Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
Volume 40 , Issue 5
Showing 1-31 articles out of 31 articles from the selected issue
Current Topics - Brain Damage and Potential Therapeutic Interventions
Current Topics: Reviews
  • Masanori Hijioka, Masatoshi Inden, Daijiro Yanagisawa, Yoshihisa Kitam ...
    2017 Volume 40 Issue 5 Pages 548-552
    Published: May 01, 2017
    Released: May 01, 2017
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    DJ-1, encoded in a causative gene of familial Parkinson’s disease (PARK7), has multiple functions: it works as an antioxidant, in transcriptional regulation, as a molecular chaperone and in protein degradation. Three types of pathogenic mutants of DJ-1 (M26I, D149A and L166P) have been reported to disrupt proper structures and lead to a loss of function. DJ-1 receives oxidation at the cysteine residue, and the degree of oxidation at the C106 residue determines DJ-1 activity. In this decade, DJ-1 has been reported to suppress the progression of various neurodegenerative disorders in animal models. The administration of recombinant wild-type DJ-1 protein suppresses the neuronal loss associated with both Parkinson’s disease and ischemic stroke in rats. Furthermore, in studies focused on DJ-1 as the therapeutic target, compounds that have the capacity of binding to DJ-1 at the C106 residue have been reported to exert therapeutic effects on various neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease and ischemic stroke. DJ-1 and DJ-1-targeting molecules/compounds will be useful therapeutic targets for various neurodegenerative disorders due to their various functions such as antioxidant capacity, chaperone function and as a proteolytic pathway.

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  • Toshiaki Kume
    2017 Volume 40 Issue 5 Pages 553-556
    Published: May 01, 2017
    Released: May 01, 2017
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    Oxidative stress is recognized as an important mediator of brain disorders. Nevertheless, there are few antioxidants approved for brain diseases. There are two types of mechanisms as antioxidant systems in vivo, antioxidants and antioxidant enzymes. Antioxidants are consumed by the reaction with reactive oxygen species. Thus, it is important to maintain high concentrations at the requisite site. On the other hand, antioxidant capacity is maintained for around a half-day to one day once antioxidant enzymes are induced. Therefore, low molecular-weight compounds that could induce antioxidant enzymes are considered to be suitable for the treatment and prevention of brain diseases. The nuclear factor erythroid 2-related factor 2 (Nrf2)–antioxidant response element (ARE) pathway is known as a system for inducing these antioxidant enzymes. Here, the potential for low molecular-weight compounds capable of activating the Nrf2–ARE pathway to become therapeutic agents for brain diseases is discussed.

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  • Yuri Ikeda-Matsuo
    2017 Volume 40 Issue 5 Pages 557-563
    Published: May 01, 2017
    Released: May 01, 2017
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    Prostaglandin E2 (PGE2) has been thought to be an important mediator of inflammation in peripheral tissues, but recent studies clearly show the involvement of PGE2 in inflammatory brain diseases. In some animal models of brain disease, the genetic disruption and chemical inhibition of cyclooxygenase (COX)-2 resulted in the reduction of PGE2 and amelioration of symptoms, and it had been thought that PGE2 produced by COX-2 may be involved in the progression of injuries. However, COX-2 produces not only PGE2, but also some other prostanoids, and thus the protective effects of COX-2 inhibition, as well as severe side effects, may be caused by the inhibition of prostanoids other than PGE2. Therefore, to elucidate the role of PGE2, studies of microsomal prostaglandin E synthase-1 (mPGES-1), an inducible terminal enzyme for PGE2 synthesis, have recently been an active area of research. Studies from mPGES-1 deficient mice provide compelling evidence for its role in a variety of inflammatory brain diseases, such as ischemic stroke, Alzheimer’s disease and epilepsy, and clues for developing new therapeutic treatments for brain diseases by targeting mPGES-1. Considering that COX inhibitors may non-selectively suppress the production of many types of prostanoids that are essential for normal physiological functioning of the brain and peripheral tissues, as well as induce gastro-intestinal, renal and cardiovascular complications, mPGES-1 inhibitors are expected to be injury-selective and have fewer side-effects when treating human brain diseases. Thus, this paper focuses on recent studies that have demonstrated the involvement of mPGES-1 in pathological brain diseases.

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  • Hiroshi Katsuki, Masanori Hijioka
    2017 Volume 40 Issue 5 Pages 564-568
    Published: May 01, 2017
    Released: May 01, 2017
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    Intracerebral hemorrhage (ICH) is a neurological disorder frequently accompanied by severe dysfunction. Critical pathogenic events leading to poor prognosis should be identified for the development of novel effective therapies for ICH. Here we focus on the injury of the axonal tract, particularly of the internal capsule, with reference to its contribution to ICH pathology and potential therapeutic interventions in addition to its cellular mechanisms. Studies on human ICH patients and rodent models of ICH suggest that invasion of hematoma into the internal capsule greatly worsens the severity of post-ICH symptoms. A blood-derived protease thrombin may play an important role in the acute phase of axonal tract injury in the internal capsule that includes compromised axonal transport and fragmentation of axonal structures. Several agents such as clioquinol, melatonin and Am80 (a retinoic acid receptor agonist) have been shown to produce therapeutic effects on rodent models of ICH associated with injury of the internal capsule. In the course of examinations on the effect of Am80, we obtained evidence for the involvement of CXCL2, a neutrophil chemotactic factor, in the pathogenesis of ICH. Accordingly, we also refer to the potential roles of infiltrating neutrophils and inflammatory responses in axonal tract injury and resultant neurological dysfunction in ICH.

