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Sorensen K.K.,University of Tromsø | McCourt P.,University of Tromsø | Berg T.,University of Oslo | Crossley C.,University of Tasmania | And 4 more authors.
American Journal of Physiology - Regulatory Integrative and Comparative Physiology | Year: 2012

To maintain homeostasis, the animal body is equipped with a powerful system to remove circulating waste. This review presents evidence that the scavenger endothelial cell (SEC) is responsible for the clearance of blood-borne waste macromolecules in vertebrates. SECs express pattern-recognition endocytosis receptors (mannose and scavenger receptors), and in mammals, the endocytic Fc gamma-receptor IIb2. This cell type has an endocytic machinery capable of super-efficient uptake and degradation of physiological and foreign waste material, including all major classes of biological macromolecules. In terrestrial vertebrates, most SECs line the wall of the liver sinusoid. In phylogenetically older vertebrates, SECs reside instead in heart, kidney, or gills. SECs, thus, by virtue of their efficient nonphagocytic elimination of physiological and microbial substances, play a critical role in the innate immunity of vertebrates. In major invertebrate phyla, including insects, the same function is carried out by nephrocytes. The concept of a dual-cell principle of waste clearance is introduced to emphasize that professional phagocytes (macrophages in vertebrates; hemocytes in invertebrates) eliminate larger particles (>0.5 μm) by phagocytosis, whereas soluble macromolecules and smaller particles are eliminated efficiently and preferentially by clathrin-mediated endocytosis in nonphagocytic SECs in vertebrates or nephrocytes in invertebrates. Including these cells as important players in immunology and physiology provides an additional basis for understanding host defense and tissue homeostasis. © 2012 the American Physiological Society.


Kuroda N.,Tsurumi University | Inoue K.,Tsurumi University | Ikeda T.,Tsurumi University | Hara Y.,Tsurumi University | And 3 more authors.
PLoS ONE | Year: 2014

HMGB1 is a nuclear component involved in nucleosome stabilization and transcription regulation, but extracellularly it is able to serve as a potential late mediator of lethality. In the present study, we explored inflammation-promoting activity of HMGB1 and blockade of extracellular release of HMGB1 by glycyrrhizin (GL) in LPS/GalN-triggered mouse liver injury. At 1 to 10 h after LPS/GalN-treatment, mice were anesthetized to collect blood from heart puncture, and serum transaminase and HMGB1 were evaluated. Administration of LPS/GalN precipitated tissue injury associated with time-dependent alteration in HMGB1 serum levels. At 8 h nuclear immunoreactive products were remarkably reduced and extracellular HMGB1 expression was found exclusively in the pericentral foci. The treatment with GL significantly down-regulated the serum levels of ALT, AST, and HMGB1 in addition to the strong inhibition of tissue injury and extracellular immunoreactivity to HMGB1 and to acetylated-lysine. Furthermore, GL brought about a significant decrease in the number of apoptotic hepatocytes labeled with TUNEL-method. On the basis of these results, three apoptosis-associated genes were identified with microarray analysis and real-time PCR. The ChIP-assay revealed the binding of HMGB1 protein to Gsto1 promoter sequence in LPS/GalN-treated mice and the remarkable decrease in combined HMGB1 protein by GL. The current findings claim that a single injection of LPS/GalN might stimulate apoptosis of hepatocytes through the binding of HMGB1 protein to Gsto1 promoter region and that GL-treatment might prevent the apoptosis and inflammatory infiltrates caused with LPS/GalN-injection by disturbing the binding of HMGB1 protein to Gsto1 promoter sequence. © 2014 Kuroda et al.


Wake K.,Tsurumi University | Wake K.,Minophagen Pharmaceutical Co. | Sato T.,Tsurumi University
Anatomical Record | Year: 2015

The hepatic sinusoid with its associated sinusoidal cells is a multifunctional cell-complex in the liver. Despite recent advances in research on the hepatic sinusoid, no investigator has played a more basic role in its characterization than Charles Sedgwick Minot (1852-1914), a pioneer who distinguished the sinusoid from the blood-capillary as early as 1900. According to Minot, sinusoids are typically larger in diameter than capillaries, particularly at the early embryonic stage. They closely approach the parenchymal tissue, are formed passively by the adjacent parenchymal tissue, and are on rare occasion surrounded with connective tissue. Sinusoids (sinus-like) are small blood-channels formed by subdivision of the lumen of large blood vessels (sinuses) by the invasion of developing parenchymal cell-cords. Although some of Minot's definitions may no longer be accepted, he described some fundamental and interesting characteristics of sinusoids, to which we have not paid much attention. Here, we have attempted to illustrate lessons we have learned from Minot's view point of sinusoids at this occasion of centenary of his death. © 2015 Wiley Periodicals, Inc.


