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Biomedical subjects

Hideaki Shimada

Publications and source records attributed to Hideaki Shimada.

At least 37 records · Page 2Linked to original sources
PubMed2005

Characteristics and inhibition by flavonoids of 20alpha-hydroxysteroid dehydrogenase activity in mouse tissues.

Progesterone was stereoselectively reduced to a metabolite 20alpha-hydroxy-4-pregnen-3-one in the cytosolic fraction from the liver of male mice, indicating that the reduction of progesterone is catalyzed by 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD). The cytosolic 20alpha-HSD activity was observed not only in the liver, but also in the kidney and lung. In liver cytosol, both NADPH and NADH were effective as cofactors for 20alpha-HSD activity, although NADPH was better than NADH for the enzyme activity. On the other hand, 20alpha-HSD activity in kidney cytosol required only NADPH as a cofactor. No significant sex-related difference of 20alpha-HSD activity was observed in liver and kidney cytosols. Flavonoids have been reported to inhibit the biosynthesis and metabolism of steroids. However, little is known about inhibitory effects of flavonoids on 20alpha-HSD activity. Thus, the effects of 16 flavonoids on 20alpha-HSD activity were examined, using liver cytosol of male mice. Among flavonoids tested, fisetin, apigenin, naringenin, luteolin, quercetin and kaempferol exhibited high inhibitory potencies for the 20alpha-HSD activity. We propose the possibility that these flavonoids augment progesterone signaling by inhibiting potently 20alpha-HSD activity in non-reproductive tissues.

20-alpha-Hydroxysteroid Dehydrogenase↗
PubMed2005

Involvement of carbonyl reductase in superoxide formation through redox cycling of adrenochrome and 9,10-phenanthrenequinone in pig heart.

The effects of adrenochrome, a metabolite of epinephrine (adrenaline), and 9,10-phenanthrenequinone (PQ), a component of diesel exhaust particles, on the stereoselective reduction of 4-benzoylpyridine (4-BP) were examined in pig heart cytosol. PQ was a potent inhibitor for the 4-BP reduction, while adrenochrome was a poor inhibitor. A similar result was observed in the effects of adrenochrome and PQ on the reduction of all-trans retinal. Furthermore, although PQ mediated efficiently the formation of superoxide anion radical through its redox cycling in pig heart cytosol, adrenochrome had no ability to mediate the superoxide formation. These may be because the reactivity for adrenochrome, catalyzed by pig heart carbonyl reductase (PHCR), is much lower than that for PQ. The optimal pH for the reduction of PQ in pig heart cytosol was around 5.5. Dicumarol, a potent inhibitor of DT-diaphorase, had little effect on the time course of NADPH oxidation during the reduction of PQ. Therefore, it is concluded that PHCR plays a critical role in superoxide formation through redox cycling of PQ.

Adrenochrome↗
PubMed2005

Centromere protein H is up-regulated in primary human colorectal cancer and its overexpression induces aneuploidy.

Chromosomal instability (CIN) has been recognized as a hallmark of human cancer and is caused by continuous chromosome missegregation during mitosis. Proper chromosome segregation requires a physical connection between spindle microtubules and centromeric DNA and this attachment occurs at proteinaceous structures called kinetochore. Several centromere proteins such as CENP-A and CENP-H are the fundamental components of the human active kinetochore, and inappropriate expression of the centromere proteins could be a major cause of CIN. We have previously shown that CENP-A was overexpressed in primary human colorectal cancer. In this study, we show that CENP-H was also up-regulated in all of 15 primary human colorectal cancer tissues as well as in CIN tumor cell lines. Surprisingly, transient transfection of CENP-H expression plasmid into the diploid cell line HCT116 remarkably induced aneupoidy. Moreover, CENP-H stable transfectant of mouse embryonic fibroblast/3T3 cell lines showed aberrant interphase micronuclei, characteristic of chromosome missegregation. In these CENP-H overexpressed cells, CENP-H completely disappeared from the centromere of mitotic chromosomes, which might be the cause of the chromosome segregation defect. These results suggest that the aberrant expression and localization of a kinetochore protein CENP-H plays an important role in the aneuploidy frequently observed in colorectal cancers.

3T3 Cells↗
PubMed2005

Prolonged skin allograft survival by IL-10 gene-introduced CD4 T cell administration.

