Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
Volume 36 , Issue 8
Showing 1-24 articles out of 24 articles from the selected issue
Current Topics
  • Naoki Inagaki
    2013 Volume 36 Issue 8 Pages 1227
    Published: August 01, 2013
    Released: August 01, 2013
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  • Yasushi Kuraishi
    2013 Volume 36 Issue 8 Pages 1228-1234
    Published: August 01, 2013
    Released: August 01, 2013
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    Very few approved medications are indicated for the treatment of pruritus, and drug development for pruritic diseases is awaited. During the past two decades, progress has been made in understanding the molecular basis of the physiology and pathophysiology of pruritus. Newly identified potential targets for pathological pruritus include receptors (histamine H4 receptor, leukotriene B4 receptors, interleukin-31 receptor A, bombesin BB2 receptor, toll-like receptor 3, α-adrenoceptor, and opioid μ- and κ-receptors), channels (transient receptor potential (TRP) V3 and TRPA1 channels), and enzymes (histidine decarboxylase, sphingomyelin glucosylceramide deacylase, 5-lipoxygenase, leukotriene A4 hydrolase, and autotaxin). The development of specific, effective blockers and agonists/antagonists of these targets is awaited.
  • Akihiko Ikoma
    2013 Volume 36 Issue 8 Pages 1235-1240
    Published: August 01, 2013
    Released: August 01, 2013
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    The unique physiological features of histamine-sensitive C-fibers and spinothalamic tract neurons support the hypothesis of itch specific pathway, whereas subsequent studies on cowhage-induced itch have provided evidence against it, suggesting the presence of multiple neural pathways for itch. Not only peripheral pruritogens but also spinal neural receptors are involved in the control of itch, and will be the target of treatment. Itch sensitization in chronic pruritus is another crucial factor that needs to be considered in the treatment. Neuropathic itch is the type of itch that occurs when nerve fibers are damaged or injured and spontaneous firing of nerves takes place, and plays a major role in itch accompanying some pathological conditions such as herpes zoster. The complexity of itch is due to the broad range of mediators involved and the large variety of neural mechanisms behind.
  • Mitsutoshi Tominaga, Kenji Takamori
    2013 Volume 36 Issue 8 Pages 1241-1247
    Published: August 01, 2013
    Released: August 01, 2013
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    Histamine H1-receptor blockers are used to treat all types of itch resulting from serious skin diseases such as atopic dermatitis, as well as from renal and liver diseases. However, they often lack efficacy in chronic itch, a profound clinical problem that decreases quality of life. The development of effective treatments requires a full understanding of the fundamental mechanisms of itch. Recent studies have indicated that the pathogenic mechanisms of itch also involve agonists other than histamine, including proteases, neuropeptides, cytokines, and opioids, as well as their cognate receptors. Release of these pruritogenic mediators and modulators into the periphery may directly activate itch-mediating C-fibers via specific receptors on the nerve terminals. Histological observations have shown increased epidermal nerve densities in patients with atopic dermatitis, suggesting that the higher density is at least partly responsible for itch sensitization. This hyperinnervation is likely induced by an imbalance between nerve elongation and repulsion factors produced by keratinocytes. Neuronal matrix metalloproteinases are also involved in the penetration of nerve fibers into the extracellular matrix. Moreover, itch-mediating fibers such as gastrin-releasing peptide+ (GRP+) and Mas-related G-protein coupled receptor A3+ (MrgprA3+) fibers are present in the skin. Clinically, emollients or UV-based therapies can partly control epidermal nerve density, but new substances and classes of antipruritic drugs are needed. This review highlights recent knowledge regarding epidermal nerve fibers that are partly involved in itch sensitization, and discuss peripheral mechanisms and treatments of itch, especially in atopic dermatitis.
