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Volume 134, Issue 10
Displaying 1-12 of 12 articles from this issue
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Reviews
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Yukio Takano2014 Volume 134 Issue 10 Pages 997-1005
Published: October 01, 2014
Released on J-STAGE: October 01, 2014
JOURNAL FREE ACCESSPain control is very important since, even today, 20 million people suffer from neuropathic pain. Although many basic science and clinical researchers have made efforts to control pain, the mechanism of neuropathic pain is unfortunately still not fully understood. Morphine, a prototypical opioid, is a useful medicine to relieve severe pain. However, repeated or continuous use of morphine and other opioids are associated with a potential risk of analgesic tolerance, which requires an increase in dosage to maintain the same efficacy. In addition, morphine is not always effective in neuropathic pain. In this review we focus on: (1) the role of muscarinic receptors in the spinal cord and anterior cingulate cortex (ACC) in neuropathic pain, (2) how chemokine (C-C motif) ligand 1 (CCL-1) is involved in neuropathic pain, and (3) the novel mechanism of morphine tolerance. The findings in this study may cast new light on novel mechanism of neuropathic pain and development of novel clinical medicines in the future.
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Hisamitsu Hayashi2014 Volume 134 Issue 10 Pages 1007-1011
Published: October 01, 2014
Released on J-STAGE: October 01, 2014
JOURNAL FREE ACCESSSignificant technological advances in gene sequence analysis and construction of genetically-modified animals during the last two decades made it possible to reveal that many transporters are associated with diseases. The bile salt export pump (BSEP/ABCB11), a member of the family of ATP-binding cassette transporters, is localized on the canalicular membrane of hepatocytes and predominantly mediates the biliary excretion of bile salts. A hereditary defect of BSEP results in severe cholestasis called progressive familial intrahepatic cholestasis type 2 (PFIC2). Without liver transplantation, this disease progresses to liver failure and death before adulthood; therefore the development of new, less invasive medical therapy for PFIC2 is of the highest priority. We have previously shown that in many cases of PFIC2 patients, the dysfunction of BSEP is attributable to decreased BSEP expression on the hepatocanalicular membrane and that 4-phenylbutyrate (4PB), an approved drug for urea cycle disorder, may be a compound with potential to restore BSEP expression. This drug inhibits ubiquitination of cell surface-resident BSEP and thereby its clathrin-mediated endocytosis through the AP2 adaptor complex, leading to increase in BSEP expression on the canalicular membrane. Clinical studies to investigate the efficacy of 4PB in the treatment of PFIC2 revealed that 4PB therapy biochemically and histologically improved liver function without any side effect. Therefore, 4PB therapy may become the preferred choice, instead of liver transplantation, for PFIC2 patients. The strategy employed and findings in this study would be valuable for the drug development of transporter-related disorders.
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Hirotsugu Hiramatsu2014 Volume 134 Issue 10 Pages 1013-1020
Published: October 01, 2014
Released on J-STAGE: October 01, 2014
JOURNAL FREE ACCESSAnalyses of the structure and properties of identified pathogenic proteins are important for elucidating the molecular basis of diseases and in drug discovery research. Vibrational spectroscopy has advantages over other techniques in terms of sensitivity of detection of structural changes. Spectral analysis, however, is complicated because the spectrum involves a substantial amount of information. This article includes examples of structural analysis of disease-related proteins using vibrational spectroscopy in combination with additional techniques that facilitate data acquisition and analysis. Residue-specific conformation analysis of an amyloid fibril was conducted using IR absorption spectroscopy in combination with 13C-isotope labeling, linear dichroism measurement, and analysis of amide I band features. We reveal a pH-dependent property of the interacting segment of an amyloidogenic protein, β2-microglobulin, which causes dialysis-related amyloidosis. We also reveal the molecular mechanisms underlying pH-dependent sugar-binding activity of human galectin-1, which is involved in cell adhesion, using spectroscopic techniques including UV resonance Raman spectroscopy. The decreased activity at acidic pH was attributed to a conformational change in the sugar-binding pocket caused by protonation of His52 (pKa 6.3) and the cation-π interaction between Trp68 and the protonated His44 (pKa 5.7). In addition, we show that the peak positions of the Raman bands of the C4=C5 stretching mode at approximately 1600 cm−1 and the Nπ-C2-Nτ bending mode at approximately 1405 cm−1 serve as markers of the His side-chain structure. The Raman signal was enhanced 12 fold using a vertical flow apparatus.
