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Search Results: 1 - 10 of 1886 matches for " Masahito Shimizu "
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Synergistic Effects of PPAR Ligands and Retinoids in Cancer Treatment
Masahito Shimizu,Hisataka Moriwaki
PPAR Research , 2008, DOI: 10.1155/2008/181047
Abstract: Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily. The activation of PPARs by their specific ligands is regarded as one of the promising strategies to inhibit cancer cell growth. However, recent clinical trials targeting several common cancers showed no beneficial effect when PPAR ligands are used as a monotherapy. Retinoid X receptors (RXRs), which play a critical role in normal cell proliferation as a master regulator for nuclear receptors, preferentially form heterodimers with PPARs. A malfunction of RXR due to phosphorylation by the Ras/MAPK signaling pathway is associated with the development of certain types of human malignancies. The activation of PPAR/RXR heterodimer by their respective ligands synergistically inhibits cell growth, while inducing apoptosis in human colon cancer cells when the phosphorylation of RXR was inhibited. We here in review the synergistic antitumor effects produced by the combination of the PPAR, especially PPAR, ligands plus other agents, especially retinoids, in a variety of human cancers. We also focus on the phosphorylation of RXR because the inhibition of RXR phosphorylation and the restoration of its physiological function may activate PPAR/RXR heterodimer and, therefore, be a potentially effective and critical strategy for the inhibition of cancer cell growth.
Esophageal Carcinogenesis  [PDF]
Naoki Watanabe, Masahito Shimizu, Takahiro Kochi, Yohei Shirakami, Takuji Tanaka
Open Journal of Pathology (OJPathology) , 2014, DOI: 10.4236/ojpathology.2014.44021
Abstract: Esophageal cancer is the sixth leading cause of cancer death and remains one of the least survivable cancers. Esophageal cancers show wide variations in incidence in different population, suggesting that environmental or lifestyle risk factors could be controlled to reduce risk of these diseases. There are two major histopathologic types (squamous cell carcinoma and adenocarcinoma) of esophageal epithelial malignancy. Recently, the rate of adenocarcinoma is increasing in developed countries: in the United States, 50% or more is adenocarcinoma and, in about 70%, the increase especially in a white male serves as adenocarcinoma. Esophageal adenocarcinoma develops in the lower esophagus. In contrast, in Japan, the increase in adenocarcinoma is not clear and most (90%) of esophageal cancers are squamous cell carcinoma. Such squamous cell carcinoma occurs onto the middle part esophagus mostly, and 60% or more of the whole esophagus cancer also develops in the middle and upper parts. These differences also influence the treatment results. The scope of this article is to discuss carcinogenesis in the esophagus by giving an overview about its histopathological characteristics and molecular mechanisms.
Targeting Receptor Tyrosine Kinases for Chemoprevention by Green Tea Catechin, EGCG
Masahito Shimizu,Yohei Shirakami,Hisataka Moriwaki
International Journal of Molecular Sciences , 2008, DOI: 10.3390/ijms9061034
Abstract: Tea is one of the most popular beverages consumed worldwide. Epidemiologic studies show an inverse relationship between consumption of tea, especially green tea, and development of cancers. Numerous in vivo and in vitro studies indicate strong chemopreventive effects for green tea and its constituents against cancers of various organs. (–)-Epigallocatechin-3-gallate (EGCG), the major catechin in green tea, appears to be the most biologically active constituent in tea with respect to inhibiting cell proliferation and inducing apoptosis in cancer cells. Recent studies indicate that the receptor tyrosine kinases (RTKs) are one of the critical targets of EGCG to inhibit cancer cell growth. EGCG inhibits the activation of EGFR (erbB1), HER2 (neu/erbB2) and also HER3 (neu/erbB3), which belong to subclass I of the RTK superfamily, in various types of human cancer cells. The activation of IGF-1 and VEGF receptors, the other members of RTK family, is also inhibited by EGCG. In addition, EGCG alters membrane lipid organization and thus inhibits the dimerization and activation of EGFR. Therefore, EGCG inhibits the Ras/MAPK and PI3K/Akt signaling pathways, which are RTK-related cell signaling pathways, as well as the activation of AP-1 and NF-κB, thereby modulating the expression of target genes which are associated with induction of apoptosis and cell cycle arrest in cancer cells. These findings are significant because abnormalities in the expression and function of RTKs and their downstream effectors play a critical role in the development of several types of human malignancies. In this paper we review evidence indicating that EGCG exerts anticancer effects, at least in part, through inhibition of activation of the specific RTKs and conclude that targeting RTKs and related signaling pathway by tea catechins might be a promising strategy for the prevention of human cancers.
