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Biomedical subjects

K Tanabe

Publications and source records attributed to K Tanabe.

At least 19 recordsLinked to original sources
PubMed2006

Endostatin peptide, an inhibitor of angiogenesis, prevents the progression of peritoneal sclerosis in a mouse experimental model.

Peritoneal sclerosis is a major and serious complication in patients on long-term continuous ambulatory peritoneal dialysis (PD). The involvement of angiogenesis and proangiogenic factors such as vascular endothelial growth factor (VEGF)-A in progressing peritoneal sclerosis has been reported. We previously reported the therapeutic efficacy of endostatin peptide, a potent inhibitor of angiogenesis derived from type XVIII collagen, in a mouse diabetic nephropathy model. Here, we examined the therapeutic effect of endostatin peptide in preventing progression in a mouse peritoneal sclerosis model. Male ICR mice received intraperitoneal injections of chlorhexidine gluconate (CG) every other day to induce peritoneal sclerosis. Endostatin peptide (1 or 4 mg/kg/day) was administered via subcutaneously implanted osmotic minipumps. Peritoneal sclerosis (day 24) was significantly suppressed by endostatin peptide in a dose-dependent manner. Peritoneal accumulation of type III collagen was significantly suppressed by endostatin peptide. Increase in the number of CD31(+) blood vessels, F4/80(+) monocyte/macrophage accumulation, and 5-bromodeoxyuridine(+) proliferating cells was significantly inhibited by endostatin peptide. Increase in peritoneal expression of VEGF-A, profibrotic transforming growth factor-beta1, and alpha-smooth muscle actin was suppressed by endostatin peptide. Immunoreactivity for endogenous endostatin (whole molecule) and endostatin receptor alpha5beta1-integrin was increased and colocalized to CD31(+) blood vessels in the thickened peritonea of CG-injected mice. These results demonstrate the potential use of antiangiogenic endostatin peptide as a novel therapeutic agent in preventing peritoneal sclerosis, a severe complication in patients undergoing long-term PD.

Actins↗
PubMed2006

Different effects of high molecular weight sodium hyaluronate and NSAID on the progression of the cartilage degeneration in rabbit OA model.

OBJECTIVE: We examined the effects of nonsteroidal anti-inflammatory drug (NSAID) and intra-articular injections of sodium hyaluronate (HA) on cartilage degeneration in rabbit knee osteoarthritis (OA) model induced by partial meniscectomy. METHODS: Loxoprofen sodium (LOX) was used as the NSAID, administered p.o. once daily for 14 days at a dose of 4 mg/kg, starting from the day of meniscectomy. Suvenyl(SVE) was used as the high molecular weight HA, injected intra-articularly into injured knee every 3 days from the day of surgery. The effect on pain was assessed by an Incapacitance Tester, and the damage of cartilage was evaluated by visual assessment and histopathology at 14 days after the surgery. RESULTS: Hind paw weight bearing on the injured paw decreased time-dependently in the control group. In other three groups, the decrease of hind paw weight distribution was suppressed, demonstrating an analgesic effect. Visible damage and histopathological findings of cartilage degeneration were evident in the cartilages of the control group at day 14. In the SVE group, the damaged cartilage area decreased and cartilage degeneration was ameliorated. In contrast, in the LOX group, the cartilage degeneration was augmented compared with the control group. And, this exacerbated cartilage degeneration induced by LOX was reversed by the concomitant use of SVE. CONCLUSION: Our data show that the treatment with high molecular weight HA from earlier stage is strongly recommended to preserve the structure of cartilage.

Adjuvants, Immunologic↗
PubMed2006

Antisense and nonantisense effects of antisense Bcl-2 on multiple roles of Bcl-2 as a chemosensitizer in cancer therapy.

Bcl-2 is an oncoprotein that plays a critical role in inhibiting apoptotic cell death in the mitochondria-dependent pathway in cancer chemotherapy. As a strategy for blocking Bcl-2 for enhancement of the chemotherapeutic effect, antisense Bcl-2 (AS Bcl-2; G3139, oblimersen sodium, Genasense) has shown promise, and there are several ongoing clinical studies with hematological malignancies as well as solid tumors. Although several preclinical and clinical studies have shown the therapeutic efficacy of Bcl-2 in combination with an anticancer drug as a chemosensitizer, in clinical trials the downregulation of Bcl-2 has not been observed with a high frequency in tumor cells. Nevertheless, previous studies showed nonantisense effects such as production of reactive oxygen species and immunostimulatory action through cytosine-phosphate-guanosine-motif in the antisense oligodeoxynucleotides. Further, Bcl-2 is able to inhibit Beclin 1-dependent autophagic cell death, which is a nonapoptotic cell death. The current status and future directions of AS Bcl-2 and the potential mechanisms for multiple roles that Bcl-2 has in cancer therapy are reviewed.

