Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
最新号
選択された号の論文の29件中1~29を表示しています
Review
  • Tadahaya Mizuno, Katsuhisa Morita, Hiroyuki Kusuhara
    2020 年 43 巻 10 号 p. 1435-1442
    発行日: 2020/10/01
    公開日: 2020/10/01
    ジャーナル フリー HTML

    Profile data is defined as data which describes the properties of an object. Omics data of a specimen is profile data because its comprehensiveness supports the idea that omics data is numeric information which reflects biological information of the specimen. In general, omics data analysis utilizes an existing body of biological knowledge, while some profile data analysis methods are independent of existing knowledge, which is suitable for uncovering unidentified aspects of a specimen of interest. The effects of a small compound, such as drugs, are multiple, and include unrecognized effects, even by the developers. To uncover such unrecognized effects, it is useful to employ profile data analysis independent of existing knowledge. In this review, we summarize what profile data is, properties of profile data analysis, and current applications of profile data in order to understand and utilize the effects of small compounds, in particular, in a recently developed method to decompose multiple effects of a drug.

    Graphical Abstract Fullsize Image
Communications to the Editor
  • Haiyan Fang, Yingqin Wei, Yaqi Li, Guowei Zhou
    2020 年 43 巻 10 号 p. 1443-1447
    発行日: 2020/10/01
    公開日: 2020/10/01
    ジャーナル フリー HTML

    One-pot process for the production of ginsenoside Rd by coupling enzyme-assisted extraction with selective enzymolysis was explored in this paper. Several detection methods including HPLC-MS were used to identify and quantify the products in the enzymolysis solution of pectinase. Results showed that ginsenoside Rd was the main component in enzymolysis solution, pectinase specifically hydrolyzes protopanaxadiol (PPD)-type ginsenoside and was a selective enzyme to convert ginsenoside Rb1 to Rd in a way. In addition the influencing factors on the yield of ginsenoside Rb1 and Rd were optimized using L9(34) orthogonal design data. The enzymolysis conditions for the higher yield of Rd were 52.5 °C, pH 6 and 1 h with a yield of 0.8314 from 50 mg drug material. The controllable transformation hypothesis of the PPD-type ginsenoside was also explored from the perspective of the molecular steric hindrance. Pectinase could be used as an efficient enzyme for one-pot producing ginsenoside Rd.

    Graphical Abstract Fullsize Image
  • Akiko Watanabe, Takashi Yamamoto, Hiroki Matsuhara, Hitoshi Matsui, Hi ...
    2020 年 43 巻 10 号 p. 1448-1450
    発行日: 2020/10/01
    公開日: 2020/10/01
    [早期公開] 公開日: 2020/08/04
    ジャーナル フリー HTML
    電子付録

    Japanese allergic subjects are commonly sensitized to both house dust mite (HDM) and Japanese cedar pollen (JCP) and combined treatment with sublingual immunotherapy (SLIT) tablets is desirable. However, mixing extracts of two non-homologous allergens may compromise allergen stability and affect the clinical outcome. Therefore, we investigated the stability of major allergens and total allergenic reactivity of HDM and JCP SLIT-tablets following dissolution in human saliva or artificial gastric juice. Two fast-dissolving freeze-dried SLIT-tablets were completely dissolved and incubated at 37 °C. Major allergen concentrations and total allergenic reactivity were measured. After mixing and co-incubation of HDM and JCP SLIT tablets in human saliva for 10 min at 37°C, there were no statistically significant changes in major allergen concentrations. In addition, no loss of allergenic reactivity of the mixed two SLIT-tablet solutions was seen. In contrast, complete loss of allergenic reactivity and detectable major allergen concentrations occurred when the two SLIT-tablets were dissolved and incubated in artificial gastric juice. These results demonstrate that HDM or JCP major allergens and the total allergenic reactivity of both SLIT-tablets measured here remain intact after dissolution and co-incubation in human saliva, supporting the possibility of a dual HDM and JCP SLIT-tablet administration regimen if clinically indicated. The complete loss of allergenic reactivity after incubation in artificial gastric juice can furthermore be taken to indicate that the immunological activity of the allergen extracts contained in the two SLIT-tablets is likely to be lost or severely compromised upon swallowing.

