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author:("tanaka, A")
1.  Histamine H3 receptor agonists decrease hypothalamic histamine levels and increase stereotypical biting in mice challenged with methamphetamine 
Neurochemical research  2011;36(10):1824-1833.
The effects of the histamine H3 receptor agonists (R)-α-methylhistamine, imetit and immepip on methamphetamine (METH)-induced stereotypical behavior were examined in mice. The administration of METH (10 mg/kg, i.p.) to male ddY mice induced behaviors including persistent locomotion and stereotypical behaviors, which were classified into four categories: stereotypical head-bobbing (1.9%), circling (1.7%), sniffing (14.3%), and biting (82.1%). Pretreatment with (R)-α-methylhistamine (3 and 10 mg/kg, i.p.) significantly decreased stereotypical sniffing, but increased stereotypical biting induced by METH, in a dose-dependent manner. This effect of (R)-α-methylhistamine on behavior was mimicked by imetit or immepip (brain-penetrating selective histamine H3 receptor agonists; 10 mg/kg, i.p. for each drug). Hypothalamic histamine levels 1 h after METH challenge were significantly increased in mice pretreated with saline. These increases in histamine levels were significantly decreased by pretreatment with histamine H3 receptor agonists, effects which would appear to underlie the shift from METH-induced stereotypical sniffing to biting.
doi:10.1007/s11064-011-0500-8
PMCID: PMC4133108  PMID: 21573995
Methamphetamine; Histamine; Hypothalamus; Behavior
2.  A single administration of methamphetamine to mice early in the light period decreases running wheel activity observed during the dark period 
Brain research  2011;1429:155-163.
Repeated intermittent administration of amphetamines acutely increases appetitive and consummatory aspects of motivated behaviors as well as general activity and exploratory behavior, including voluntary running wheel activity. Subsequently, if the drug is withdrawn, the frequency of these behaviors decrease, which is thought to be indicative of dysphoric symptoms associated with amphetamine withdrawal. Such decreases may be observed after chronic treatment or even after single drug administrations. In the present study, the effect of acute methamphetamine (METH) on running wheel activity, horizontal locomotion, appetitive behavior (food access), and consummatory behavior (food and water intake) was investigated in mice. A multi-configuration behavior apparatus designed to monitor the five behaviors was developed, where combined measures were recorded simultaneously. In the first experiment, naïve male ICR mice showed gradually increasing running wheel activity over three consecutive days after exposure to a running wheel, while mice without a running wheel showed gradually decreasing horizontal locomotion, consistent with running wheel activity being a positively motivated form of natural motor activity. In experiment 2, increased horizontal locomotion and food access, and decreased food intake, were observed for the initial 3 h after acute METH challenge. Subsequently, during the dark phase period decreased running wheel activity and horizontal locomotion were observed. The reductions in running wheel activity and horizontal locomotion may be indicative of reduced dopaminergic function, although it remains to be seen if these changes may be more pronounced after more prolonged METH treatments.
doi:10.1016/j.brainres.2011.10.037
PMCID: PMC4133111  PMID: 22079320
Methamphetamine; Running wheel activity; Motivated behavior; Attention deficit hyperactivity disorder
3.  Pretreatment with nomifensine or nomifensine analogue 4-phenyl-1,2,3,4-tetrahydroisoquinoline augments methamphetamine-induced stereotypical behavior in mice 
Brain research  2011;1439:15-26.
Nomifensine is a dopamine/norepinephrine reuptake inhibitor. Nomifensine and some of its structural analogues produce behavioral effects indicative of indirect dopaminergic agonist properties, such as hyperlocomotion. By contrast, the deaminated and demethylated nomifensine analogue 4-phenyl-1,2,3,4-tetrahydroisoquinoline (PTIQ) is reported to have amphetamine-antagonistic properties, as demonstrated by inhibition of methamphetamine (METH)-induced dopamine release in the nucleus accumbens and METH-induced hyperlocomotion in rats. In the present study, we examined the effect of PTIQ (10 mg/kg, i.p.) and nomifensine (3 mg/kg, i.p.) on METH (5 or 10 mg/kg ,i.p.)-induced stereotypical behavior in mice in order to determine whether PTIQ and nomifensine inhibit and augment, respectively, METH-induced stereotypical behavior. Unexpectedly, our observations demonstrated that both PTIQ and nomifensine significantly augmented METH-induced stereotypical behavior and locomotion in mice. This augmentation is likely the result of additive effects on dopaminergic function by METH in combination with PTIQ or nomifensine. These results suggest that, contrary to some reports, PTIQ may display dopaminergic agonist properties in mice.
