Negative-ion FAB-MS of neutral tris- and bis(L-alpha-amino acidato)-chromium(III) complexes.
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Journal Article↗
Biomedical subjects
R Nakata
Publications and source records attributed to R Nakata.
Change in caspase-3-like protease in the liver and plasma during rat liver regeneration following partial hepatectomy.
Recent studies have shown that many factors orchestrate liver regeneration after a two-thirds partial hepatectomy (PH). However, the termination mechanism in liver regeneration has not been thoroughly studied. In this paper, we report that the activity of liver caspase-3-like protease, which is specifically activated in apoptosis, increases 18, 36, and 48 hr after PH during maximal hepatocyte proliferative activity. This is the first study that shows the activation of an apoptosis-executing enzyme during physiological liver regeneration. These results suggest that apoptosis is induced in each surge of DNA synthesis as the termination mechanism. When phenoxybenzamine, an alpha-blocker that has been reported to inhibit DNA synthesis during liver regeneration, was injected 8 hr after PH, the caspase-3-like activity in the liver peaked at 15 hr after PH and the enzyme activity also increased in plasma at 18 and 24 hr after PH in sharp contrast to the case of normal regeneration. These results indicate that extensive apoptosis is caused by phenoxybenzamine and that the secondary necrosis of apoptotic cells results in the increase of caspase-3-like protease activity in the plasma.
Animals↗
Different turnover rate of hepatitis C virus clearance by different treatment regimen using interferon-beta.
BACKGROUND/AIM: Since patients with high viral load and HCV subtype 1b are known to respond poorly to interferon (IFN) therapy, the viral dynamics of HCV RNA after initiation of interferon therapy were examined in the present study with respect to two different administration regimens, once vs. twice a day. METHODS: Twenty-two patients with chronic hepatitis C confirmed by liver biopsy and with >1 Meq/ml of HCV RNA and HCV subtype 1b were randomly assigned to two different IFN administration regimens (6 million units of IFN once a day or 3 million units of IFN twice a day), and the serum HCV RNA level was serially measured. RESULTS: Graphs of HCV RNA levels vs. treatment time showed an initial rapid fall, followed by a slower clearance phase. Fitting the data to a model for HCV decay proposed by Neumann et al. showed that the treatment efficacy was significantly higher with twice daily administration. Negativity for HCV RNA measured by Amplicor assay in the twice-a-day administration group was 18%, 73% and >89% at 1, 2 and 3 weeks, respectively, in contrast to 0%, 0%, and 18%, respectively, with once-a-day administration. However, a significant reduction of platelet count and albumin level, a marked increase in serum aspartate aminotransferase/alanine aminotransferase, and a high incidence of renal toxicity (proteinuria) were found in patients receiving IFN twice a day in comparison with those receiving it once a day. CONCLUSION: The twice-a-day administration of IFN accelerated the clearance of HCV RNA from serum, leading to a more efficient virological response for patients with chronic hepatitis C, but with a high rate of renal toxicity.
Adult↗
Sustained viral response is rarely achieved in patients with high viral load of HCV RNA by excessive interferon therapy.
Adequate dosing of interferon (IFN) and its cost-effectiveness for sustained virological response were evaluated in relation to viral load and subtype. Prospective analysis of IFN therapy on 326 patients with chronic hepatitis C free from cirrhosis was performed using 9 or 6 million unit (MU) of IFN for six months daily and/or three times a week. Sustained virological response was achieved in 50-94% of patients with < or =2 x 10(4) copies/ml (competitive RT-PCR) or <100 x 10(3) copies/ml (Amplicor monitor) of HCV RNA by 468-1206 MU of IFN, but response was only 0-25% of the patients with > or =2 x 10(5.5) copies/ml (competitive RT-PCR) or >200 x 10(3) copies/ml (Amplicor monitor), even with 468-1206 MU of IFN. A high sustained rate was demonstrated in patients with 100-200 x 10(3) copies/ml of HCV RNA by 901-1206 MU of IFN, in comparison to that with < or =900 MU of IFN. Multivariate analysis showed that IFN dose had a significant value for the efficacy of IFN therapy in patients presenting 100-200 x 10(3) copies/ml of HCV RNA. Cost efficacy analysis indicated that it cost approximately $10,000, $26,000, and $50,000-227,000 for one person-viral eradication in the patients with <100, 100-200, and >200 x 10(3) copies/ml, respectively. High-dose IFN is only cost effective in patients with intermediate viral loads, and IFN therapy could be recommended in patients with <200 x 10(3) copies/ml of HCV RNA.