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Hiroki Tsukamoto2014 Volume 134 Issue 10 Pages 1021-1027
Published: October 01, 2014
Released on J-STAGE: October 01, 2014
JOURNAL FREE ACCESSAllogeneic hematopoietic stem cell transplantation is performed in patients with hematologic malignancies refractory to chemotherapy. However, its efficacy is often limited by the development of graft-versus-host disease (GVHD) secondary to the allogeneic interaction of donor T cells with host dendritic cells. On the other hand, the antihost cytotoxicity of donor T cells enhances the graft-versus-tumor (GVT) effect. Extracellular adenosine generated by CD73/ecto-5′-nucleotidase from ATP via AMP plays pleiotropic roles under physiological and pathological conditions by engaging four adenosine receptors. One study recently demonstrated that ATP released from damaged cells exacerbates GVHD by activating the P2X7 receptor on host dendritic cells. In this review, we summarize our recent findings on the immunosuppressive role of extracellular adenosine in GVHD and the GVT effect. We have shown that in MHC-mismatched bone marrow transplantation, CD73 deficiency, particularly in the recipient, enhanced GVHD severity because of excessive donor T-cell expansion. Severe GVHD was enhanced by repeated administration of a CD73 inhibitor or an adenosine receptor antagonist. A competitive engraftment assay identified endogenous A2AAR signaling in donor T cells as part of a regulatory mechanism by CD73-generated adenosine. Pharmacological inhibition of CD73 enhanced the GVT effect against B-cell lymphoma and improved survival in tumor-relapsing mice after transplantation. Along with our findings, we herein introduce a novel concept that CD73-generated adenosine counteracts the ATP-evoked allogeneic immune reaction as a negative regulatory mechanism in GVHD. Pharmacological manipulation of CD73 activity could be a therapeutic strategy to limit GVHD and to preserve the GVT effect against hematopoietic malignancy.
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Taku Nagai2014 Volume 134 Issue 10 Pages 1029-1035
Published: October 01, 2014
Released on J-STAGE: October 01, 2014
JOURNAL FREE ACCESSAbnormalities in early brain development contribute to the etiology of many neurological disorders in later life. Recent advances in genome analysis indicate that large numbers of common gene variants shape any individual's disease risk, including that for major mental illnesses. Polyriboinosinic-polyribocytidilic acid (polyI:C) is known to induce strong innate immune responses that mimic immune activation by viral infections. Our previous findings suggest that activation of the innate immune system in astrocytes results in impairments of neurite outgrowth and spine formation, which lead to behavioral abnormalities in adulthood. Although glial cells are classically thought to provide structural and metabolic support to neurons, they are now widely recognized as essential regulators of neuronal development including neuronal migration, axon and dendrite growth, formation of synapses, and synaptic plasticity. Astrocytes also play critical roles in regulating CNS immune function by responding to inflammatory mediators and producing additional cytokines and chemokines. Most of the functions of astrocytes are mediated by the release of humoral factors through a close interaction with neurons. However, the mechanism by which innate immune activation of astrocytes affects neuronal development remains to be determined. To explore the alteration in proteins secreted from murine astrocytes after polyI:C stimulation, astrocyte-conditioned medium (ACM) was analyzed by 2-dimensional fluorescence difference gel electrophoresis (2D-DIGE). We identified matrix metalloproteinase-3 (Mmp3) as a potential mediator of polyI:C/ACM-induced neurodevelopmental impairment. Here, we provide an overview of the mechanism of neurodevelopmental impairment following polyI:C-induced innate immune activation of astrocytes.
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Ikuo Kimura2014 Volume 134 Issue 10 Pages 1037-1042
Published: October 01, 2014
Released on J-STAGE: October 01, 2014
JOURNAL FREE ACCESSFood intake regulates energy balance, and its dysregulation leads to metabolic disorders such as obesity and diabetes. Free fatty acids are not only essential nutrients but also act as signaling molecules in various cellular processes. Recent studies have shown that the receptors GPR40, GPR41, GPR43, and GPR120 are new drug targets for treating metabolic disorders because they are activated by free fatty acids. Two of these receptors, GPR41 and GPR43, are activated by short-chain fatty acids (SCFAs: acetate, propionate, and butyrate), which are important energy sources for the host. During feeding, SCFAs are produced by the microbial fermentation of dietary fiber in the gut. The gut microbiota affect nutrient acquisition and energy regulation of the host, and can influence the development of obesity, insulin resistance, and diabetes. Hence, GPR41 and GPR43 are also a focus of research into energy regulation via SCFAs. We report that these SCFA receptors are involved in energy homeostasis: GPR41 regulates sympathetic activity, and GPR43 regulates adipose-insulin signaling by sensing SCFAs produced by gut microbiota. We believe that these results will provide valuable insight into therapeutic targets for treating metabolic disorders and diabetes, as well as in the use of probiotics to control gut microbiota.
