ACE activity in CSF of patients with mild cognitive impairment and Alzheimer disease.
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Aged↗
Biomedical subjects
N Tomita
Publications and source records attributed to N Tomita.
Acceleration of wound healing by combined gene transfer of hepatocyte growth factor and prostacyclin synthase with Shima Jet.
Although skin diseases are one of the target diseases for gene therapy, there has been no practical gene transfer method. First, we examined gene transfer efficiency of the spring-powered jet injector, Shima Jet, which was originally developed as a non-needle jet injector of insulin. Local gene expression was about 100 times higher when the luciferase plasmid was transferred by the Shima Jet than by a needle. Gene transfer of beta-galactosidase revealed gene expression in the epidermis. Based on these results, we then examined the potential of gene therapy using the Shima Jet for wound healing. An increase of cellular proliferation of the epidermis and the number of microvessels in the granulation tissue was observed after hepatocyte growth factor (HGF) gene transfer. An increase in blood flow around the wound was observed after prostacyclin synthase (PGIS) gene transfer. Moreover, promotion on wound healing was observed in HGF gene transferred group, and further promotion was observed in combined gene transferred group as assessed by measuring wound area. These results indicate that co-transfer of HGF and PGIS genes by the Shima Jet could be an effective strategy to wound healing.
Animals↗
[Esophageal cancer surgery; importance of surgical quality control].
In esophageal cancer, the rate of lymphatic metastasis is higher than any other gastrointestinal cancer. The morbidity and mortality rate of esophageal surgery is still high. In order to reduce high morbidity and mortality rate, esophageal cancer surgery is recommended to be performed at a high-volume hospital in Europe and United States. In Japan, "3-field lymph nodes dissection surgery" has been established for complete lymphatic clearance, and the overall survival has improved. This surgical procedure is now recognized as a standard surgery for advanced esophageal cancer by "Japan Esophageal Society". However, even in Japan, the morbidity and mortality rate of esophageal cancer surgery is higher than gastric or colonic cancer surgery. For rationale of esophageal cancer surgery, we have to continue to improve our surgical quality such as preserving bronchial artery or pulmonary branches of the vagal nerve.
Adenocarcinoma↗
Effects of brain-penetrating ACE inhibitors on Alzheimer disease progression.
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Aged↗
Effect of a static magnetic field on ion transport in a cellulose membrane.
A cellulose membrane was exposed to the static magnetic field (SMF) in the presence of KCl solution and ion transport through the membrane was measured before and after the SMF exposure. SMF at 0.24 T significantly enhanced the rate of ion transport, especially after the first exposure (p<0.05), while the increased ion transport rate did not return to the initial basal level after exchange of the aqueous medium. These results suggest that an irreversible, temporal conformation change took place on the cellulose membrane or on the water bound to the cellulose surface. The accelerating effect of SMF on the ion transport seems to have occurred as a result of stabilized hydration layer on the cellulose surface.
Biological Transport↗
Antisense oligonucleotides as a powerful molecular strategy for gene therapy in cardiovascular diseases.
Antisense oligonucleotides (ODN) technology is one of the most promising therapeutic strategies to prevent the progress of diseases through inhibiting the specific gene expression. They are well established to serve as molecular tools for several biologic applications, from the study of single gene function up to complex target validations. From the theoretical simple action, sequence-specific inhibition of mRNA functions after complex formation and presumably enzymatic degradation of the target mRNA, they obviously carry a high therapeutic potential to treat human diseases. In addition to the potential for the treatment, antisense ODN may be applicable for investigations of the mechanism and stereochemistry of biochemical reactions, mapping of nucleic acid protein interactions, and diagnostic applications. However, the design of antisense ODN, is very difficult because many factors affecting their activity and stability must be considered. Especially, the modifications of ODN are very critical and many researchers are trying to establish ODN which have resistance to nucleolytic degradation, high affinity to complementary nucleic acid, high selectivity in binding with complementary nucleic acid, the ability to activate ribonuclease H that selectively degrades the RNA strand of ODN-RNA complex, cell permeability, and favorable pharmacokinetic and pharmacodynamic attributes. In this review we would like to introduce some modifications of ODN design and examples of our applications of antisense ODN in cardiovascular disease in animal models.
Animals↗
Improvement of endothelial dysfunction by angiotensin II blockade accompanied by induction of vascular hepatocyte growth factor system in diabetic spontaneously hypertensive rats.
