Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
Volume 42 , Issue 7
Showing 1-27 articles out of 27 articles from the selected issue
Reviews
  • Takuya Sasaki
    2019 Volume 42 Issue 7 Pages 1059-1063
    Published: July 01, 2019
    Released: July 01, 2019
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    The central nervous system controls the activity states of the peripheral organs in response to various environmental changes. However, the physiological interactions across multiple organs remain largely unknown. Recently, we have developed an electrophysiological recording system that simultaneously captures neuronal population activity patterns in the brain, heartbeat signals, muscle contraction signals, respiratory signals, and vagus nerve action potentials in freely moving rodents. This paper summarizes several recent insights obtained from this recording system, including the observations that some but not all brain activity patterns are associated with peripheral organ activity in a behavioral test, and that functions across cortical networks can predict stress-induced changes in cardiac function in rats. The evidence suggests that adding information on peripheral physiological signals to behavioral data assists in a more accurate estimation of animals’ mental states. The concept of such a research approach opens a new field of large-scale analysis of systemic physiological signals, termed “physiolomics,” which is expected to unveil further physiological issues involving mind–body associations in health and disease.

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  • Keisuke Obara, Yoshio Tanaka
    2019 Volume 42 Issue 7 Pages 1064-1068
    Published: July 01, 2019
    Released: July 01, 2019
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    Distigmine bromide (distigmine) is a reversible carbamate cholinesterase (ChE) inhibitor. Its principle clinical application is in the treatment of myasthenia gravis. Distigmine is also used as a remedy for dysuria and glaucoma. Its effectiveness in the management of dysuria has been demonstrated in several clinical reports. Distigmine may improve (enhance) urinary bladder smooth muscle (UBSM) contraction during micturition by inhibiting acetylcholine (ACh) decomposition. However, the pharmacological effects of distigmine on UBSM have not been adequately studied so far. In this review article, we summarize the reported effects of distigmine on the contractile responses elicited by exogenous and endogenous ACh in isolated UBSM preparations. We also discuss the effects of distigmine on the UBSM basal tone and the contractile response of UBSM to ATP, which is co-released with ACh from parasympathetic nerve terminals.

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Current Topics - The Target Factor of Heavy Metal Toxicity and Its Molecular Mechanism
Current Topics: Reviews
  • Haruna Tamano, Atsushi Takeda
    2019 Volume 42 Issue 7 Pages 1070-1075
    Published: July 01, 2019
    Released: July 01, 2019
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    The basal concentrations of extracellular Zn2+ and intracellular Zn2+, which are approximately 10 nM and 100 pM, respectively, in the brain, are markedly lower than those of extracellular Ca2+ (1.3 mM) and intracellular Ca2+ (100 nM), respectively, resulting in much less attention paid to Zn2+ than to Ca2+. However, intracellular Zn2+ dysregulation, which is closely linked with glutamate- and amyloid β-mediated extracellular Zn2+ influx, is more critical for cognitive decline and neurodegeneration than intracellular Ca2+ dysregulation. It is estimated that the age-dependent increase in the basal concentration of extracellular Zn2+ in the hippocampus plays a key role in cognitive decline and neurodegeneration. The characteristics of extracellular Zn2+ influx in the hippocampus may be modified age-dependently, probably followed by modification of intracellular Zn2+ buffering that is closely linked with age-related cognitive decline and neurodegeneration. Reduction of intracellular Zn2+-buffering capacity may be linked with the pathophysiology of progressive neurodegeneration such as Alzheimer’s disease. This paper deals with age-dependent modification of intracellular Zn2+ buffering in the hippocampus and its impact. On the basis of the estimated impact, we propose a potential defense strategy against Zn2+-mediated neurodegeneration, i.e., metallothionein induction in the hippocampus.

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  • Hitomi Fujishiro, Seiichiro Himeno
    2019 Volume 42 Issue 7 Pages 1076-1082
    Published: July 01, 2019
    Released: July 01, 2019
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    ZIP8, a Zrt-/Irt-related protein encoded by Slc39A8, was originally discovered as a zinc transporter, but since then its roles as a transporter for cadmium (Cd) and manganese (Mn) have also been well characterized. ZIP8 is highly expressed in the S3 segment of the proximal tubules of the mouse kidney and may play a significant role in reabsorption of both toxic Cd and essential Mn from the lumen to the epithelial cells of the proximal tubule. In recent years, associations between various human diseases and genetic variations of ZIP8 have been reported. Missense mutations in the human SLC39A8 gene are associated with serious disorders of Mn metabolism, showing symptoms similar to congenital glycosylation deficiency. Enhanced excretion of Mn via bile or urine might be the cause of extremely low blood Mn levels in ZIP8-mutated patients, leading to the defects in Mn-dependent glycosylation. Several genome-wide association studies have demonstrated the associations of multiple diseases and ZIP8 SNPs constituting missense mutations. These findings suggest that ZIP8 plays more important roles than previously expected as a modulator of Mn homeostasis in the body. Elucidation of biochemical mechanisms regarding the metal-transporting ability of ZIP8 and its alteration by mutation is required for better understanding of the role of ZIP8 in human diseases.