  • Yosuke Amagai, Hiroshi Matsuda, Akane Tanaka
    2013 Volume 36 Issue 8 Pages 1248-1252
    Published: August 01, 2013
    Released: August 01, 2013
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    Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by dryness and itchy skin. Genetic factors as well as other factors, including abnormality in skin barrier function, hypersensitivity of itch sensory nerves, and dysfunction of the immune system, strongly affect the onset and exacerbation of AD. Recently, it has become clear that itch sensation is closely related to pain sensation. By using NC/Tnd mice, a unique spontaneous animal model for human AD, we found abnormalities in sensitivity against external stimuli as compared to two standard strains, BALB/c and B6 mice. Particularly, in conventional NC/Tnd mice with AD, stimulation against transient receptor potential (TRP) V1 reduced the scratching behavior, suggesting the possibility of a TRPV1 modulator in the treatment of atopic itch. The review outlines observations regarding itch sensation and skin barrier function in NC/Tnd mice by using a novel itch quantification system for the laboratory animals, which may bring great progress in the future study of itch.
  • Hirotaka Yamashita, Hiroyuki Tanaka, Naoki Inagaki
    2013 Volume 36 Issue 8 Pages 1253-1257
    Published: August 01, 2013
    Released: August 01, 2013
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    Atopic dermatitis is a common skin disease accompanied by intense itching. Relapsing eczema is caused by immune imbalances and skin-barrier disruption. The immunopathy and barrier dysfunction are closely related to the onset of itching and subsequent scratching, and intractable dermatitis is amplified by the itch-scratch cycle. The standard therapy for atopic dermatitis is topical corticosteroids and immunosuppressants to lessen the inflammation, along with moisturizing agents to improve the physiologic skin dysfunction. Corticosteroids are the primary treatment for the inflammation in atopic dermatitis. Some clinical trials demonstrated a tendency for the alleviation of pruritus with long-term treatment. Tacrolimus results in instant burning and itching in the short term, but they resolve a few days after the beginning of use and then are relieved. Substance P is a neuropeptide released from sensory nerve fibers and a neurotransmitter of pain and itching. Basic experimental reports indicated that the antipruritic effect of tacrolimus is probably dependent on depleting substance P, followed by transient induction. Oral administration of antihistamines and antiallergics is used as adjunctive pharmacotherapy for pruritus. It is known that second-generation antihistamines are less sedative or nonsedative drugs compared with the first generation, and the drugs have additional efficacy in blocking some chemical mediators. Japanese traditional Kampo medicines are also used for the treatment of atopic dermatitis. This paper discusses the efficacy of representative Kampo medicines in the treatment of inflammation and itching based on murine atopic dermatitis models. Information on the mechanism of action of Kampo medicines will result in more choice of pharmacotherapeutic agents for complex diseases such as atopic dermatitis.
Communication to the Editor
  • Yoko Matsumoto, E Cao, Ryuichi Ueoka
    2013 Volume 36 Issue 8 Pages 1258-1262
    Published: August 01, 2013
    Released: August 01, 2013
    [Advance publication] Released: May 21, 2013
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    Novel liposomes composed of L-α-dimyristoylphosphatidylcholine (DMPC) and trehalose surfactant (DMTre) were produced and inhibitory effects of DMTre on the growth of human colon carcinoma (HCT116) and gastric carcinoma (MKN45) in vitro were examined. The remarkably high inhibitory effects of DMTre on the growth of HCT116 and MKN45 cells were obtained without affecting the growth of normal cells. The thickness of fixed aqueous layer of DMTre was larger than that of DMPC liposomes and increased in a dose-dependent manner. The induction of apoptosis by DMTre was revealed on the basis of flow cytometric analysis. DMTre induced apoptosis through the activation of caspases and mitochondria via Bax. It is noteworthy that remarkable inhibitory effects of DMTre on the growth of human colon and gastric carcinoma cells leading to apoptosis were obtained for the first time.
Regular Articles
  • Li-xia Zhao, An-chang Liu, Shu-wen Yu, Zeng-xin Wang, Xiao-qian Lin, G ...