Clinical Trials as Topic↗
PubMed2006

Extranuclear expression of hormone receptors in primary breast cancer.

BACKGROUND: Hormone receptor (HR)-positive breast cancer cells grow through estrogen receptor (ER)-signaling pathways that mediate both genomic and nongenomic actions, which cross-talk with growth factors associated with resistance to tamoxifen. The aim of this study was to explore the cross-talk between extranuclear expression of ER and progesterone receptor (PR) and growth factor signaling pathways in primary breast cancer. PATIENTS AND METHODS: The extranuclear expression of ER and PR was examined in 219 primary breast cancers by immunohistochemical staining. Specimens showing such expression were further examined for the expression of pAkt and aromatase. Staining reactions were scored on the basis of intensity and distribution in the tumors. RESULTS: Extranuclear expression of ER or PR was observed in 21 cases (9.5%), which included four cases for ER and 20 cases for PR. Among these patients, HER-2, pAkt, and aromatase-positivity were observed in 14 cases (66.6%), 13 cases (61.9%), and 14 cases (66.6%), respectively. On the basis of nuclear HR expression, 11 of these cases were categorized as ER-positive/PR-negative, while two were ER-negative/PR-positive. Of these 13 cases, increased pAkt staining was found in 11 cases (84.6%). In particular, among the 11 ER-positive/PR-negative cases, elevated pAkt and aromatase were found in 10 (90.9%; P<0.01) and nine cases (81.8%), respectively. CONCLUSIONS: PR is expressed extranuclearly more frequently than ER in primary breast cancer, and extranuclear HRs cross-talk with the Akt/HER-2-signaling pathways and activation of aromatase. These observations may explain the more beneficial effects of aromatase inhibitors than tamoxifen for ER-positive/PR-negative patients.

Adult↗
PubMed2006

The role of apoptotic or nonapoptotic cell death in determining cellular response to anticancer treatment.

AIMS: Apoptosis, an early response cell death, is a useful marker for predicting tumour response after anticancer treatment; however, late-response cell death or nonapoptotic cell death, autophagy, can also be observed. This article reviews a rational model for predicting tumour response by assessing the influence of nonapoptotic cell death, and thereby developing a more efficient strategy for enhancing the therapeutic effect of anticancer treatment. METHOD: Literature search of clinical and experimental studies on "cell death and cancer" using established databases, including PUBMED. FINDINGS: Although induction of apoptosis may not contribute to overall tumour response, nonapoptotic cell death such as autophagy, which may be triggered by apoptosis, still occurs. Anticancer treatment-induced apoptosis is regulated by the balance of proapoptoic and antiapoptoic proteins through mitochondria, and resistance to apoptosis is mediated by Bcl-2-dependent and Akt-dependent pathways. Bcl-2 partially inhibits nonapoptotic cell death as well as apoptosis, whereas Akt inhibits both apoptotic and nonapoptotic cell death through several target proteins. CONCLUSIONS: Drug sensitivity is likely correlated with the accumulation of apoptotic and nonapoptotic cell deaths, which may influence overall tumour response in anticancer treatment. The ability to predict overall tumour response from the modulation of several important cell death-related proteins may result in a more efficient strategy for improving the therapeutic effect.

Animals↗
PubMed2006

Regulation and interplay of apoptotic and non-apoptotic cell death.