doi:10.1016/j.brainres.2011.12.043
PMCID: PMC4093904  PMID: 22265332
Nomifensine; 4-Phenyl-1,2,3,4-tetrahydroisoquinoline; Methamphetamine; Persistent locomotion; Stereotypical behavior
4.  Straub tail reaction in mice treated with σ1 receptor antagonist in combination with methamphetamine 
Brain research  2012;1482:40-46.
Straub tail reaction (STR) was observed in male ddY mice after simultaneous administration with BMY 14802 (a non-specific σ receptor antagonist) and methamphetamine (METH). The intensity and duration of STR depended on the dose of BMY 14802. The tail reaction was inhibited completely by (+)-SKF 10,047 (a putative σ1 receptor agonist) and partially by PB 28 (a putative σ2 receptor agonist). The STR was mimicked in mice treated with BD 1047 (a putative σ1 receptor antagonist), but not SM-21, a putative σ2 receptor antagonist, in combination with METH. STR evoked with BD 1047 plus METH was inhibited by (+)-SKF 10,047. STR induced by BMY 14802 and METH was abolished by naloxone (a relatively non-selective opioid receptor antagonist) or U-50,488H (a selective κ-agonist), suggesting that the STR may be mediated by activation of opioid receptor system.
doi:10.1016/j.brainres.2012.09.001
PMCID: PMC3922199  PMID: 22981417
Methamphetamine; σ ligand; Straub tail reaction; Opioid receptor system
5.  Sigma1 receptor antagonists determine the behavioral pattern of the methamphetamine-induced stereotypy in mice 
Psychopharmacology  2008;203(4):781-792.
Objective
The effects of sigma receptor antagonists on methamphetamine (METH)-induced stereotypy have not been examined. We examined the effects of sigma antagonists on METH-induced stereotypy in mice.
Results
The administration of METH (10 mg/kg) to male ddY mice induced stereotyped behavior consisting of biting (90.1%), sniffing (4.2%), head bobbing (4.1%), and circling (1.7%) during an observation period of 1 h. Pretreatment of the mice with BMY 14802 (α-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol; 1, 5, and 10 mg/kg), a non-specific sigma receptor antagonist, significantly increased METH-induced sniffing (19.2, 30.5, and 43.8% of total stereotypical behavior) but decreased biting (76.6, 66.9, and 49.3% of total stereotypical behavior) in a dose-dependent manner. This response was completely abolished by (+)-SKF 10,047 ([2S-(2α,6α,11R)]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol; 4 and 10 mg/kg), a putative sigma1 receptor agonist, and partially by PB 28 (1-cyclohexyl-4-[3-(1,2,3,4-tetrahydro-5-methoxy-1-naphthalen-1-yl)-n-propyl]piperazine; 1 and 10 mg/kg), a putative sigma2 receptor agonist. The BMY 14802 action on METH-induced stereotypy was mimicked by BD 1047 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine; 10 mg/kg), a putative sigma1 receptor antagonist, but not by SM-21 ((±)-tropanyl 2-(4-chlorophenoxy)butanoate; 1 mg/kg), a putative sigma2 receptor antagonist. The BD 1047 effect on METH-induced stereotypy was also abolished completely by (+)-SKF 10,047 and partially by PB 28. The overall frequency of METH-induced stereotypical behavior was unchanged with these sigma receptor ligands, despite the alteration in particular behavioral patterns. The BMY 14802 action on METH-induced stereotypy was unaffected by pretreatment with centrally acting histamine H1 receptor antagonists (pyrilamine or ketotifen, 10 mg/kg), suggesting that these effects are independent of histamine H1 receptor signaling systems.