Targeting Receptor Tyrosine Kinases for Chemoprevention by Green Tea Catechin, EGCG
Masahito Shimizu,Yohei Shirakami,Hisataka Moriwaki
International Journal of Molecular Sciences , 2008,
Abstract: Tea is one of the most popular beverages consumed worldwide. Epidemiologic studies show an inverse relationship between consumption of tea, especially green tea, and development of cancers. Numerous in vivo and in vitro studies indicate strong chemopreventive effects for green tea and its constituents against cancers of various organs. ( ¢ € “)-Epigallocatechin-3-gallate (EGCG), the major catechin in green tea, appears to be the most biologically active constituent in tea with respect to inhibiting cell proliferation and inducing apoptosis in cancer cells. Recent studies indicate that the receptor tyrosine kinases (RTKs) are one of the critical targets of EGCG to inhibit cancer cell growth. EGCG inhibits the activation of EGFR (erbB1), HER2 (neu/erbB2) and also HER3 (neu/erbB3), which belong to subclass I of the RTK superfamily, in various types of human cancer cells. The activation of IGF-1 and VEGF receptors, the other members of RTK family, is also inhibited by EGCG. In addition, EGCG alters membrane lipid organization and thus inhibits the dimerization and activation of EGFR. Therefore, EGCG inhibits the Ras/MAPK and PI3K/Akt signaling pathways, which are RTK-related cell signaling pathways, as well as the activation of AP-1 and NF- oB, thereby modulating the expression of target genes which are associated with induction of apoptosis and cell cycle arrest in cancer cells. These findings are significant because abnormalities in the expression and function of RTKs and their downstream effectors play a critical role in the development of several types of human malignancies. In this paper we review evidence indicating that EGCG exerts anticancer effects, at least in part, through inhibition of activation of the specific RTKs and conclude that targeting RTKs and related signaling pathway by tea catechins might be a promising strategy for the prevention of human cancers.
Chemoprevention of Head and Neck Cancer by Green Tea Extract: EGCG—The Role of EGFR Signaling and “Lipid Raft”
Muneyuki Masuda,Takahiro Wakasaki,Satoshi Toh,Masahito Shimizu,Seiji Adachi
Journal of Oncology , 2011, DOI: 10.1155/2011/540148
Abstract: Over the past decade dose-intensified chemo-radiotherapy or molecular targeted therapy has been introduced into the treatments of head and neck squamous cell carcinoma (HNSCC) to improve the outcomes of this dismal disease. However, these strategies have revealed only limited efficacy so far. Moreover, the frequent occurrences of second primary tumor further worsen the prognosis of patients. In this context, early detection and chemoprevention appear to be a realistic and effective method to improve the prognosis as well as quality of life in patients with HNSCC. In this short paper, we discuss the potential of green tea extract, (-)-epigallocatechin-3-galate (EGCG) in HNSCC chemoprevention, focusing on two aspects that are provided recently: (1) evidence of clinical efficacy and (2) unique biological effects on “lipid raft” that emerged as an important platform of numerous biophysical functions, for example, receptor tyrosin kinases (RTKs) signalings including epidermal growth factor receptor (EGFR), which play critical roles in HNSCC carcinogenesis. 1. Introduction Head and neck squamous cell carcinoma (HNSCC), the sixth most common cancer worldwide, often generates from critical organs including the larynx, pharynx, oral cavity, and tongue that play indispensable roles in social, respiratory, communicative, and nutritional functions [1]. Surgical intervention for these organs often leads to a considerable impairment of the patient’s quality of life (QOL), albeit recent remarkable progresses in reconstructive surgery. Accordingly, the intensity of conventional DNA-damaging therapies (i.e., irradiation and chemotherapy) has been strengthened to the upper limit of human tolerance of acute toxicities during the last decade [2]. Short-term results of these treatments seem to be promising. However, it is still under debate whether these dose-intensified types of protocols would lead to the long-term overall survival as well as “functional” organ preservation, because these protocols occasionally cause considerable complications (e.g., requirement for feeding tube due to severe laryngeal and pharyngeal dysfunction) and potential treatment-related death [2–4]. Ongoing molecular targeted therapies in HNSCC revealed only marginal effects so far [5]. In addition, the frequent occurrences of second primary tumor further worsen the prognosis of patients with HNSCC [1, 6]. As a result, the dishonorable phrase that is routinely used in the Introduction of HNSCC studies: “Despite recent advancements in treatment modalities, the overall survival and QOL of patients
Nutraceutical Approach for Preventing Obesity-Related Colorectal and Liver Carcinogenesis
Masahito Shimizu,Masaya Kubota,Takuji Tanaka,Hisataka Moriwaki
International Journal of Molecular Sciences , 2012, DOI: 10.3390/ijms13010579
Abstract: Obesity and its related metabolic abnormalities, including insulin resistance, alterations in the insulin-like growth factor-1 (IGF-1)/IGF-1 receptor (IGF-1R) axis, and the state of chronic inflammation, increase the risk of colorectal cancer (CRC) and hepatocellular carcinoma (HCC). However, these findings also indicate that the metabolic disorders caused by obesity might be effective targets to prevent the development of CRC and HCC in obese individuals. Green tea catechins (GTCs) possess anticancer and chemopreventive properties against cancer in various organs, including the colorectum and liver. GTCs have also been known to exert anti-obesity, antidiabetic, and anti-inflammatory effects, indicating that GTCs might be useful for the prevention of obesity-associated colorectal and liver carcinogenesis. Further, branched-chain amino acids (BCAA), which improve protein malnutrition and prevent progressive hepatic failure in patients with chronic liver diseases, might be also effective for the suppression of obesity-related carcinogenesis because oral supplementation with BCAA reduces the risk of HCC in obese cirrhotic patients. BCAA shows these beneficial effects because they can improve insulin resistance. Here, we review the detailed relationship between metabolic abnormalities and the development of CRC and HCC. We also review evidence, especially that based on our basic and clinical research using GTCs and BCAA, which indicates that targeting metabolic abnormalities by either pharmaceutical or nutritional intervention may be an effective strategy to prevent the development of CRC and HCC in obese individuals.