Various death triggers including DNA damage, oxidative stress, and growth factor deprivation promote the loss of mitochondrial membrane potential, leading to the production of reactive oxidative species (ROS) or enhanced permeability of the mitochondrial membrane, otherwise known as mitochondrial membrane permeabilization, by insertion of Bax/Bak into the outer membrane where it interacts with voltage-dependent anion channel (VDAC)/adenine nucleotide transporter (ANT). MMP leads to the release of small pro-apoptotic molecules, which induce caspase-dependent and -independent apoptotic cell death. The production of ROS due to the loss of mitochondrial membrane potential enhances the permeability of lysosomal membranes, resulting in the release of lysosomal proteases, which contribute to mitochondrial membrane permeabilization and the lysosomal degradation mechanism of autophagic cell death. Although defects in apoptotic and non-apoptotic cell death pathways can be carcinogenic, these pathways are more or less preserved within cancer cells and can therefore influence cell death and mediate resistance to cancer treatment. This paper discusses recent advances in determining the molecular mechanisms behind regulation of apoptotic and non-apoptotic cell death, as well as the interplay between these two processes, which may lead to the development of new strategies by which to enhance the therapeutic effects of chemotherapeutic agents.

Animals↗
PubMed2006

Role of the unfolded protein response in cell death.

Unfolded protein response (UPR) is an important genomic response to endoplasmic reticulum (ER) stress. The ER chaperones, GRP78 and Gadd153, play critical roles in cell survival or cell death as part of the UPR, which is regulated by three signaling pathways: PERK/ATF4, IRE1/XBP1 and ATF6. During the UPR, accumulated unfolded protein is either correctly refolded, or unsuccessfully refolded and degraded by the ubiquitin-proteasome pathway. When the unfolded protein exceeds a threshold, damaged cells are committed to cell death, which is mediated by ATF4 and ATF6, as well as activation of the JNK/AP-1/Gadd153-signaling pathway. Gadd153 suppresses activation of Bcl-2 and NF-kappaB. UPR-mediated cell survival or cell death is regulated by the balance of GRP78 and Gadd153 expression, which is coregulated by NF-kappaB in accordance with the magnitude of ER stress. Less susceptibility to cell death upon activation of the UPR may contribute to tumor progression and drug resistance of solid tumors.

Animals↗
PubMed2006

A pathological analysis of lymphatic vessels in early renal allograft.

Lymphatic vessels are an essential part of the immunological response. Nevertheless, little is known about the pathology of renal transplant rejection. In part the reason may be not distinguishing peritubular capillaries from lymphatic vessels by periodic acid-Schiff (PAS) staining. This study examined the morphology of lymphatic vessels in early renal allografts using double staining with PAS and podoplanin. The 41 cases were divided into four categories: (I) acute antibody-mediated rejection, (II) acute cellular rejection, (III) peritubular capillaritis only, and (IV) controls. I through III had the evidence of peritubular capillaritis exceeding grade 1 on a biopsy obtained an average of 17.3 +/- 5.5 days after kidney transplantation. In addition, each lymphatic vessel density (LVD) and nodular lesion of lymphocytes (NL) were quantified as the number of each podoplanin-positive vascular profiles and NL per unit area of cortex measured Lumina Vision (Mitani). The average of the LVD was 73.0, 35.1, 37.1, and 8.1 per 10 mm2 for groups I to IV and the average of NL was 2.8, 5.5, 1.3, 0.9, respectively. There was a significant correlation between LVD and NL. NL showed a strong relation to the accumulation of lymphocytes in lymphatic vessels (AL); 22% of the AL scores were greater than the peritubular capillaritis grade. We found lymphatic vessels to be strongly associated with any kind of inflammatory process that occurred unexpectedly soon after kidney transplantation. In addition, to avoid misdiagnosis of peritubular capillaritis, NL in early renal allograft must especially be excluded.

Adult↗
PubMed2006

Functional roles of immature dendritic cells in impaired immunity of solid tumour and their targeted strategies for provoking tumour immunity.

Dendritic cells play a crucial role in initiating tumour immunity as well as in the immune response for invading foreign pathogens such as bacteria and viruses. For bacterial and viral infections, the immature dendritic cells (iDCs) residing in peripheral tissues are efficiently activated and matured by pathogen signals for performing the immune response. In contrast, for self-antigens, the naive T cells are not activated by iDCs but proceed to anergy/deletion, and the generation of regulatory T cells for immune tolerance. The induction of immune response and tolerance is regulated strictly by iDCs as the sensor for homeostasis of immune response in the host. Despite the identification of some tumour antigens, tumour immunity is not provoked successfully. Even though there are some critical obstacles to inhibit effective tumour immunity, tumour cells are able to exploit the functional roles of iDCs for tumour progression, which are induced by tumour-derived soluble factors such as vascular endothelial growth factor (VEGF) and functionally modulated in the microenvironment. The iDCs still remain as the critical target for provoking tumour immunity. In this review, the functional roles of tumour-associated iDCs and the strategy for targeting iDCs in effective tumour immunity for the cancer patient are discussed.