Hepatocyte growth factor (HGF) is a unique growth factor with many protective functions. Previously, we demonstrated that HGF stimulated growth of endothelial cells without replication of vascular smooth muscle cells (VSMC) and that angiotensin (Ang) II significantly decreased local HGF production in VSMC. Moreover, we also reported that high glucose significantly decreased local vascular HGF production. Therefore, we examined effects of Ang II blockade on vascular HGF expression and endothelial injury in diabetic hypertensive rats. An angiotensin-converting enzyme inhibitor (quinapril) and an Ang II type 1 receptor antagonist (GA-0113) or vehicle was administrated to diabetic spontaneously hypertensive rats (SHR-DM), in whom diabetes was induced by streptozotocin. Endothelial function was evaluated by the vasodilator response to acetylcholine, and the expression of vascular HGF and its receptor, c-met, was examined by immunohistochemistry. Both quinapril and GA-0113 significantly improved the vasodilator response to acetylcholine ( P < 0.01), while vehicle did not as compared to untreated normotensive Wistar-Kyoto rats (WKY). We next examined the effects of Ang II blockade on vascular HGF expression in SHR-DM. Importantly, the vascular HGF level was markedly decreased in SHR-DM as compared to WKY, while Ang II blockade by quinapril or GA-0113 significantly increased positive staining for HGF in SHR-DM. Similarly, staining of its specific receptor, c-met, was less in the blood vessels of SHR-DM as compared to WKY. In contrast, Ang II blockade also significantly increased c-met production in SHR-DM. The present data demonstrated the improvement of endothelial dysfunction by Ang II blockade in SHR-SM, accompanied by an increase in vascular HGF and c-met.
Acetylcholine↗
Transfection of NFkappaB-decoy oligodeoxynucleotides using efficient ultrasound-mediated gene transfer into donor kidneys prolonged survival of rat renal allografts.
Nuclear factor kappaB (NFkappaB) plays a pivotal role in the coordinated transactivation of a series of genes of cytokines and adhesion molecules that are highly involved in the onset of acute rejection in organ transplantation. We previously developed decoy cis-elements oligo deoxyribonucleic acid against NFkappaB (NFkappaB-decoy) that effectively inhibited the activation of major inflammatory mediators in vitro and in vivo. Accordingly, we hypothesized that transfection of NFkappaB-decoy into the donor kidney would prevent acute rejection and prolong graft survival, and thus provide effective therapy for renal acute rejection. To transfect NFkappaB-decoy, we employed a novel approach using ultrasound exposure with an echocardiographic contrast agent, Optison, and clearly demonstrated successful transfection of NFkappaB-decoy into renal tissue. The therapeutic effect of NFkappaB-decoy on renal allografts was then evaluated in a rat renal allograft model (Wistar-Lewis). In the control group, graft function significantly deteriorated with marked destruction of renal tissue, accompanied by increased production of major inflammatory mediators, and all animals died of renal failure by 9 days. In contrast, graft function (serum creatinine on day 2, NFkappaB-treated: 0.97+/-0.16 versus control: 1.84+/-0.23 mg/dl, P<0.01) and histological structure were well preserved with significantly decreased expression of NFkappaB-regulated cytokines and adhesion molecules, including IL-1, iNOS, MCP-1, TNF-alpha, and ICAM-1, in allografts transfected with NFkappaB-decoy. As a result, animal survival was significantly prolonged in this group as compared to controls (14.2+/-5.2 versus 7.1+/-1.2 days, P<0.01). Thus, we established a novel ultrasound-Optison-mediated gene transfection approach and demonstrated the significant prolongation of graft survival by the successful transfection of NFkappaB-decoy into the donor kidney in a rat renal allograft model.
Albumins↗
Histopathologic effects of neoadjuvant therapies for advanced squamous cell carcinoma of the esophagus: multivariate analysis of predictive factors and p53 overexpression.