Adolescent↗
High viral eradication with a daily 12-week natural interferon-beta treatment regimen in chronic hepatitis C patients with low viral load. IFN-beta Research Group.
Virological sustained response (SR) is achieved in 31-49% of patients with chronic hepatitis C with combination therapy using interferon (IFN)-alpha and ribavirin for 24-48 weeks. However, as a period of 24-48 weeks is a burden for patients, we investigated the effect of daily intravenous administration of natural IFN-beta for 12 weeks in this study. In all, 112 patients were enrolled and received a daily administration of 6 MU of natural IFN-beta intravenously for 12 weeks. Serum HCV-RNA before treatment was assessed by the competitive reverse-transcription polymerase chain reaction assay. The patients were divided into two groups according to pretreatment viral load: the low viral load group (N = 25, <6.3 x 10(5) copies/ml), and the high viral load group (N = 87, > or =6.3 x 10(5) copies/ml) who were additionally administered IFN-beta thrice weekly for subsequent 14 weeks at the patients' request. Virological SR was obtained in 37% (41/112) of all the patients; 88% of those with a low viral load, and 22% of patients with a high viral load. Virological SR was attained in 21% of patients with HCV subtype 1, and in 67% of those with subtype 2a. In patients with HCV subtype 1b, virological SR was obtained in patients with the mutant-type (> or =4 amino acid mutations in the NSSA2209-48) having a low viral load (4/4), but not in those having a high viral load (0/3). The results suggest that a daily intravenous administration of natural IFN-beta for 12 weeks showed high therapeutic efficacy in patients with a low viral load despite the shorter treatment period and that the therapeutic efficacy depends on viral load rather than on the number of NS5A2209-48 amino acid mutations.
Adolescent↗
Accumulation of quercetin conjugates in blood plasma after the short-term ingestion of onion by women.
Quercetin is a typical flavonoid present mostly as glycosides in plant foods; it has attracted much attention for its potential beneficial effects in disease prevention. In this study, we examined human volunteers after the short-term ingestion of onion, a vegetable rich in quercetin glucosides. The subjects were served diets containing onion slices (quercetin equivalent: 67.6-93.6 mg/day) with meals for 1 wk. Quercetin was only found in glucuronidase-sulfatase-treated plasma, and its concentration after 10 h of fasting increased from 0.04 +/- 0.04 microM before the trial to 0.63 +/- 0.72 microM after the 1-wk trial. The quercetin content in low-density lipoprotein (LDL) after glucuronidase-sulfatase treatment corresponded to <1% of the alpha-tocopherol content. Human LDL isolated from the plasma after the trial showed little improvement of its resistance to copper ion-induced oxidation. It is therefore concluded that conjugated metabolites of quercetin accumulate exclusively in human blood plasma in the concentration range of 10(-7) approximately 10(-6) M after the short-term ingestion of vegetables rich in quercetin glucosides, although these metabolites are hardly incorporated into plasma LDL.
Adult↗
Determination of folate derivatives in rat tissues during folate deficiency.
A method for the sensitive and specific determination of folate derivatives was developed. The method involves hydrolysis by gamma-glutamyl hydrolase and high-performance liquid chromatography with electrochemical detection. The method was applied to measure the change in the level of folate derivatives in the liver, kidney, spleen and brain of rats during folate deficiency. 5,6,7,8-Tetrahydrofolic acid was the major folate derivative in the liver, kidney, spleen and brain. Total concentration of folate derivatives decreased from the second week of folate deficiency in the liver, kidney, spleen and brain followed by anemia, which appeared at the fifth week. The level of 5,6,7,8-tetrahydrofolic acid in the brain did not change during folate deficiency, but it significantly decreased in the liver, kidney and spleen.