Autoantigens↗
PubMed2006

Effect of spontaneous exercise on antioxidant capacity in rat muscles determined by electron spin resonance.

AIMS: The effect of physical activity on antioxidant capacity in muscle remains unknown. This study investigated the effect of spontaneous exercise on antioxidant capacity in rat muscles determined by electron spin resonance (ESR), which is a technique for the direct detection of free radicals. METHODS: Ten-week-old male Wistar rats were housed individually in cages with a running wheel. Rats were classified as high activity (HA), middle activity (MA) or low activity group (LA), based on an assessment of running distance covered over a 23-week period. After 23 weeks of housing, soleus (Sol), plantaris (Pl), gastrocnemius [deep/surface portions (GasD/GasS)] and heart (Hrt) muscles were isolated, and scavenging activity against superoxide anions (O(2)(*-)) and hydroxyl radicals (HO(*)) was determined by ESR using a spin-trap chemical. The citrate synthase (CS) activity was used as a marker of mitochondrial oxidative phosphorylation capacity. RESULTS: Among the parameters measured, only O(2)(*-) scavenging activity in GasD significantly correlated with the running distance. The highest scavenging activity was observed in Hrt of HA rats. The O(2)(*-) scavenging activity in Pl of MA rats was significantly higher than that of LA rats. The O(2)(*-) scavenging activity of Sol and GasS was not significantly different between the three groups. Furthermore, the HO(*) scavenging activity of any muscle specimens was similar among the three groups and did not correlate with running distance at all. CS activity did not significantly differ between the three groups. CONCLUSION: These data suggest that O(2)(*-) scavenging activity in specific types of muscle tissues would increase especially in spontaneously active animals. However, HO(*) scavenging activity would not.

Animals↗
PubMed2005

Possible involvement of urokinase-type plasminogen activator release from human peripheral blood lymphocytes in the pathophysiology of chronic allograft nephropathy.

BACKGROUND: Little is known of the fibrinolytic host immune mechanisms responsible for induction of chronic allograft nephropathy (CAN), defined as a loss in glomerular filtration rate (GFR) caused by tubular atrophy and interstitial fibrosis, often with fibrous intimal thickening in the small arteries. However, chronic rejection has been reported to be associated with decreased activity of the fibrinolytic system. In our previous study, [Deamino-Cys1, D-Arg8]-vasopressin (dDAVP) induced urokinase-type plasminogen activator (uPA) release from human peripheral T lymphocytes via arginine vasopressin (AVP) V2-receptor-mediated reaction enhanced by an AVP V1-receptor antagonist. Therefore, we examined the level of uPA released from peripheral T lymphocytes by AVP in transplant patients with CAN in comparison with control groups. PATIENTS AND METHODS: In this study, we evaluated in vitro uPA releasing activity of lymphocytes obtained from renal allograft patients with well-functioning grafts (n = 9), CAN (n = 5), or acute rejection episodes (n = 5) compared with lymphocytes from healthy volunteers with normal renal function (n = 12) or patients with renal insufficiency (n = 5). RESULTS: Lymphocytes prepared from patients with chronic allograft nephropathy showed a significantly lower increase in uPA release induced by the combination of the V1-receptor antagonist and dDAVP compared with those from the other groups. CONCLUSION: This finding suggested that a decrease in uPA release from human peripheral blood lymphocytes by AVP-related peptides may be potentially involved in the pathophysiology of CAN.

Adult↗
PubMed2004

Transplantation of pediatric cadaveric kidneys into adult or pediatric recipients.