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  • Maki Tokumoto, Jin-Yong Lee, Masahiko Satoh
    2019 Volume 42 Issue 7 Pages 1083-1088
    Published: July 01, 2019
    Released: July 01, 2019
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    Cadmium (Cd) is a harmful heavy metal widely present in the environment which can cause severe kidney damage. The proximal tubular cells are the main target of renal Cd toxicity. The consequences of Cd cytotoxicity involve apoptosis and necrosis. Recently, we and others have focused on how Cd affects transcription factors and the regulation of their target genes. Those studies showed that transcription factors initiate numerous pathways upon Cd exposure, leading to apoptosis, autophagic cell death, disruption of cell–cell adhesion, and generation of mitochondrial reactive oxygen species. Of particular note, Cd induces endoplasmic reticulum stress, resulting in not only apoptosis but also autophagic dysregulation, which can trigger cell damage. In some cases, however, Cd-regulated transcription factors can induce cell survival signaling. This review centers on our own research to elucidate the transcription factor-downstream gene cascades that are central to Cd-induced renal toxicity.

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Current Topics: Regular Article
  • Kayoko Kita, Yu Imai, Nanami Asaka, Toshihide Suzuki, Takafumi Ochi
    2019 Volume 42 Issue 7 Pages 1089-1097
    Published: July 01, 2019
    Released: July 01, 2019
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    Thio-dimethylarsinic acid (thio-DMA) was detected in human urine after exposure to inorganic arsenic and arsenosugars consumed by marine algae. Our previous studies have shown that thio-DMA disturbed the cell cycle progression and arrested cells in mitosis, though the biological significance or the mechanism by which thio-DMA-induced mitotic phase accumulation occurs is yet to be understood. In this study, we showed that thio-DMA promotes the phosphorylation of BubR1 protein, which is one of the constituents of the spindle assembly checkpoint (SAC) complex and accumulates in the cell in mitotic phase. Binding of Mad2 to CDC20, also known as the marker of the mitotic checkpoint complex (MCC) formation during the activation of SAC, was enhanced and mitotic associated cell death by apoptosis was promoted in HeLa cells but not in HepG2 cells. Basal BubR1 protein level in HepG2 was 10-times lower than that of HeLa cells. Consequently, BubR1 knockdown HeLa cells were generated by small interfering RNA (siRNA) technique. The MCC formation and mitotic arrest induced by thio-DMA were completely inhibited in BubR1 knockdown cells. Moreover, BubR1 knockdown cells could survive in the medium containing higher concentrations of thio-DMA with some abnormalities such as larger cell size, huge nucleus, multiple nuclei, and abnormal DNA contents. Especially, cyclin B1 negative tetraploid cells, which signify interphase cells with tetraploid, increased and survived after 48–72 h treatment with thio-DMA. Thus, these results suggest that BubR1-mediated SAC activation and MCC formation are one of the defense systems for preventing the accumulation and survival of abnormal cells induced by thio-DMA.

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Communication to the Editor
  • Miko Taniguchi, Masakazu Hatano, Hiroyuki Kamei, Risa Inagaki, Shigeki ...
    2019 Volume 42 Issue 7 Pages 1098-1101
    Published: July 01, 2019
    Released: July 01, 2019
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    Long-acting injection (LAI) is a drug administration method that reduces symptoms and prevents recurrence or relapse of schizophrenia. We examined factors related to the continuation of LAI treatment. The study population included patients with schizophrenia who were undergoing LAI treatment involving risperidone, paliperidone, or aripiprazole at Fujita Health University Hospital between October 2009 and June 2017. We assessed the continuation rate of LAI treatment at six months, and collected patient characteristics such as medication history. Furthermore, we classified patients into two clusters according to the reason for introducing LAI based on a previous study (Prog. Neuropsychopharmacol. Biol. Psychiatry, 2008, Heres et al.). The study included 82 patients (mean age, 44.9 ± 15.0 years); the continuation rate of LAI after six months was 63.4%. Factors that affected LAI continuation included cluster II [adjusted odds ratio (OR): 5.74, p = 0.017], switching from the same component as LAI (adjusted OR: 7.13, p < 0.001), and diazepam conversion rate (adjusted OR: 0.88, p < 0.001). LAI significantly improved the continuation rate of treatment in the patient group belonging to cluster II. Furthermore, based on other factors and reasons for discontinuation, LAI should be preferably commenced in patients with a more stable condition.