Both CD4 and CD8 T cells play crucial roles in immune responses in transplantation. Immunosuppressive drugs, such as FK506 and cyclosporin A, block the priming of alloreactive CD4 T(h) cells and the subsequent induction of allospecific CD8 cytotoxic effector T cells and inhibit allograft rejection. However, the desire to minimize chronic complications that may arise from the use of immunosuppressive agents drives the search for additional strategies for immunosuppression of allograft rejection. In this study, CD4 or CD8 T cells into which the IL-10 gene is introduced using an adenovirus vector containing human IL-10 (hIL-10) cDNA (Ad-hIL-10) and into mouse T cells transgenic for the Coxsackie virus and adenovirus receptor form a model system to study the effect of administration of IL-10-secreting T cells on the survival of the allogenic skin grafts. Ad-hIL-10-infected CD4 and CD8 T cells secreted a large amount of hIL-10 for 3-4 days in culture in vitro. Ad-hIL-10-infected CD4 T cells administered in vivo could be detected in the spleen for 7 days post-transfer. Significantly prolonged survival of grafts was observed in animals that received either Ad-hIL-10-infected activated CD4 T cells or T(h)2-skewed CD4 T cells as compared with controls. Furthermore, substantial enhancement of the effect was observed in B6.C-H2(bm1)/ByJ transplants. Thus, a direct manipulation of T cells through the introduction of the immunosuppressive cytokine gene IL-10 may be a novel strategy for the control of allograft rejection.

Adenoviridae↗
PubMed2005

Recombinant Sendai virus vector induces complete remission of established brain tumors through efficient interleukin-2 gene transfer in vaccinated rats.

PURPOSE: Sendai virus (SeV), a murine parainfluenza virus type I, replicates independent of cellular genome and directs high-level gene expressions when used as a viral vector. We constructed a nontransmissible recombinant SeV vector by deleting the matrix (M) and fusion (F) genes from its genome (SeV/DeltaMDeltaF) to enhance its safety. We also estimated the therapeutic efficacy of the novel vector system against a rat glioblastoma model. EXPERIMENTAL DESIGN: We administered the recombinant SeV vector carrying the lacZ gene or the human interleukin-2 (hIL-2) gene into established 9L brain tumors in vivo simultaneous with peripheral vaccination using irradiated 9L cells. Sequential monitoring with magnetic resonance imaging was used to evaluate the therapeutic efficacy. RESULTS: We found extensive transduction of the lacZ gene into the brain tumors and confirmed sufficient amounts of interleukin 2 (IL-2) production by hIL2-SeV/DeltaMDeltaF both in vitro and in vivo. The magnetic resonance imaging study showed that the intracerebral injection of hIL2-SeV/DeltaMDeltaF brought about significant reduction of the tumor growth, including complete elimination of the established brain tumors. The (51)Cr release assay showed that significant amounts of 9L-specific cytotoxic T cells were induced by the peripheral vaccination. Immunohistochemical analysis revealed that CD4(+) T cells and CD8(+) T cells were abundantly infiltrated in the target tumors. CONCLUSION: The present results show that the recombinant nontransmissible SeV vector provides efficient in vivo gene transfer that induces significant regression of the established brain tumors and suggest that it will be a safe and useful viral vector for the clinical practice of glioma gene therapy.

Animals↗
PubMed2005

Cardioprotection without cardiosuppression by SEA0400, a novel inhibitor of Na+-Ca2+ exchanger, during ischemia and reperfusion in guinea-pig myocardium.

The effect of SEA0400, a novel Na+-Ca2+ exchanger inhibitor, on mechanical and electrophysiological parameters of coronary-perfused guinea-pig right ventricular tissue preparation was examined during no-flow ischemia and reperfusion. Contractile force and action potential duration were decreased during no-flow ischemia, while the resting tension was increased. Upon reperfusion, transient arrhythmias were observed and contractile force returned to less than 50% of preischemic values. SEA0400 (1 microM) had no effect on the decline in contractile force during the no-flow ischemia, but abolished the rise in resting tension. SEA0400 significantly improved the recovery of contractile force after reperfusion to about 80% of the preischemic value. SEA0400 had no effect on the action potential under normal conditions and during ischemia, but significantly improved the recovery of action potential duration after reperfusion. Enhancement of the recovery of contractile force during reperfusion by SEA0400 was also observed when the drug was applied only before and during the ischemic period and when the drug was applied only during reperfusion. The present results indicate that inhibition of Na+-Ca2+ exchanger either during ischemia or during reperfusion exerts cardioprotective effects and enhances the recovery of myocardial contractile function.

Aniline Compounds↗
PubMed2005

Inhibitory effects of flavonoids on the reduction of progesterone to 20alpha-hydroxyprogesterone in rat liver.