Garenoxacin Prophylaxis for Febrile Neutropenia after Chemotherapy in Hematological Malignancies  [PDF]
Nobuhiko Nakamura, Takeshi Hara, Soranobu Ninomiya, Yuhei Shibata, Takuro Matsumoto, Hiroshi Nakamura, Junichi Kitagawa, Yasuhito Nannya, Masahito Shimizu, Nobuo Murakami, Hisashi Tsurumi
Open Journal of Internal Medicine (OJIM) , 2016, DOI: 10.4236/ojim.2016.64018
Abstract: Background: Febrile neutropenia is one of the most serious adverse events in patients with hematological malignancies and chemotherapy. The routine use of fluoroquinolone prophylaxis in patients with hematological malignancies is controversial. Therefore, we prospectively evaluated the efficacy and safety of prophylactic use of garenoxacin for febrile neutropenia. Patients and Methods: Consecutive adult patients with hematological malignancies who were at risk for chemotherapy-induced neutropenia lasting more than seven days were eligible for present study. They received oral garenoxacin (400 mg daily) from the neutrophil count decreased to less than 1000/μl and continued until the neutropenia had resolved. The primary endpoint was incidence of febrile neutropenia, and the secondary endpoints were the type and incidence of adverse events. Results: We enrolled 46 consecutive patients (median age, 59 years). The underlying diseases comprised acute myeloid leukemia (n = 17), acute lymphoblastic leukemia (n = 3), malignant lymphoma (n = 23), and multiple myeloma (n = 3). There were 23 febrile neutropenia episodes and 2 episodes of bacteremia. There were no grade 3 or 4 adverse events; however serum creatinine levels were significantly elevated after garenoxacin administration. The overall prophylactic efficacy of garenoxacin was 50%, and there were no infection-related deaths. Conclusions: Prophylactic use of garenoxacin is effective and safe in patients with hematological malignancies. (Clinical trial registration number: UMIN000004979).
Endoscopic Examination for Patients with Diarrhea after Allogeneic Stem Cell Transplantation  [PDF]
Junichi Kitagawa, Takuro Matsumoto, Yuhei Shibata, Nobuhiko Nakamura, Hiroshi Nakamura, Soranobu Ninomiya, Yasuhito Nannya, Masahito Shimizu, Takeshi Hara, Hiroshi Araki, Hisashi Tsurumi
Open Journal of Internal Medicine (OJIM) , 2017, DOI: 10.4236/ojim.2017.74011
Abstract: Objective: Intestinal graft-versus-host disease (GVHD) represents one of the most serious complications of allogeneic stem cell transplantation (allo-SCT). Endoscopic and histological proof is required due to the number of differential diagnoses manifesting as diarrhea. We investigated the safety of endoscopic biopsies, and the role of conducting biopsies and inspections of the terminalileum. Patients: Thirty two colonoscopic examinations and 29 biopsies were performed for 19 patients after allo-SCT in our institute between October 2011 and May 2015. Results: Endoscopic examinations and biopsies were performed safely under the policy of transfusing platelets for thrombocytopenia (<30 × 103/μL). For biopsied cases, the diagnostic consistency rate with endoscopic findings was 60%, with a tendency toward negative correlations with early examinations after diarrhea onset (25% for 0 - 1 days; 62.5% for later) or low-grade GVHD according to Freiburg criteria (41.2% for grade 1, 66.7% for grade 2, 100% for higher). The terminal ileum was inspected with colonoscopy in 13 cases. Endoscopic diagnoses of the ileum were provided in 11 cases and histological diagnoses in 9 cases. Diagnostic consistency for diagnosis of the terminal ileum between endoscopy and histology was 77.8%. Conclusion: Because endoscopic and histopathological findings do not always match, caution is required when focusing on endoscopic findings alone, as there is a risk of misdiagnosis. Extensive inspection of the terminal ileum with biopsy appears useful to identify otherwise undetected lesions. Our data thus support invasive endoscopic examinations for gastrointestinal complications, including ileac inspection and biopsies under appropriate management.