Anemia↗
Prospective study of interferon therapy for compensated cirrhotic patients with chronic hepatitis C by monitoring serum hepatitis C RNA.
Because interferon therapy exhibits low efficacy for cirrhotic patients infected with hepatitis C virus, this prospective study was conducted to determine effective interferon regimens tailored to treatment response by monitoring HCV RNA status. A total of 157 cirrhotic patients were enrolled to receive 9 million units (MU) of interferon three times a week. The HCV RNA values were drawn 8 weeks apart and the patients were randomized to a further 16 or 32 weeks of treatment after two sequential findings of negativity for HCV RNA. A total of 73 out of 157 patients (46%) proceeded to randomization to different durations of treatment, 37 short-course and 36 long-course (duration: 38 +/- 8 and 49 +/- 13 weeks; total amount of interferon: 940 +/- 240 and 1130 +/- 390 MU, respectively). The remaining 84 patients without two sequential negative serum HCV RNA determinations received 44.8 +/- 27.4 weeks of interferon (IFN) therapy with total amount of 993 +/- 633 MU. Of these 157 patients, sustained virological and biochemical response was shown in 32 (20%) and 37 patients (24%), respectively. Sustained virological and biochemical response rate in the randomized patients was significantly higher than in nonrandomized patients (41% vs. 2%, and 38% vs. 11%; each P <.01). Of the 73 randomized patients, the rate of sustained virological response in patients with long-course treatment (50%) was significantly higher than that of patients with short-course treatment (32%) (P =.026: log-rank test), and in patients with early disappearance of HCV RNA especially within 8 weeks, in patients with low virus load (</=10(6.3) copies/mL) and with HCV 2a. Multivariate analysis revealed that HCV RNA level and subtypes were the most important factors contributing to sustained virological response. Interferon is effective even in cirrhotic patients with low viral load and HCV 2a, but requires a longer course of administration.
Adult↗
Facile degradation of apolipoprotein B by radical reactions and the presence of cleaved proteins in serum.
A facile cleavage of peptide bonds of apolipoprotein B (apoB) by radical reaction is reported. When human LDL was subjected to oxidative damage using Cu2+, extensive degradation of apoB was observed based on immunoblotting. The degradation of apoB was inhibited by radical scavengers (beta-mercaptoethanol, butylated hydroxytoluene, and probucol) and promoted by a radical initiator [2, 2'-azobis(2-amidinopropane)dihydrochloride]. When human serum was treated with Cu2+, a similar cleavage pattern of apoB was observed. The cleaved apoB proteins were also detected in normal serum on the basis of immunoblots. These results suggest that apoB is highly reactive toward radicals in vitro and in vivo, with reaction resulting in the cleavage of peptide bonds.
Adult↗
Real-time monitoring of HCV-RNA by single tube assay kit and potential importance for predicting virological sustained response in patients with chronic hepatitis C.
In an attempt to predict virological sustained responders among patients with chronic hepatitis C after interferon therapy, HCV-RNA in serum was measured by a one tube RT-PCR assay kit using the RNA corresponding to 5 microL serum (standard assay) or 300 microL serum (enhanced-sensitivity assay). Dilution analysis revealed that sensitivity of the 'enhanced-sensitivity assay' increased by 10-100-fold when compared with a 'standard assay'. Using these assays, prospective study of interferon therapy on 38 HCV-RNA seropositive cases with chronic hepatitis (total amount 702 MU; duration of treatment 5-6 months) was performed. At the end of treatment, six were still positive and 32 became negative by the "standard assay', whereas an additional eight cases became positive (total 14 cases positive; the remaining 24 cases negative) by the 'enhanced-sensitivity assay'. Hepatitis C viral RNA state at the end of treatment remained the same 6 months later in 23 cases (61%) by a 'standard assay' and in 31 (82%) by the 'enhanced-sensitivity assay'. Of importance was that all patients (14 cases) demonstrating HCV-RNA in serum at the end of therapy, even by the "enhanced-sensitivity assay', did not show the disappearance of HCV-RNA in serum despite the long follow up. From these results, in order to improve our treatment efficacy, we should try to modify our treatment protocol to the extent that at least HCV-RNA becomes undetectable. That can be only feasible during treatment by real-time monitoring of HCV-RNA.