    Graphical Abstract Fullsize Image
  • Nobuhiko Taguchi, Takumi Homma, Hitomi Aoki, Takahiro Kunisada
    2020 年 43 巻 10 号 p. 1451-1454
    発行日: 2020/10/01
    公開日: 2020/10/01
    ジャーナル フリー HTML

    Hair follicular keratinocyte stem cells (HFKSC) which provide a functional niche for melanocyte stem cells (MSC) are the primary target of hair graying. However, little research has been done on anti-hair graying medicines targeting HFKSC. We focused on Eriodictyon angustifolium (Ea), which reduces human hair graying when applied topically. To investigate the protective effect of dietary Ea tea (EaT) on hair pigmentation, we used an acute mouse model of hair graying that mimics X-ray-induced DNA damage associated with age-related hair graying. Our results suggest that dietary EaT maintained the niche HFKSC function against X-ray-induced DNA damage and hair graying. These results indicate that dietary EaT may prevent age-related hair graying and serve as an anti-hair graying herbal medicine.

    Graphical Abstract Fullsize Image
Regular Articles
  • Xiuzhen Lei, Manli An, Yulong Wang, Shenghua Yi, Yeke Zhu, Shuangyan H ...
    2020 年 43 巻 10 号 p. 1455-1462
    発行日: 2020/10/01
    公開日: 2020/10/01
    [早期公開] 公開日: 2020/08/04
    ジャーナル フリー HTML

    The aim of this study was to investigate the influences of acute and chronic inflammation on the dynamics of fluid shift of Ringer’s solution and hemodynamics in patients during surgery. Thirty-seven patients with the American Society of Anesthesiologists (ASA) grades I–II were enrolled and allocated to two study groups according to the type of disease and operation and inflammation, including patients undergoing emergency appendectomy (Acute group, n = 19) and patients undergoing elective cholecystectomy (Chronic group, n = 18). All of the patients were administered 15 mL/kg of Ringer’s lactated (LR) solution at a constant rate over 35 min before the induction of anesthesia. Plasma dilution (PD), volume expansion (VE), volume expansion efficiency (VEE), and extravascular volume (EVV) were calculated based on the concentration of hemoglobin within 2 h post-infusion. Heart rate (HR), arterial blood pressure and urine output were also recorded. PD and VE peaked at the end of infusion, while VEE peaked at the beginning of infusion in all of the patients. After infusion, PD, VE and VEE in the Acute group were all higher than those in the Chronic group (p < 0.05). PD and VE were higher during anesthesia or surgery than during awake or non-surgery (p < 0.001). The mean arterial pressure (MAP) and diastolic pressure (DBP) in the Acute group were significantly lower (p < 0.001) and HR was significantly higher (p < 0.001) than in the Chronic group during the study periods. It was suggested that patients with acute inflammation be treated with individualized fluid therapy during surgery.

    Graphical Abstract Fullsize Image
  • Miko Kondo, Shunsaku Nakagawa, Satoru Orii, Kotaro Itohara, Mitsuhiro ...
    2020 年 43 巻 10 号 p. 1463-1468
    発行日: 2020/10/01
    公開日: 2020/10/01
    ジャーナル フリー HTML

    Vancomycin is a glycopeptide antibiotic used for the treatment of Gram-positive infections. For adult patients, treatment with vancomycin requires effective therapeutic drug-monitoring (TDM) to achieve clinical outcomes and reduce the incidence of adverse effects. However, it remains still unclear whether the TDM with vancomycin is beneficial in yielding better clinical outcomes in pediatrics. The objective of our study was to evaluate whether the clinical response to treatment was associated with initial trough concentrations of vancomycin in pediatric patients. A retrospective observation study of 60 patients (age: 1 month–15 years) who had completed and qualified for analysis was conducted at Kyoto University Hospital. The response to treatment was assessed by the time to resolution of fever and time to 50% decline in C-reactive protein (CRP). In addition, we explored whether vancomycin trough level was associated with the baseline characteristics. Trend analysis showed that there were significant correlations between vancomycin trough level and age, body weight, estimated glomerular filtration rate, and serum albumin levels. The time to resolution of fever of the patients with higher initial trough level (≥ 5 µg/mL) was significantly lower than that of the patients with lower trough level (< 5 µg/mL). The higher vancomycin concentration tended to be associated with the shorter time to 50% decline in CRP. The findings suggest that initial trough concentration is important in achieving better outcomes with vancomycin treatment in pediatrics.