Manns M.P.,Hannover Medical School | Wedemeyer H.,Hannover Medical School | Singer A.,PharmaPart GmbH | Khomutjanskaja N.,Lugansk State Medical University | And 5 more authors.
Journal of Viral Hepatitis | Year: 2012

Chronic hepatitis C patients often fail to respond to interferon-based therapies. This phase III study aimed at confirming the efficacy and safety of glycyrrhizin in interferon + ribavirin-based therapy non-responders. A randomised, double-blind, placebo-controlled, comparison of glycyrrhizin, administered intravenously 5×/or 3×/week, and 5×/week placebo for 12 weeks to 379 patients, was followed by a randomised, open comparison of glycyrrhizin i.v. 5×/versus 3×/week for 40 weeks. Primary endpoints were: (1) the proportion of patients with â¥50% ALT (alanine aminotransferase) reduction after 12 weeks double-blind phase, and (2) the proportion of patients with improvement of necro-inflammation after 52 weeks as compared with baseline. The proportion of patients with ALT reduction â¥50% after 12 weeks was significantly higher with 5×/week glycyrrhizin (28.7%, P < 0.0001) and 3×/week glycyrrhizin (29.0%, P < 0.0001) compared with placebo (7.0%). The proportion of patients with improvement in necro-inflammation after 52 weeks was 44.9% with 5×/week and 46.0% with 3×/week, respectively. Glycyrrhizin exhibited a significantly higher ALT reduction compared to placebo after 12 weeks of therapy and an improvement of necro-inflammation and fibrosis after 52-weeks treatment. Generally, glycyrrhizin treatment was well tolerated. © 2012 Blackwell Publishing Ltd.


Akasaka Y.,Minophagen Pharmaceutical Co. | Sakai A.,Nippon Medical School | Takasu K.,Nippon Medical School | Tsukahara M.,Minophagen Pharmaceutical Co. | And 3 more authors.
Journal of Pharmacological Sciences | Year: 2011

Glycyrrhetinic acid (GA), an aglycone of glycyrrhizin, isolated from the licorice root (Glycyrrhizia), and its semi-synthetic derivatives have a wide range of pharmacological effects. To investigate whether GA derivatives may be used as a new class of analgesics, we examined the effects of these compounds on human tachykinin receptors expressed in CHO-K1 cells. Among the GA derivatives examined, the disodium salt of olean-11,13(18)-dien-3β,30-O-dihemiphthalate inhibited the mobilization of [Ca 2+] i induced by substance P, neurokinin A, and neurokinin B in CHO-K1 cells expressing the human NK 1, NK 2, and NK 3 tachykinin receptors, respectively. In an inflammatory pain model, Compound 5 suppressed the capsaicin-induced flinching behavior in a dose-dependent manner. Compound 5 was also effective in suppressing pain-related behaviors in the late phase of the formalin test and reducing thermal hyperalgesia in the neuropathic pain state caused by sciatic nerve injury. Collectively, Compound 5 may be an analgesic candidate via tachykinin receptor antagonism. © The Japanese Pharmacological Society.


Sekihata K.,Minophagen Pharmaceutical Co. | Akasaka Y.,Minophagen Pharmaceutical Co. | Hatta A.,Minophagen Pharmaceutical Co. | Inoue H.,Minophagen Pharmaceutical Co.
Japanese Pharmacology and Therapeutics | Year: 2015

Objective The intravenous preparation of glycyrrhizin (GL) has been used for chronic and antihistamine-resistant pruritus, for example, in hemodialysis (HD) patients. To understand how GL shows anti-pruritic effects, we examined the effects of GL on scratching behavior elicited by histamine, substance P (SP), protease-activated receptor-2 (PAR-2) agonistic peptide, or leukotriene B4 (LTB4) in mice. Methods Thirty minutes after intravenous administration of GL, each pruritogen; histamine (100 nmol/site), SP (100 nmol/site), PAR-2 agonistic peptide (50 nmol/site), or LTB4 (0.03 nmol/site), was intradermally injected into the back of ICR mice, and the number of scratching was counted. Further, using MiaPaca-2 human pancreatic cancer cells, the effect of GL on LTB4-induced extracellular signal regulated kinase (ERK) 1/2 phosphorylation via BLT1 was also investigated by western blot analysis. Results Intravenously injected GL significantly and dose-dependently reduced scratching induced by SP, PAR-2 agonistic peptide, or LTB4, though GL did not significantly inhibit histamine-induced scratching. Furthermore, GL reduced LTB4-induced ERK 1/2 phosphorylation in MiaPaca-2 cells. Conclusions We demonstrate for the first time that GL has anti-pruritic effects in animal studies as reported in the clinic. Our data suggest that GL exhibits anti-pruritic effects through a different pathway than existing drugs, such as antihistamines.