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  • Shotaro Michinaga, Yutaka Koyama
    2017 Volume 40 Issue 5 Pages 569-575
    Published: May 01, 2017
    Released: May 01, 2017
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    Severe brain damage by trauma, ischemia, and hemorrhage lead to fatal conditions including sudden death, subsequent complications of the extremities and cognitive dysfunctions. Despite the urgent need for treatments for these complications, currently available therapeutic drugs are limited. Blood–brain barrier (BBB) disruption is a common pathogenic feature in many types of brain damage. The characteristic pathophysiological conditions caused by BBB disruption are brain edema resulting from an excessive increase of brain water content, inflammatory damage caused by infiltrating immune cells, and hemorrhage caused by the breakdown of microvessel structures. Because these pathogenic features induced by BBB disruption cause fatal conditions, their improvement is a desirable strategy. Many studies using experimental animal models have focused on molecules involved in BBB disruption, including vascular endothelial growth factors (VEGFs), matrix metalloproteinases (MMPs) and endothelins (ETs). The inhibition of these factors in several experimental animals was protective against BBB disruption caused by several types of brain damage, and ameliorated brain edema, inflammatory damage, and hemorrhagic transformation. In patients with brain damage, the up-regulation of these factors was observed and was related to brain damage severity. Thus, BBB protection by targeting VEGFs, MMPs, and ETs might be a novel strategy for the treatment of brain damage.

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Regular Articles
  • Hyunwoo Ju, Taewan Kim, Chan-Moon Chung, Junsoo Park, Takeshi Nikawa, ...
    2017 Volume 40 Issue 5 Pages 576-582
    Published: May 01, 2017
    Released: May 01, 2017
    [Advance publication] Released: February 03, 2017
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    The homeostasis of muscle properties depends on both physical and metabolic stresses. Whereas physical stress entails metabolic response for muscle homeostasis, the latter does not necessarily involve the former and may thus solely affect the homeostasis. We here report that metabolic suppression by the hypometabolic agent 3-iodothyronamine (T1AM) induced muscle cell atrophy without physical stress. We observed that the oxygen consumption rate of C2C12 myotubes decreased 40% upon treatment with 75 µM T1AM for 6 h versus 10% in the vehicle (dimethyl sulfoxide) control. The T1AM treatment reduced cell diameter of myotubes by 15% compared to the control (p<0.05). The cell diameter was reversed completely by 9 h after T1AM was removed. The T1AM treatment also significantly suppressed the expression levels of heat shock protein 72 and αB-crystallin as well as the phosphorylation levels of Akt1, mammalian target of rapamycin (mTOR), S6K, forkhead box O1 (FoxO1) and FoxO3. In contrast, the levels of ubiquitin E3 ligase MuRF1 and chymotrypsin-like activity of proteasome were significantly elevated by T1AM treatment. These results suggest that T1AM-mediated metabolic suppression induced muscle cell atrophy via activation of catabolic signaling and inhibition of anabolic signaling.

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  • Wen-chen Wang, Yan-min Xia, Bo Yang, Xiang-ni Su, Jia-kuan Chen, Wei L ...
    2017 Volume 40 Issue 5 Pages 583-593
    Published: May 01, 2017
    Released: May 01, 2017
    [Advance publication] Released: February 10, 2017
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    Tyrosol (Tyr) is a natural antioxidant that displays anti-oxidant and anti-inflammatory properties. The present study aimed to investigate the effect and mechanism of Tyr on lipopolysaccharide (LPS)-induced acute lung injury (ALI). In a mouse model, we found that pretreatment with Tyr significantly improved survival rate, attenuated lung permeability, ameliorated histopathological alterations, reduced expression of the inflammatory mediators and improved expression of the antioxidant enzyme. Further study revealed that Tyr markedly inhibited nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) activation at both in vivo and in vitro levels. To investigate the underlying mechanism, we examined the impact of Tyr on the heme oxygenase (HO)-1/nuclear factor erythroid-2 related factor 2 (Nrf2) pathway in vivo and in vitro. The results showed that Tyr significantly improved the expression of HO-1 and the activation of Nrf2. This study offers novel evidence to support the efficacy of Tyr against ALI, which helps to clarify the underlying causes of the therapeutic effects behind Tyr.

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  • Maiko Akutagawa, Yohei Kawasaki, Atsuko Kawasaki, Kazuki Ide, Hiroshi ...
    2017 Volume 40 Issue 5 Pages 594-597
    Published: May 01, 2017
    Released: May 01, 2017
    [Advance publication] Released: February 15, 2017
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    Economic evaluation of drugs is used in decision-making on medical care and public policy. Recently, real-world data (RWD) have been used in the analysis. In this study, we discuss the risk and benefits of using RWD for economic evaluation. We conducted a cost-outcome description with RWD from a nationwide registry providing information on hepatitis treatment in Japan and estimated the utility of the analysis. We evaluated the cost-outcome description of peginterferon plus ribavirin (PEG-IFN-α2b+RBV) treatment in hepatitis C virus (HCV)-infected patients. Simulations were based on a Markov model. The cohorts were set using data from the registry and we assumed a societal perspective for the calculation of costs. The dose and drug cost were chosen based on the Japanese Guidelines for the Management of Hepatitis C Virus Infection or package inserts. Model details and parameters were as described in previous studies. The simulations were performed for a period of 10 years with no discount rate. We estimated 2.5 million JPY per Quality Adjusted Life Year (QALY) in 48-week PEG-IFN-α2b+RBV treatment for a period of 10 years. The results of this study are in agreement with previous HCV treatment economic evaluation studies in Japan. We analyzed the statistics of the HCV-infected patients at each disease stage using the data in our registry and calculated the costs. The results of this study more closely reflect a real-world clinical situation compared to the widely used randomized clinical trial method, which estimates clinical trial results and scenarios.