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Regular Articles
  • Zhengyi Zhang, Changhong Lu, Ying Meng, Qiongying Wang, Xiaoli Guan, J ...
    2019 Volume 42 Issue 7 Pages 1102-1111
    Published: July 01, 2019
    Released: July 01, 2019
    [Advance publication] Released: March 14, 2019
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    This study aimed to evaluate the effects of combined use of tetrahydrobiopterin (BH4) and nebivolol on cardiac diastolic dysfunction in spontaneously hypertensive rats (SHRs). Twelve-week-old male SHRs were treated with BH4, nebivolol, or a combination of both. Left ventricle function was evaluated, and reactive oxygen species (ROS) production (including dihydroethidium (DHE) and 3-nitrotyrosine (3-NT)), nitric oxide synthase (NOS) activity and the level of NO in myocardial tissue were determined. The expression levels of endothelial NOS (eNOS), phospholamban (PLN), sarcoplasmic reticulum Ca2+ ATPase (SERCA2a), β3-adrenoceptor, cyclic guanosine monophosphate (cGMP), and protein kinase G (PKG) were assayed. Treatment with BH4, nebivolol, or both reversed the noninvasive indexes of diastolic function, including E/E′ and E′/A′, and the invasive indexes, including time constant of isovolumic left ventricle (LV) relaxation (tau), −dP/dtmin, −dP/dtmin/LV systolic pressure (LVSP), and LV end-diastolic pressure (LVEDP) in SHRs. mRNA and protein expression levels of eNOS dimer, phosphorylated PLN, SERCA2a, cGMP, and PKG in the myocardium of treated SHRs were significantly up-regulated compared with those in control rats (p < 0.05 or p < 0.01). The expression levels of 3-NT and DHE were reduced in all treated groups (p < 0.05 or p < 0.01). Notably, combined use of BH4 and nebivolol had better cardioprotective effects than monotherapies. BH4 or nebivolol has a protective effect on diastolic dysfunction in SHRs, and BH4 combined with nebivolol may exert a synergistically cardioprotective effect through activation of β3-adrenoceptor and the NO/cGMP/PKG signaling pathway.

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  • Canhong Wang, Shuai Wang, Deqian Peng, Zhangxin Yu, Peng Guo, Jianhe W ...
    2019 Volume 42 Issue 7 Pages 1112-1119
    Published: July 01, 2019
    Released: July 01, 2019
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    Agarwood is used to treat gastrointestinal diseases. Although our previous studies demonstrated that agarwood ethanol extract produced by the whole-tree agarwood-inducing technique (WTAAE) improves intestinal peristalsis, the intestinal protective effect of WTAAE remains unclear. This study aimed to evaluate the protective effect of WTAAE on the intestinal injury induced by fluorouracil (5-FU) and explore its potential mechanism. Institute of Cancer Research (ICR) mice were given agarwood ethanol extracts (AAEs) (details in materials part), including WTAAE (0.71, 1.42 and 2.84 g/kg), wild agarwood ethanol extract (WAAE) and burning-chisel-drilling agarwood ethanol extract (FBAAE) (2.84 g/kg). A colon injury model was induced by 5-FU. After 14 d of treatment, the histopathology and biochemical and molecular parameters were measured. Our results indicated that WTAAE enhanced the intestinal advancing rate and alleviated the severity of colon injury similar the WAAE and better than FBAAE. Simultaneously, WTAAE reduced the nitric oxide (NO) concentration and increased the glutathione (GSH) and superoxide dismutase (SOD) levels. WTAAE also reduced the levels of interleukin-17 (IL-17) and IL-33 and elevated the level of IL-10. Furthermore, WTAAE upregulated the mRNA expression of the nuclear factor-E2-related factor 2–antioxidant response element (Nrf2–ARE) pathway and downregulated the mRNA levels of the nuclear factor-kappaB (NF-κB) pathway. WTAAE had a mitigating effect on intestinal damage, suggesting that it could be used as an intestinal protective and adjuvant therapy drug for intestinal injury induced by chemical drugs.

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  • Yutaka Yonezawa, Tohru Kihara, Kanata Ibi, Masanori Senshu, Hiroaki Ne ...
    2019 Volume 42 Issue 7 Pages 1120-1127
    Published: July 01, 2019
    Released: July 01, 2019
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    Hydroxytyrosol (HT) is a simple phenol compound present in olive oil. In a previous in vitro study, we showed that HT downregulated lipopolysaccharide-mediated expression of inducible nitric oxide synthase, cyclooxygenase-2 (COX-2), tumor necrosis factor alpha, and interleukin-1β, resulting in reduced nitric oxide and prostaglandin E2 production. In the present study, we aimed to determine whether HT suppresses COX-2-induced inflammation in a carrageenan-induced rat paw edema model. Additionally, we compared its activity with those of the selective COX-2 inhibitor, celecoxib for a comparative control, and a representative nonsteroidal anti-inflammatory drug (NSAID), indomethacin for a positive control. HT, celecoxib, and indomethacin significantly suppressed swelling in carrageenan-injected rat paws. Although HT was less effective than celecoxib and indomethacin, it had a delayed onset of action. Moreover, we evaluated whether HT aggravates gastric damage, which is a typical adverse effect associated with NSAIDs and COX-2 inhibitors under low dose aspirin (LDA) treatment, in an aspirin-induced gastric damage rat model. Unlike celecoxib and indomethacin, HT did not cause gastric damage when co-administered with aspirin. Our results indicate that HT exerts a delayed but sustained anti-inflammatory effect against COX-2-mediated inflammation. Finally, the combination of short-acting conventional anti-inflammatory drugs and long-acting HT can be considered a new, safe, and effective anti-inflammatory treatment modality even when continuously administered for a long period under LDA treatment.