Conclusion
In summary, modulation of central sigma1 receptors alters the pattern of METH-induced stereotypy, producing a shift from stereotypical biting to stereotypical sniffing, without affecting the overall frequency of stereotypical behavior.
doi:10.1007/s00213-008-1425-z
PMCID: PMC3157915  PMID: 19052726
methamphetamine; stereotypy; sniffing; biting; BMY14802; sigma ligand; sigma receptor
6.  Alterations in the levels of heterotrimeric G protein subunits induced by psychostimulants, opiates, barbiturates, and ethanol: Implications for drug dependence, tolerance, and withdrawal 
Synapse (New York, N.Y.)  2008;62(9):689-699.
Neuronal adaptations have been found to occur in multiple brain regions after chronic intake of abused drugs, and are therefore thought to underlie drug dependence, tolerance, and withdrawal. Pathophysiological changes in drug responsiveness as well as behavioral sequelae of chronic drug exposure are thought to depend largely upon the altered state of heterotrimeric GTP binding protein (G protein)-coupled receptor (GPCR)-G protein interactions. Responsiveness of GPCR-related intracellular signaling systems to drugs of abuse is heterogeneous, depending on the types of intracellular effectors to which the specific Gα protein subtypes are coupled and GPCR-G protein coupling efficiency, factors influenced by the class of drug, expression levels of G protein subunits, and drug treatment regimens. To enhance understanding of the molecular mechanisms that underlie the development of pathophysiological states resulting from chronic intake of abused drugs, this review focuses on alterations in the expression levels of G protein subunits induced by various drugs of abuse. Changes in these mechanisms appear to be specific to particular drugs of abuse, and specific conditions of drug treatment.
doi:10.1002/syn.20543
PMCID: PMC2644661  PMID: 18566973
drug of abuse; amphetamine; cocaine; opiate; morphine; barbiturate; ethanol; gene expression; heterotrimeric G protein subunit; intracellular effector
7.  Modification of Monoaminergic Activity by MAO Inhibitors Influences Methamphetamine Actions 
Drug Target Insights  2006;1:19-28.
Methamphetamine (METH) abuse is a serious health and social problem worldwide. At present, however, there are no effective medications for the treatment of METH abuse. Of the intracellular METH target proteins, monoamine oxidase (MAO) is involved in the regulation of monoaminergic tone in the brain, resulting in the modulation of METH-induced behavioral abnormalities in mammals. The METH-induced expression of increased motor activity, stereotypy, and sensitization is closely associated with monoaminergic transmission in the brain. Modification of MAO activity by MAO inhibitors can influence METH action. Of the MAO inhibitors, the propargylamine derivative clorgyline, an irreversible MAO-A inhibitor, effectively blocks METH-induced hyperlocomotion and behavioral sensitization in rodents. Analysis of the associated monoaminergic activity indicates an involvement of altered striatal serotonergic transmission as well as an increased dopaminergic tone. Some effects of MAO inhibitors on METH action appear to be independent of MAO, suggesting complex mechanisms of action of MAO inhibitors in METH abuse. This review describes current research to find effective treatment for METH abuse, using MAO inhibitors.
PMCID: PMC3155216  PMID: 21901055
methamphetamine; hyperlocomotion; stereotypy; behavioral sensitization; clorgyline; selegiline; monoamine turnover; monoamine oxidase; 5-HT; striatum
9.  Characterization of Multidrug-Resistant Group B Streptococci with Reduced Penicillin Susceptibility Forming Small Non-Beta-Hemolytic Colonies on Sheep Blood Agar Plates 
Journal of Clinical Microbiology  2014;52(6):2169-2171.
We isolated and characterized three multidrug-resistant clinical isolates of group B streptococci with reduced penicillin susceptibility (PRGBS) that formed small non-beta-hemolytic colonies on sheep blood agar plates but grew well on chocolate agar plates. They can be overlooked in the bacterial identification step, leading to clinical misdiagnosis and treatment failure.
doi:10.1128/JCM.00226-14
PMCID: PMC4042806  PMID: 24622103
10.  Invasive Infection Caused by Carbapenem-Resistant Acinetobacter soli, Japan 
Emerging Infectious Diseases  2014;20(9):1574-1576.
doi:10.3201/eid2009.140117
PMCID: PMC4178423  PMID: 25151987
carbapenem resistance; Acinetobacter soli; invasive; infection; bacteria; antimicrobial resistance; Japan
11.   