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    Editor’s picks

    Economic evaluation has been recently carried out using real-world data instead of clinical trial data. Akutagawa et al. conducted a cost-outcome description based on a nationwide registry providing information on hepatitis treatment in Japan and estimated the utility of the analysis. Specifically, they evaluated the cost-outcome description of a 48-week peginterferon plus ribavirin treatment in patients infected by the hepatitis C virus. Simulations were based on a Markov model. After setting the cohorts using data from the registry, and assuming a societal perspective for the calculation of costs, they estimated 2.5 million JPY per quality-adjusted life years (QALY) for treatments over a 10-year period. They analyzed patients’ statistics at each disease stage using their registry data and calculated the costs. Their results reflect more closely a real-world clinical situation as compared to the widely used clinical trial method.



  • Fei Li, Rong Tang, Ling-Bo Chen, Ke-Sheng Zhang, Xiao-Ping Huang, Chan ...
    2017 Volume 40 Issue 5 Pages 598-609
    Published: May 01, 2017
    Released: May 01, 2017
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    Danggui Buxue Tang (DBT), a combination of Astragalus and Angelica at a 5 : 1 ratio, mainly promotes hematopoiesis. However, in the clinic, the combination ratio of Astragalus and Angelica to treat low hematopoietic function is not an absolute 5 : 1 ratio, suggesting that the herbs may promote hematopoiesis better after being combined at a certain range of ratios. The objective of this study is to investigate the effect of different ratio combinations of Astragalus and Angelica on bone marrow hematopoiesis suppression induced by cyclophosphamide (CTX) and to probe the interaction and mechanism of Astragalus combined with Angelica in promoting hematopoiesis. Following establishment of the model, mice were administered with Astragalus (6.00 g·kg−1), Angelica (3.00 g·kg−1), and combinations of Astragalus and Angelica at different ratios, including 10 : 1 (Astragalus 9.81 g·kg−1+Angelica 0.98 g·kg−1), 5 : 1 (Astragalus 9.00 g·kg−1+Angelica 1.80 g·kg−1), 2 : 1 (Astragalus 7.71 g·kg−1+Angelica 3.08 g·kg−1), 1 : 1 (Astragalus 5.40 g·kg−1+Angelica 5.40 g·kg−1), 1 : 2.5 (Astragalus 3.08 g·kg−1+Angelica 7.71 g·kg−1), 1 : 5 (Astragalus 1.80 g·kg−1+Angelica 9.00 g·kg−1), and 1 : 10 (Astragalus 0.98 g·kg−1+Angelica 9.81 g·kg−1). Our results suggested that Astragalus mixed with Angelica synergistically promoted hematopoiesis best when the combination ratio of Astragalus and Angelica was 1 : 1, 1 : 2.5 or 1 : 5; moreover, the effect of Angelica was greater than that of Astragalus. The potential mechanisms of the combinations of Astragalus and Angelica that promote hematopoiesis include the dissolution of the effective components, promoting the synthesis and secretion of hematopoietic growth factor (HGF) and the proliferation of hematopoietic progenitor cells (HPCs).

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  • Zhaoyu Xing, Wanma Pan, Jing Zhang, Xianlin Xu, Xuemei Zhang, Xiaozhou ...
    2017 Volume 40 Issue 5 Pages 610-615
    Published: May 01, 2017
    Released: May 01, 2017
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    The current research was designed to study the role of hydrogen in renal fibrosis and the renal epithelial to mesenchymal transition (EMT) induced by transforming growth factor-β1 (TGF-β1). Hydrogen rich water (HW) was used to treat animal and cell models. Unilateral ureteral obstruction (UUO) was performed on Balb/c mice to create a model of renal fibrosis. Human kidney proximal tubular epithelial cells (HK-2 cells) were treated with TGF-β1 for 36 h to induce EMT. Serum creatinine (Scr) and blood urea nitrogen (BUN) were measured to test renal function, in addition, kidney histology and immunohistochemical staining of alpha-smooth muscle actin (α-SMA) positive cells was performed to examine the morphological changes. The treatment with UUO induced a robust fibrosis of renal interstitium, shrink of glomerulus and partial fracture of basement membrane. Renal function was also impaired in the experimental group with UUO, with an increase of Scr and BUN in serum. After that, Western-blot was performed to examine the expression of α-SMA, fibronectin, E-cadherin, Smad2 and Sirtuin-1 (Sirt1). The treatment with HW attenuated the development of fibrosis and deterioration of renal function in UUO model. In HK-2 cells, the pretreatment of HW abolished EMT induced by TGF-β1. The down-regulation the expression of Sirt1 induced by TGF-β1 which was dampened by the treatment with HW. Sirtinol, a Sirt1 inhibitor, reversed the effect of HW on EMT induced by TGF-β1. HW can inhibit the development of fibrosis in kidney and prevents HK-2 cells from undergoing EMT which is mediated through Sirt1, a downstream molecule of TGF-β1.