    2013 Volume 36 Issue 8 Pages 1263-1270
    Published: August 01, 2013
    Released: August 01, 2013
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    Puerarin (PUE) is a good candidate for treating stroke, but its low concentration in brain after administration limits its curative efficacy. The aim of the present work was to design and characterize PUE loaded poly(butylcyanoacrylate) nanoparticles (PBCN) coated with polysorbate 80 (Ps 80), and to evaluate the effect of PBCN on the permeability of PUE across the blood–brain barrier (BBB) and the effect of PUE loaded PBCN on the cerebral ischemia/reperfusion injury. PUE loaded PBCN were successfully prepared by anionic polymerization method with the mean particle size of 201.2 nm and the zeta potential of −7.72 mV. The in vitro release behavior of PUE from the nanoparticles showed a biphasic profile manner with an initial burst release followed by a sustained release. The results of pharmacokinetic and biodistribution to brain performed in mice after intravenous administration showed that the drug concentrations in blood and brain for PUE loaded PBCN were both greater than these for the free drug. Moreover, compared with free drug, the vein injection of PUE loaded PBCN exerted the better neuroprotective effect in rats with focal cerebral ischemic injury via significantly decreasing neurological deficit scores, increasing body weight, lowing brain water content, and reducing the infarct volume. The results indicated that this preparation may reduce the total dose required for the stroke therapy with concurrent reduction in dose related toxicity. All these findings suggest that PBCN could enhance the transport of PUE to brain and have a potential as a neuroprotective agent in the focal cerebral ischemic injury.
  • Tadashi Uramatsu, Tomoya Nishino, Yoko Obata, Yohei Sato, Akira Furusu ...
    2013 Volume 36 Issue 8 Pages 1271-1277
    Published: August 01, 2013
    Released: August 01, 2013
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    Stroke-prone spontaneously hypertensive (SHRsp) rats develop severe hypertension resulting in renal injury. We investigated apoptosis inhibitor of macrophages (AIM) expression in nephrosclerotic rats and the involvement of AIM in olmesartan (OLM)- and azelnidipine (AZN)-induced decreases in the number of macrophages infiltrating the kidney. We randomly assigned 20-week-old male SHRsp rats to receive one of the following substances every day for 12 weeks: water (vehicle), hydralazine (HYD), OLM, or AZN. Renal damage was assessed by Masson trichrome staining. Expressions of ED-1, AIM, and oxidized low-density lipoprotein (oxLDL) were immunohistochemically detected. Apoptosis was analyzed by terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) staining. All treatment groups showed significantly less renal interstitial fibrosis than the vehicle group. AZN and OLM groups had significantly fewer AIM-expressing cells than the HYD and vehicle groups. The ratios AIM-positive cells/ED-1-positive macrophages and TUNEL-positive cells/ED-1-positive macrophages in the AZN and OLM groups were lower and higher, respectively, than the the HYD and vehicle groups. oxLDL expression in the renal interstitium was significantly lower in treatment groups compared to vehicle group. OLM and AZN inhibited interstitial fibrosis progression in SHRsp rats by suppressing AIM expression in macrophages, followed by reducing the number of infiltrating macrophages.
  • Hiroyuki Nishikawa, Hitomi Hayashi, Satoko Kubo, Maho Tsubota-Matsunam ...
    2013 Volume 36 Issue 8 Pages 1278-1282
    Published: August 01, 2013
    Released: August 01, 2013
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    Hydrogen sulfide (H2S), a gasotransmitter, plays a variety of roles in the mammalian body including the cardiovascular system. Given evidence that H2S donors including NaHS inhibit human platelet aggregation, we examined and characterized the effects of NaHS on rabbit platelet aggregation and cytosolic Ca2+ mobilization. Rabbit platelet aggregation was determined in platelet-rich plasma (PRP) and washed platelets. Intracellular Ca2+ levels were monitored in Fura2-loaded washed platelets. NaHS prevented rabbit platelet aggregation induced by collagen or ADP, and the effective concentration range of NaHS was 0.1–0.3 mM in PRP and 1–3 mM in washed platelets. In washed platelets, NaHS attenuated cytosolic Ca2+ mobilization induced by collagen or ADP and also reduced platelet aggregation induced by ionomycin, a Ca2+ ionophore. The anti-platelet effect of NaHS was blocked by an adenylyl cyclase inhibitor and enhanced by a phosphodiesterase inhibitor. H2S thus suppresses rabbit platelet aggregation by interfering with both upstream and downstream signals of cytosolic Ca2+ mobilization in a cAMP-dependent manner.
  • Dongfeng Yin, Wenqing Liang, Shuxing Xing, Zhixiang Gao, Wei Zhang, Zh ...