Tanifuji S.,Keio University | Aizu-Yokota E.,Keio University | Funakoshi-Tago M.,Keio University | Sonoda Y.,Keio University | And 2 more authors.
International Immunopharmacology | Year: 2010

Mast cells play a key role in allergic inflammation by releasing various mediators, such as histamine, serotonin, leukotrienes and cytokines. A signaling cascade of events activated by stimulation with antigens contributes to the regulation of mast cell degranulation. While various anti-inflammatory and anti-allergic drugs have been developed that inhibit degranulation of mast cells, the inhibitory mechanism has been poorly understood. Licochalcone A (Lico A) is a retrochalcone isolated from the root of Xinjiang liquorice and has been reported to exhibit various biological activities such as anti-inflammatory activity. We examined the effects of Lico A and related chalcones on degranulation in a rat basophilic leukemia cell line, RBL-2H3. Whereas Lico A and licochalcone C (Lico C) exhibited inhibitory activity with cytotoxicity, licochalcone D (Lico D) significantly inhibited the degranulation in RBL-2H3 cells with low cytotoxicity. Moreover, Lico D significantly inhibited the Ca2+ influx and phosphorylation of extracellular signal regulated kinase (ERK) and MEK. These results suggest that Lico D inhibits mast cell degranulation via the inhibition of both extracellular Ca2+ influx and activation of the MEK-ERK pathway. © 2010 Elsevier B.V. All rights reserved.


Higashi K.,Sumitomo Chemical | Tomigahara Y.,Sumitomo Chemical | Shiraki H.,Sumitomo Chemical | Miyata K.,Sumitomo Chemical | And 6 more authors.
Journal of Biological Chemistry | Year: 2011

Transforming growth factor-β (TGF-β) is considered to be a major factor contributing to liver fibrosis. We have previously shown that nuclear translocation of YB-1 antagonizes the TGF-β/Smad3 signaling in regulating collagen gene expression. More recently, we have demonstrated that the novel small compound HSc025 promotes nuclear translocation of YB-1, resulting in the improvement of skin and pulmonary fibrosis. Here, we presented evidence as to the mechanism by which HSc025 stimulates nuclear translocation of YB-1 and the pharmacological effects of HSc025 on a murine model of hepatic fibrosis. A proteomics approach and binding assays using HSc025-immobilized resin showed that HSc025 binds to the amino acid sequence within the C-tail region of YB-1. In addition, immunoprecipitation experiments and glutathione S-transferase pulldown assays identified poly(A)-binding protein (PABP) as one of the cytoplasmic anchor proteins of YB-1. HSc025 directly binds to YB-1 and interrupts its interaction with PABP, resulting in accelerated nuclear translocation of YB-1. Transfection of cells with PABP siRNA promoted nuclear translocation of YB-1 and subsequently inhibited basal and TGF-β-stimulated collagen gene expression. Moreover, HSc025 significantly suppressed collagen gene expression in cultured activated hepatic stellate cells. Oral administration of HSc025 to mice with carbon tetrachloride-induced hepatic fibrosis improved liver injury as well as the degree of hepatic fibrosis. Altogether, the results provide a novel insight into therapy for organ fibrosis using YB-1 modulators. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.


Matsumoto Y.,Japan National Institute of Infectious Diseases | Matsumoto Y.,Jikei University School of Medicine | Matsuura T.,Jikei University School of Medicine | Aoyagi H.,Japan National Institute of Infectious Diseases | And 13 more authors.
PLoS ONE | Year: 2013

Glycyrrhizin (GL) has been used in Japan to treat patients with chronic viral hepatitis, as an anti-inflammatory drug to reduce serum alanine aminotransferase levels. GL is also known to exhibit various biological activities, including anti-viral effects, but the anti-hepatitis C virus (HCV) effect of GL remains to be clarified. In this study, we demonstrated that GL treatment of HCV-infected Huh7 cells caused a reduction of infectious HCV production using cell culture-produced HCV (HCVcc). To determine the target step in the HCV lifecycle of GL, we used HCV pseudoparticles (HCVpp), replicon, and HCVcc systems. Significant suppressions of viral entry and replication steps were not observed. Interestingly, extracellular infectivity was decreased, and intracellular infectivity was increased. By immunofluorescence and electron microscopic analysis of GL treated cells, HCV core antigens and electron-dense particles had accumulated on endoplasmic reticulum attached to lipid droplet (LD), respectively, which is thought to act as platforms for HCV assembly. Furthermore, the amount of HCV core antigen in LD fraction increased. Taken together, these results suggest that GL inhibits release of infectious HCV particles. GL is known to have an inhibitory effect on phospholipase A2 (PLA2). We found that group 1B PLA2 (PLA2G1B) inhibitor also decreased HCV release, suggesting that suppression of virus release by GL treatment may be due to its inhibitory effect on PLA2G1B. Finally, we demonstrated that combination treatment with GL augmented IFN-induced reduction of virus in the HCVcc system. GL is identified as a novel anti-HCV agent that targets infectious virus particle release. © 2013 Matsumoto et al.


Patent
Minophagen Pharmaceutical Co. | Date: 2010-07-07

There is provided a medicament capable of enhancing the antimicrobial peptide production ability. The medicament contains, as an active ingredient, a compound which is glycyrrhizin or a pharmaceutically acceptable salt thereof and capable of inhibiting the production of at least one of interleukin-10 (IL-10) and chemokine CCL2. The antimicrobial peptide is preferably defensin or cathelicidin.

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