Journal of Pharmacological Sciences
Online ISSN : 1347-8648
Print ISSN : 1347-8613
ISSN-L : 1347-8613
Volume 125, Issue 2
Displaying 1-15 of 15 articles from this issue
Current Perspective
  • Shiroh Kishioka, Norikazu Kiguchi, Yuka Kobayashi, Fumihiro Saika
    2014 Volume 125 Issue 2 Pages 117-124
    Published: June 20, 2014
    Released on J-STAGE: June 19, 2014
    Advance online publication: May 31, 2014
    JOURNAL FREE ACCESS
    Nicotine (NIC) is an exogenous ligand of the nicotinic acetylcholine receptor (nAChR), and it influences various functions in the central nervous system. Systemic administration of NIC elicits the release of endogenous opioids (endorphins, enkephalins, and dynorphins) in the supraspinal cord. Additionally, systemic NIC administration induces the release of methionine-enkephalin in the spinal dorsal horn. NIC has acute neurophysiological actions, including antinociceptive effects, and the ability to activate the hypothalamic–pituitary-adrenal (HPA) axis. The endogenous opioid system participates in NIC-induced antinociception, but not HPA axis activation. Moreover, NIC-induced antinociception is mediated by α4β2 and α7 nAChRs, while NIC-induced HPA axis activation is mediated by α4β2, not α7, suggesting that the effects of NIC on the endogenous opioid system are mediated by α7, not α4β2. NIC has substantial physical dependence liability. The opioid-receptor antagonist naloxone (NLX) elicits NIC withdrawal after repeated NIC administration, and NLX-induced NIC withdrawal is inhibited by concomitant administration of an opioid-receptor antagonist. NLX-induced NIC withdrawal is also inhibited by concomitant administration of an α7 antagonist, but not an α4β2 antagonist. Taken together, these findings suggest that NIC-induced antinociception and the development of physical dependence are mediated by the endogenous opioid system, via the α7 nAChR.
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  • Kenji Iizuka, Takuji Machida, Masahiko Hirafuji
    2014 Volume 125 Issue 2 Pages 125-131
    Published: June 20, 2014
    Released on J-STAGE: June 19, 2014
    Advance online publication: May 23, 2014
    JOURNAL FREE ACCESS
    Skeletal muscle plays a key role in postural retention as well as locomotion for maintaining the physical activities of human life. Skeletal muscle has a second role as an elaborate energy production and consumption system that influences the whole body’s energy metabolism. Skeletal muscle is a specific organ that engenders a physical force, and exercise training has been known to bring about multiple benefits for human health maintenance and/or improvement. The mechanisms underlying the improvement of the human physical condition have been revealed: skeletal muscle synthesizes and secretes multiple factors, and these muscle-derived factors, so-called as myokines, exert beneficial effects on peripheral and remote organs. In this short review, we focus on the third aspect of skeletal muscle function — namely, the release of multiple types of myokines, which constitute a broad network for regulating the function of remote organs as well as skeletal muscle itself. We conclusively show that skeletal muscle is one of the endocrine organs and that understanding the mechanisms of production and secretion of myokines may lead to a new pharmacological approach for treatment of clinical disorders.
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Full Paper
  • Xiaoya Zhai, Jufang Chi, Weiliang Tang, Zheng Ji, Fei Zhao, Chengjian ...