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  • Tomoaki Ishida, Michiro Iizuka, Yanglan Ou, Shunpei Morisawa, Ayumu Hi ...
    2019 Volume 42 Issue 7 Pages 1128-1133
    Published: July 01, 2019
    Released: July 01, 2019
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    In diabetic patients, skeletal muscle atrophy occurs due to increased oxidative stress and inflammation. Skeletal muscle atrophy reduces the QOL of patients and worsens life prognosis. Therefore, development of preventive therapy for muscle atrophy in hyperglycemic state is eagerly awaited. Juzentaihoto is a medicinal herb that has a function to supplement physical strength, and it is expected to prevent muscle atrophy. To determine the preventive effect of juzentaihoto on muscle atrophy in hyperglycemic state, streptozotocin (STZ) was administered to induce diabetes in mice and the preventive effect of juzentaihoto was evaluated. Mice that received juzentaihoto extract (JTT) showed that the decrease in muscle fiber cross-sectional area in the gastrocnemius muscle was reversed. Additionally, the expression level of tumor necrosis factor α (TNF-α), an inflammatory cytokine, in serum decreased, and that of ubiquitin ligase (atrogin-1, muscle RING-finger protein-1) mRNA in skeletal muscle decreased. An anti-inflammatory cytokine interleukin-10 showed increased levels in the serum and increased levels in spleen cell culture supernatant collected from mice that received JTT. JTT had no effect on the blood glucose level. These results suggest that prophylactic administration of JTT to STZ-induced diabetic mice affects immune cells such as in spleen, causing an anti-inflammatory effect and inhibiting excessive activation of the ubiquitin-proteasome system, to reverse muscle atrophy.

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  • Masahiko Imai, Hiromasa Yokoe, Masayoshi Tsubuki, Noriko Takahashi
    2019 Volume 42 Issue 7 Pages 1134-1139
    Published: July 01, 2019
    Released: July 01, 2019
    [Advance publication] Released: April 12, 2019
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    Cancer is the leading cause of death and there is a particularly pressing need to develop effective treatments for breast and prostate cancer. In the current study, we show the inhibitory effects of cinnamic acid derivatives, including caffeic acid phenethyl ester (CAPE, 1), on the growth of breast and prostate cancer cells. Among the compounds examined, 3,4,5-trihydroxycinnamic acid decyl ester (6) showed the most potent inhibition of cancer cell growth by the induction of apoptosis. Compound 6 could be a new anti-cancer agent for use against breast and prostate cancer.

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  • Takuya Ohba, Shinichi Domoto, Miyu Tanaka, Shinsuke Nakamura, Masamits ...
    2019 Volume 42 Issue 7 Pages 1140-1145
    Published: July 01, 2019
    Released: July 01, 2019
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    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by disabling fatigue of at least 6 months, in addition to symptoms such as muscle pain and muscle weakness. There is no treatment provides long-term benefits to most patients. Recently, clinical research suggested the involvement of pyruvate dehydrogenase (PDH) in ME/CFS. PDH is a crucial enzyme in the mitochondria matrix that links glycolysis to the tricarboxylic acid cycle and oxidative phosphorylation. However, it is little known whether PDH could be a therapeutic target. The purpose of this study was to establish ME/CFS in mice and to investigate the involvement of PDH in ME/CFS. To induce the chronic fatigue in mice, a repeated forced swimming test was conducted. To evaluate fatigue, we measured immobility time in forced swimming test and starting time of grooming. An open field test was conducted on day 8. After 25 d of the forced swimming test, the mitochondrial fraction in gastrocnemius muscle was isolated and PDH activity was measured. Moreover, we evaluated the effect of PDH activation by administering sodium dichloroacetate (DCA). In ME/CFS mice group, the immobility time and starting time of grooming increased time-dependently. In addition, the moved distance was decreased in ME/CFS mice. PDH activity was decreased in the mitochondrial fraction of the gastrocnemius muscle of the forced swimming group. DCA treatment may be beneficial in preventing fatigue-like behavior in ME/CFS. These findings indicate that ME/CFS model was established in mice and that a decrease in mitochondrial PDH activity is involved with the symptom of ME/CFS.

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    Editor’s picks

    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has few beneficial treatments for patients.  Recently, the involvement of pyruvate dehydrogenase (PDH) in ME/CFS has been reported.  However, it is little known whether PDH could be a therapeutic target of ME/CFS.  In this paper, Ohba et al. established ME/CFS model in mice and investigated the involvement of PDH.  In an ME/CFS group, PDH activity was decreased in the mitochondrial fraction of the gastrocnemius muscle.  Sodium dichloroacetate (DCA), which is a PDH activator, recovered fatigue-like behavior in ME/CFS group.  These findings indicate that PDH might be an important therapeutic target for treatment of ME/CFS.




  • Xu-Yi Li, Wei-Wei Qi, Yuan-Xiang Zhang, Si-Yan Jiang, Bin Yang, Lei Xi ...
    2019 Volume 42 Issue 7 Pages 1146-1154
    Published: July 01, 2019
    Released: July 01, 2019
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    Helicid (4-formylphenyl-O-β-D-allopyranoside), an active component found in seeds from the Chinese herb Helicia nilagirica, has been reported to exert sedative, analgesic, hypnotic and antidepressant effects. The present study was designed to evaluate the antidepressant, learning and cognitive improvement effects of helicid in a chronic unpredictable mild stress (CUMS) model of depression in rats and to explore cAMP/protein kinase A (PKA)/cAMP response element-binding (CREB) signaling pathway. Sprague-Dawley rats were randomly assigned to six groups (n = 10): control; CUMS; CUMS + fluoxetine (5 mg/kg) and CUMS + helicid at 8, 16 and 32 mg/kg. All rats were subjected to 12 weeks of CUMS protocols and drug administration during the last 6 weeks of CUMS. Our results showed that helicid, at a dose of 32 mg/kg, significantly reversed decreases in body weight and sucrose consumption, increased the distance and number of crossings in the open-field test (OFT), reduced immobility times in the forced swimming test (FST) and improved spatial memory in the Morris water maze (MWM); all of these effects had been induced by CUMS paradigm. Immunohistochemistry showed that administration of helicid could promoted the proliferation of neurons in the hippocampal CA1 and dentate gyrus (DG) regions. CUMS rats treated with helicid had dramatically decreased protein levels of serotonin transporters (SERTs). In addition, CUMS resulted in a significant reduction in the expression of cAMP, PKA C-α and p-CREB, each of which were partially attenuated by helicid administration. These results indicated that helicid could improve depressive behaviors, learning and cognitive deficits and increase hippocampal neurogenesis, which may be mediated by the regulation of SERTs, activation of the cAMP/PKA/CREB signaling pathway and upregulation of p-CREB levels in hippocampal.