In 97 patients (60, chemotherapy; 22, chemoradiotherapy; 15, radiotherapy), histopathologic effects were evaluated microscopically, and histologic response rates were compared among three neoadjuvant treatment modalities. Predictive factors for neoadjuvant therapies were analyzed by logistic regression, including the results of p53 immunohistochemical staining. In the chemoradiotherapy group, the pathologic response rate was 86.4%, and was significantly higher than that for chemotherapy (P < 0.0001) or for radiotherapy (P = 0.0031). In patients with normal p53 protein expression, the histopathologic response rate to chemotherapy was 20.0%, a higher rate than that for patients with abnormal p53 overexpression. In the chemoradiotherapy or radiotherapy group, however, the response rates were almost the same, irrespective of p53 oncoprotein status. From multivariate analysis, the neoadjuvant treatment modality itself was identified as the most powerful predictive factor for the effect. Chemoradiotherapy had the most powerful effect on advanced esophageal cancer, and p53 status did not influence the clinical outcome in this group.
Adult↗
Impaired endothelial dysfunction in diabetes mellitus rats was restored by oral administration of prostaglandin I2 analogue.
We have previously reported that a decrease in hepatocyte growth factor (HGF), which has many protective functions against endothelial damage by high d-glucose, might be a trigger of endothelial injury. However, the regulation of vascular HGF in diabetes mellitus (DM) has not been clarified in vivo, although vascular disease is frequently observed in DM patients. In addition, our previous report revealed that a prostaglandin I(2) (PGI(2)) analogue prevented endothelial cell death through the induction of vascular HGF production in cultured human epithelial cells. Thus, in this study, we examined the effects of a PGI(2) analogue in the regulation of the local HGF system using DM rats. A PGI(2) analogue (beraprost sodium; 300 and 600 micro g/kg per day) or vehicle was administered to 16-week-old DM rats induced by administration of streptozotocin for 28 days. Endothelial function was evaluated by the vasodilator response to acetylcholine, and the expression of vascular HGF mRNA was measured by Northern blotting. Of importance, expression of HGF mRNA was significantly decreased in the blood vessels of DM rats as compared with non-DM (P<0.01). In addition, the in vitro vasodilator response of the abdominal aorta to acetylcholine was markedly impaired in DM rats. Importantly, the vasodilator response was restored by PGI(2) treatment in a dose-dependent manner (P<0.01), whereas N(omega)-nitro-l-arginine methyl ester inhibited the restoration of endothelial function. Of particular interest, vascular HGF mRNA and protein were significantly increased in the blood vessels of DM rats treated with PGI(2) as compared with vehicle. Similarly, an increase in HGF protein was also confirmed by immunohistochemical analysis. In addition, the specific HGF receptor, c-met, was also increased by PGI(2) treatment. Overall, this study demonstrated that treatment with a PGI(2) analogue restored endothelial dysfunction in DM rats, accompanied by the induction of vascular HGF and c-met expression. Increased local vascular HGF production by a PGI(2) analogue may prevent endothelial injury, potentially resulting in the improvement of endothelial dysfunction.
Acetylcholine↗
Detection of loop-mediated isothermal amplification reaction by turbidity derived from magnesium pyrophosphate formation.
The loop-mediated isothermal amplification (LAMP) is a novel nucleic acid amplification method that uses only one type of enzyme. One of the characteristics of the LAMP method is its ability to synthesize extremely large amount of DNA. Accordingly, a large amount of by-product, pyrophosphate ion, is produced, yielding white precipitate of magnesium pyrophosphate in the reaction mixture. Judging the presence or absence of this white precipitate allows easy distinction of whether nucleic acid was amplified by the LAMP method. Since an increase in the turbidity of the reaction mixture according to the production of precipitate correlates with the amount of DNA synthesized, real-time monitoring of the LAMP reaction was achieved by real-time measurement of turbidity.
Base Sequence↗
Construction of preferential cDNA microarray specialized for human colorectal carcinoma: molecular sketch of colorectal cancer.
cDNA microarray analyses can be used to identify candidate genes that play important roles in human carcinogenesis. To gain insight into the molecular sketch of colorectal cancer, we have constructed cDNA microarrays specialized for colorectal cancer, which we named "Colonochip" by selecting genes that are expressed in colorectal cancer, normal colonic mucosa, and liver metastatic cancer tissues. This microarray contained 4608 nonredundant cDNA clones from over 30,000 cDNA clones derived from the three types of human cDNA libraries, as well as clones from 170 additional conventional major genes suspected to be involved in colorectal carcinogenesis, according to literatures. Using this "Colonochip," we were able to identify 59 genes showing twofold or more differential expression between primary cancer and normal colonic mucosa, potent candidates for diagnosis, and therapy of colorectal cancer for further studies.