The first aim of this study is to characterize the reduction of progesterone in rat liver. Progesterone was mainly reduced to 20alpha-hydroxyprogesterone in the cytosolic fraction of rat liver. The amount of 20alpha-hydroxyprogesterone formed from progesterone in the cytosolic fraction was significantly larger in the males than in the females and this enzyme reaction proceeded not only in the presence of NADPH, but also in the presence of NADH. Furthermore, we attempted to evaluate the inhibitory effects of 15 flavonoids on the NADPH-dependent reduction of progesterone to 20alpha-hydroxyprogesterone in liver cytosol of male rats. The order of the inhibitory potencies was luteolin>apigenin>quercetin>myricetin=fisetin=kaempferol. Other flavonoids exhibited lower inhibitory potencies. Energy-minimized molecular models demonstrated that a planar benzopyrone ring (A and C rings) with a coplanar phenyl ring (B ring) is a structural characteristic determining the inhibitory effects of flavonoids other than isoflavones.

Animals↗
PubMed2005

Protection from spontaneous hepatocellular damage by N-benzyl-d-glucamine dithiocarbamate in Long-Evans Cinnamon rats, an animal model of Wilson's disease.

The Long-Evans Cinnamon (LEC) rat is a mutant strain that accumulates excessive tissue copper (Cu) and models the clinical symptoms and biological features of Wilson's disease in humans. We compared the effects of three metal chelating agents, N-benzyl-d-glucamine dithiocarbamate (BGD), d-penicillamine (D-PEN), and triethylenetetramine (TETA), on the biliary and urinary excretions of Cu using LEC rats. The animals were treated ip with each chelating agent (1 mmol/kg body weight) and then the bile and urine samples were collected for 3 h. Because single treatment with BGD markedly stimulated biliary excretion of Cu, the protective effect of repeated BGD injection on spontaneous hepatocellular damage was further examined. Separate groups received two weekly injections of BGD starting at 11 weeks of age and were compared to saline-injected controls. Serum alanine aminotransferase (ALT) activity and bilirubin level were significantly increased in control LEC rats by 19 weeks of age and histopathological analysis demonstrated extensive hepatic damage in these rats. However, repeated BGD injections prevented the increases in serum ALT and bilirubin and blocked the histopathological changes in the liver. Furthermore, although Cu rapidly accumulated in the liver, kidney, spleen, and serum of control LEC rats during the test period, repeated BGD injection largely prevented these increases. These results indicate that BGD treatment is effective in blocking excessive Cu accumulation in LEC rats that, in turn, provides protection from spontaneous liver damage.

Animals↗
PubMed2005

Concentrations and compositions of organochlorine contaminants in sediments, soils, crustaceans, fishes and birds collected from Lake Tai, Hangzhou Bay and Shanghai city region, China.

Contamination by persistent organochlorines (OCs), such as DDTs, hexachlorocyclohexane isomers (HCHs), chlordane compounds (CHLs), hexachlorobenzene (HCB) and polychlorinated biphenyls (PCBs) were examined in sediments, soils, fishes, crustaceans, birds, and aquaculture feed from Lake Tai, Hangzhou Bay, and in the vicinity of Shanghai city in China during 2000 and 2001. OCs were detected in all samples analyzed, and DDT and its metabolites were the predominant contaminants in most sediments, soils and biota. Concentrations of p,p'-DDT and ratio of p,p'-DDT to SigmaDDTs were significantly higher in marine fishes than those in freshwater fishes. While the use of DDTs has been officially banned in China since 1983, these results indicate a recent input of technical DDTs into the marine environment around Hangzhou Bay. Comparison of organochlorine concentrations in fishes collected from Lake Tai and Hangzhou Bay suggests the presence of local sources of HCHs, chlordanes and PCBs at Lake Tai. Higher proportions of penta- and hexa-PCB congeners in fishes at Lake Tai may suggest the use of highly chlorinated PCB product, such as PCB(5), around this lake. To our knowledge, this is a first comprehensive study to examine the present status of organochlorine contamination in various environmental media, such as sediments, soils and wildlife, in China.

Animals↗
PubMed2005

Differential pharmacokinetics of acetohexamide in male Wistar-Imamichi and Sprague-Dawley rats: role of microsomal carbonyl reductase.