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  • Katsuhiro Ohyama, Haruna Kawakami, Michiko Inoue
    2017 Volume 40 Issue 5 Pages 616-620
    Published: May 01, 2017
    Released: May 01, 2017
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    Topical prostaglandin F2α (PGF2α) analogs are widely used as the first line of therapy for glaucoma. Systemic PGF2α is suggested to increase blood pressure. Some ophthalmic formulations with β-receptor blocking or α-receptor stimulating actions are reported to cause systemic adverse events such as a decrease in heart rate and blood pressure. The objective of this study was to evaluate the association between topical PGF2α analogs and blood pressure elevation. We analyzed the reports obtained from the Food and Drug Administration Adverse Event Reporting System (FAERS) database from the first quarter of 2004 until the end of 2015 and the Japanese Adverse Drug Event Report (JADER) database from April 2004 to January 2016 for signal detection using reporting odds ratio (ROR), a method of disproportionality analyses. Signals are considered significant if the ROR estimates and lower bound of the 95% confidence interval (CI) exceed 1. Preferred terms in the Medical Dictionary for Regulatory Activities were utilized to define blood pressure elevation. A total of 6156081 reports from the FAERS and 351226 reports from the JADER were analyzed. The significant RORs with 95% CI were calculated to be 1.82 (95% CI: 1.55–2.13) for bimatoprost, 1.69 (95% CI: 1.53–1.85) for latanoprost, and 2.17 (95% CI: 1.82–2.59) for travoprost from the FAERS. From the JADER, 5.01 (95% CI: 1.59–15.8) was calculated for bimatoprost and 8.02 (95% CI: 2.94–21.9) for tafluprost. The resulting data suggest the necessity for further clinical research on blood pressure elevation associated with topical PGF2α analogs and close monitoring.

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  • Wanchai Panthavee, Masafumi Noda, Narandalai Danshiitsoodol, Takanori ...
    2017 Volume 40 Issue 5 Pages 621-629
    Published: May 01, 2017
    Released: May 01, 2017
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    In the present study, we have obtained two exopolysaccharide (EPS)-producing thermophilic lactic acid bacteria (LAB) that were isolated from tropical fruits of Thailand. The two strains, designated LY45 and PY45, were identified as Pediococcus pentosaceus and Lactobacillus amylovorus, respectively. Both plant-derived LAB strains, which produce neutral EPSs together with the acidic one, can grow vigorously at 45°C and even at 50°C. Hyaluronidase (EC 3.2.1.35), which catalyzes the degradation of hyaluronic acid, activates an inflammatory reaction. Interestingly, EPSs produced by the LY45 and PY45 strains were found to inhibit hyaluronidase activity at the same order of IC50 values as did sodium cromoglicate and dipotassium glycyrrhizinate, which are well-known as anti-inflammatory agents. The LY45-derived neutral EPS consists of glucose and mannose as monosaccharide components, whereas the acidic one contains mainly mannose, together with glucose and galactose. On the other hand, although Lactobacillus amylovorus PY45 also produces neutral and acidic EPSs, the main monosaccharide in both EPSs is mannose, and glucose is a minor component. Furthermore, the PY45 strain may be probiotically and industrially useful because the microorganism can utilize starch and glycogen as carbon sources.

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  • Do Ik Lee, Su Kil Jang, Da Woon Park, Seung Tae Kim, Jun Sub Park, Bo ...
    2017 Volume 40 Issue 5 Pages 630-637
    Published: May 01, 2017
    Released: May 01, 2017
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    The aim of the present study was to examine the inhibitory roles and mechanisms of hirsutenone (HTN) in the regulation of osteoclastogenesis. Gene levels were compared to assure the effects of HTN on osteoclastogenesis in mouse splenocytes/CD4+ T cells, mouse macrophage-like cell line RAW264.7 (preosteoclast), MG63 (osteoblast), and RPMI1788 (B cell) cells. The mechanism by which HTN regulates the degradation of tumor necrosis factor receptor-associated factor 6 (TRAF6) and inhibits inhibitor of kappaB (IκB) and nuclear factor-kappaB (NF-κB) signaling was examined by Western blotting and luciferase reporter assays. Our results demonstrated that HTN effectively downregulated the expression of interferon γ (IFNγ), interleukin-22 (IL-22), IL-1β, and tartrate-resistant acid phosphatase (TRAP) in splenocyte-/CD4+-RAW264.7 co-culture system. Moreover, receptor activator of nuclear factor-κB ligand (RANKL) and CD25 expression were also significantly inhibited in MG63 and CD4+ single culture system, suggesting an additional independent effect of HTN on osteoclastogenesis. Notably, TRAF6 was markedly degraded along with a decrease in nuclear factor of activated T-cells (NFATc) and NF-κB activities in RAW264.7 cells. Finally, we concluded that HTN directly or indirectly inhibits osteoclastogenesis via the inhibition of NF-κB signaling by promoting TRAF6 degradation, and plays a crucial role in suppressing the expression of RANKL and cytokines expressed in IFNγ-producing T-helper 1 (Th1) cells. These findings suggest that HTN may be a promising therapeutic candidate for diseases resulting from bone loss.

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  • Takeshi Matsutani, Kazuhiro Tamura, Masahiko Kutsukake, Akihisa Matsud ...
    2017 Volume 40 Issue 5 Pages 638-644
    Published: May 01, 2017
    Released: May 01, 2017
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    Pioglitazone improves sepsis-induced organ injury accompanied with anti-inflammatory effects on visceral adipose tissue. However, its action in adipose immune cells remains to be ascertained. We investigated the effects of pioglitazone on visceral adipose macrophage population and polarisation in cecal ligation and puncture (CLP)-induced sepsis mice. Eight-week-old male mice were assigned to 3 groups: 1) sham-operated group, 2) CLP group, or 3) pioglitazone-treated CLP group. Pioglitazone (10 mg/kg) was injected intraperitonally for 7 d and CLP surgery was performed. Visceral adipose tissues were collected 24 h after the surgery. mRNA expression of several macrophage markers (inducible nitric oxide synthase (iNOS) for M1, arginase1 (Arg1) and interleukin (IL)-10 for M2, CD163 and F4/80 for mature macrophages) and inflammatory adipokines (IL-6, monocyte chemoattractant protein-1: MCP-1) was quantified by real-time RT-PCR. Tissue sections were subjected to the immunohistochemical analysis and the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay. CLP significantly enhanced Arg1, IL-10 and iNOS mRNA expressions as compared with the sham group, and pioglitazone significantly increased the mRNA level of CD163 and F4/80 in CLP mice. Expression of IL-6 and MCP-1 stimulated by CLP was reduced by pioglitazone treatment. Increased CD11b/c- and CD163-positive cells as well as apoptotic cells were observed in the CLP group and the pioglitazone-treated group. The data indicate that M1/M2 macrophage activation of visceral adipose tissues is induced in CLP-induced mice, and the function of macrophages recruited from surrounding organs may be modulated by pioglitazone treatment.