    2013 Volume 36 Issue 8 Pages 1283-1291
    Published: August 01, 2013
    Released: August 01, 2013
    [Advance publication] Released: May 15, 2013
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    Percutaneous immune method is becoming an attractive alternative for DNA vaccine as a lot of antigen presenting cells are existed in the viable epidermis. However, due to the barrier function of stratum corneum, it would be hard for DNA vaccine to reach the viable epidermis of the skin. In order to deliver the DNA vaccine successfully cross the stratum corneum, pentagram silicon microneedle array was prepared in this study, and fluorescently labeled nanoparticle was taken as the model to observe the situation inside the skin processed by microneedle. Via microneedle nanoparticles could enter the skin through the micro-channel (diameter about 20–30 µm) and its amount is greatly larger than that enter though the hair follicle of intact skin. A new type of gene vector Pluronic P123-modified polyethyleneimine (P123-PEI) was synthesized by high molecular weight polyethylenimine and Pluronic P123 with the molar ratio of 1 : 1 to take the advantage of P123-PEI as low cytotoxicity and high transfection efficiency. Mice were immunized percutaneously with Hepatitis B DNA vaccine/P123-PEI nano-complexes by microneedle. The humoral and cellular immunity generated in percutaneously immunized mice through microneedle array by Hepatitis B DNA vaccine/P123-PEI nano-complex was significantly higher than that of DNA vaccine intramuscular administration.
  • Yuriko Saito, Takako Furukawa, Takayuki Obata, Tsuneo Saga
    2013 Volume 36 Issue 8 Pages 1292-1298
    Published: August 01, 2013
    Released: August 01, 2013
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    Aquaglycero-aquaporins (agAQPs) are one of the water channel proteins located in the cell membrane that transport not only water but also some small solutes such as glycerol. Since agAQPs are involved in cancer proliferation and malignancy, it might be possible to utilize them as new targets for cancer molecular imaging. In this study, we investigated whether agAQPs can be specifically targeted by using [14C]-labeled glycerol ([14C]glycerol), which passes through agAQPs. In the in vitro experiments, comparing the cancer cell lines with different expression levels of AQP3 and AQP9, major agAQPs known to be expressed in cancers, and examining the effect of their inhibitors on these cells, the expression of AQP3 and AQP9 in cell lines was shown to be closely related to [14C]glycerol uptake. When [14C]glycerol was injected into tumor-bearing mice, Spearman’s rank coefficient analysis revealed that radioactivity levels in tumor and in plasma were mutually correlated only in tumors expressing agAQPs at a high level. These results indicate the possibility of using agAQPs as new targets to characterize cancer using radiolabeled glycerol as a molecular probe.
  • Thongchai Koobkokkruad, Tatsuya Kadotani, Nobuaki Mizutani, Shin Yoshi ...
    2013 Volume 36 Issue 8 Pages 1299-1304
    Published: August 01, 2013
    Released: August 01, 2013
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    We previously reported that a combination of 4 monoclonal antibodies (mAbs) (cocktail A) to type II collagen (CII), including immunoglobulin G (IgG)2b (C2B-9 and C2B-14) and IgG2a (C2A-7 and C2A-12), induced arthritis in DBA/1J mice. In this study, we found that C2B-9 and C2A-7 as well as C2B-14 and C2A-12 recognized the same or similar epitopes on CII. Based on these data, we hypothesized that the combination of more than 3 mAbs recognizing different epitopes on CII may more efficiently induce arthritis. Therefore, in addition to C2B-9 and C2B-14, which show high binding activity to CII compared with C2A-7 and C2A-12, we developed two more mAbs including IgG2b (C2B-17) and IgG2a (C2A-16), to make a new cocktail (cocktail B) consisting of these 4 mAbs. To compare the ability of cocktail B to induce arthritis with cocktail A, DBA/1J mice were injected with these cocktails. The results showed that cocktail B was able to induce more severe arthritis than cocktail A, especially more markedly affecting rear paws. Histologically, there was more marked proliferation of synovial tissues, massive infiltration by inflammatory cells, and severe destruction of cartilage and bone in mice treated with cocktail B than with cocktail A. Collectively, the new combination of 4 mAbs recognizing different respective epitopes appears to effectively induce arthritis in mice. Thus, the results may provide insights into the selection of mAbs associated with the development of arthritis.
