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Volume 122, Issue 1
Displaying 1-10 of 10 articles from this issue
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Reviews: Update and Perspectives of Studies on Proteases and Diseases
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Nobuhisa IWATA, Takaomi C. SAIDOArticle type: Reviews
2003 Volume 122 Issue 1 Pages 5-14
Published: 2003
Released on J-STAGE: June 24, 2003
JOURNAL FREE ACCESSThe deposition of amyloid-β peptide (Aβ) causes the long-term pathological cascade of Alzheimer's disease (AD). Neprilysin is a rate-limiting peptidase, which participates in Aβ degradation in brain. As demonstrated by reverse genetics, the disruption of neprilysin gene causes an elevation in endogenous Aβ levels in the mouse brain in a gene-dose-dependent manner. Therefore, a reduction of neprilysin activity will contribute to Aβ deposition and thus to AD development. Neprilysin is localized at presynapses and on axons, and its expression levels are decreased at the terminal zones and on axons of the lateral perforant pathway and the mossy fibers with aging in mice, suggesting that local concentrations of Aβ are likely to be elevated at the sites, which play crucial roles on certain forms of learning and memory and are highly vulnerable to AD. Overexpression of neprilysin decreased both extracellular and intracellular Aβ levels in primary cortical neurons. These results indicate that up-regulation of neprilysin activity would be a relevant strategy for therapy and prevention through reduction of the Aβ levels. Recently, we have found that a certain neuropeptide regulates the expression of neprilysin in primary neurons. Since a number of receptors for neuropeptides are G-protein-coupled receptors, we would control brain Aβlevels pharmacologically by the manipulation of neprilysin activity.
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Takayuki TSUKUBA, Kenji YAMAMOTOArticle type: Reviews
2003 Volume 122 Issue 1 Pages 15-20
Published: 2003
Released on J-STAGE: June 24, 2003
JOURNAL FREE ACCESSCathepsin E is an intracellular aspartic proteinase expressed predominantly in immune cells and skin. We show that cathepsin E-deficient mice spontaneously develop atopic dermatitis (AD)-like skin lesions comparable to human AD when kept under conventional circumstances, but not under specific pathogen-free conditions. These mice displayed AD-associated phenotypes including eosinophilia; increased serum IgE, IL-18, and IL-1β; and enhanced production of Th2 cytokines. Cathepsin E deficiency also resulted in greater decrease of the rate of degradation for serum IL-18 and IL-1β. Interestingly, cathepsin E levels in blood cells were significantly decreased in AD patients and the AD model NC/Nga mice compared to healthy donors and the control mice, respectively. Our results indicate that deficiency or defective production of cathepsin E strongly induces AD in humans and mice, probably due to the systemic accumulation of IL-18 and IL-1β, leading to stimulation of Th2 responses, and that cathepsin E-deficient mice are a newly discovered model to analyze pathologic mechanisms of human AD.
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Hiroyuki SORIMACHI, Yukiko KAWABATAArticle type: Reviews
2003 Volume 122 Issue 1 Pages 21-29
Published: 2003
Released on J-STAGE: June 24, 2003
JOURNAL FREE ACCESSCalpain, a Ca2+-requiring cytoplasmic cysteine protease, plays indispensable roles in various cellular functions such as signal transduction, cell growth and differentiation, apoptosis, necrosis, and so on. Although most of the detailed physiological functions of calpains have not yet been elucidated, the importance of calpain is obvious from the increasing numbers of papers describing relationships between human disease states (such as Alzheimer's disease, cataract, and muscular dystrophies) and malfunction of calpain. One of the recent remarkable topics of calpain is that a single nucleotide polymorphism of CAPN10, the gene for calpain 10, is related to type 2 diabetes. However, physiological functions of calpain 10 and its relation to diabetes are still unclear. Among 14 human calpain genes, mutations in CAPN3, the gene for p94/calpain 3a and Lp82/calpain 3b, are the only example that genetically connects the calpain gene and human disease, in this case, limb-girdle muscular dystrophy type 2A (LGMD2A). p94 has unique characteristics such as apparent Ca2+-independent activation and very rapid autolytic activity, which are dependent on p94-specific regions, NS, IS1, and IS2. Based on the 3D structures of µ- and m-calpain, molecular functions of p94 in relation to LGMD2A are discussed, with the hope of providing us with some clues to understand calpain functions and its relationships to human diseases.