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  • Kazuki Ide, Yohei Kawasaki, Ryo Iketani, Naohiko Masaki
    2017 Volume 40 Issue 5 Pages 645-649
    Published: May 01, 2017
    Released: May 01, 2017
    [Advance publication] Released: February 17, 2017
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    In this study, a nationwide database was used to identify the risk factors for treatment discontinuation due to adverse events during telaprevir, peginterferon, and ribavirin (T/PR) treatment, and estimate the increase in the occurrence of adverse events when patients have multiple risk factors at the same time. The risk factors were identified using univariate logistic regression analysis, and a Cochran–Armitage trend test was used to analyze the correlation between the number of risk factors and treatment discontinuation due to adverse events. Of the 25989 individuals registered in the database, 1668 (age, mean±standard deviation (S.D.): 58.0±9.9) were included in the study. Of these, 188 (11.3%) discontinued T/PR therapy due to adverse events. In the univariate logistic regression analysis, sex, age, aspartate aminotransferase (AST) level, and platelet count were found to significantly affect the incidence of T/PR treatment discontinuation (p<0.05). Furthermore, the incidence of treatment discontinuation gradually increased from 4.6 to 27.2% as the number of risk factors increased from 0 to 4, and the Cochran–Armitage trend test showed a significant correlation (p<0.001). In conclusion, this study not only revealed the risk factors for treatment discontinuation but also showed that patients with multiple risk factors are more likely to discontinue treatment due to adverse events compared to patients with fewer risk factors.

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  • Hongshan Li, Hao Ying, Airong Hu, Yaoren Hu, Dezhou Li
    2017 Volume 40 Issue 5 Pages 650-657
    Published: May 01, 2017
    Released: May 01, 2017
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    Nonalcoholic steatohepatitis (NASH) is the most frequent cause of liver dysfunction and a common global problem. Gypenosides can decrease pathological modifications of high-fat diet-induced rat atherosclerosis; however, its effect and mechanism on NASH remain unclear. In this study, rats were randomly divided into normal control and model groups. Model rats were fed with a high-fat diet and treated with gypenosides, rosiglitazone, or water for 6 weeks. We found that liver tissues showed significant hepatic steatosis and vacuolar degeneration with significantly higher triglyceride (TG), free fatty acid (FFA) and malonyl CoA, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (GGT) activities in model group versus normal control group (p<0.01). Liver tissue mRNA and protein levels of sterol regulatory element binding protein-1c (SREBP-1c), carbohydrate response element binding protein (ChREBP), acetyl-CoA carboxylase (ACCase), and stearoyl CoA desaturase enzyme 1 (SCD1) were significantly increased, while the carnitine palmitoyl transferase-1 (CPT-1) level was significantly decreased in the model group versus the normal control group (p<0.01). Pathological changes of hepatic steatosis; body weight and liver wet weight; liver tissue TG, FFA and malonyl CoA concentrations; serum ALT, AST and GGT activities; liver tissue mRNA and protein levels of SREBP-1c, ChREBP, ACCase, and SCD-1 were significantly decreased; protein and mRNA levels of CPT-1 were significantly increased in the gypenosides group versus model group (p<0.01). In conclusion, gypenosides has therapeutic effect on NASH through regulating key transcriptional factors and lipogenic enzymes involved in fatty acid oxidation during hepatic lipogenesis.

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  • Momoka Yamaguchi, Shin-ya Saito, Ryota Nishiyama, Misuzu Nakamura, Ken ...
    2017 Volume 40 Issue 5 Pages 658-664
    Published: May 01, 2017
    Released: May 01, 2017
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    During liver injury, hepatic stellate cells (HSCs) are activated by various cytokines and transdifferentiated into myofibroblast-like activated HSCs, which produce collagen, a major source of liver fibrosis. Therefore, the suppression of HSC activation is regarded as a therapeutic target for liver fibrosis. Several epidemiological reports have revealed that caffeine intake decreases the risk of liver disease. In this study, therefore, we investigated the effect of caffeine on the activation of primary HSCs isolated from mice. Caffeine suppressed the activation of HSC in a concentration-dependent manner. BAPTA-AM, an intracellular Ca2+ chelator, had no effect on the caffeine-induced suppression of HSC activation. None of the isoform-selective inhibitors of phosphodiesterase1 to 5 affected changes in the morphology of HSC during activation, whereas CGS-15943, an adenosine receptor antagonist, inhibited them. Caffeine had no effect on intracellular cAMP level or on the phosphorylation of extracellular signal-regulated kinase (ERK)1/2. In contrast, caffeine significantly decreased the phosphorylation of Akt1. These results suggest that caffeine inhibits HSC activation by antagonizing adenosine receptors, leading to Akt1 signaling activation.