Medical History  2014;58(3):453-454.
doi:10.1017/mdh.2014.35
PMCID: PMC4103398
12.  Targeting the K-Ras - JNK axis eliminates cancer stem-like cells and prevents pancreatic tumor formation 
Oncotarget  2014;5(13):5100-5112.
Cancer cells with self-renewal and tumor-initiating capacity, either quiescent (cancer stem cells, CSCs) or proliferating (cancer stem-like cells, CSLCs), are now deemed responsible for the pervasive therapy resistance of pancreatic cancer, one of the deadliest human cancers characterized by high prevalence of K-Ras mutation. However, to date, much remains unknown how pancreatic CSCs/CSLCs are regulated. Here we show that the K-Ras – JNK axis plays a pivotal role in the maintenance of pancreatic CSCs/CSLCs. In vitro inhibition of JNK, either pharmacological or genetic, caused loss of the self-renewal and tumor-initiating capacity of pancreatic CSLCs. Importantly, JNK inhibition in vivo via systemic JNK inhibitor administration, which had no discernible effect on the general health status of mice, efficiently depleted the CSC/CSLC population within pre-established pancreatic tumor xenografts. Furthermore, knockdown of K-Ras in pancreatic CSLCs with K-Ras mutation led to downregulation of the JNK pathway as well as in loss of self-renewal and tumor-initiating capacity. Together, our findings suggest that pancreatic CSCs/CSLCs are dependent on K-Ras activation of JNK and also suggest that the K-Ras – JNK axis could be a potential target in CSC/CSLC-directed therapies against pancreatic cancer.
PMCID: PMC4148125  PMID: 24947996
pancreatic ductal adenocarcinoma (PDAC); xenograft analysis; tumorigenicity; cancer initiating cell
13.  Conventional surgical repair of traumatic rupture of the thoracic aorta 
Objective
Traumatic rupture of the thoracic aorta is a life-threatening injury requiring urgent surgical intervention. Despite recent improvements in resuscitation and emergency operative techniques, the outcomes of patients with multiple injuries are still associated with a high mortality rate. We retrospectively examined the preoperative demographic data, associated complications and mortality rate of these patients.
Materials and methods
We analyzed the data (1991–2009) of 18 patients with acute traumatic rupture of the thoracic aorta. Most patients had rupture limited to the aortic isthmus and severe associated injuries in other organs. The aorta was repaired by direct suturing, patch plasty (n = 5; 27.7 %) or graft interposition (n = 9; 50 %).
Results
The overall mortality rate was 33.3 %. All six patients who underwent emergency surgery within 2 h died, four intra-operatively and two postoperatively. The causes of the intra-operative mortality were uncontrollable hemorrhage and irreversible cardiac arrest due to penetrating injury of the thoracic aorta and intercostal arteries in three patients, and uncontrollable hemorrhage due to severe liver laceration in one. The surgical complications (42.8 %) were acute lung injury (n = 2), liver insufficiency (n = 2), acute renal failure (n = 1) and cerebral infarction (n = 1). No patients had postsurgical paraplegia. The mean period between arrival and treatment and the mean Injury Severity Score were significantly higher in group D than in group A.
Conclusion
To improve the outcome of traumatic thoracic aortic injury, the degree of multi-organ damage, the priority of treatment be evaluated accurately is important.
doi:10.1007/s11748-014-0422-x
PMCID: PMC4254169  PMID: 24902929
Traumatic aortic rupture; Revised Trauma Score (RTS); Injury Severity Score (ISS); Surgical repair
14.  Molecular phylogenetics and character evolution of morphologically diverse groups, Dendrobium section Dendrobium and allies 
AoB Plants  2014;6:plu045.