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Kazuma Higashisaka2014 Volume 134 Issue 10 Pages 1043-1048
Published: October 01, 2014
Released on J-STAGE: October 01, 2014
JOURNAL FREE ACCESSNanomaterials are defined as substances that have at least one dimension <100 nm. They have unique physicochemical properties and innovative functions compared with conventional materials of submicron size. As such, they have many applications in nanomedicine, such as in drug delivery or diagnostic and imaging systems. However, there are a number of safety concerns regarding the use of nanomaterials. Therefore it is essential not only to obtain more information about nanomaterials to ensure their safety, but also to identify novel biomarkers that may predict adverse biological effects induced by nanomaterials. In this regard, neutrophil activation is thought to be involved in some biological responses that are induced after exposure to nanomaterials. However, the detailed mechanisms involved in these events are poorly understood. Here, we examine neutrophil activation induced by nanomaterials. In addition, to develop a safe and effective form of a nanomaterial, we attempted to develop potential biomarkers of silica nanoparticles by proteomics analysis. We believe that our data could provide information of value in nanomaterial risk management and in the establishment of guidelines for assessment of their use.
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Susumu Hama2014 Volume 134 Issue 10 Pages 1049-1054
Published: 2014
Released on J-STAGE: October 01, 2014
JOURNAL FREE ACCESSSuccessful cancer gene therapy is dependent upon the development of nanocarriers that exhibit anti-cancer effects via delivery of nucleic acids to the target site in tumor tissue. The effectiveness of such systems has typically relied on the potency of the anti-cancer nucleic acids, as conventional carriers do not exhibit inherent anti-cancer activity, serving only as vehicles for delivery. Ideal nanocarriers for effective cancer gene therapy should not only serve as delivery systems for transporting anti-cancer nucleic acids to the target tumor tissue, but should also exhibit their own inherent anti-cancer activity. α-tocopheryl succinate (TS) has attracted attention as a unique anti-cancer agent for its ability to induce apoptosis in various cancer cells; moreover, TS readily forms nanovesicles (TS-NVs). Thus, vesicles comprised of TS represent prospective tools for use as drug delivery systems (DDS) for cancer therapy. Owing to the low vesicle stability in the presence of divalent cations or serum, however, TS-NVs are not suitable for encapsulating nucleic acids, and require passive targeting delivery to tumor tissue via an enhanced permeability and retention effect. To improve the stability of TS-NVs, we developed novel nanovesicles comprised of TS and egg phosphatidylcholine (EPC), which can form a stable lamellar structure (TS-EPC-NVs). In this review, we introduce the development of nanovesicles comprised of TS as a novel DDS carrier and demonstrate the anti-cancer activity of both the encapsulated nucleic acids and the carrier itself.
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Shinichi Harada2014 Volume 134 Issue 10 Pages 1055-1060
Published: October 01, 2014
Released on J-STAGE: October 01, 2014
JOURNAL FREE ACCESSI recently found that cerebral ischemic stress per se causes hyperglycemia (i.e., post-ischemic glucose intolerance) and suppression of post-ischemic glucose intolerance might be important to improve prognosis. Here, I analyzed the efficacy of suppression of post-ischemic glucose intolerance using orexin-A (OXA) endogenous neuropeptide as a novel therapeutic strategy against cerebral ischemic neuronal damage. OXA in hypothalamus plays a role in many physiological functions including regulation of glucose metabolism. I previously found that the development of post-ischemic glucose intolerance is suppressed by OXA. Other reports have shown that the communication system between brain and peripheral tissues through the autonomic nervous system is important for maintaining glucose and energy metabolism. The aim of this study was to determine the involvement of the hepatic vagus nerve on hypothalamic OXA-mediated suppression of post-ischemic glucose intolerance and neuronal damage. Intrahypothalamic administration of OXA significantly suppressed the development of post-ischemic glucose intolerance on day 1 and of neuronal damage on day 3 after middle cerebral artery occlusion (MCAO). In the liver, MCAO-induced decrease in insulin receptors and increase in gluconeogenic enzymes on day 1 was recovered to control levels by OXA; these effects were reversed by hepatic vagotomy. In the medulla oblongata, OXA induced co-localization of the cholinergic neuronal marker choline acetyltransferase with orexin-1 receptor and c-Fos. These results suggest that the vagus nerve projecting from the medulla oblongata plays an important role in the recovery of post-ischemic glucose intolerance and mediates neuroprotection by hypothalamic OXA.