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  • Takakuni Matsuda, Shogo Hiraoka, Hiroki Urashima, Ako Ogura, Tatsuhiro ...
    2017 Volume 40 Issue 5 Pages 665-674
    Published: May 01, 2017
    Released: May 01, 2017
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    A 2% commercially available, milky-white, rebamipide micro-particle suspension is used to treat dry eyes, and it causes short-term blurring of the patient’s vision. In the current study, to improve the transparency of a rebamipide suspension, we attempted to obtain a clear rebamipide suspension by transforming the rebamipide particles to an ultrafine state. In the initial few efforts, various rebamipide suspensions were prepared using a neutralizing crystallization method with additives, but the suspensions retained their opaque quality. However, as a consequence of several critical improvements in the neutralizing crystallization methods such as selection of additives for crystallization, process parameters during crystallization, the dispersion method, and dialysis, we obtained an ultrafine rebamipide suspension (2%) that was highly transparent (transmittance at 640 nm: 59%). The particle size and transparency demonstrated the fewest level of changes at 25°C after 3 years, compared to initial levels. During that period, no obvious particle sedimentation was observed. The administration of this ultrafine rebamipide suspension (2%) increased the conjunctival mucin, which was comparable to the commercially available micro-particle suspension (2%). The corneal and conjunctival concentration of rebamipide following ocular administration of the ultrafine suspension was slightly higher than that of the micro-particle suspension. The ultrafine rebamipide suspension (eye-drop formulation) with a highly transparent ophthalmic clearness should improve a patient’s QOL by preventing even a shortened period of blurred vision.

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  • Toshiyuki Takasu, Yuka Hayashizaki, Jiro Hirosumi, Hideaki Minoura, No ...
    2017 Volume 40 Issue 5 Pages 675-680
    Published: May 01, 2017
    Released: May 01, 2017
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    Sodium glucose cotransporter 2 (SGLT2) inhibitors improve hyperglycemia in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion. In addition to their antihyperglycemic effect, SGLT2 inhibitors also reduce body weight and fat mass in obese and overweight patients with T2DM. However, whether or not SGLT2 inhibitors similarly affect body composition of non-obese patients with T2DM remains unclear. In this study, we investigated the effect of the SGLT2 inhibitor ipragliflozin on body composition in a Goto–Kakizaki (GK) rat model of non-obese T2DM. GK rats were treated with ipragliflozin once daily for 9 weeks, starting at 23 weeks of age. Body composition was then analyzed using dual-energy X-ray absorptiometry. Treatment with ipragliflozin increased urinary glucose excretion, reduced hemoglobin A1c (HbA1c) levels and suppressed body weight gain as the dose increased. Body composition analysis revealed that body fat mass was lower in the ipragliflozin-treated groups than in the control group, while lean body mass and bone mineral contents were comparable between groups. Thus, an SGLT2 inhibitor ipragliflozin was found to promote preferential loss of fat mass in a rat model of non-obese T2DM. Ipragliflozin might also promote preferential loss of fat in non-obese patients with T2DM.

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  • Hiroyoshi Koide, Daiki Hira, Masayuki Tsujimoto, Yurie Katsube, Tetsuy ...
    2017 Volume 40 Issue 5 Pages 681-686
    Published: May 01, 2017
    Released: May 01, 2017
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    Febuxostat has currently played pivotal role in the treatment of hyperuricemia, but there is little comprehensive information for the determinants of individual difference in efficacy of febuxostat. Therefore, the present study, a retrospective investigation, was carried out to analyze the effects of patient characteristics on the efficacy of febuxostat. A total of 225 patients who were continuously prescribed the same dose of febuxostat for 8–12 weeks from the initial therapy were enrolled in the present study. The data, including patient information and laboratory data, were collected from electronic medical records. Serum urate lowering effects of febuxostat were evaluated by calculating the change in serum urate level at baseline and at 8–12 weeks after starting febuxostat. The multiple regression analysis showed the change in serum urate level was significantly lower in male patients and in those with a lower baseline serum urate level, higher previous dose of allopurinol, lower dose of febuxostat and lower body surface area-unadjusted estimated glomerular filtration rate. Concomitantly administered drugs did not show a significantly influence on the efficacy of febuxostat. In conclusion, it should be noted that the serum urate lowering efficacy of febuxostat may decrease in patients with a higher previous dose of allopurinol, renal impairment or male patients. The basic findings of the present study are believed to contribute to the proper use of febuxostat.

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  • Ryo Iketani, Kazuki Ide, Hiroshi Yamada, Yohei Kawasaki, Naohiko Masak ...
    2017 Volume 40 Issue 5 Pages 687-692
    Published: May 01, 2017
    Released: May 01, 2017
    [Advance publication] Released: February 09, 2017
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    This study was designed to evaluate the safety profile of adding telaprevir to therapy using pegylated interferon-alfa-2b and ribavirin (PR) using real world patient data obtained from a nationwide Japanese interferon database. This retrospective cohort study compared telaprevir-based triple therapy (T/PR) with PR therapy. The study population comprised patients with genotype 1 chronic hepatitis C represented in the database between December 2009 and August 2015. The primary endpoint was dropout from treatment due to adverse events during the relevant standard treatment duration based on guidelines from the Japan Society of Hepatology. The dropout odds ratio (OR) and 95% confidence interval (95% CI) were calculated using univariate logistic regression analysis. Covariates were detected using a stepwise logistic regression analysis, and the adjusted OR and 95% CI were calculated. A total of 25989 patients were registered, and 4619 patients (T/PR: 1334, PR: 3285) were appropriate for primary endpoint analysis. The dropout rate due to adverse events was lower in the T/PR group (13.4%) than in the PR group (22.6%) (OR: 0.530; 95% CI, 0.444–0.633). After adjustment for the covariates detected by stepwise selection, the OR was 0.529 (95% CI, 0.441–0.634). Our study showed that there was a difference in dropout rate between real world T/PR and PR therapy in Japan. Although the addition of telaprevir to PR therapy may improve treatment continuity under the care of hepatologists, this study could not fully determine which therapy was safer or the factors influencing this result. Therefore, additional research will be required to confirm this.

