentiation in hematopoiesis, gametogenesis, and melanogenesis. Recently, we have demonstrated that both SCF and c-kit are expressed in the bile duct epithelial cells of the rat liver and are highly up-regulated during activation of the normally dormant hepatic stem cell compartment. In the present study, we used sl/sld and w/wv mice, which have mutation of either SCF or c-kit, to study the possible involvement of the SCF/c-kit system in the bile duct proliferation. Bile duct ligation was performed to induce the proliferation of bile duct epithelial cells. The transcripts for both SCF and c-kit were clearly increased after bile duct ligation in both control and mutant mice. Moreover, both Sl and W mice responded to the bile duct ligation, similar to the control mice, by developing new bile ducts. Recently, a novel tyrosine kinase receptor, flt-3 receptor, has been identified in the fetal liver. It has been reported that the flt-3 ligand (FL)/flt-3 system can synergize with the SCF/c-kit system and stimulate the proliferation of hematopoietic cells. Therefore, we hypothesized that the FL/flt-3 system might compensate for the compromised SCF/c-kit system in the liver of Sl and W mice. The expression of both FL and flt-3 were significantly increased in bile duct-ligated liver from both normal and mutant mice, and the transcripts for the flt-3 receptor were selectively located on bile duct epithelial cells. Based on these results, we postulate the existence of a compensatory/additive function between the FL/flt-3 and the SCF/c-kit signal transduction systems in hepatic cell biology.
Animals↗
Precursor-product relationship between oval cells and hepatocytes: comparison between tritiated thymidine and bromodeoxyuridine as tracers.
The expansion and differentiation of oval cells in the acetylaminofluorene (AAF)/partial hepatectomy (PH) model was studied utilizing pulse-chase labeling with both tritiated thymidine ([3H]TdR) and bromodeoxyuridine (BUdR). Animals in which a significant decrease in serum albumin and increase in alanine aminotransferase and bilirubin were observed demonstrated the most prominent differentiation of oval cells into hepatocytes. Administration of [3H]TdR or BUdR, either individually or together, to the animals on day 6 after partial hepatectomy resulted in labeling of the majority of the oval cells by days 7 and 9 after PH. A striking difference in the distribution of [3H]TdR- and BUdR-labeled cells in the double labeling experiments was observed on day 11, at which time the number of [3H]TdR-labeled cells increased 6-fold and that of double labeled cells decreased 2-fold. Furthermore, on day 11 the basophilic foci were weakly positive for BUdR and negative at later time points in animals receiving BUdR alone or together with [3H]TdR. In contrast, the cells in basophilic foci as well as transitional cells were positive for [3H]TdR. Cells heavily labeled with both [3H]TdR and BUdR were present at all time points, indicating an inhibition of the proliferative activity. Pulse labeling of rat liver epithelial cells with BUdR in vitro demonstrated that immunodetection of BUdR was lost after three or more cell divisions. We conclude that the BUdR tagging method is particularly sensitive to label dilution during cell cycling and may not be suitable for establishment of a precursor-product relationship between cell lineages when the progenitor population proliferates more than three times.
2-Acetylaminofluorene↗
Expression of transforming growth factor alpha/epidermal growth factor receptor, hepatocyte growth factor/c-met and acidic fibroblast growth factor/fibroblast growth factor receptors during hepatocarcinogenesis.