The genus Dendrobium, one of the largest genera in Orchidaceae, exhibits enormous vegetative diversification. Such a situation has hindered the establishment of consistent classification systems. To clarify phylogenetic relationships in Dendrobium section Dendrobium and allied groups, we performed molecular phylogenetic analyses of 210 taxa. The results showed that many sections are not monophyletic. Most of the morphological characters that have been believed to reflect phylogenetic relationships are, in fact, the results of convergence. Consequently, recircumscription of the infrageneric classification is required.
It is always difficult to construct coherent classification systems for plant lineages having diverse morphological characters. The genus Dendrobium, one of the largest genera in the Orchidaceae, includes ∼1100 species, and enormous morphological diversification has hindered the establishment of consistent classification systems covering all major groups of this genus. Given the particular importance of species in Dendrobium section Dendrobium and allied groups as floriculture and crude drug genetic resources, there is an urgent need to establish a stable classification system. To clarify phylogenetic relationships in Dendrobium section Dendrobium and allied groups, we analysed the macromolecular characters of the group. Phylogenetic analyses of 210 taxa of Dendrobium were conducted on DNA sequences of internal transcribed spacer (ITS) regions of 18S–26S nuclear ribosomal DNA and the maturase-coding gene (matK) located in an intron of the plastid gene trnK using maximum parsimony and Bayesian methods. The parsimony and Bayesian analyses revealed 13 distinct clades in the group comprising section Dendrobium and its allied groups. Results also showed paraphyly or polyphyly of sections Amblyanthus, Aporum, Breviflores, Calcarifera, Crumenata, Dendrobium, Densiflora, Distichophyllae, Dolichocentrum, Holochrysa, Oxyglossum and Pedilonum. On the other hand, the monophyly of section Stachyobium was well supported. It was found that many of the morphological characters that have been believed to reflect phylogenetic relationships are, in fact, the result of convergence. As such, many of the sections that have been recognized up to this point were found to not be monophyletic, so recircumscription of sections is required.
doi:10.1093/aobpla/plu045
PMCID: PMC4172198  PMID: 25107672
Dendrobium; evolution; ITS; matK; Orchidaceae; phylogeny; systematics; taxonomy.
15.  Toward better annotation in plant metabolomics: isolation and structure elucidation of 36 specialized metabolites from Oryza sativa (rice) by using MS/MS and NMR analyses 
Metabolomics  2013;10(4):543-555.
Metabolomics plays an important role in phytochemical genomics and crop breeding; however, metabolite annotation is a significant bottleneck in metabolomic studies. In particular, in liquid chromatography–mass spectrometry (MS)-based metabolomics, which has become a routine technology for the profiling of plant-specialized metabolites, a substantial number of metabolites detected as MS peaks are still not assigned properly to a single metabolite. Oryza sativa (rice) is one of the most important staple crops in the world. In the present study, we isolated and elucidated the structures of specialized metabolites from rice by using MS/MS and NMR. Thirty-six compounds, including five new flavonoids and eight rare flavonolignan isomers, were isolated from the rice leaves. The MS/MS spectral data of the isolated compounds, with a detailed interpretation of MS fragmentation data, will facilitate metabolite annotation of the related phytochemicals by enriching the public mass spectral data depositories, including the plant-specific MS/MS-based database, ReSpect.
Electronic supplementary material
The online version of this article (doi:10.1007/s11306-013-0619-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s11306-013-0619-5
PMCID: PMC4097337  PMID: 25057267
Oryza sativa; Rice; Tandem mass spectrometry (MS/MS); Nuclear magnetic resonance (NMR); Specialized metabolites; Flavonoid
16.  Glioma-Initiating Cell Elimination by Metformin Activation of FOXO3 via AMPK 
Stem Cells Translational Medicine  2012;1(11):811-824.
In this study metformin, an antidiabetic agent, is identified as a therapeutic activator of FOXO3. The study demonstrates that targeting glioma-initiating cells via the AMP-activated protein kinase- FOXO3 axis is a viable therapeutic strategy against glioblastoma, with metformin being the most clinically relevant drug ever reported for targeting of glioma-initiating cells.