Acetohexamide (AH) is reduced to its alcohol metabolite by carbonyl reductase. We have previously shown that carbonyl reductase present in the liver microsomes of rats is a male-specific and androgen-dependent enzyme. In the present study, the role of microsomal carbonyl reductase in the pharmacokinetics of AH was examined in male Wistar-Imamichi (WI) and Sprague-Dawley (SD) rats after its intravenous administration. AH was eliminated more slowly from plasma in the WI strain, which lacks most of the microsomal carbonyl reductase, than in the SD strain. Furthermore, several pharmacokinetic parameters were derived from the data for the plasma concentrations of AH. The plasma clearance (CL(p)) of AH (72.8+/-11.2 ml/h/kg) in male WI rats was significantly smaller than that (105.5+/-11.1 ml/h/kg) in male SD rats. Testectomy caused a marked decrease, from 105.5+/-11.1 to 44.3+/-11.8 ml/h/kg, in the CL(p) of AH in male SD rats. These results indicate that microsomal carbonyl reductase plays a critical role in the differential pharmacokinetics of AH in male WI and SD rats.

Acetohexamide↗
PubMed2005

Serological identification of tumor antigens of esophageal squamous cell carcinoma.

Autoantibodies are often detected in the patients with esophageal cancer. We applied serological analysis of recombinant cDNA expression libraries (SEREX) to a case of esophageal squamous cell carcinoma in order to identify tumor antigens. A cDNA library derived from an esophageal cancer cell line was bacterially expressed and screened for interaction with antibodies in five allogeneic sera of patients with esophageal squamous cell carcinoma. To examine the specific immunoreactivity of the antigens, sera from 16 more patients with esophageal squamous cell carcinoma, 16 patients with gastric cancer, 16 patients with colon cancer, 16 patients with breast cancer and 37 healthy volunteers were screened. We identified 11 independent cDNA clones that potentially encoded esophageal cancer tumor antigens. The identified cDNA clones were SURF1, HOOK2, CENP-F, ZIC2, hCLA-iso, Ki-1/57, enigma, HCA25a, SPK and two EST clones named LOC146223 and AGENCOURT_7565913. The sero-positive rates of antibodies against SURF1 (48%), LOC146223 (38%), HOOK2 (14%) and AGENCOURT_7565913 (14%) were significantly higher in esophageal cancer patients than in healthy controls. At least one of these antibodies was detected in 18 (86%) of 21 sera from esophageal cancer patients. A disease-specific humoral immune response against SURF1, LOC146223, HOOK2 or AGENCOURT_7565913 was observed in most patients with esophageal squamous cell carcinoma. Antibodies against these SEREX antigens may represent a pool of candidates for serum tumor markers of esophageal squamous cell carcinoma.

Adult↗
PubMed2005

[Gene therapy for esophageal cancer].

Since surgical resection alone rarely results in long-term survival in esophageal cancer patients, efforts now are focused on combined multi modality treatment in an attempt to improve local control and eliminate micro metastasis present at time of surgery. We have reported that the importance of alteration of p53 gene in progression and prognosis of esophageal cancer. Based on the research of p53 gene therapy for esophageal cancer, we started phase I/II study in 2000. So far, ten patients were enrolled into this clinical study. Six of ten patients were alive more than one-year after initiation of gene therapy. No severe side effects were observed. Although no significant response was observed, seven cases showed stable disease.

Adult↗
PubMed2005

Increased infectivity of adenovirus type 5 bearing type 11 or type 35 fibers to human esophageal and oral carcinoma cells.

Esophageal and oral carcinomas are relatively resistant to adenovirus serotype 5 (Ad5)-mediated gene transfer, primarily because expression of the cellular receptors for Ad5, the coxsackievirus and adenovirus receptor, is often downregulated in these types of tumor. The types of Ad in which the receptor expression is not suppressed in tumors are therefore better vectors for gene transfer into tumors. CD46, a cellular receptor for Ad subtype B2, such as Ad11 and Ad35, is well expressed in a number of esophageal and oral tumor cells. Since the infectivity of Ad to target cells is mainly influenced by the interaction between their fibers and the cellular receptors, we examined the infectivity of chimeric Ad5, whose fiber structure was substituted with that of type 11 or 35 (Ad5/11 or Ad5/35), to 6 human oral and 11 esophagus carcinoma cells. We found that the chimeric Ad, in particular Ad5/35, infected more effectively than Ad5 in all the tumors tested. However, the efficacy of Ad5/35- and Ad5/11-mediated transduction was not correlated with the expression level of CD46 or CD80/86, a cellular receptor of the Ad subtype B1, in the target cells. These data suggest that the Ad subtype B2 are suitable vectors of gene transfer for human squamous cell carcinomas of the upper gastrointestinal tract, and that the infectivity of the Ad subtype B2 can possibly be regulated by other receptors besides CD46.

Adenoviridae↗
PubMed2004

Serological identification of TROP2 by recombinant cDNA expression cloning using sera of patients with esophageal squamous cell carcinoma.