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  • Hiraku Onishi, Yuri Ikeuchi-Takahashi, Kumi Kawano, Yoshiyuki Hattori
    2019 Volume 42 Issue 7 Pages 1155-1163
    Published: July 01, 2019
    Released: July 01, 2019
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    A conjugate between chondroitin sulfate (CS) and glycyl-prednisolone (GP), named CS-GP, was produced by carbodiimide coupling at a high GP/CS ratio. CS-GP was not water-soluble and gave a nanogel (NG) in aqueous solution. Two types of nanogels, NG(I) and NG(II), with prednisolone (PD) contents of 5.5 and 21.1% (w/w), respectively, were obtained. They had particle sizes of approximately 280 and 570 nm, respectively, and showed negative ζ-potentials of approximately −40 mV. The PD release rate was slower in the nanogels than in a solution of CS-GP with a PD content of 1.4% (w/w). The PD release rate was slower in NG(II) than in NG(I), and was elevated at pH 7.4 than at pH 6.8. NG(II) was applied in vivo to rats with trinitrobenzene sulfonic acid (TNBS)-induced colitis, and its therapeutic efficacy and pharmacokinetic features were investigated. The therapeutic efficacy of NG(II) was slightly better than that of PD alone. Drug delivery to the lower intestines was enhanced with NG(II). The CS-GP nanogel has potential as a potent DDS for the treatment of ulcerative colitis.

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  • Shinya Suzuki, Mayako Uchida, Yukio Suga, Hideki Sugawara, Hideya Koku ...
    2019 Volume 42 Issue 7 Pages 1164-1171
    Published: July 01, 2019
    Released: July 01, 2019
    [Advance publication] Released: April 17, 2019
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    No nationwide study on polypharmacy in palliative care among Japanese community pharmacies has yet been conducted. We conducted an online questionnaire survey for community pharmacist members of The Japanese Society for Pharmaceutical Palliative Care and Sciences regarding their contributions to cancer patients who regularly used six or more drugs, including opioids, in service during the two-month period from October to November 2017. Of 579 community pharmacists, 83 responded to the survey (14.3%). Among them, 47.0 and 27.7% of respondents replied that more than 40% of opioid-using and non-using cancer patients were prescribed six or more regular medications, respectively. The proportion of patients with polypharmacy was marginally higher among opioid-using than non-using patients. Additionally, 31.3 and 22.9% of respondents replied that a low or moderate rate of opioid-using and non-using patients with polypharmacy received inappropriate prescriptions, respectively, including “unnecessary medications,” “adverse drug reactions” and “duplication of pharmacological effect.” The proportion of patients who received inappropriate prescriptions was significantly higher among opioid-using than non-using patients. Furthermore, 37.3 and 19.3% of respondents replied that pharmacist’s recommendations contributed to drug reduction in opioid-using and non-using patients with polypharmacy who received inappropriate prescriptions, respectively. The responders with higher confidence in palliative care showed more success rate for reducing inappropriate medications. Our findings suggest that opioid use can be associated with an increased risk of polypharmacy in cancer patients, and that recommendations by a population of community pharmacists can reduce inappropriate medications and improve adverse drug reactions in both opioid-using and non-using cancer patients with polypharmacy.

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  • Qiaomei Dai, Meiqiao Wang, Yaozhang Li, Ji Li
    2019 Volume 42 Issue 7 Pages 1172-1178
    Published: July 01, 2019
    Released: July 01, 2019
    [Advance publication] Released: April 23, 2019
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    To study the role of asarinin on collagen-induced arthritis (CIA) and its treatment mechanism on dendritic cells (DCs) and T cells. Before the onset of arthritis, asarinin were given orally to CIA mouse. Macroscopic scoring and micrometer caliper measurement were used to assess arthritis. The occurrence of cartilage destruction and bone erosion were assessed by histology of knee. Sandwich enzyme-linked immunosorbent assay (ELISA) and PCR were used to assess the level of cytokines in hindpaw and arthritic joint. The CD11c MicroBeads were employed to isolate CD11c+ cells from the spleen. Quantitative PCR was used to determine DCs surface molecules of spleen. Macroscopic score and the frequency of arthritis were inhibited by asarinin. Swelling of hindpaws, inflammatory cell infiltration in the synovium, cartilage destruction, and bone erosion were delayed with asarinin. Asarinin treatment suppressed the expression of T helper type 1 (Th1) cytokines and increased the levels of Th2 cytokines (interleukin (IL)-10), transforming growth factor (TGF)-β and Foxp3 in the synovium and hindpaw, however T-bet mRNA levels in synovium decreased. Lower expression of toll-like receptor 9 (TLR9) and nuclear factor-kappaB (NF-κB) were found in DCs after asarinin treatment. There was no difference in the expression of intercellular cell adhesion molecule-1(ICAM-1), OX40-L, and 4-1BBL in spleen DCs between the asarinin group and model control group. Asarinin can treat CIA. TLR9/NF-κB pathway may be involved in the asarinin treatment of CIA by skewing the balance of Th1/Th2/regulatory T (Treg) to a Th2 type.