  • Nobuyasu Yamaguchi, Syuhei Matsukawa, Yoko Shintome, Tomoaki Ichijo, M ...
    2013 Volume 36 Issue 8 Pages 1305-1309
    Published: August 01, 2013
    Released: August 01, 2013
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    Assessing microbiological quality assurance by monitoring bacteria in various sources of freshwater used for human consumption, recreation, and food preparation is important for a healthy life. Bacterial number and their community structure in freshwater should be determined as quickly as possible, and “real-time” and “on-site” microbiological methods are required. In this study, we examined the protocol for microchip-based terminal restriction fragment length polymorphism (T-RFLP) analysis, which uses microchip electrophoresis for rapid microbial community analysis. The availability of microchip-based T-RFLP was compared with conventional T-RFLP analysis, which uses a capillary electrophoresis system, with freshwater samples (spring water, river water, groundwater, and hydroponics solution). The detection limit of targeted bacteria by on-chip T-RFLP analysis was 1% (103 cells/mL). The fragment sizes determined by the two analysis methods were highly correlated (r2=0.98). On-chip T-RFLP analysis was completed within 15 min. T-RFLP profiles of nine hydroponics solution samples were analyzed by multidimensional scaling. Considerable changes and stability in bacterial community structure during hydroponic culture were detected by both analyses. These results show that on-chip T-RFLP analysis can monitor changes in bacterial community structure, as well as conventional T-RFLP analysis. The present results indicate that on-chip T-RFLP analysis is an effective tool for rapid and “on-site” bacterial community profiling in freshwater environments, as well as freshwater used for medical and industrial purposes.
  • Ruiling Guo, Guoming Wu, Haidong Li, Pin Qian, Juan Han, Feng Pan, Wen ...
    2013 Volume 36 Issue 8 Pages 1310-1316
    Published: August 01, 2013
    Released: August 01, 2013
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    Although aberrant DNA methylation has been implicated in the pathophysiology of lung cancer, the role of methylation in multidrug resistance (MDR) of lung cancer has remained unclear. To investigate whether certain distinct DNA methylation pattern is associated with acquired MDR of lung adenocarcinoma, methylated-DNA immunoprecipitation-chromatin immunoprecipitation (MeDIP-ChIP) was utilised to compare the genome-wide promoter methylation of the human lung adenocarcinoma MDR A549/cisplatin (A549/DDP) cells with its progenitor A549 cells. The comparison identified 3617 genes with differentially methylated promoter, of which 1581 were hypermethylated and 2036 were hypomethylated. Then, bisulphite sequencing polymerase chain reaction (PCR) (BSP) and quantitative reverse transcription (RT)-PCR (Q-PCR) were used to validate the promoter methylation of five candidate genes and to determine whether the expression of genes was associated with the promoter methylation. BSP confirmed that the promoter methylation incidence of the hypermethylated genes, G protein-coupled receptor 56 isoform 3 (GPR56), metallothionein 1G (MT1G), and RAS association domain family gene 1 (RASSF1), was significantly higher in A549/DDP cells compared with A549 cells (p<0.001, p=0.0099, and p=0.0165), whereas no significant difference was found in that of the other two genes, CCNL2 and BAD (p=0.0594 and p=0.5546). Additionally, Q-PCR showed that the mRNA expression of the three hypermethylated genes was significantly lower in A549/DDP cells compared with A549 cells (all p<0.001). In conclusion, this study reported for the first time that a distinct promoter methylation pattern is associated with MDR of lung adenocarcinoma A549/DDP cells and suggested that GPR56, MT1G, and RASSF1 might be the potential methylation markers associated with acquired MDR of lung adenocarcinoma.
  • Da-guang Wang, Xi-hui Xu, Hui-jun Ma, Cheng-rang Li, Xue-zhuang Yue, J ...