In Japan, nationwide cadaveric organ sharing for kidney transplantation by the Japan Organ Transplant Network (JOTN) has operated since April 1995. This study retrospectively analyzed the long-term results of single pediatric donor kidneys transplanted into adult or pediatric recipients at a single center. From March 1983 to December 2002, 281 cadaveric renal allografts were transplanted at our center, including, 17 recipients of cadaveric kidneys from donors aged less than 16 years. We divided these 17 recipients into two groups: 10 adult recipients (group 1; G1) and seven pediatric recipients (group 2; G2). HLA-AB, -DR mismatches were 1.3 +/- 1.3, 0.7 +/- 0.5 in G1 and 2.6 +/- 1.3, 1.4 +/- 0.8 in G2, respectively (P < .05 for both). The end of the observation of this study was March 2003. Among G1, two recipients died with functioning grafts and one died after graft loss. Among G2, no recipients died. Patient survival rates at 1 and 5 years were 90% and 80% in G1 and 100% and 100% in G2, respectively. At the end of the observation in this study, five recipients among G1 and six recipients among G2 had functioning grafts. Graft survival rates at 1 and 5 years were 90% and 80% in G1 and 85.7% and 85.7% in G2, respectively. Our results demonstrate that transplantation of pediatric cadaveric kidneys into pediatric recipients was excellent compared to adult recipients in terms of survival. Priority to pediatric patients should be given especially in cases of pediatric donors.

Adolescent↗
PubMed2004

Impact of fluvastatin on hyperlipidemia after renal transplantation.

BACKGROUND: Renal transplant recipients are at increased risk of atherosclerotic vascular disease with hyperlipidemia. Many recipients have preexisting cardiovascular disease at the time of transplantation, and immunosuppressive therapy may aggravate existing risk factors or promote development of new risk factors, notably hyperlipidemia and hypertension. Fluvastatin is one of the statins, an HMG-CoA reductase inhibitor, which has been shown to be effective in lowering cholesterol levels. We treated hyperlipidemia after renal transplantation with Fluvastatin for more than 6 months. We attempted to clarify the efficacy of fluvastatin on hyperlipidemia in renal transplant recipients. MATERIALS: Forty-five renal transplant recipients with hyperlipidemia were enrolled in this study. The mean age was 44.2 years, with 23 men and 22 women. Thirty-seven transplantations were from a living related donors and eight from cadaveric donors. Thirty-three recipients were ABO-compatible, seven recipients had minor mismatches, and five recipients were ABO-incompatible. The dose of fluvastatin was 20 mg per day. Levels of total cholesterol (TC), triglyceride (TG), HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), serum creatinine (s-Cr), ALT, ALP, uric acid (UA), hematocrit (Ht), CPK, and blood pressure were examined in all recipients before treatment as well as 1, 3, and 6 months after Fluvastatin administration. RESULTS: The mean levels of TC and TG were significantly reduced from 256, to 224 and 215 mg/dL, and from 188 to 170 and 147 mg/dL at 1 and 6 months after treatment, respectively. The mean levels of HDL-C were 72 mg/dL before treatment, 81 mg/dL at 1 month, and 80 mg/dL at 6 months after treatment. The mean levels of LDL-C were 153 mg/dL before treatment, 145 mg/dL at 1 month, and 145 mg/dL at 6 months after treatment. Fluvastatin significantly produced a reduction rate in TC of 16%, TG of 22%, and LDL-C of 5% after 6 months of treatment, respectively. The mean levels of HDL-C of were increased 10% after 6 months of treatment. The serum creatinine and CPK were not significantly different. There were no clinically significant differences in other factors. No significant adverse effects were observed. CONCLUSIONS: Fluvastatin seemed to be safe and highly effective to control TC, TG, LDL-C, and HDL-C in renal transplant recipients.

Adult↗
PubMed2004

Efficacy of IgM anti-blood type antibody monitoring by enzyme-linked immunosorbent assay after renal transplantation across the blood barrier: high-dose immunoglobulin administration blocks IgM rather than IgG anti-blood type antibodies.

We used an enzyme linked immunosorbent assay (ELISA) to investigate the presence of subtypes of anti-blood-type antibodies in patients with biopsy-proven humoral rejection after ABO-incompatible renal transplantation. High agglutinin IgG and IgM anti-blood type antibodies from 12 ABO-incompatible recipients with vascular rejection were separately assessed using an ELISA. Patients who exhibited excellent renal function despite high agglutinin titers of anti-blood-type antibodies(n = 8) were also examined. All 12 rejection patients exhibited highly elevated titers of IgG and IgM, while the eight stable patients exhibited only slightly elevated IgG titers, but not IgM. IgG and IgM titers did not change after plasmapheresis and steroid pulse therapy, whereas IVIg treatment significantly blocked both IgG and IgM, with IgM being blocked to a larger extent than IgG. Blocking of IgM seems to play an important role in improving ABO-incompatible grafts.

Antibodies, Anti-Idiotypic↗