    2014 Volume 125 Issue 2 Pages 132-141
    Published: June 20, 2014
    Released on J-STAGE: June 19, 2014
    Advance online publication: May 23, 2014
    JOURNAL FREE ACCESS
    Many epidemiological studies have strongly suggested an inverse correlation between dietary polyphenol consumption and reduced risks of cardiovascular diseases. Yellow rice wine is a Chinese specialty and one of the three most ancient wines in the world (Shaoxing rice wine, beer, and grape wine). There is a large amount of polyphenol substances in yellow rice wine. This experiment was designed to study the potential beneficial effects of yellow wine polyphenolic compounds (YWPC) from yellow rice wine on progression of atherosclerosis in vivo and to further explore its underlying mechanisms. Six-week-old male LDL-receptor–knockout mice were treated with high-fat diet to establish the mouse model with atherosclerosis. Animals received 10, 30, or 50 mg/kg per day of YWPC or 10 mg/kg per day rosuvastatin or water (vehicle) for 14 weeks. The results indicated that YWPC and rosuvastatin significantly decreased circulating total cholesterol and low-density lipoprotein cholesterol. Compared to the control group, the atherosclerosis lesion area in the rosuvastatin-intervention group and YWPC at doses of 10, 30, and 50 mg/kg per day intervention groups decreased by 74.14%, 18.51%, 40.09%, and 38.42%, respectively. YWPC and rosuvastatin decreased the expression and activity of matrix metalloproteinases (MMP)-2, 9, whereas the expression of the endogenous inhibitors of these proteins, namely, tissue inhibitors of matrix metalloproteinases (TIMP)-1, 2, increased when compared to the control group. It can be concluded that the YWPC is similar to the benefic effects of rosuvastatin on cardiovascular system. These effects may be attributed to their anti-atherosclerotic actions by lowering lipid and modulating the activity and expression of MMP-2, 9 and TIMP-1, 2.
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  • Yan Gong, Yewei Chen, Qin Li, Zhiping Li
    2014 Volume 125 Issue 2 Pages 142-149
    Published: June 20, 2014
    Released on J-STAGE: June 19, 2014
    Advance online publication: May 16, 2014
    JOURNAL FREE ACCESS
    To obtain more information regarding the influence of various covariates on the disposition of digoxin in Chinese neonates and infants, routine clinical pharmacokinetic data were retrospectively collected from 131 hospitalized patients. A nonlinear mixed effects modeling (NONMEM) method was applied to the data. A one-compartment/first-order absorption model was employed to estimate the influence of total body weight (allometric power model), postnatal age, serum creatinine, gender, presence of heart congestive failure, and concomitant medications on apparent total clearance and apparent drug distribution of digoxin. Pharmacokinetic parameter estimates for CL/F and V/F were 0.147 L∙h−1∙kg−1 and 15.7 L/kg, respectively. Total body weight and postnatal age were identified as the important factors affecting total clearance of digoxin; total body weight was the covariate identified to influence the apparent distribution volume. Both internal (bootstrap method, visual predictive checks, and normalized prediction distributed error) and external validation supported the stable and predictive performance of the final model. We concluded that the model can be used to choose an appropriate dose regimen in Chinese neonates and infants.
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  • Shun-Bin Luo, Chuan-Bao Li, Da-Peng Dai, Shuang-Hu Wang, Zhen-He Wang, ...
    2014 Volume 125 Issue 2 Pages 150-156
    Published: June 20, 2014
    Released on J-STAGE: June 19, 2014
    JOURNAL FREE ACCESS
    Supplementary material
    Warfarin is the most frequently prescribed anticoagulant for the long-term treatment in the clinic. Recent studies have shown that polymorphic alleles within the CYP2C9, VKORC1, and CYP4F2 genes are related to the warfarin dosage requirement. In this study, a novel non-synonymous mutation (1009C>A) in CYP2C9 was detected in a warfarin-hypersensitive patient, while the other two candidate genes were both found to be homozygous for the wild-type alleles. The newly identified point mutation results in an amino acid substitution at position 337 of the CYP2C9 protein (P337T) and has been designated as the novel allele CYP2C9*58. When expressed in insect cell microsomes, the relative intrinsic clearance values of the CYP2C9.58 variant for tolbutamide and losartan were quite similar to those of the typical defective variant CYP2C9.3, whereas the clearance value of CYP2C9.58 for diclofenac was slightly higher than that of another typical defective variant CYP2C9.2. These data suggested that when compared with wild-type CYP2C9.1, the enzymatic activity of the novel allelic variant has been greatly reduced by the 1009C>A mutation. If patients carrying this allele take drugs metabolized by CYP2C9, their metabolic rate might be slower than that of wild-type allele carriers and thus much more attention should be paid to their clinical care.