    2013 Volume 36 Issue 8 Pages 1317-1325
    Published: August 01, 2013
    Released: August 01, 2013
    [Advance publication] Released: June 03, 2013
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    In conjunction with matrix proteins, stem cell factor (SCF) plays an important role in the migration of melanocyte precursors (MPs) derived from the mouse embryo. However, no studies have demonstrated an effect of SCF on human follicular MPs migration in vitro. In this report, first we demonstrate the immature state of the follicular MPs. Then cell attachment rate was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. Standard 48-well chemotaxis chambers were used for a transfilter migration assay. F-actin was labeled by rhodamine-conjugated phalloidin, and then organization of the actin cytoskeleton was observed by confocal microscope. In the results, we directly show that MPs adhere more strongly to fibronectin (FN), laminin (LN) and type IV collagen (CIV) than to the negative control. SCF decreased the adhesion of MPs to FN and CIV. A chemotaxis analysis showed that FN and CIV have chemotactic effects on MPs. FN showed an obvious increase in chemotactic effects on MPs with SCF treatment comparing with the control group, but there were no significant changes in the levels of chemotaxis with CIV and LN when the cells were treated with SCF. SCF was chemotactic to MPs, and the presence of FN caused a statistically significant increase in MPs migration at various concentrations of SCF. Furthermore, we showed that SCF, in combination with FN, could induce an apparent increase in actin stress fiber formation in MPs. Our results indicate that SCF, in combination with matrix proteins and in particular with FN, regulates the movement of MPs by both altering cell attachment and increasing cell chemotaxis.
  • Yuichi Nakamura, Satoshi Suzuki, Shu-ichi Saitoh, Yasuchika Takeishi
    2013 Volume 36 Issue 8 Pages 1326-1331
    Published: August 01, 2013
    Released: August 01, 2013
    [Advance publication] Released: June 01, 2013
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    After an acute myocardial infarction (MI), neurohumoral systems including renin-angiotensin-aldosterone system (RAAS) are activated which in turn aggravate cardiac remodeling. Angiotensin receptor blockers (ARBs) are useful drugs for suppression of RAAS. The purpose of this study was to evaluate a new ARB, azilsartan, for suppressing cardiac remodeling and progression to heart failure after MI. We created MI by left anterior descending coronary artery ligation in male mice, and these mice were orally administered saline (0.2 mL) in the control group (Group C), 0.1 mg/kg/d of azilsartan in the low dose group (Group L), and 1.0 mg/kg/d in the high dose group (Group H) everyday. Blood pressure was decreased in Group H, but not in Group L, compared to Group C. At 2 weeks after MI creation, infarct size and fibrotic change at the site remote to the myocardial infarcted area were attenuated in Group L and Group H compared to Group C. Echocardiography revealed that cardiac remodeling was suppressed in Group L and Group H compared to Group C. Increases of mRNA expression levels related to fibrotic change were attenuated in Group L and Group H compared to Group C. The new ARB, azilsartan, had a cardiac remodeling suppression effect after MI, and this effect was observed without blood pressure lowering.
  • Tetsuro Marunouchi, Mao Murata, Norio Takagi, Kouichi Tanonaka
    2013 Volume 36 Issue 8 Pages 1332-1340
    Published: August 01, 2013
    Released: August 01, 2013
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    It is supposed that an increase in the level of heat shock protein 72 (HSP72) in the failing heart would be beneficial for reducing the myocardial damage. However, the induction of HSP72 after an exposure to heat shock is blunted in the failing rat heart following myocardial infarction. In this study, to clarify the possible mechanisms underlying this reduction in the ability for HSP72 induction in the failing heart, the possible involvement of heat-shock factor-1 (HSF1), an HSP transcription factor, in this reduction was examined. When hemodynamic parameters of rats with myocardial infarction 8 weeks after coronary artery ligation were measured, the animals showed the signs of chronic heart failure. The HSF1 content was increased in the viable myocardium in the failing heart. The ability to induce cardiac HSP72 was reduced after an exposure to hyperthermia. The level of HSF1 in the cytosolic fraction from the failing heart with or without exposure to hyperthermia was increased, whereas that of HSF1 in the nuclear fraction was reduced. In the failing heart, the level of HSF1 on its serine 303 (Ser303) residue, which phosphorylation represses HSF1, was increased. These findings suggest that HSF1 translocation from the cytosol into the nucleus was attenuated after an exposure to hyperthermia and that an increase in the phosphorylation of HSF1 Ser303 was involved in the impairment of heat shock-induced HSP72 induction in the failing heart following myocardial infarction.