It is widely believed that abnormal production of polypeptide growth factors, together with other molecular alterations, play an important role in neoplastic development. Transforming growth factor alpha (TGFalpha), hepatocyte growth factor (HGF) and acidic fibroblast growth factor (aFGF) are the three major growth factors that contribute to liver regeneration occurring via both hepatocyte replication and oval cell proliferation. It is not clear, however, whether and to what extent these growth factors are also involved in hepatocarcinogenesis. In the present study, the gene expression of TGFalpha, HGF and aFGF and their corresponding receptors was examined by Northern blotting and in situ hybridization during hepatocarcinogenesis induced by the Solt-Farber protocol. All three growth factor/receptor systems, TGFalpha/epidermal growth factor receptor (EGFR), HGF/c-met and aFGF/FGF receptors (flg and bek) were significantly elevated at early time points when oval cells were proliferating. Their respective expression decreased after 1 month and remained at a low level until the development of liver tumors. In all hepatocellular carcinomas (HCC) examined, the transcripts of TGFalpha and aFGF were highly expressed, while those of HGF were low. With regard to the receptor expression in the tumors, EGFR was present at varying levels, c-met was expressed at higher levels and flg increased significantly, whereas bek remained at low levels. These data suggest that TGFalpha and aFGF are the major growth factors involved in the progression of HCC, and that the signal of aFGF is mainly transduced by the receptor flg in HCC. Furthermore, HCC cells were phenotypically very similar to oval cells with regard to the gene expression of growth factor/receptor systems. These results, along with the finding that all the HCC cells are positive for the oval cell antigen OV6, and that cytokeratin 19 is heavily expressed in both tumor and oval cells, strongly suggest that at least some of the HCC induced by the Solt-Farber protocol may be derived from oval cells.
Animals↗
Expression of leukemia inhibitory factor and its receptor during liver regeneration in the adult rat.
Leukemia inhibitory factor (LIF) is a polyfunctional cytokine that was discovered in the conditioned medium from Buffalo rat liver cells. In the liver, LIF is known to induce acute phase proteins in the hepatocytes. No comprehensive study has yet been performed on the physiological role of this cytokine during liver regeneration. Thus, we studied the level of expression and cellular distribution of transcripts for LIF, its receptor (LIFR), and signal transducing subunit gp13O during rat liver regeneration after both simple partial hepatectomy (PH) and the oval cell activation induced by the combination of 2-acetylaminofluorene and PH. In addition, the expression of an acute phase protein alpha1-acidglycoprotein was examined. The level of transcripts for LIF and its receptor subunits increased and remained elevated during oval cell expansion. In contrast, after PH, the transcripts were induced only transiently, showing a peak 24 hours after the operation. LIF and receptor subunits were expressed in both parenchymal and nonparenchymal fractions in the 2-acetylaminofluorene/PH model, but the level of expression was most pronounced in the nonparenchymal fraction. In situ hybridization clearly revealed a strong expression of LIF, LIFR, and gp13O in the oval cells and demonstrated only a weak expression in the parenchyma. Interestingly, transcripts of alpha1-acidglycoprotein were exclusively detected in the parenchyma. These results suggest a phenotypic difference between oval cells and hepatocytes in their signaling through gp130. We hypothesize that the LIF/LIFR gp130 system may be involved in the expansion and differentiation of the liver stem cell compartment.
Acute-Phase Proteins↗
Effect of vitamin A deficiency on the integrity of hepatocytes after partial hepatectomy.
The effect of vitamin A deficiency on hepatic regeneration in male and female rats was studied after partial hepatectomy. A fourfold increase in the number of positive dUTP end-labeled nuclei was observed in the deficient animals as early as 30 minutes after partial hepatectomy and their number reached a peak by 8 hours after the operation. The bile duct cells were both morphologically and biochemically intact at all time points. Administration of retinyl palmitate 1 hour before partial hepatectomy significantly reduced the number of positive nuclei, and treatment with retinyl palmitate 24 or 48 hours before the operation reduced the number of positive cells to the level observed in control vitamin A-supplemented rats. The level of transcripts for c-jun, c-fos, c-myc, and transforming growth factor-beta 1 were increased for an extended period of time in livers of deficient animals, whereas the expression of both p53 and max were unchanged. Immunocytochemistry demonstrated the presence of latent transforming growth factor-beta 1 in cells showing evident apoptotic or necrotic changes in their nuclei. This study demonstrates the importance of vitamin A for the survival of hepatocytes both in intact vitamin A-deficient liver and after partial hepatectomy, whereas the ductal cells appear to be less sensitive to vitamin A deficiency.
Animals↗
Ca2+ influx initiates death of hepatocytes injured by activation of complement.