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  • Yuji Odagaki, Masakazu Kinoshita, Ryoichi Toyoshima
    2014 Volume 125 Issue 2 Pages 157-168
    Published: June 20, 2014
    Released on J-STAGE: June 19, 2014
    Advance online publication: May 20, 2014
    JOURNAL FREE ACCESS
    The functional activation of Gi/o proteins coupled to muscarinic acetylcholine receptors (mAChRs) was investigated with the conventional guanosine-5′-O-(3-[35S]thio) triphosphate ([35S]GTPγS) binding assay in rat brain membranes. The most efficacious stimulation elicited by acetylcholine or carbachol (CCh) was obtained in striatal membranes. The pharmacological properties of mAChR-mediated [35S]GTPγS binding determined with a series of muscarinic agonists and antagonists were almost identical among the three brain regions investigated, i.e., cerebral cortex, hippocampus, and striatum, except for the apparent partial agonist effects of (αR)-α-cyclopentyl-α-hydroxy-N-[1-(4-methyl-3-pentenyl)-4-piperidinyl]benzeneacetamide fumarate (J 104129) observed only in the hippocampus, but not in the other two regions. Among the muscarinic toxins investigated, only MT3 attenuated CCh-stimulated [35S] GTPγS binding. The highly selective allosteric potentiator at the M4 mAChR subtype, 3-amino-N-[(4-chlorophenyl)methyl]-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide (VU 10010), shifted the concentration–response curve for CCh leftwards as well as upwards. On the other hand, neither thiochrome nor brucine N-oxide was effective. The increases induced by CCh and 5-HT were essentially additive, though not completely, indicating that the mAChRs and 5-HT1A receptors were coupled independently to distinct pools of Gi/o proteins. Collectively, all of the data suggest that functional activation of Gi/o proteins coupled to mAChRs, especially the M4 subtype, is detectable by means of CCh-stimulated [35S]GTPγS binding assay in rat discrete brain regions.
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  • Masashi Tawa, Ayman Geddawy, Takashi Shimosato, Hirotaka Iwasaki, Take ...
    2014 Volume 125 Issue 2 Pages 169-175
    Published: June 20, 2014
    Released on J-STAGE: June 19, 2014
    Advance online publication: May 23, 2014
    JOURNAL FREE ACCESS
    Supplementary material
    Hypoxia or hypoxia/reoxygenation impairs nitric oxide (NO)-mediated relaxation through the increase in superoxide generation in monkey coronary arteries. Soluble guanylate cyclase (sGC), the target enzyme of NO, has been shown to change from the NO-sensitive reduced form to the NO-insensitive oxidized/heme-free form under substantial oxidative stress, so the present study investigated whether hypoxia or hypoxia/reoxygenation influences sGC redox equilibrium. In isolated monkey coronary arteries without endothelium, the relaxation caused by the sGC stimulator BAY 41-2272 (Emax: 93.3% ± 2.2%) was somewhat impaired under hypoxia (Emax: 86.3% ± 2.6%) or hypoxia/reoxygenation (Emax: 86.1% ± 3.2%), whereas that by the sGC activator BAY 60-2770 (Emax: 86.0% ± 3.2%) was significantly augmented under hypoxia (Emax: 94.4% ± 1.3%) or hypoxia/reoxygenation (Emax: 95.5% ± 1.1%). In addition, cGMP formation in response to BAY 41-2272 and BAY 60-2770 was inhibited and stimulated, respectively, under hypoxia or hypoxia/reoxygenation. The effects of hypoxia or hypoxia/reoxygenation on BAY 41-2272– and BAY 60-2770–induced vasorelaxation were completely canceled by the treatment with the superoxide dismutase mimetic tempol. These findings suggest that sGC redox equilibrium in the coronary artery is shifted towards the NO-insensitive form under hypoxia or hypoxia/reoxygenation and that superoxide seems to play an important role in this shift.
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  • Xi-Lan Tang, Jian-Xun Liu, Wei Dong, Peng Li, Lei Li, Cheng-Ren Lin, Y ...