  • You Jung Kim
    2013 Volume 36 Issue 8 Pages 1341-1347
    Published: August 01, 2013
    Released: August 01, 2013
    [Advance publication] Released: June 04, 2013
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    Rhamnetin is a naturally occurring polyphenolic compound. In this report, experimental evidence is presented on the suppression of melanogenesis by rhamnetin using B16 murine melanoma cells (B16 cells). To document the underlying anti-melanogenic action of rhamnetin, several key biochemical mediators were quantified: superoxide (O2•−), nitric oxide (·NO) and peroxynitrite (ONOO) in vitro, and total reactive species (RS) generation, O2•−, ·NO and ONOO, reduced glutathione (GSH)/GSH-to-oxidized glutathione (GSSG) ratio, prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) in B16 cells. Results revealed that rhamnetin inhibited murine tyrosinase activity, suppressed melanin content and oxidative stress, reducing O2•−,·NO and ONOO in vitro and total RS generation, O2•−, ·NO and ONOO in B16 cells, while maintaining a well-balanced GSH/GSSG ratio in B16 cells. Results further revealed that rhamnetin suppressed key pro-inflammatory mediators such as PGE2 and TXB2. Thus, these results strongly indicate that rhamnetin has powerful anti-melanogenic properties through its anti-oxidative and anti-inflammatory actions.
  • Zheng Deng, Zhan-Cheng Gao, Hui-Qi Ge, Liang-Ren Zhang, Jun-Jun Zhou, ...
    2013 Volume 36 Issue 8 Pages 1348-1355
    Published: August 01, 2013
    Released: August 01, 2013
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    Airway hyperresponsiveness (AHR) and airway inflammation are key pathophysiological features of many respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). To evaluate the treatment responses of procaterol and CD38 inhibitors in an ozone-induced AHR mice model, we hypothesized that procaterol and two synthetic CD38 inhibitors (Compounds T and H) might have therapeutic effects on the ozone-induced AHR mice model, and the nuclear factor-kappaB (NF-κB) pathway and the CD38 enzymatic activity might be involved in the mechanisms. With the exception of the Control group, ozone exposure was used to establish an AHR model. Male Kunming mice in the Procaterol and CD38 inhibitors groups were treated with an emulsifier of procaterol hydrochloride, Compound T or H. Results indicated that (1) no drug showed severe toxicity in this study; (2) ozone exposure induced airway inflammation and AHR; (3) intragastric treatment with procaterol and Compound T achieved potent therapeutic effects, but Compound H did not show any therapeutic effect; (4) the NF-κB pathway was involved in both the pathogenic mechanisms of ozone and therapeutic mechanisms of procaterol and Compound T; (5) however, the in vivo effect of Compound T was not caused by its inhibitory activity on CD38. Taken together, procaterol and Compound T are potentially good drugs to treat asthma and COPD complicated with ozone exposure.
  • Qand Agha Nazari, Toshiaki Kume, Naotaka Izuo, Yuki Takada-Takatori, A ...
    2013 Volume 36 Issue 8 Pages 1356-1362
    Published: August 01, 2013
    Released: August 01, 2013
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    Curcumin, a polyphenolic compound extracted from Curcuma longa, has several pharmacological activities such as anticancer, anti-inflammatory, and antioxidant effects. The purpose of this study was to investigate the protective effects of curcumin and THERACURMIN, a highly bioavailable curcumin, against sodium nitroprusside (SNP)-induced oxidative damage in primary striatal cell culture. THERACURMIN as well as curcumin significantly prevented SNP-induced cytotoxicity. To elucidate the cytoprotective effects of curcumin and THERACURMIN, we measured the intracellular glutathione level in striatal cells. Curcumin and THERACURMIN significantly elevated the glutathione level, which was decreased by treatment with SNP. Moreover, curcumin showed potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging ability. Finally, a ferrozine assay showed that curcumin (10–100 µg/mL) has potent Fe2+-chelating ability. These results suggest that curcumin and THERACURMIN exert potent protective effects against SNP-induced cytotoxicity by free radical-scavenging and iron-chelating activities.
Notes
  • Tadahiro Etoh, Yong Pil Kim, Ayumi Ohsaki, Kanki Komiyama, Masahiko Ha ...