Control of the cancer stem/initiating cell population is considered key to realizing the long-term survival of glioblastoma patients. Recently, we demonstrated that FOXO3 activation is sufficient to induce differentiation of glioma-initiating cells having stem-like properties and inhibit their tumor-initiating potential. Here we identified metformin, an antidiabetic agent, as a therapeutic activator of FOXO3. Metformin activated FOXO3 and promoted differentiation of such stem-like glioma-initiating cells into nontumorigenic cells. Furthermore, metformin promoted FOXO3 activation and differentiation via AMP-activated protein kinase (AMPK) activation, which was sensitive to extracellular glucose availability. Importantly, transient, systemic administration of metformin depleted the self-renewing and tumor-initiating cell population within established tumors, inhibited tumor formation by stem-like glioma-initiating cells in the brain, and provided a substantial survival benefit. Our findings demonstrate that targeting glioma-initiating cells via the AMPK-FOXO3 axis is a viable therapeutic strategy against glioblastoma, with metformin being the most clinically relevant drug ever reported for targeting of glioma-initiating cells. Our results also establish a novel, direct link between glucose metabolism and cancer stem/initiating cells.
doi:10.5966/sctm.2012-0058
PMCID: PMC3659661  PMID: 23197693
Cancer; Cell biology; Cell signaling; Glioma
17.  Inhibitory effect of chemical constituents from Artemisia scoparia Waldst. et Kit. on triglyceride accumulation in 3T3-L1 cells and nitric oxide production in RAW 264.7 cells 
Journal of Natural Medicines  2013;68(2):414-420.
We investigated the anti-obesity effect of the aerial part of Artemisia scoparia Waldst. et Kit. (Compositae). An 80 % aqueous EtOH extract of the aerial part inhibited triglyceride (TG) accumulation and the nitric oxide (NO) production activity. A new chromane derivative was isolated from the aerial part of A. scoparia Waldst. et Kit. along with 18 known compounds. The structure of the new chromane, scopariachromane (1), was elucidated by spectroscopic analyses. The inhibitory effects of the compounds on TG accumulation activity were examined. Among these, cirsiliol (11) inhibited TG accumulation in 3T3-L1 preadipocytes. Jaceosidin (12) inhibited NO production in a murine macrophage-like cell line (RAW 264.7). These results indicate that the 80 % aqueous EtOH extract and compounds isolated from the aerial part of A. scoparia Waldst. et Kit. may improve obesity-related insulin resistance.
doi:10.1007/s11418-013-0799-3
PMCID: PMC3948510  PMID: 24142543
Artemisia scoparia Waldst. et Kit.; Chromane; Triglyceride; Nitric oxide
18.  Cephalhematoma and petechial rashes associated with acute parvovirus B19 infection: a case report 
BMC Infectious Diseases  2013;13:465.
Background
Parvovirus B19 can cause petechial rashes in the acute phase of illness as well as erythema infectiosum (fifth disease) during convalescence. This petechial rash is often called “gloves and socks” syndrome because of the typical distribution of the eruption. However, involvement of other sites (e.g., intertriginous area) and generalized involvement have been recently recognized. We report here a patient with parvovirus-associated petechiae and cephalhematoma.
Case presentation
The patient was a previously healthy 10-year-old boy. There was a family history of fatal bleeding; his sister died of intracranial bleeding with an uncertain cause at the age of 5 months. The patient was admitted to our hospital because of sudden onset of cephalhematoma associated with fever. He reported that he had no recent head trauma but that he massaged his scalp on the day before admission. On admission, his temperature was 38.8°C; otherwise, he was in a stable condition. Besides cephalhematoma, petechial rashes were present on his trunk and limbs. The initial laboratory tests were essentially normal, including platelet count and coagulation tests. Expanded laboratory tests were repeated to explore the etiology of his skin hemorrhage, all of which indicated that hematological disorders were unlikely. His symptoms subsided spontaneously over the next few days and he was discharged uneventfully. Anti-parvovirus IgM titer was elevated during hospitalization and typical erythema infectiosum was seen approximately 1 week after discharge. During 6 months follow-up, he remained stable without recurrence of a hemorrhagic episode. Finally, we concluded that his cephalhematoma was responsible for acute parvoviral infection.