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  • Tomohiro Arakawa, Haruki Okubo, Midori Mae, Tomofumi Okuno, Hirofumi O ...
    2019 Volume 42 Issue 7 Pages 1179-1184
    Published: July 01, 2019
    Released: July 01, 2019
    [Advance publication] Released: April 12, 2019
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    The effect of seleno-L-methionine (SeMet) on immunoglobulin (Ig) E-mediated allergic responses were investigated using rat basophilic leukemia RBL-2H3 cells. Cells were first treated with or without SeMet, sensitized with anti-dinitrophenyl IgE and stimulated with the antigen dinitrophenyl-human serum albumin, before the measurement of degranulation, calcium mobilization, mRNA expression and protein secretion of interleukin (IL)-4 and tumor necrosis factor (TNF)-α, and phosphorylation of spleen tyrosine kinase (Syk), Akt, and mitogen-activated protein kinases (MAPKs). The antigen-induced β-hexosaminidase release, a degranulation marker, was significantly inhibited by SeMet treatment. SeMet also significantly suppressed antigen-induced calcium mobilization. Antigen-induced increases in the mRNA expression and protein secretion of IL-4 and TNF-α were both significantly attenuated by SeMet treatment. In addition, SeMet significantly suppressed antigen-induced phosphorylation of Syk, Akt, and MAPKs. These results demonstrate that SeMet suppresses antigen-induced degranulation, and mRNA expression and protein secretion of IL-4 and TNF-α, and inhibits antigen-induced mobilization of calcium and activation of Syk, Akt, and MAPKs. Our study provides valuable information that may be useful in the prevention and treatment of allergic diseases.

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  • Hideki Sugawara, Mayako Uchida, Shinya Suzuki, Yukio Suga, Yoshihiro U ...
    2019 Volume 42 Issue 7 Pages 1185-1191
    Published: July 01, 2019
    Released: July 01, 2019
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    Opioid-induced respiratory depression is a potentially life-threatening adverse drug event. The purpose of this study was to evaluate the incidence of respiratory depression using the Japanese Adverse Drug Event Report (JADER) Database to obtain data to promote proper use of opioids. The JADER database from April 2004 to March 2017 was obtained from the Pharmaceuticals and Medical Devices Agency. We calculated the reporting odds ratios (RORs) of suspected opioids (morphine, fentanyl, oxycodone, tapentadol, methadone, tramadol, pentazocine, buprenorphine, and codeine phosphate hydrate), analyzed the daily dose at first appearance and the time-to-onset profile, and assessed the hazard type using the Weibull shape parameter. ROR analysis detected adverse event signals for all opioids. Morphine showed a large ROR value with statistical significance in elderly (≥70 years old) patients. The median daily doses of oral morphine and oxycodone for inducing respiratory depression were comparably low (30 mg/d as oral morphine equivalent dose), while that of transdermal fentanyl was 120 mg/d (oral morphine equivalent dose). On time-to-onset analysis using the Weibull distribution, those opioids were classified as the early failure type. The median time-to-onset of oral morphine, oral oxycodone and transdermal fentanyl was 5.5, 11 and 12.5 d, respectively, and almost 50% of cases were reported within 30 d. Taken together, our results suggest that it is important to monitor patients carefully for at least the first one week to one month, even if opioids are administered at a relatively low dose, especially in elderly patients administered morphine.

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  • Toshinori Hirai, Yutori Ishikawa, Yuya Kawagoe, Yukari Ogawa, Ryuichi ...
    2019 Volume 42 Issue 7 Pages 1192-1198
    Published: July 01, 2019
    Released: July 01, 2019
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    Although recurrent falls during hospitalization lead to discharge to nursing homes, their association with medications has not been comprehensively assessed. We aimed to assess risk factors for recurrent falls focusing on medications during hospitalization in an acute-care setting. This retrospective descriptive study was conducted in Tokyo Women’s Medical University, Medical Center East. Patients who experienced a fall during hospitalization were included and the incidence of recurrent falls was assessed during hospitalization. Multivariate logistic regression analysis was performed to assess the relationship between recurrent falls and medications and to calculate odds ratio and 95% confidence interval. Sensitivity analysis was performed on data stratified by sex or age. This study included 124 patients with an incidence of 20 (16%) recurrent falls. Multivariate logistic regression analysis revealed that selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and noradrenergic and specific serotonergic antidepressants were associated with recurrent falls (odds ratio = 5.98, 95% confidence interval: 1.38–25.9, p = 0.02). Additionally, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and noradrenergic and specific serotonergic antidepressants were significant risk factors for recurrent falls in women and those aged > 80 years. Selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and noradrenergic and specific serotonergic antidepressants were associated with an increased risk of recurrent falls during hospitalization in an acute-care setting. Clinicians should pay attention to patients receiving selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and noradrenergic and specific serotonergic antidepressants, especially women and aged > 80 years old.