Adult↗
Effect of splenectomy on hepatic metastasis of colon carcinoma and natural killer activity in the liver.
We have previously demonstrated that administration of killed streptococcal preparation (OK432), a biological modifier, increased the number of asialo GM1-positive cells in the liver, enhanced NK activity of hepatic mononuclear cells, and reduced the number of hepatic metastases of colon 38 adenocarcinoma that were inoculated into the superior mesenteric vein of C57BL/6 strain mice. In the present study, to clarify the role of the spleen in immune surveillance of the liver, the effect of splenectomy on hepatic metastasis of colon carcinoma and on hepatic NK activity has been examined. The number of hepatic metastasis increased in the splenectomized mice, compared with that in sham-operated mice. Administration of OK432 increased the number of asialo GM1-positive cells in the liver and enhanced NK activity of hepatic mononuclear cells in both groups, but NK activity of hepatic mononuclear cells in the splenectomized mice was less than that of the sham-operated mice. An enhanced NK activity of these cells was abolished by treatment with anti-asialo-GM1 antibody plus complement in vitro. Interleukin-2 mRNA expression was increased in the spleen 2 hr after OK432 administration and persisted until 8 hr, but was scarcely noted in the liver. On the other hand, NK activity of hepatic mononuclear cells in the asialo GM1-positive cell-depleted (previous administration of antiserum against asialo GM1) mice was enhanced after OK432 administration in the sham operated and splenectomized mice, but an enhanced NK activity in these mice was only partially or not at all abolished by treatment with anti-asialo GM1 antibody plus complement in vitro, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Chemotactic factors released from hepatocytes exposed to acetaminophen.
To clarify the mechanism of neutrophil infiltration in the liver of acetaminophen-induced hepatic injury, chemotactic factor released from hepatocytes exposed to acetaminophen has been investigated. Hepatocytes exposed to acetaminophen release nondialyzable chemotactic factor, although acetaminophen in itself inhibits chemotaxis of neutrophils. Chemotactic activity of the nondialyzable chemotactic factor was reduced after treatment with heat (56 degrees C, 30 min) or trypsin. Chemotactic activity was demonstrated at the molecular weights of around 25 and 55 kDa. Chemotactic activity of the conditioned medium was not significantly reduced in the presence of antibody against rat KC/gro protein (interleukin-8-related cytokine in rodent). Chemotactic activity of a 25-kDa factor was reduced by the antibody against the antibody against KC/gro protein, but that of a 55-kDa factor was not reduced. Immunoblot analysis revealed that the peptide reacted with antibody against rat KC/gro protein was demonstrated at a molecular weight of around 20-25 kDa, but not around 55kDa, when the conditioned medium of acetaminophen-treated hepatocytes was electrophoresed. These results suggest that hepatocytes exposed to acetaminophen release two types of chemotactic factors for neutrophils and that a major part of the chemotactic factor could be different from a member of interleukin-8 family.
Acetaminophen↗
Growth regulation of rabbit gastric epithelial cells and protooncogene expression.
We recently developed a primary culture system for gastric epithelial cells from adult rabbits that allows the investigation of growth regulation at the cellular level. In this study, we demonstrated that epidermal growth factor (EGF), insulin, and dibutyryl adenosine 3',5'-cyclic monophosphate (dBcAMP) all stimulated cell proliferation. Insulin and dBcAMP potentiated the stimulation of cell proliferation by EGF, while transforming growth factor-beta 1 (TGF-beta 1) inhibited it. Expression of c-fos and c-myc was induced in response to the stimulation by these growth regulators, but the degree of expression did not necessarily correlate with the effects of these agents on cell proliferation. In conclusion, EGF, insulin, and dBcAMP were positive growth regulators, while TGF-beta 1 was a negative regulator in gastric epithelial cells. These growth modulators may exert their effects by distinct pathways from a standpoint of the expression of c-fos and c-myc.