Conclusions
This is believed to be the first report describing a possible association between parvovirus B19 infection and cephalhematoma. Parvovirus B19 infection should be considered in the differential diagnosis of children who present with unexplained hemorrhage such as cephalhematoma or petechiae.
doi:10.1186/1471-2334-13-465
PMCID: PMC3851625  PMID: 24093148
Parvovirus B19 infection; Erythema infectiosum; Fifth disease; Papular–purpuric gloves and socks syndrome; Cephalhematoma
19.  JNK Signaling in the Control of the Tumor-Initiating Capacity Associated with Cancer Stem Cells 
Genes & Cancer  2013;4(9-10):388-396.
Deregulation of c-Jun NH2-terminal kinase (JNK) signaling occurs frequently in a variety of human cancers, yet the exact role(s) of JNK deregulation in cancer cell biology remains to be fully elucidated. Our recent demonstration that the activity of JNK is required not only for self-renewal of glioma stem cells but also for their tumor initiation has, however, identified a new role for JNK in the control of the stemness and tumor-initiating capacity of cancer cells. Significantly, transient JNK inhibition was sufficient to cause sustained loss of the tumor-initiating capacity of glioma stem cells, suggesting that the phenotype of “lost tumor-initiating capacity” may be as stable as the differentiated state and that the tumor-initiating capacity might therefore be under the control of JNK through an epigenetic mechanism that also governs stemness and differentiation. Here, in this article, we review the role and mechanism of JNK in the control of this “stemness-associated tumor-initiating capacity” (STATIC), a new hypothetical concept we introduce in this review article. Since the idea of STATIC is essentially applicable to both cancer types that do and do not follow the cancer stem cell hypothesis, we also give consideration to the possible involvement of JNK-mediated control of STATIC in a wide range of human cancers in which JNK is aberrantly activated. Theoretically, successful targeting of STATIC through JNK could contribute to long-term control of cancer. Issues to be considered before clinical application of therapies targeting this JNK-STATIC axis are also discussed.
doi:10.1177/1947601912474892
PMCID: PMC3863334  PMID: 24349636
cancer stem cell; epigenetic control; glioblastoma; JNK; stemness; tumor-initiating capacity
20.  3EZ,20Ac-ingenol, a catalytic inhibitor of topoisomerases, downregulates p-Akt and induces DSBs and apoptosis of DT40 cells 
Archives of Pharmacal Research  2013;36(8):1029-1038.
We have previously reported that many ingenol compounds derived from Euphorbia kansui exhibit topoisomerase (topo) II inhibitory activity. Of these compounds, 3EZ,20Ac-ingenol inhibited topo I activity. Camptothecin, which inhibits the religation activity of topo I without interfering with the binding of topo I to DNA and induces topo I-mediated DNA cleavage, was used as a positive control. In this study, we found that 3EZ,20Ac-ingenol did not hamper the binding of topo I to DNA in the same manner as camptothecin but affected the inhibition of cleavage of one DNA strand. 3EZ,20Ac-ingenol inhibited cell proliferation by blocking cell cycle progression in the G2/M phase. To define the mechanism of inhibition of DT40 cell proliferation, the change in Akt activity was observed because Akt activity is regulated in response to DNA damage. Western blot analysis revealed that 3EZ,20Ac-ingenol downregulated the expression of p-Akt, and apoptosis was detected by the presence of DNA double-strand breaks and caspase 3 activation.
doi:10.1007/s12272-013-0108-4
PMCID: PMC3731510  PMID: 23595550
Both topoisomerase I and II inhibitor; Catalytic inhibitor; Apoptosis; Double-strand breaks; Caspase 3; p-Akt
21.  Targeting JNK for therapeutic depletion of stem-like glioblastoma cells 
Scientific Reports  2012;2:516.