    2014 Volume 125 Issue 2 Pages 176-183
    Published: June 20, 2014
    Released on J-STAGE: June 19, 2014
    JOURNAL FREE ACCESS
    Supplementary material
    Protocatechuic acid (PCA), a phenolic compound and one of the main metabolites of complex polyphenols, has been found to possess various biological activities, and it may have a potential in the treatment of ischemic heart diseases. This study explored the cardioprotective effect of PCA on myocardial ischemia/reperfusion (MI/R) injury and the underlying mechanisms. In an in vivo rat model of MI/R injury, myocardial infarct size, serum TNF-α level, and platelet aggregation were measured. In a primary neonatal rat cardiomyocyte model of hypoxia/reoxygenation (H/R) injury, the apoptotic rate, expressions of cleaved caspase-3, and phosphorylated Akt were observed. We found that PCA significantly reduced myocardial infarct size, serum TNF-α level, and platelet aggregation. In vitro experiments revealed that PCA significantly inhibited the apoptotic rate and the expression of cleaved caspase-3, and it upregulated the expression of phosphorylated Akt in cardiomyocytes subjected to H/R injury. Our results suggest that PCA can provide a significant protection against MI/R injury, which may be at least partially attributed to its inhibitions against injury induced by MI/R including the inflammatory response, platelet aggregation, and cardiomyocytes apoptosis.
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  • Jin-Lei Guo, Yang Yu, Yan-Yan Jia, Yun-Zi Ma, Bo-Yu Zhang, Pei-Qing Li ...
    2014 Volume 125 Issue 2 Pages 184-192
    Published: June 20, 2014
    Released on J-STAGE: June 19, 2014
    Advance online publication: May 28, 2014
    JOURNAL FREE ACCESS
    Transient receptor potential melastatin 7 (TRPM7), a Ca2+-nonselective cation channel, plays a key role in the pathophysiological response of multiple cell types. However, the role of TRPM7 channels in hydrogen peroxide (H2O2)-induced cardiac fibrosis remains unclear. This study aimed to explore whether TRPM7 channels are involved in H2O2-induced cardiac fibrosis and the underlying mechanisms. Our results showed that 2-aminoethoxydiphenylborate (2-APB), which is commonly used to block TRPM7 channels, inhibited H2O2-induced cardiac fibrosis via attenuating the overexpression of important fibrogenic biomarkers and growth factors in cardiac fibroblasts, including collagen type I (Col I), fibronectin (FN), smooth muscle α-actin (α-SMA), connective tissue growth factor (CTGF), and transforming growth factor-β1 (TGF-β1). In addition, 2-APB also decreased H2O2-mediated elevation of the concentration of intracellular Ca2+ ([Ca2+]i). Meanwhile, silencing TRPM7 channels by shRNA interference also impaired the increased [Ca2+]i and upregulation of Col I, FN, α-SMA, CTGF, and TGF-β1 induced by H2O2. Furthermore, we found that H2O2-mediated activation of extracellular signal–regulated kinase 1/2 (ERK1/2) decreased in TRPM7-shRNA cells and Ca2+-free culture media. These results demonstrated that TRPM7 channels contributed to H2O2-induced cardiac fibrosis and suggested that this contribution may be through mediating Ca2+ influx and phosphorylation of ERK1/2.
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  • Chunliu Mi, Juan Ma, Hui Shi, Jing Li, Fei Wang, Jung Joon Lee, Xuejun ...