To clarify the role of cytosolic Ca2+ in hepatocellular death, we exposed cultured hepatocytes to human serum and a monoclonal antibody directed against rat liver plasma membranes to produce complement-mediated cell injury. The change in cytosolic Ca2+ concentration was measured by fura2 and fluo3 fluorescence. With the addition of monoclonal antibody, an increase in cytosolic Ca2+ was observed, followed by cell death. Both the increase in intracellular Ca2+ and cell death were prevented by intracellular Ca2+ chelation or removal of extracellular Ca2+. We conclude that an increase in cytosolic Ca2+ plays a major role in hepatocellular injury induced by exposure of the cell membrane to monoclonal antibody.
Animals↗
Evaluation of serum uric acid to creatinine ratio in fulminant hepatitis.
Of the eight patients with fulminant hepatitis placed under total parenteral nutrition with an amino acid solution rich in branched chain amino acids and treated by plasma exchange, four survived and four died from hepatic failure. Serum uric acid levels in the non-survived group were significantly lower on days 1-6 compared with the survived group. The concentration ratios of uric acid to creatinine and prothrombin time were significantly lower on days 5-8 and days 3-8, respectively, in a similar comparison. Thus, the uric acid to creatinine ratio, which corrects for the possible renal dysfunction associated with acute hepatic failure, may serve as a clinically useful prognostic indicator for patients with fulminant hepatitis.
Adolescent↗
Administration of a branched-chain amino acid preparation during hepatic failure: a study emphasizing ammonia metabolism.
We administered a branched-chain amino acid (BCAA) infusion to 16 patients with hepatic failure and two healthy subjects, and then evaluated its effects on ammonia metabolism and amino acid metabolic pool. Immediately after the BCAA infusion, the venous blood ammonia concentration increased in 12 of 15 patients with hepatic failure and in both two healthy subjects. Glutamine (Gln) also rose in all cases following the BCAA infusion, and this rise was particularly marked in the hepatic failure group. The increase in Gln due to the BCAA infusion and the arteriovenous difference in the pre-administration ammonia concentration showed a good correlation. These results suggest an increase in glutamine cycle capacity in patients with hepatic failure.
Adult↗
The combined effect of lymphokine activated killer cell and radiation therapy on rat brain tumor in vitro.
The in vitro effect of a combined treatment with lymphokine activated killer (LAK) cell and radiation therapy on rat brain tumor was examined using 51Cr release assay. The tumor cell-line used in this experiment was 9L rat brain tumor derived from a Fischer 344 rat. LAK cells were obtained by culturing rat lymphocytes with recombinant human interleukin 2 for at least 3 days. The cytotoxic activity of the LAK cells was examined by 51Cr release assay. Irradiation was done by exposing the microtiter plate in which the 51Cr labeled 9L cells and LAK cells were cultured to a 137Cs gamma cell unit. Without irradiation, there was 18% cytotoxicity in the 1:100 tumor-to-LAK cell ratio specimen after 24 hrs cocultivation. However, if 5 Gy of irradiation was given, followed by 12 hrs incubation, the cytotoxicity was enhanced significantly at the same cell ratio (30%). This enhancement effect was the most prominent when the cell ratio was 1:100 and the irradiation dose was 5 Gy. To generate the enhancement effect, an incubation time of over 8 hrs both before and after irradiation was required. The supernatant of the LAK cells showed 19.8% and 11.4% cytotoxicity with and without irradiation, respectively. This result indicates the participation of a cytotoxic factor released from LAK cells.
Animals↗
The role of Kupffer cells in complement activation in D-Galactosamine/lipopolysaccharide-induced hepatic injury of rats.