    2013 Volume 36 Issue 8 Pages 1363-1369
    Published: August 01, 2013
    Released: August 01, 2013
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    Erythraline, isolated from the bark of Erythrina crista-galli which are used as Brazilian medicine plant for the treatment of inflammation diseases, suppressed nitric oxide (NO) production and induction of inducible nitric oxide synthase (iNOS) expression in RAW264.7 cells stimulated by lipopolysaccharide (LPS). Because of Toll-like receptor (TLR) 4 and its signal transduction are indispensable to the production of NO and iNOS expression by LPS, we investigated the effects of erythraline on TLR signaling molecules. Western blot analysis revealed that the degradation of inhibitor of nuclear factor (NF)-κB (IκB) by LPS was suppressed by erythraline. Moreover, erythraline inhibited not only LPS-induced phosphorylation of IκB kinase (Ikk) but also phosphorylation of mitogen-activated protein kinases (MAPKs). However, it showed no effect on LPS -induced phosphorylation of transforming growth factor (TGF)-β-activated kinase (TAK) 1 that exists upstream of Ikk and MAPKs, and is required for the activation of these signaling molecules on TLR signaling pathway. These results suggested that erythraline might have inhibited the kinase activity of TAK1. Furthermore, these results were supported from the inhibitory pattern of erythraline on TLR signaling molecules when the cells were stimulated by TLR2 ligand, peptidoglycan which activates the same pathway as LPS on TLR signal transduction.
  • Yue Lu, Seung-Lark Hwang, Jong Keun Son, Hyeun Wook Chang
    2013 Volume 36 Issue 8 Pages 1370-1374
    Published: August 01, 2013
    Released: August 01, 2013
    [Advance publication] Released: May 28, 2013
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    The authors investigated the effect of manassantin B (Man B) isolated from Saururus chinensis (S. chinensis) on cyclooxygenase-2 (COX-2)-dependent prostaglandin D2 (PGD2) generation in mouse bone marrow derived-mast cells (BMMCs). Man B inhibited the generation of PGD2 dose-dependently by inhibiting COX-2 expression in immunoglobulin E (IgE)/Ag-stimulated BMMCs. To elucidate the mechanism responsible for the inhibition of COX-2 expression by Man B, the effects of Man B on the activation of nuclear factor-kappaB (NF-κB), a transcription factor essential and mitogen-activated protein kinases (MAPKs) for COX-2 induction, were examined. Man B attenuated the nuclear translocation of NF-κB p65 and its DNA-binding activity by inhibiting inhibitors of kappa Bα (IκBα) degradation and concomitantly suppressing IκB kinase (IKK) phosphorylation. In addition, Man B suppressed phosphorylation of MAPKs including extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun NH2-terminal kinase (JNK) and p38. It was also found that Man B suppressed Fyn kinase activation and consequent downstream signaling processes, including those involving Syk, Gab2, and Akt. Taken together, the present results suggest that Man B suppresses COX-2 dependent PGD2 generation by primarily inhibiting Fyn kinase in FcεRI-mediated mast cells.
  • Sae-Jin Park, Yong-Hyeon Lee, Kwang Ho Lee, Tack-Joong Kim
    2013 Volume 36 Issue 8 Pages 1375-1379
    Published: August 01, 2013
    Released: August 01, 2013
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    Atopic dermatitis (AD) is a chronic, allergic, and inflammatory skin disease associated with eczema and dermatitis symptoms. Our previous studies have reported that eriodictyol extract inhibits immunoglobulin E (IgE)/Ag-induced type I hypersensitivity by suppressing the activation of proinflammatory cytokines, such as interleukin-4 (IL-4), and the expression of ceramide kinase. In this study, we investigated the inhibitory effect of eriodictyol on 2,4-dinitrochlorobenzene (DNCB)-induced AD-like skin lesions in ICR mice. Treatment with 2 mg/mL eriodictyol for DNCB-induced AD-like skin lesions in ICR mice improved scratching behavior and skin severity score. Histological analysis demonstrated that thickening of the skin lesions were significantly reduced in the eriodictyol-treated group. Also, eriodictyol suppressed the DNCB-mediated elevation of IgE serum levels. These results suggest that eriodictyol may be a potential therapeutic resource for AD and an adjunctive agent to control itchiness in AD.
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