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  • Reiko Ikeda, Yuki Ogasawara, Kazuhiko Takatori, Tomoe Ichikawa, Miki N ...
    2017 Volume 40 Issue 5 Pages 693-697
    Published: May 01, 2017
    Released: May 01, 2017
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    In the co-culture of Staphylococcus epidermidis and Trichosporon asahii, a fungal pathogen, it was observed that live S. epidermidis inhibited the growth of T. asahii. Soluble active anti-T. asahii substances were speculated to be produced by S. epidermidis in culture medium. Using 1H- and 13C-NMR spectra and electron ionization-high resolution mass spectrometry (HR-negative-FAB-MS), we separated the active molecule and identified it as lactic acid. Commercially available L-lactic acid and D-lactic acid inhibited the growth of T. asahii. These results show that metabolites from bacterial populations are involved in the interactions of pathogenic fungi. The use of antibacterial agents to treat primary diseases could lead to the disruption of normal microbial communities and could cause opportunistic infections such as trichosporonosis.

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  • Hiroko Hayashi, Akio Suzuki, Koichi Ohata, Masashi Ishihara, Yushi Kub ...
    2017 Volume 40 Issue 5 Pages 698-702
    Published: May 01, 2017
    Released: May 01, 2017
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    Management of constipation in patients receiving cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) or CHOP-like chemotherapy regimens is important for prevention of paralytic ileus. We reported earlier that the laxative action of magnesium oxide is reversed by the concomitant use of antacids in cancer patients receiving opioid analgesics. Here, we assessed the prevalence of prophylactic laxative medication for the control of constipation in patients receiving CHOP or CHOP-like regimens for non-Hodgkin’s lymphoma. Data obtained from 211 eligible patients were retrospectively analyzed. Almost all patients (99%) received anti-ulcer agents such as proton pump inhibitors and H2 receptor antagonists for the prophylaxis of gastric disorders associated with prednisolone. Prophylactic laxatives were prescribed in 86 patients (40.8%), in which magnesium oxide was used most predominantly (88.4%). However, magnesium oxide at doses of ≦2000 mg/d was not effective for prevention of constipation, although the compound totally inhibited the incidence of constipation at doses higher than 2000 mg/d. Therefore, it is important to avoid negative drug interaction between magnesium oxide and antacids in patients receiving CHOP chemotherapy.

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  • Rui Wang, Qing-xuan Zheng, Wei Wang, Ling Feng, Hui-jing Li, Qi-yong H ...
    2017 Volume 40 Issue 5 Pages 703-710
    Published: May 01, 2017
    Released: May 01, 2017
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    A series of new glycyrrhetinic acids and oleanolic acids has been designed and synthesized based on the principles of combinatorial chemical synthesis. Their anticancer activities were further studied by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method with hepatocellular carcinoma (Hep-G2), breast cancer (MCF-7) cell lines and a normal hepatic cell (LO2). Cytotoxicity tests (in vitro) indicated that compound 6a showed the highest cytotoxicity with the lowest IC50 values of 23.34 µM on Hep-G2 cells, 12.23 µM on MCF-7 cells, and 44.47 µM on LO2, which would widen the structural diversity of these anticancer targets and confirm the perspectives of further investigations.

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  • Takuya Sasaki, Yuya Nishimura, Yuji Ikegaya
    2017 Volume 40 Issue 5 Pages 711-715
    Published: May 01, 2017
    Released: May 01, 2017
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    Understanding physiological interactions between the central and peripheral nervous systems requires an experimental strategy to simultaneously monitor activity patterns of the brain and peripheral organs. In this study, we developed a novel method to record extracellular field potential signals from a wide range of brain regions together with electrocardiograms, electromyograms, and breathing signals from a freely moving rodent. This method collects all recorded signals into a single device mounted on an animal’s head, allowing the reduction of experimental costs and the simplification of data processing. The methodological concept is applicable to a number of biological research issues of how the brain–body association is altered in response to various environmental changes, emotional challenges, and acute and chronic dysfunction of internal organs.

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Notes
  • Hiroshi Takeda, Tsukasa Tominari, Michiko Hirata, Kenta Watanabe, Chih ...
    2017 Volume 40 Issue 5 Pages 716-721
    Published: May 01, 2017
    Released: May 01, 2017
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    Lutein is a member of the xanthophyll family of carotenoids, which are known to prevent hypoxia-induced cell damage in the eye by removing free radicals. However, its role in other tissues is controversial, and the effects of lutein on bone tissues are unknown. To identify a possible role of lutein in bone tissues, we examined the effects of lutein on bone formation and bone resorption and on femoral bone mass in mice. Lutein enhanced the formation of mineralized bone nodules in cultures of osteoblasts. On the other hand, lutein clearly suppressed 1α, 25-dihydroxyvitamin D3-induced bone resorption as measured by pit formation in organ culture of mouse calvaria. In co-cultures of bone marrow cells and osteoblasts, lutein suppressed 1α, 25-dihydroxyvitamin D3-induced osteoclast formation. In cultures of bone marrow macrophages, lutein suppressed soluble RANKL, the receptor activator of nuclear factor-kappaB (NF-κB) ligand, induced osteoclast formation. When five-week-old male mice were orally administered lutein for 4 weeks, the femoral bone mass was clearly enhanced in cortical bone, as measured by bone mineral density in dual X-ray absorptiometry and micro computed tomography (µCT) analyses. The present study indicates that lutein enhances bone mass in growing mice by suppressing bone resorption and stimulating bone formation. Lutein may be a natural agent that promotes bone turnover and may be beneficial for bone health in humans.