Animals↗
Churg-Strauss syndrome (allergic granulomatous angiitis) with multiple perforating ulcers of the small intestine, multiple ulcers of the colon, and mononeuritis multiplex.
A case of Churg-Strauss syndrome with multiple perforations of the small intestine is described. A 31-year-old woman was admitted with a complaint of epigastric pain. She had a history of bronchial asthma. One week before admission, white blood cell count was 20,800/mm3 with 59% eosinophils. Neurological examination on admission disclosed mononeuritis multiplex with paresthesia in both the lower and upper extremities. At colonoscopy, there were scattered aphthous ulcers in the colon. Ophthalmological examination revealed allergic conjunctivitis. After admission, hypereosinophilia increased to as high as 36,000/mm3. Oral administration of prednisolone (60 mg/day) was begun. On the 3rd day of the treatment, the eosinophil count decreased dramatically, to 400/mm3, while severe abdominal pain developed. Since abdominal X-ray film revealed free air in the abdominal cavity, emergency laparotomy was performed and multiple intestinal ulcers with perforations were found. Partial ileectomy was performed. Pathological findings of the resected specimen were interpreted as a necrotizing angiitis with extravascular granuloma. Since the operation, the patient has been asymptomatic, except for neurological symptoms. Hypereosinophilia has decreased without treatment to counts averaging 270/mm3, within 3 months. On the basis of the clinical features and histopathological findings, a diagnosis of Churg-Strauss syndrome was established.
Adult↗
[A case of ischemic colitis due to polyarteritis nodosa].
A 78-year-old female was admitted to our hospital with acute abdomen (abdominal pain and bloody stool). Abdominal examination revealed mild rebound tenderness on the right side. The laboratory data revealed severe inflammation (WBC: 33100/microliters, CRP:35.5 mg/dl). Panperitonitis was suspected because of diffuse and severe abdominal pain and rebound tenderness on the next day. X-ray examination by gastrografin showed mucosal irregularity and tubular narrowing of the tubular narrowing of the ascending colon which indicated ischemic colitis, and an emergency operation was performed. Histological examination of the pathologic specimens revealed fibrinoid necrosis and destruction of the internal lamina in small and medium-size arteries. We report a case diagnosed as ischemic colitis due to polyarteritis nodosa by the findings of its pathologic specimens.
Aged↗
Regulation of thymidylate synthase in regenerating rat liver after partial hepatectomy.
Level of thymidylate synthase (TS) mRNA elevated about 6-fold compared with the normal in 24 h-regenerating rat liver after partial hepatectomy. This elevation of TS mRNA level was coupled with that of the activity. After 24h, the TS mRNA level began to decline steeply and returned to the normal level at 72h, when TS activity remained at the maximal level. alpha-Adrenergic regulation of liver regeneration after partial hepatectomy, which was shown in our previous paper, was found to be occurred at mRNA level of TS. The administration of cycloheximide resulted in the decreases of both TS activity and TS mRNA level while actinomycin D had no effect. This suggested that the increase of TS mRNA in regenerating liver required the de novo synthesis of some activator protein(s).
Animals↗
Two different promoters direct expression of two distinct forms of mRNAs of human platelet-activating factor receptor.
The human platelet-activating factor (PAF) receptor gene exists as a single copy on chromosome 1. We identified two 5'-noncoding exons, each of which has distinct transcriptional initiation sites. These exons are alternatively spliced to a common splice acceptor site on a third exon that contains the total open reading frame to yield two different species of functional mRNA (Transcript 1 and 2). Transcript 1 has consensus sequences for transcription factor NF-kappa B and Sp-1, and the Initiator (Inr) sequence homologous to the murine terminal deoxynucleotidyltransferase gene. Transcript 2 also contains consensus sequences for transcription factor AP-1, AP-2, and Sp-1. Transcripts 1 and 2 were both detected in heart, lung, spleen, and kidney, whereas only Transcript 1 was found in peripheral leukocytes, a differentiated human eosinophilic cell line (EoL-1 cells), and brain. Existence of distinct promoters was thus suggested to play a role in the regulatory control of PAF receptor gene expression in different human tissues and cells.
Alternative Splicing↗