    2014 Volume 125 Issue 2 Pages 193-201
    Published: June 20, 2014
    Released on J-STAGE: June 19, 2014
    JOURNAL FREE ACCESS
    4′,6-Dihydroxy-4-methoxyisoaurone (ISOA) is an isoaurone compound isolated from Trichosanthes kirilowii seeds, which was identified as an inhibitor of tumor growth. However, the mechanism by which ISOA inhibits hypoxia-inducible factor-1 (HIF-1)-mediated tumor growth is not fully understood. We here demonstrated the effect of ISOA on HIF-1 activation. ISOA showed a potent inhibitory activity against HIF-1 activation induced by hypoxia in various human cancer cell lines. This compound markedly decreased the hypoxia-induced accumulation of HIF-1α protein dose-dependently, whereas it did not affect the expressions of HIF-1β and topoisomerase-I (Topo-I). Further analysis revealed that the suppression of HIF-1α accumulation by ISOA was closely correlated with strong dephosphorylation of Akt, mammalian target of rapamycin (mTOR), and its effectors ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), a pathway known to regulate HIF-1α expression at the translational level. Furthermore, ISOA prevented hypoxia-induced expression of HIF-1 target genes and suppresses the invasiveness of tumor cells. Taken together, our results suggested that ISOA is an effective inhibitor of HIF-1 through targeting Akt/mTOR/p70S6K/4E-BP1 pathway, thereby, providing new perspectives into the mechanism of its anticancer activity.
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  • Yanhong Li, Xueying Lu, Hongxue Qi, Xiaobo Li, Xiangwen Xiao, Jianfeng ...
    2014 Volume 125 Issue 2 Pages 202-210
    Published: June 20, 2014
    Released on J-STAGE: June 19, 2014
    Advance online publication: May 30, 2014
    JOURNAL FREE ACCESS
    Ursolic acid (UA), a natural pentacyclic triterpenoid compound, has been demonstrated to induce apoptosis in various tumors. The aim of the present study was to elucidate the molecular mechanisms of UA-induced apoptosis in HeLa cells. Here, we reported that UA induced apoptosis through the mitochondrial intrinsic pathway in HeLa cells, as shown by release of cytosol cytochrome c, activation of caspase-9 and -3, reduction of Bcl-2 and Bcl-xL, and increase of Bax and Bak. UA down-regulated the phosphorylation of ERK1/2 and p38, whereas phosphorylation of JNK was unchanged. The roles of ERK1/2 and p38 were further confirmed using the ERK1/2 inhibitor (U0126) and p38 inhibitor (SB203580). U0126 markedly increased UA-induced the Bax/Bcl-2 ratio, the increase of cytosol cytochrome c, and the levels of cleaved caspase-3, but SB203580 had little effects on the above characters, suggesting the ERK1/2 signaling pathway is required for apoptosis. Furthermore, UA up-regulated DUSP 1, 2, 4, 5, 6, 7, 9, and 10 mRNA expressions, which may be a clue for the role of dephosphorylation of ERK1/2 and p38. These data suggested that the apoptotic mechanism of UA treatment in HeLa cells was through the mitochondrial intrinsic pathway and closely associated with the suppression of the ERK1/2 signaling pathway.
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  • Belinda L. Ash, Tim Quach, Spencer J. Williams, Andrew J. Lawrence, El ...
    2014 Volume 125 Issue 2 Pages 211-216
    Published: June 20, 2014
    Released on J-STAGE: June 19, 2014
    Advance online publication: May 30, 2014
    JOURNAL FREE ACCESS
    The neuropeptide galanin has a role in promoting alcohol consumption and general feeding behavior. The galanin-3 receptor (GALR3) subtype is implicated in modulating the consumption of alcohol and has therefore been identified as a potential target for new pharmacotherapies to treat alcohol use disorders. We have previously shown that the selective GALR3 antagonist SNAP 37889 reduced voluntary alcohol consumption in iP (alcohol-preferring) rats. The present study firstly aimed to investigate the effect of GALR3 antagonism on the motivational properties of alcohol. Secondly, the potential of GALR3 as a therapeutic target in the prevention of relapse was investigated in response to alcohol-conditioned cues. Administration of SNAP 37889 (30 mg/kg, i.p.) significantly reduced the breakpoint for ethanol under a progressive-ratio operant responding schedule of reinforcement. SNAP 37889 also significantly reduced reinstatement of alcohol-seeking in response to re-exposure to conditioned cues that were previously associated with the availability of alcohol. Collectively, results from the current study provide new evidence of GALR3 involvement in cue-induced relapse and provide further evidence that GALR3 antagonism reduces the motivational drive to consume alcohol. These findings validate further research in to the potential use of SNAP 37889 and other GALR3 antagonists to treat alcohol abuse disorders in humans.