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  • Hiroyuki Yoshida, Hiroko Shibata, Ken-ichi Izutsu, Yukihiro Goda
    2017 Volume 40 Issue 5 Pages 722-725
    Published: May 01, 2017
    Released: May 01, 2017
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    The current Japanese Ministry of Health Labour and Welfare (MHLW)’s Guideline for Bioequivalence Studies of Generic Products uses averaged dissolution rates for the assessment of dissolution similarity between test and reference formulations. This study clarifies how the application of model-independent multivariate confidence region procedure (Method B), described in the European Medical Agency and U.S. Food and Drug Administration guidelines, affects similarity outcomes obtained empirically from dissolution profiles with large variations in individual dissolution rates. Sixty-one datasets of dissolution profiles for immediate release, oral generic, and corresponding innovator products that showed large variation in individual dissolution rates in generic products were assessed on their similarity by using the f2 statistics defined in the MHLW guidelines (MHLW f2 method) and two different Method B procedures, including a bootstrap method applied with f2 statistics (BS method) and a multivariate analysis method using the Mahalanobis distance (MV method). The MHLW f2 and BS methods provided similar dissolution similarities between reference and generic products. Although a small difference in the similarity assessment may be due to the decrease in the lower confidence interval for expected f2 values derived from the large variation in individual dissolution rates, the MV method provided results different from those obtained through MHLW f2 and BS methods. Analysis of actual dissolution data for products with large individual variations would provide valuable information towards an enhanced understanding of these methods and their possible incorporation in the MHLW guidelines.

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  • Takashi Nagano, Kazuya Nagano, Hiromi Nabeshi, Tokuyuki Yoshida, Haruh ...
    2017 Volume 40 Issue 5 Pages 726-728
    Published: May 01, 2017
    Released: May 01, 2017
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    We previously reported that unmodified silica nanoparticles with diameters of 70 nm (nSP70) induced liver damage in mice, whereas nSP70 modified with carboxyl or amino groups did not. In addition, we have found that both unmodified and modified nSP70s localize in both Kupffer cells and parenchymal hepatocytes. We therefore evaluated the contributions of nSP70 uptake by these cell populations to liver damage. To this end, we pretreated mice with gadolinium (III) chloride hydrate (GdCl3) to prevent nSP70 uptake by Kupffer cells, subsequently injected the mice with either type of nSP70, and then assessed plasma levels of alanine aminotransferase (ALT). In mice given GdCl3, unmodified nSP70 increased ALT levels. From these data, we hypothesized that in GdCl3-treated mice, the unmodified nSP70 that was prevented from entering Kupffer cells was shunted to parenchymal hepatocytes, where it induced cytotoxicity and increased liver damage. In contrast, GdCl3 pretreatment had no effect on ALT levels in mice injected with surface-modified nSP70s, suggesting that modified nSP70s spared parenchymal hepatocytes and thus induced negligible liver damage. In cytotoxicity analyses, the viability of a parenchymal hepatocyte line was greater when exposed to surface-modified nSP70s than to unmodified nSP70s. These findings imply that the decreased liver damage associated with surface-modified compared with unmodified nSP70 is attributable to decreased cytotoxicity to parenchymal hepatocytes.

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  • Kento Tanaka, Tomomi Yoshitomi, Kazuki Hirahara
    2017 Volume 40 Issue 5 Pages 729-732
    Published: May 01, 2017
    Released: May 01, 2017
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    Chemokine receptors CXCR1 and CXCR2 are conserved between guinea pigs and humans, but the distinct role of each receptor in chemotactic responses of neutrophils against chemokine ligands has not been elucidated due in part to the lack of specific inhibitors against these receptors in guinea pigs. In this study, we investigated the roles of guinea pig CXCR1 and CXCR2 on neutrophils in chemotactic responses to guinea pig interleukin (IL)-8 and growth-regulated oncogene (GRO)α by using specific inhibitory antibodies against these receptors. Neutrophil migration induced by IL-8 was partially inhibited by either anti-CXCR1 antibody or anti-CXCR2 antibody. In addition, the migration was inhibited completely when both anti-CXCR1 and anti-CXCR2 antibodies were combined. On the other hand, neutrophil migration induced by GROα was not inhibited by anti-CXCR1 antibody while inhibited profoundly by anti-CXCR2 antibody. These results indicated that CXCR1 and CXCR2 mediated migration induced by the IL-8 synergistically and only CXCR2 mediated migration induced by GROα in guinea pig neutrophils. Our findings on ligand selectivity of CXCR1 and CXCR2 in guinea pigs are consistent with those in humans.

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  • Atena Sugiyama, Naomichi Fukushima, Takeshi Sato
    2017 Volume 40 Issue 5 Pages 733-737
    Published: May 01, 2017
    Released: May 01, 2017
    [Advance publication] Released: February 23, 2017
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    Increased expression of β4-galactosyltransferase (β4GalT) 4 has been shown to be associated with metastatic ability and poor prognosis of colon cancer cells. To solve the up-regulation of β4GalT4 in colon cancer cells at transcriptional level, we examined the transcriptional mechanism of the β4GalT4 gene in SW480 human colon cancer cell line. Luciferase assay using the deletion constructs revealed that the promoter activity of the β4GalT4 gene is associated with the region between nucleotides −122 and −55 relative to the transcriptional start site, which contained one Specificity protein 1 (Sp1)-binding site. The mutation into the Sp1-binding site resulted in dramatic decreased promoter activity. Meanwhile, ectopic Sp1 expression stimulated the promoter activity significantly. The present study suggests that the expression of the β4GalT4 gene is controlled by Sp1, and Sp1 plays a key role in the activation of the β4GalT4 gene in colon cancer cells.

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