We applied serological analysis of recombinant cDNA expression libraries (SEREX) to cases of esophageal squamous cell carcinoma (SCC) to identify tumor antigens. One of the clones identified was TROP2, which is known as calcium signal transducer. To evaluate the clinical significance of serum anti-TROP2 antibodies (s-TROP2-Abs) in patients with esophageal SCC, the presence of s-TROP2-Abs was analyzed by Western blotting using bacterially expressed TROP2 protein. We found that 23 of 75 (31%) patients were positive for s-TROP2-Abs. Positivity in terms of s-TROP2-Abs showed a significant association with tumor size but not with other clinicopathological features. The protein expression levels of TROP2 were much higher in esophageal SCC cell lines as compared to those in normal esophageal mucosa and its immortalized cells although the mRNA expression levels were not necessarily elevated in malignant cell lines and tissues. Immunohistochemical studies showed that the expression of TROP2 protein in esophageal SCC specimens was noticeably higher than that found in mild hyperplasia of esophageal mucosae. Thus, s-TROP2-Abs seemed useful in the diagnosis of SCC and may be a candidate for serum tumor markers.

Aged↗
PubMed2004

The R(-)-enantiomer of efonidipine blocks T-type but not L-type calcium current in guinea pig ventricular myocardium.

In guinea pig ventricular cardiomyocytes, the R(-)-enantiomer of efonidipine concentration-dependently blocked T-type Ca2+ current with 85% inhibition at 1 microM. In contrast, R(-)-efonidipine (1 microM) had no effect on the L-type Ca2+ current and Ca2+ transient in cardiomyocytes and contractile force in papillary muscles. Thus, R(-)-efonidipine is a highly selective blocker of the T-type Ca2+ current in native myocardia.

Animals↗
PubMed2004

Strain differences of cadmium-induced hepatotoxicity in Wistar-Imamichi and Fischer 344 rats: involvement of cadmium accumulation.

We previously reported that Wistar-Imamichi (WI) rats have a strong resistance to cadmium (Cd)-induced lethality compared to other strains such as Fischer 344 (Fischer) rats. The present study was designed to establish biochemical and histological differences in Cd toxicity in WI and Fischer rats, and to clarify the mechanistic basis of these strain differences. A single Cd (4.5 mg/kg, s.c.) treatment caused a significant increase in serum alanine aminotransferase activity, indicative of hepatotoxicity, in Fischer rats, but did not in WI rats. This difference in hepatotoxic response to Cd was supported by pathological analysis. After treatment with Cd at doses of 3.0, 3.5 and 4.5 mg/kg, the hepatic and renal accumulation of Cd was significantly lower in the WI rats than in the Fischer rats, indicating a kinetic mechanism for the observed strain differences in Cd toxicity. Thus, the remarkable resistance to Cd-induced hepatotoxicity in WI rats is associated, at least in part, with a lower tissue accumulation of the metal. Hepatic and renal zinc (Zn) contents after administration were similarly lower in WI than in Fischer rats. When Zn was administered in combination with Cd to Fischer rats, it decreased Cd contents in the liver and kidney, and exhibited a significant protective effect against the toxicity of Cd. We propose the possibility that Zn transporter plays an important role in the strain difference of Cd toxicity in WI and Fischer rats.

Alanine Transaminase↗
PubMed2004

Detection of sentinel lymph nodes in gastric cancers based on immunohistochemical analysis of micrometastases.

BACKGROUND AND OBJECTIVES: The sentinel lymph node (SN) theory has the potential to change the trend of surgery for gastric cancer that is based on wide resection of the stomach with dissection of regional lymph nodes. However, feasibility tests of SN mapping procedures in gastric cancers with analysis of micrometastasis are rare. This study aimed to estimate the clinical usefulness of SN mapping using a dual procedure with dye- and gamma probe-guided techniques for gastric cancers, based on immunohistochemical staining (IHC) analysis. METHODS: SN mapping procedures were performed on 41 patients with T1-T2 gastric cancer, and gastrectomy with D2 lymphadenectomy followed. All SNs and non-SNs obtained from the patients were tested by IHC analysis using anti-cytokeratin antibodies. RESULTS: Using the dual mapping procedure, SNs were detected in all patients (100%). SN was positive in all patients with lymph node metastasis except in one with non-solid type poorly differentiated adenocarcinoma with marked lymphatic permeation, thus achieving an accuracy rate of 98%. CONCLUSIONS: The method was accurate in predicting nodal status and could be an indicator for less invasive treatment in patients with gastric cancer.

Feasibility Studies↗