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  • Tianli Zhang, Jun Fang, Hiroyasu Tsutsuki, Katsuhiko Ono, Waliul Islam ...
    2019 Volume 42 Issue 7 Pages 1199-1206
    Published: July 01, 2019
    Released: July 01, 2019
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    Metalloporphyrin derivatives have been investigated for their therapeutic potential for oxidative stress-related diseases because of their scavenging of reactive oxygen species (ROS). Here, we describe the synthesis, physicochemical properties, and ROS-scavenging activities of one such derivative—polyethylene glycol (PEG)-conjugated manganese protoporphyrin (PEG-MnPP). Carboxyl groups of the protoporphyrin ring at the C6 and C7 positions were first conjugated with ethylenediamine to introduce amino groups into the protoporphyrin structure. The amino groups were then reacted with succinimidyl PEG, with an average molecular weight of 2000, to obtain pegylated protoporphyrin (PEG-PP). Manganese was chelated to the protoporphyrin ring by incubating PEG-PP and manganese acetate in methanol. Dynamic light scattering and fluorescent spectrometry analyses revealed that PEG-MnPP self-assembled into nanoparticles in aqueous media with an apparent diameter of 70 nm. PEG-MnPP effectively eliminated hydrogen peroxide from cell culture media and protected cultured mammalian cells from toxic insults induced by hydrogen peroxide exposure or by 6-hydroxydopamine treatment. Intravenous administration of PEG-MnPP to mice significantly suppressed acute liver failure that had been induced by acetaminophen overdose. These data warrant additional investigation to study the therapeutic potential of PEG-MnPP as a water-soluble metalloporphyrin-based catalase mimic for oxidative stress-associated diseases.

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  • Kritsanaporn Tansathien, Puvamin Suriyaaumporn, Ponwanit Charoenputtak ...
    2019 Volume 42 Issue 7 Pages 1207-1215
    Published: July 01, 2019
    Released: July 01, 2019
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    Sponge spicules are needle-like structures and used for dermabrasive treatment of the skin. This research aimed to develop an effective delivery system by using sponge spicules for enhancing skin permeation of bioactive proteins and growth factors from deer antler velvet (DAV). DAV was extracted by sonication and bioactivity studies were evaluated. The size of microspicules (MSs) was reduced and mixed with DAV extract cream. In vitro skin permeation was analyzed by using bovine serum albumin–fluorescein isothiocyanate conjugate (BSA–FITC) as a model macromolecular compound. For in vivo study, DAV extract formulations were applied on the skin of healthy humans, and effects were evaluated. Results showed that DAV extract containing proteins and growth factors increased the proliferation and migration of skin fibroblast cells. This extract was homogeneously mixed with spicule cream. Without blending, MS was 11.89 µm wide and 176.77 µm long; blending time exhibited short and broken MSs (MBs) for short blending (30 s) and fine powder (MF) for long blending (10 min). MS cream showed the highest permeation of BSA–FITC through the skin (2.26-fold enhancement), but it resulted in skin irritation. Therefore, MB cream that increased the permeation of BSA–FITC by 1.94-fold was not significantly different from MS formulations chosen for in vivo study. Applying DAV-containing MB cream on the skin for 14 d decreased the melanin content and erythema value but increased elasticity and hydration. Therefore, the MB-containing cream can enhance the macromolecule delivery through the skin, improve the skin properties, and avoid skin irritation.

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  • Hisako Ibaraki, Takanori Kanazawa, Takumi Kurano, Chihiro Oogi, Yuuki ...
    2019 Volume 42 Issue 7 Pages 1216-1225
    Published: July 01, 2019
    Released: July 01, 2019
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    Small interfering RNA (siRNA) has been proposed as a novel treatment for atopic dermatitis (AD) because it suppresses sequence-specific mRNA expression. Indeed siRNA-based therapy achieves an almost complete cure with fewer side effects than currently available treatments. However, the tight junctions in the granular layer of the epidermis in the atopic skin are barriers to siRNA delivery. We previously reported the potential clinical utility of AT1002, a peptide that opens tight junctions. In the present study, we evaluated a topical siRNA-based therapy for AD using AT1002 in combination with a flexible liposome. The 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)/cholesteryl hemisuccinate (CHEMS) liposome was chosen as a carrier for siRNA because of its highly flexible structure and permeability. We prepared siRNA-encapsulated DOPE/CHEMS liposomes and examined their physical properties, safety, uptake into RAW264.7 cells, and topical application in healthy and AD-affected skin. We then assessed the efficacy of anti-nuclear factor-kappa B (NF-κB) (RelA) siRNA (siRelA)-encapsulated DOPE/CHEMS liposomes with AT1002 in AD model mice. The siRNA-DOPE/CHEMS liposomes were absorbed significantly better than siRNA alone and they enhanced siRNA skin penetration without toxicity. Moreover, siRelA-DOPE/CHEMS liposomes with AT1002 alleviated AD symptoms and reduced the levels of inflammatory cytokines in AD model mice. Therefore, the combination of AT1002 and DOPE/CHEMS liposomes could be a dermally applied RNA interference therapeutic system for effective RNA delivery and AD treatment.