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Keiji TANAKA, Shigeo MURATAArticle type: Reviews
2003 Volume 122 Issue 1 Pages 30-36
Published: 2003
Released on J-STAGE: June 24, 2003
JOURNAL FREE ACCESSThere are growing lines of evidence addressing a potential link between failure of protein quality control and neurodegeneration. Hence, it is important to know the quality control mechanism of the cell for understanding the molecular basis underlying neurodegenerative diseases. To date, it is notable that molecular chaperones and the ubiquitin-proteasome system play a central role for maintenance of protein homeostasis by catalyzing refolding and/or the immediate destruction of misfolded or impaired proteins generated in cells. However, how this proteolytic machinery recognizes abnormality of cellular proteins for selective elimination remains largely elusive. In this article, we discuss the mechanism of neurodegeneration, based on the protein quality control mediated by the ubiquitin-proteasome system in the cell.
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Tomoko KADOWAKI, Ryosuke TAKII, Atsuyo BABA, Kenji YAMAMOTOArticle type: Reviews
2003 Volume 122 Issue 1 Pages 37-44
Published: 2003
Released on J-STAGE: June 24, 2003
JOURNAL FREE ACCESSThe arginine-specific cysteine proteinase (Arg-gingipain, Rgp) and lysine-specific cysteine proteinase (Lys-gingipain, Kgp) are produced by Porphyromonas gingivalis, an etiological bacterium of periodontal disease. Rgp and Kgp have been implicated as the major virulent factors because of their degrading activity to a broad range of host proteins and of the essential roles in bacterial cell viability. Recent studies have demonstrated the association of P. gingivalis with systemic diseases such as cardiovascular diseases, preterm birth, and low birth weight. The majority of gingipains exist as the membrane-associated complexes composed of the proteinase domains of both Rgp and Kgp, the C-terminal adhesin domains of RgpA and Kgp, phospholipids, and LPS. The complex induced potent viability loss of human endothelial cells and fibroblasts. As the suppression of Rgp and Kgp seems to be the most important to overcome the P. gingivalis-induced systemic disorders as well as the periodontal disease, we have thus designed and synthesized novel proteinase inhibitors specific to Rgp and Kgp on the basis of cleavage sites. Some of them suppressed the characteristic features of P. gingivalis associated with its pathogenicity such as degradation of host proteins, hemagglutination, enhancement of vascular permeability, disruption of leukocytes function, and induction of host cell death.
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Hiroshi KIDO, Ye CHEN, Hiroshi YAMADA, Yuushi OKUMURAArticle type: Reviews
2003 Volume 122 Issue 1 Pages 45-53
Published: 2003
Released on J-STAGE: June 24, 2003
JOURNAL FREE ACCESSThe pathogenesis of the influenza and Sendai viruses is primarily determined by host cellular trypsin-type processing proteases that activate viral fusion activity and infectivity. We isolated three secretory trypsin-type proteases from rat lungs, such as tryptase Clara, mini-plasmin, and ectopic anionic trypsin, candidates for the processing proteases of viral envelope glycoproteins. These enzymes specifically cleave the precursor of fusion glycoprotein hemagglutinin (HA) of influenza virus at Arg325 and the F0 of Sendai virus at Arg116 in the consensus cleavage motif, Gln(Glu)-X-Arg, resulting in the induction of infectivity of these viruses. These proteases show different localization in the airway and susceptibility for the processing of various subtypes of influenza virus HA, suggesting that these processing proteases determine the viral pathogenicity. Influenza virus readily infects and replicates in the airway epithelial cells but occasionally replicates in the central nervous system, particularly in children below 5-6 years of age and Reye's syndrome patients. We found an invasion by a non-neurovirulent influenza virus in cerebral capillaries with progressive brain edema of mice having impaired mitochondrial fatty acid metabolism congenitally or posteriorly in the newborn period. In the brain of these mice, mini-plasmin, which potentiates viral-multiplication in vivo and destroys the blood-brain barrier, accumulated with virus antigen in the brain capillaries but only a little in the control mice without impaired mitochondrial fatty acid metabolism.
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Review
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Sumio OHTSUKI, Satoko HORI, Tetsuya TERASAKIArticle type: Review
2003 Volume 122 Issue 1 Pages 55-64
Published: 2003
Released on J-STAGE: June 24, 2003
JOURNAL FREE ACCESSThe blood-brain barrier (BBB) segregates the circulating blood from interstitial fluid in the brain and restricts drug permeability into the brain. Recent studies have revealed that the BBB exhibits not only blood-to-brain influx transport for the supply of nutrients, but also brain-to-blood efflux transport to excrete drugs and endogenous compounds. The influx transport system allows drugs to enter the brain. L-DOPA is transported into the brain by the large neutral amino acid transport system, system L. A cationic µ-opioid peptide analogue enters the brain by adsorptive-mediated endocytosis. In contrast, efflux transport limits the distribution of drugs in the brain. The ATP binding cassette transporter B1 (ABCB1) mediates the efflux transport of lipophilic drugs at the BBB by using ATP energy. Furthermore, organic anion transporter 3 (OAT3) is expressed at the BBB and mediates the efflux transport of homovanillic acid, a dopamine metabolite. This efflux transport is also likely to be involved in the transport of anionic drugs such as 6-mercaptopurine and acyclovir. Clarifying the BBB transport could give us important information allowing the development of better CNS drugs and improving our understanding of the relationship between CNS diseases and BBB functions.