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Takuhiro Uto2014 Volume 134 Issue 10 Pages 1061-1067
Published: October 01, 2014
Released on J-STAGE: October 01, 2014
JOURNAL FREE ACCESSHerbal medicines have recently attracted much importance owing to the rising interest in their health benefits. Hence, further elucidation of the functions and mechanisms of these natural compounds is necessary. Our laboratory has established more than 30 kinds of monoclonal antibodies (MAbs) against bioactive natural compounds. Moreover, we have developed highly sensitive measurement systems for natural compounds, such as enzyme-linked immunosorbent assay (ELISA) and eastern blotting using MAbs. To expand the application of these MAbs to the functional analysis of natural compounds, we established a new approach for the isolation of the target compound from plant extracts using an immunoaffinity column conjugated with an anti-natural compound MAb. Through one-step purification using a MAb-conjugated immunoaffinity column, we have succeeded in preparing a knockout (KO) extract containing all components except the target compound, used as a hapten. Furthermore, we examined the pharmacological effects of the KO extract to identify the precise roles of the bioactive compound in the plant extract. To confirm another beneficial use of MAbs, we investigated the cellular localization and target molecules of natural compounds by immunocytochemistry (ICC) and Western blotting using MAbs. Our results demonstrated that MAbs clearly determined the cellular localization and target molecules of the natural compounds. These approaches may make it possible to determine the potential functions and target molecules of bioactive natural compounds in herbal medicines.
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Regular Articles
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Tomoyuki Hamamoto, Ayaka Serizawa, Kaori Ohtsuki, Junko Kawakami, Keni ...2014 Volume 134 Issue 10 Pages 1069-1080
Published: October 01, 2014
Released on J-STAGE: October 01, 2014
JOURNAL FREE ACCESSMolecularly targeted anticancer agents cause a variety of adverse reactions compared with conventional anticancer agents because of their unique mechanisms of action. Sources of drug information such as package inserts (PIs) provide primarily document-based and numerical information. Therefore it is not easy to obtain a complete picture of drugs with similar effects, or to understand differences among drugs. In this study we used the self-organizing map (SOM) technique to visualize the adverse reactions indicated on PIs of 23 molecularly targeted anticancer agents as of March 2013. In both the presence/absence version and the frequency version, SOM was divided into domains according to mechanism of action, antibody drug or low-molecular weight drug, and molecular target. The component planes of the 753 adverse reaction items in the frequency version enabled us to grasp all available information and differences among the drugs. In some component planes in the presence/absence version, an adverse reaction that had not been reported for a drug but had already been reported for its proximally positioned drug(s) as of March 2013, was found to be reported thereafter by the Drug Safety Update (DSU) or the Adverse Event Report Search System “CzeekV,” which is based on FDA Adverse Event Reporting System (FAERS). Our results suggest that visualization of the adverse reactions of molecularly targeted anticancer agents by the SOM technique is useful not only to acquire all available information and differences among drugs, but also to predict the appearance of adverse reactions.
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Makiko Ishizaki, Hatsuo Maeda, Ikuko Okamoto2014 Volume 134 Issue 10 Pages 1081-1092
Published: October 01, 2014
Released on J-STAGE: October 01, 2014
JOURNAL FREE ACCESSColor-weak persons, who in Japan represent approximately 5% of male and 0.2% of female population, may not be able to discriminate among colors of tablets. Thus using color-weak simulation by VariantorTM we evaluated the effects of background colors (light, medium, and dark gray, purple, blue, and blue green) on discrimination among yellow, yellow red, red, and mixed group tablets by our established method. In addition, the influence of white 10-mm ruled squares on background sheets was examined, and the change in color of the tablets and background sheets through the simulation measured. Variance analysis of the data obtained from 42 volunteers demonstrated that with color-weak vision, the best discrimination among yellow, yellow red, or mixed group tablets was achieved on a dark gray background sheet, and a blue background sheet was useful to discriminate among each tablet group in all colors including red. These results were compared with those previously obtained with healthy and cataractous vision, suggesting that gap in color hue and chroma as well as value between background sheets and tablets affects discrimination with color-weak vision. The observed positive effects of white ruled squares, in contrast to those observed on healthy and cataractous vision, demonstrate that a background sheet arranged by two colors allows color-weak persons to discriminate among all sets of tablets in a sharp and feasible manner.
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