Control of the stem-like tumour cell population is considered key to realizing the long-term survival of patients with glioblastoma, one of the most devastating human malignancies. To date, possible therapeutic targets and targeting methods have been described, but none has yet proven to target stem-like glioblastoma cells in the brain to the extent necessary to provide a survival benefit. Here we show that targeting JNK in vivo, the activity of which is required for the maintenance of stem-like glioblastoma cells, via transient, systemic administration of a small-molecule JNK inhibitor depletes the self-renewing and tumour-initiating populations within established tumours, inhibits tumour formation by stem-like glioblastoma cells in the brain, and provide substantial survival benefit without evidence of adverse events. Our findings not only implicate JNK in the maintenance of stem-like glioblastoma cells but also demonstrate that JNK is a viable, clinically relevant therapeutic target in the control of stem-like glioblastoma cells.
doi:10.1038/srep00516
PMCID: PMC3400080  PMID: 22816039
23.  Triterpenes from Kadsura coccinea 
In vitro anti-allergic screening of medicinal herbal extracts revealed that the 80% acetone extract of the rhizome of Kadsura coccinea inhibited nitric oxide (NO) production in a lipopolysaccharide (LPS) and recombinant mouse interferon-γ (IFN-γ) activated murine macrophage like cell line, RAW264.7. Further fractionation of the EtOAc extract led to the isolation of one new 3,4-seco-lanostane type triterpene named kadsuracoccin acid A (1) together with two known triterpenes anwuweizonic acid (2) and neokadsuranic acid B (3). Compounds 1−3 did not exhibit any inhibitory activities for NO production and IFN-γ activation.
PMCID: PMC3942918  PMID: 24716128
Kadsura coccinea; Triterpene; NO production inhibitory activities
24.  Dual blocking of mTor and PI3K elicits a prodifferentiation effect on glioblastoma stem-like cells 
Neuro-Oncology  2010;12(12):1205-1219.
Glioblastoma, the most intractable cerebral tumor, is highly lethal. Recent studies suggest that cancer stem-like cells (CSLCs) have the capacity to repopulate tumors and mediate radio- and chemoresistance, implying that future therapies may need to turn from the elimination of rapidly dividing, but differentiated, tumor cells to specifically targeting the minority of tumor cells that repopulate the tumor. However, the mechanism by which glioblastoma CSLCs maintain their immature stem-like state or, alternatively, become committed to differentiation is poorly understood. Here, we show that the inactivation of mammalian target of rapamycin (mTor) by the mTor inhibitor rapamycin or knockdown of mTor reduced sphere formation and the expression of neural stem cell (NSC)/progenitor markers in CSLCs of the A172 glioblastoma cell line. Interestingly, combination treatment with rapamycin and LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, not only reduced the expression of NSC/progenitor markers more efficiently than single-agent treatment, but also increased the expression of βIII-tubulin, a neuronal differentiation marker. Consistent with these results, a dual PI3K/mTor inhibitor, NVP-BEZ235, elicited a prodifferentiation effect on A172 CSLCs. Moreover, A172 CSLCs, which were induced to undergo differentiation by pretreatment with NVP-BEZ235, exhibited a significant decrease in their tumorigenicity when transplanted either subcutaneously or intracranially. Importantly, similar results were obtained when patient-derived glioblastoma CSLCs were used. These findings suggest that the PI3K/mTor signaling pathway is critical for the maintenance of glioblastoma CSLC properties, and targeting both mTor and PI3K of CSLCs may be an effective therapeutic strategy in glioblastoma.
doi:10.1093/neuonc/noq103
PMCID: PMC3018946  PMID: 20861085
differentiation; glioblastoma cancer stem cells; mTor; PI3K; self-renewal
25.  S-1 induced secondary acute erythroid leukemia with a chromosome inv(12)(p13;q13) 
Adjuvant chemotherapy by S-1 following gastrectomy is considered standard treatment in Japan. Analysis of follow-up data have proved the efficacy of S-1 administration, and that hematological adverse events were relatively rare. Pyrimidine anti-metabolites, including S-1, have shown relatively lower risks for secondary hematological malignancies in comparison to alkylating agents and topoisomerase-II inhibitors. We here report a case of therapy-related leukemia after S-1 administration. A patient who had received S-1as the sole adjuvant chemotherapy was diagnosed with acute erythroid leukemia. To the best of our knowledge, our patient represents the first report of S-1 induced acute leukemia.
doi:10.3748/wjg.v17.i41.4632
PMCID: PMC3225100  PMID: 22147971
S-1; Secondary leukemia; Acute erythroid Leukemia; Gastric cancer

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