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  • Ayako Jinzenji, Chiharu Sogawa, Takuya Miyawaki, Xue-fang Wen, Dan Yi, ...
    2014 Volume 125 Issue 2 Pages 217-226
    Published: June 20, 2014
    Released on J-STAGE: June 19, 2014
    Advance online publication: May 30, 2014
    JOURNAL FREE ACCESS
    The GABAergic system in the spinal cord has been shown to participate in neuropathic pain in various animal models. GABA transporters (GATs) play a role in controlling the synaptic clearance of GABA; however, their role in neuropathic pain remains unclear. In the present study, we compared the betaine/GABA transporter (BGT-1) with other GAT subtypes to determine its participation in neuropathic pain using a mouse model of sciatic nerve ligation. 1-(3-(9H-Carbazol-9-yl)-1-propyl)-4-(2-methyoxyphenyl)-4-piperidinol (NNC05-2090), an inhibitor that displays moderate selectivity for BGT-1, had an antiallodynic action on model mice treated through both intrathecally and intravenous administration routes. On the other hand, SKF89976A, a selective GAT-1 inhibitor, had a weak antiallodynic action, and (S)-SNAP5114, an inhibitor that displays selectivity for GAT-3, had no antiallodynic action. Systemic analysis of these compounds on GABA uptake in CHO cells stably expressing BGT-1 revealed that NNC05-2090 not only inhibited BGT-1, but also serotonin, noradrenaline, and dopamine transporters, using a substrate uptake assay in CHO cells stably expressing each transporter, with IC50: 5.29, 7.91, and 4.08 μM, respectively. These values were similar to the IC50 value at BGT-1 (10.6 μM). These results suggest that the antiallodynic action of NNC05-2090 is due to the inhibition of both BGT-1 and monoamine transporters.
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Short Communication
  • Hiroaki Kito, Hisao Yamamura, Yoshiaki Suzuki, Susumu Ohya, Kiyofumi A ...
    2014 Volume 125 Issue 2 Pages 227-232
    Published: June 20, 2014
    Released on J-STAGE: June 19, 2014
    Advance online publication: May 23, 2014
    JOURNAL FREE ACCESS
    Upregulation of the Kir2.1 channel during endoplasmic reticulum (ER) stress in t-BBEC117, an immortalized bovine brain endothelial cell line, caused a sustained increase in intracellular Ca2+ concentration ([Ca2+]i) and a facilitation of cell death. Expressions of Ca2+ influx channels (TRPC, Orai1, STIM1) were unchanged by ER stress. The ER stress–induced [Ca2+]i increase was mainly attributed to the deeper resting membrane potential due to Kir2.1 upregulation. ER stress arrested at the G2/M phase and it was attenuated by an inhibitor of Kir2.1. These results indicate that Kir2.1 upregulation by ER stress facilitates cell death via regulation of cell cycle progression in t-BBEC117.
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  • Tomohisa Mori, Masahiko Funada, Yuko Tsuda, Jun Maeda, Masashi Uchida, ...
    2014 Volume 125 Issue 2 Pages 233-236
    Published: June 20, 2014
    Released on J-STAGE: June 19, 2014
    Advance online publication: May 30, 2014
    JOURNAL FREE ACCESS
    Genetic factors affect locomotor activity, which mainly depends on the activation of dopaminergic systems. C57BL/6J-bgJbgJ (beige-J) mice, which exhibit deficiencies in immunological function, show behavioral hyperactivity. The present study was designed to investigate the locomotor activity of beige-J mice accompanied by a change in the dopaminergic system. Beige-J mice showed higher locomotor activity and dopamine turnover, whereas splenectomy reduced this hyperlocomotion and dopamine turnover. These results suggest that beige-J mice could be suitable as an experimental animal model for investigating hyperactivation of the dopaminergic system, and the spleen may contribute to the susceptibility of dopaminergic systems to activation.
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