To investigate the role of Kupffer cells in complement activation, we used a rat model of acute hepatic injury induced by D-Galactosamine (GalN) and lipopolysaccharide (LPS). In in vivo study, minimal histological changes were observed after i.p. GalN (200 mg/kg) single administration. Complement hemolytic activity (CH 50) decreased to 70% of its initial value 2-3 h after i.p. LPS (1.5 mg/kg) single administration. Massive hepatic necrosis was induced by simultaneous administration of GalN and LPS. After 2-3 h, CH 50 decreased to 70% of its initial value, and deposition of C3 fluorescence (C3) was observed in Kupffer cells. After 4 h, GPT was greatly increased (1286 +/- 240 IU/l), CH 50 was further reduced, and C3 was observed on hepatocyte membranes and in the cytosol. In in vitro study, we used hepatocyte cultures and co-cultures of hepatocytes and Kupffer cells to investigate the participation of GalN, LPS, complement, and Kupffer cells in hepatic cell necrosis. We found no increase of LDH (% leakage) when LPS and complement were added to the medium (22.7 +/- 5.7%). A moderate increase was observed with the addition of GalN (33.2 +/- 2.6%). A remarkable increase was observed only with the addition of GalN, LPS, and complement to the co-culture (50.0 +/- 8.8%). These results suggest that Kupffer cells activated by LPS are very important in promoting acute hepatic injury by complement.
Alanine Transaminase↗
The effect of radiation therapy combined with natural killer cells against spontaneous murine fibrosarcoma.
The effect of radiation therapy combined with lymphoid cells against spontaneous murine fibrosarcoma (FSa-II) was investigated both in vivo and in vitro. In the in vivo experiment, syngeneic C3H mice were divided into 3 groups. Animals in the first group were injected with 1 x 10(5) tumor cells into the right hind leg. Animals in the second and third groups were injected with 1 x 10(5) tumor cells mixed with 1 x 10(7) normal lymphoid cells (NLC) or effector lymphoid cells (ELC), respectively. ELC were obtained from spleen and lymph nodes of FSa-II-bearing mice and incubated in vitro for 40 hr to eliminate suppressor T cell function. NLC were obtained from normal mice and incubated in the same way. Irradiation was given using 137Cs unit 3 days after cell inoculation. 12 out of 14 mice (85.7%) inoculated with tumor cells mixed with NLC did not show any tumor growth at 60 Gy local irradiation. 12 out of 21 mice (57.1%) inoculated with tumor cells alone and 6 out of 10 (60%) with tumor cells mixed with ELC rejected tumors at the same radiation dose. This synergistic effect with NLC was not observed when NLC was inoculated after irradiation, indicating that lymphoid cells should be in contact with tumor cells before irradiation. In the 51Cr release assay, lymphoid cells obtained from whole body irradiated (WBI) mice showed 17.8% lysis without irradiation and 28.8% lysis at 5 Gy irradiation. Untreated NLC showed almost no cytotoxic effect at the same radiation dose. This synergistic effect disappeared when WBI lymphoid cells were treated with anti asialo GM1 and complement.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
[Prognosis of patients with carcinoma of the thoracic esophagus, with special reference to the number of metastatic lymph nodes and their metastatic portions].
One hundred and sixty two patients (69 patients without lymph node metastases and 93 patients with positive node metastases) out of patients with thoracic esophageal carcinoma resected within the past 12 years were studied regarding prognostic factors, with special reference to the number of positive nodes and their metastatic portions. Among patients with positive nodes, 5 years survival rates were 14.5% in patients with one or two positive nodes, 16.3% in patients with positive nodes only in the abdomen, 14.3% in patients with positive nodes only in the thorax, and 17.8% in patients with regional lymph node metastases (n1(+) and n2(+)). While among patients with distant lymph node metastases (n3(+) and n4(+)), with more than three positive nodes, or with positive nodes both in the thorax and abdomen, almost all of them expired due to recurrence within three years. Patients with one or two positive nodes and with positive nodes only in the abdomen who underwent postoperative irradiation combined with chemotherapy had a better prognosis than patients treated with postoperative irradiation alone or patients receiving no combined therapy.
Abdominal Neoplasms↗
[Elevation of the pulmonary arterial pressure as a sign of pneumothorax and hemothorax--a report of two cases].
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Aged↗
[Pulmonary complications caused by postoperative irradiation and bleomycin administration for esophageal cancer, with special reference to acute interstitial pneumonitis].
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Acute Disease↗
[Analgesic effect of Feldene (piroxicam) on pain following minor oral surgery].
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Adult↗