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Matao SAKANASHI, Kazuo ICHIHARA, Hiroyuki YOSHIDA, Toru KUBOTA, Ryuji ...Article type: Review
2003 Volume 122 Issue 1 Pages 65-72
Published: 2003
Released on J-STAGE: June 24, 2003
JOURNAL FREE ACCESSIn order to protect the heart from unfavorable conditions such as myocardial ischemia or heart failure, it seems necessarily to investigate what components are related to such conditions or what drugs affect them. For this purpose, at symposium No. 40 “Recent Advances in Cardiac Protection” at the 75th Annual Meeting of The Japanese Pharmacological Society held in Kumamoto City, the following 6 studies were presented: (1) The Role of Sarcoglycan Complex in Chronic Heart Failure (H. Yoshida et al.); (2) Heart Failure and Proinflammatory Cytokines (T. Kubota et al.); (3) Fundamental Strategies and Current Topics for Cardiac Protection During Open-Heart Surgery (R. Tominaga et al.); (4) Role of Tetrahydrobiopterin in Myocardial Ischemia/ Reperfusion Injury (K. Noguchi et al.); (5) Cardiac Protection by Nitric Oxide (T. Obata); (6) Reconsideration of Anti-oxidants as Protective Drugs on Ischemic Myocardium (K. Ichihara et al.). This review gathers the reports of studies presented at this symposium.
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Susumu OKABE, Kikuko AMAGASEArticle type: Review
2003 Volume 122 Issue 1 Pages 73-92
Published: 2003
Released on J-STAGE: June 24, 2003
JOURNAL FREE ACCESSSince Takagi et al. reported an experimental chronic gastric ulcer model [acetic acid ulcers induced by submucosal injection of acetic acid (Type 1)], we further modified the methodology and subsequently devised three more models. The second model involves inducing ulcers by serosal application of an acetic acid solution (Type 2) and the third model achieves ulcer induction by intragastric application of an acetic acid solution (Type 3). The forth model was modification of the third model by giving the acetic acid solution and the same volume of air to make one ulcer in the stomach (Type 4). In general, animals accepted the procedures without problems and no undesirable effects were noticed. More importantly, this experimental animal model allows production of ulcers that highly resemble human ulcers in terms of both pathology and healing. Indeed, relapse is even endoscopically observed for 360 days after ulceration. The ulcers produced not only respond well to various anti-ulcer medications, such as antisecretory and mucosal protective drugs and growth factors, but also demonstrate appropriate responses to ulcerogenic agents such as NSAIDs. In addition, we have recently demonstrated that H. pylori infection resulted in delayed ulcer healing and recurrence of healed acetic acid ulcers induced in Mongolian gerbils. The present article gives a brief summary of the ulcer history before establishment of acetic acid ulcers and characteristic features of acetic acid ulcer, including both their merits and shortcomings.
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Review on New Drug
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Masayuki OMOTEArticle type: Review on New Drug
2003 Volume 122 Issue 1 Pages 93-101
Published: 2003
Released on J-STAGE: June 24, 2003
JOURNAL FREE ACCESSEletriptan (Relpax®) is a new anti-migraine medication commonly referred to as triptans. Eletriptan is considered to reduce neuronal transmission of pain by causing vasoconstriction of dilated cranial vessels and inhibiting the release of neuropeptides from trigeminal nerves via activation of the 5-HT1B/1D receptors. Eletriptan showed selectivity, high affinities, and potent agonistic activity to human 5-HT1B/1D receptors. It selectively constricted the cranial artery relative to the coronary artery of the anesthetized dog and the isolated human specimen. The affinity to the 5-HT1B/1D receptors and the selectivity for the cranial artery over the coronary artery of eletriptan are higher than those of sumatriptan. Eletriptan inhibited the trigeminal nerve mediated inflammation in the rat dura mater with equal potency and efficacy to sumatriptan. Orally taken eletriptan was rapidly absorbed with good bioavailability. In clinical trials, eletriptan improved the headache response rate with rapid onset, and reduced headache recurrence. The functional impairments as well as associated symptoms such as nausea, vomiting, and photophobia were also improved by eletriptan. Eletriptan showed stable efficacy in chronic use against multiple attacks with no increase in adverse events. Eletriptan was well tolerated in patients and most adverse events were mild-to-moderate in nature.
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