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Notes
  • Kosuke Doki, Sándor Apáti, Takeshi Sakata, Masato Homma
    2019 Volume 42 Issue 7 Pages 1226-1229
    Published: July 01, 2019
    Released: July 01, 2019
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    Flecainide, an anti-arrhythmic drug, undergoes renal excretion through active renal tubular secretion in addition to passive glomerular filtration. The contribution of renal uptake and efflux transporters in active renal tubular secretion of flecainide remains unclear except that flecainide is a substrate of human multidrug resistance protein 1 (MDR1). To elucidate renal efflux and uptake transporters involved with active renal tubular secretion of flecainide, we conducted in vitro interaction studies of flecainide using organic cation transporter 2 (OCT2), multidrug and toxin extrusion (MATE) 1, and MATE2-K. Uptake transporter inhibition assays using hOCT2-Chinese hamster ovary (CHO), hMATE1-CHO, and hMATE2-K-Madin Darby canine kidney strain II (MDCKII) cells revealed that flecainide (2.5 µM) inhibited hMATE1-mediated transport by 40% with an IC50 value of 6.7 µM; however, it showed no or weak inhibitory effects on hOCT2- and hMATE2-K-mediated transport. For investigating flecainide as a substrate of hMATE1, the accumulation of flecainide in hMATE1-CHO was compared with that in control cells. Uptake transporter substrate assay revealed that flecainide (1 µM) showed 1.11-fold accumulation though the hMATE1-related active transport was significantly decreased in the presence of quinidine (42.0 ± 23.9 vs. 11.8 ± 4.1 pmol/mg in transfected cells; p < 0.05). These results suggest that flecainide is a weak substrate of hMATE1, which is involved in the renal tubular secretion of cationic drugs, and hMATE1 may be less important in the pharmacokinetic drug–drug interaction for renal excretion of flecainide. However, in vivo drug–drug interaction studies of flecainide with substrates of hMATE1 may be needed because flecainide has the potential to inhibit hMATE1.

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  • Umi Okura, Naohide Hirashima, Masahiko Tanaka
    2019 Volume 42 Issue 7 Pages 1230-1235
    Published: July 01, 2019
    Released: July 01, 2019
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    Calcineurin is a Ca2+/calmodulin-dependent protein phosphatase abundantly expressed in the nervous system. To investigate the roles of calcineurin in glial cells, we previously generated glial calcineurin B1-conditional knockout (CKO) mice and found that these mice displayed dysfunction of enteric glial cells, mucosal degeneration and inflammation in the small intestine, and growth retardation and postweaning death, suggesting a novel role of calcineurin in enteric glial cells. Although these findings raised a possibility that abnormalities in calcineurin B1-deficient enteric glial cells may cause dysregulation of gastrointestinal motility and result in maldigestion and/or malabsorption in the CKO mice, these issues remain to be elucidated. In the present study, we showed that gastrointestinal motility was reduced in the CKO mice. Degeneration of mucosal epithelium was observed in the small intestine. Glucose levels were decreased in serum, whereas starch, glucose, and lipid levels were increased in feces. Thus, calcineurin B1 deficiency in glial cells reduces gastrointestinal motility, induces mucosal epithelium degeneration in the small intestine, and results in maldigestion and/or malabsorption in mice, further supporting the important role of calcineurin in enteric glial cells.

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  • Takayuki Matsumoto, Keisuke Takayanagi, Mihoka Kojima, Tomoki Katome, ...
    2019 Volume 42 Issue 7 Pages 1236-1242
    Published: July 01, 2019
    Released: July 01, 2019
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    Upon stimulation, endothelial cells release various factors to regulate the vascular tone. In particular, vasorelaxing factors, called endothelium-derived relaxing factors (EDRFs), are altered in the production and/or release, as well as their signaling every vessel and under pathophysiological states, including cardiovascular, kidney, and metabolic diseases. Although indoxyl sulfate is known as a protein-bound uremic toxin and circulating levels are elevated in the impaired kidney functions, direct impact on the vascular function, especially EDRF’s signaling, remains unclear. In this study, we hypothesize that acute exposure to indoxyl sulfate could alter vascular relaxation in the rat superior mesenteric artery. Accordingly, we measured acetylcholine (ACh)-induced endothelium-dependent relaxation in the absence and presence of several inhibitors to divide into each EDRF, including nitric oxide (NO), vasodilator prostaglandins (PGs), and endothelium-derived hyperpolarizing factor (EDHF). Indoxyl sulfate reduced the sensitivity to ACh but not sodium nitroprusside. Under cyclooxygenase (COX) inhibition or inhibitions of COX plus source of EDHF, such as small (SKCa)- and intermediate (IKCa)-conductance calcium-activated K+ channels, the decreased sensitivity to ACh in indoxyl sulfate exposed vessel was still preserved. However, under inhibition of NO synthase (NOS) or inhibitions of NOS and COX, the difference of sensitivity to ACh between vehicle and indoxyl sulfate was eliminated. These findings indicated that acute exposure of indoxyl sulfate in the rat superior mesenteric artery specifically explicitly impaired NO signaling but not EDHF or vasodilator PGs.

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