Amphiregulin↗
Usefulness of repeated direct intratumoral gene transfer using hemagglutinating virus of Japan-liposome method for cytosine deaminase suicide gene therapy.
To investigate the feasibility of repeated gene transfection in suicide gene therapy against human solid tumors by a combination of 5- fluorocytosine (5-FC) and its converting enzyme, cytosine deaminase (CD), we repeatedly transfected the yeast CD gene into the human pancreatic cancer cell line BXPC3 using the hemagglutinating virus of Japan-liposome in a new gene transfer method. The in vivo growth of the s.c. transplanted BXPC3 tumor in nude mice given CD-gene transfection was significantly suppressed by i.p. injection of 5-FC when compared with tumors treated with the control vector. Furthermore, the tumor transfected with the CD gene during a 7-day interval was suppressed much more than that of a single transfection. These results suggest that repeated transfection of the suicide gene together with the combination of 5-FC and the yeast CD gene using the hemagglutinating virus of Japan-liposome gene transfer method may be useful for the treatment of human solid tumors, including pancreatic cancer.
Animals↗
Posttransplantation Epstein-Barr viral meningitis in a patient with chronic myelogenous leukemia.
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Adult↗
Intravenous injection of oligodeoxynucleotides to the NF-kappaB binding site inhibits hepatic metastasis of M5076 reticulosarcoma in mice.
We have developed synthetic double-stranded oligodeoxynucleotides (ODN) as 'decoy' cis elements that block the binding of nuclear factors to promoter regions of targeted genes, resulting in the inhibition of gene transactivation in vivo. In the present study, we employed decoy ODN targeting the transcription factor nuclear factor-kappaB (NF-kappaB) binding cis-elements to hepatic metastasis of murine reticulosarcoma M5076 in mice. Intravenous inoculation of M5076 into mice caused a marked increase in gene expression of interleukin-1beta, tumor necrosis factor-alpha and intercellular adhesion molecule-1 in the liver, whereas intravenous treatment with NF-kappaB decoy ODN reduced M5076-induced transactivation of these genes. Treatment with NF-kappaB decoy ODN, but not scrambled decoy ODN, significantly inhibited hepatic metastasis of M5076 in mice, and furthermore the combined treatment of NF-kappaB decoy ODN with an anti-cancer drug resulted in complete inhibition of hepatic metastasis in half of the mice, without affecting myelosuppression induced by the anti-cancer drug. Here, NF-kappaB decoy ODN inhibited hepatic metastasis of M5076 in mice possibly through a decrease in transactivation of important NF-kappaB-driven genes and also potentiated the anti-metastatic effect of an anti-cancer drug, demonstrating the first successful in vivo therapy for cancer metastasis using NF-kappaB decoy ODN as a novel molecular decoy approach.
Animals↗
Chromatin structure of yeast minichromosomes containing triplet repeat sequences associated with human hereditary neurological diseases.
Expansion of triplet repeat sequences such as (CTG)n, (CGG)n, and (GAA)n causes human genetic diseases. Since DNA is packaged into arrays of nucleosomes in eukaryotic cells, chromatin may be involved in the mechanism of triplet repeat diseases. To elucidate this issue, we have examined effects of triplet repeat sequences on the chromatin organization in vivo using well defined yeast minichromosomes. We show here that (CGG)12 disrupts an array of positioned nucleosomes, whereas (CTG)12 promotes the nucleosome formation. Thus, triplet repeat sequences can affect the chromatin organization in vivo, which may contribute to the triplet repeat expansion or alterations in the expression of genes associated with triplet repeat diseases.
Chromosomes, Fungal↗
Interferon-alpha-induced pure red cell aplasia following chronic myelogenous leukemia.
We report a case of pure red cell aplasia (PRCA) that resulted from interferon (IFN)-alpha therapy for chronic myelogenous leukemia. PRCA improved within 1 month after IFN-alpha was discontinued. This case indicates the involvement of IFN-alpha in the pathogenesis of PRCA.
Aged↗
Granulomatous tubulointerstitial nephritis induced by all-trans retinoic acid.
We report the first case of granulomatous tubulointerstitial nephritis induced by all-trans retinoic acid (ATRA) in a patient with acute promyelocytic leukemia (APL). Acute renal failure during treatment with ATRA has been previously reported as a part of an ATRA syndrome or a thrombotic complication of a hypercoagulable state. This case indicates an alternative mechanism of acute renal failure occurring during ATRA therapy.
Aged↗