C57BL/KsJ-db/db-ApcMin/+ Mice Exhibit an Increased Incidence of Intestinal Neoplasms
Kazuya Hata,Masaya Kubota,Masahito Shimizu,Hisataka Moriwaki,Toshiya Kuno,Takuji Tanaka,Akira Hara,Yoshinobu Hirose
International Journal of Molecular Sciences , 2011, DOI: 10.3390/ijms12118133
Abstract: The numbers of obese people and diabetic patients are ever increasing. Obesity and diabetes are high-risk conditions for chronic diseases, including certain types of cancer, such as colorectal cancer (CRC). The aim of this study was to develop a novel animal model in order to clarify the pathobiology of CRC development in obese and diabetic patients. We developed an animal model of obesity and colorectal cancer by breeding the C57BL/KsJ- db /db (db/db) mouse, an animal model of obesity and type II diabetes, and the C57BL/6J- ApcMin/+ (Min/+) mouse, a model of familial adenomatous polyposis. At 15 weeks of age, the N9 backcross generation of C57BL/KsJ- db /db- ApcMin/+ (db/db-Min/+) mice developed an increased incidence and multiplicity of adenomas in the intestinal tract when compared to the db/m-Min/+ and m/m-Min/+ mice. Blood biochemical profile showed significant increases in insulin (8.3-fold to 11.7-fold), cholesterol (1.2-fold to 1.7-fold), and triglyceride (1.2-fold to 1.3-fold) in the db/db-Min/+ mice, when compared to those of the db/m-Min/+ and m/m-Min/+ mice. Increases (1.4-fold to 2.6-fold) in RNA levels of insulin-like growth factor (IGF)-1, IRF-1R, and IGF-2 were also observed in the db/db-Min/+ mice. These results suggested that the IGFs, as well as hyperlipidemia and hyperinsulinemia, promoted adenoma formation in the db/db-Min/+ mice. Our results thus suggested that the db/db-Min/+ mice should be invaluable for studies on the pathogenesis of CRC in obese and diabetes patients and the therapy and prevention of CRC in these patients.
The Effect of Acyclic Retinoid on the Metabolomic Profiles of Hepatocytes and Hepatocellular Carcinoma Cells
Xian-Yang Qin, Feifei Wei, Masaru Tanokura, Naoto Ishibashi, Masahito Shimizu, Hisataka Moriwaki, Soichi Kojima
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0082860
Abstract: Background/Purpose Acyclic retinoid (ACR) is a promising chemopreventive agent for hepatocellular carcinoma (HCC) that selectively inhibits the growth of HCC cells (JHH7) but not normal hepatic cells (Hc). To better understand the molecular basis of the selective anti-cancer effect of ACR, we performed nuclear magnetic resonance (NMR)-based and capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS)-based metabolome analyses in JHH7 and Hc cells after treatment with ACR. Methodology/Principal Findings NMR-based metabolomics revealed a distinct metabolomic profile of JHH7 cells at 18 h after ACR treatment but not at 4 h after ACR treatment. CE-TOFMS analysis identified 88 principal metabolites in JHH7 and Hc cells after 24 h of treatment with ethanol (EtOH) or ACR. The abundance of 71 of these metabolites was significantly different between EtOH-treated control JHH7 and Hc cells, and 49 of these metabolites were significantly down-regulated in the ACR-treated JHH7 cells compared to the EtOH-treated JHH7 cells. Of particular interest, the increase in adenosine-5′-triphosphate (ATP), the main cellular energy source, that was observed in the EtOH-treated control JHH7 cells was almost completely suppressed in the ACR-treated JHH7 cells; treatment with ACR restored ATP to the basal levels observed in both EtOH-control and ACR-treated Hc cells (0.72-fold compared to the EtOH control-treated JHH7 cells). Moreover, real-time PCR analyses revealed that ACR significantly increased the expression of pyruvate dehydrogenase kinases 4 (PDK4), a key regulator of ATP production, in JHH7 cells but not in Hc cells (3.06-fold and 1.20-fold compared to the EtOH control, respectively). Conclusions/Significance The results of the present study suggest that ACR may suppress the enhanced energy metabolism of JHH7 cells but not Hc cells; this occurs at least in part via the cancer-selective enhancement of PDK4 expression. The cancer-selective metabolic pathways identified in this study will be important targets of the anti-cancer activity of ACR.
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