    Graphical Abstract Fullsize Image
  • Wanting Xu, Lei Li, Xiaobin Wen, Qun Liu, Yan Liu, Xingyong Wang, Lang ...
    2020 年 43 巻 10 号 p. 1469-1475
    発行日: 2020/10/01
    公開日: 2020/10/01
    [早期公開] 公開日: 2020/08/08
    ジャーナル フリー HTML
    電子付録

    Hospital-acquired infections with Pseudomonas aeruginosa have become a great challenge in caring for critically ill and immunocompromised patients. The cause of high mortality is the presence of multi-drug resistant (MDR) strains, which confers a pressing need for vaccines. Although vaccines against P. aeruginosa have been in development for more than several decades, there is no vaccine for patients at present. In this study, we purified genomic DNA of P. aeruginosa from sera of patients affected, constructed genome-wide library with random recombinants, and screened candidate protein antigens by evaluating their protective effects in vivo. After 13-round of screening, 115 reactive recombinants were obtained, among which 13 antigens showed strong immunoreactivity (more than 10% reaction to PcrV, a well-characterized V-antigen of P. aeruginosa). These 13 antigens were: PpiA, PtsP, OprP, CAZ10_34235, HmuU_2, PcaK, CarAd, RecG, YjiR_5, LigD, KinB, RtcA, and PscF. In vivo studies showed that vaccination with PscF protected against lethal P. aeruginosa challenge, and decreased lung inflammation and injury. A genomic library of P. aeruginosa could be constructed in this way for the first time, which could not only screen candidate antigens but also in a high-throughput way. PscF was considered as an ideal promising vaccine candidate for combating P. aeruginosa infection and was supported for further evaluation of its safety and efficacy.

    Graphical Abstract Fullsize Image
  • Rui Niu, Yue Chen, Yufang Xiang, Ying Liu, Jiadong Guo, Bianling Feng
    2020 年 43 巻 10 号 p. 1476-1480
    発行日: 2020/10/01
    公開日: 2020/10/01
    ジャーナル フリー HTML

    Various sources of information are available for identifying and evaluating adverse drug reactions (ADRs). However, some studies only used the ADR data from spontaneous reporting databases to evaluate the safety of post-marketing drugs. This study was performed to identify an appropriate method for evaluating the safety of post-marketing drugs by comparing the frequencies of ADRs among three datasets: randomized controlled trials, published case reports, and spontaneous reports. Taking ADR data for fluorouracil as an example, we collected the three types of data and extracted their ADR information. All listed ADRs were sorted by frequency from high to low, and the top five ADRs were chosen from each dataset. We assigned an index value of 1.0 to the frequency of one specific ADR (diarrhea) and then calculated the index values of the other ADRs relative to diarrhea. Ten different ADRs were mentioned in the top five ADRs of the three datasets, and only diarrhea and nausea/vomiting were included in all three datasets. The rank orders of the top five ADRs varied among the three datasets. Nausea and vomiting was the most frequent ADR in all three datasets; the remaining ADRs differed among the datasets. There were significant differences in the recording of ADRs and the frequency distributions among the three datasets. A comprehensive and reliable safety profile for post-marketing drugs should not be based on any one source. Spontaneous reports from monitoring institutions provided the most ADR data. Randomized controlled trials and case reports published in the literature can supplement the results from spontaneous reports.

    Graphical Abstract Fullsize Image
  • Zhuo Ma, Kai Li, Peng Chen, Jizheng Pan, Xuyang Li, Guoqing Zhao
    2020 年 43 巻 10 号 p. 1481-1489
    発行日: 2020/10/01
    公開日: 2020/10/01
    ジャーナル フリー HTML

    Stroke is a common cerebrovascular disease. Inflammation-induced neuronal death is one of the key factors in stroke pathology. Propofol has been shown to ameliorate neuroinflammatory injury, but the exact mechanism of its neuroprotective role remains to be fully elucidated. In the present study, we found that inflammation was activated in ischemic cortical neurons, and the expression of nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain-containing 1 (NLRP1), NLRP3 inflammasome and effectors in primary cortical neurons increased. However, we found that propofol could inhibit the increased expression of NLRP1 and NLRP3 inflammasome induced by oxygen-glucose deprivation (OGD). Furthermore, the effector molecule caspase-1 (casp1) was revealed to be the downstream target of NLRP1 and propofol repressed the activation of caspase-1 via inhibiting NLRP1 in cortical neurons. Moreover, propofol inhibits caspase-6 activation in neurons through the NLRP1-caspase-1 pathway. Once the expression of caspase6 increases, propofol reduced its neuroprotective effect in OGD-treated cortical neurons. In the stroke middle cerebral artery occlusion (MCAO) model, infusion of caspase-6 inhibitors enhanced the protective effect of propofol on infarct size and neurological function. In conclusion, our results suggest that propofol plays a neuroprotective role in stroke by inhibiting the inflammatory pathway of NLRP1-caspase-1-caspase-6. Overall, these data suggest that propofol plays a key role in the inflammatory-dependent pathway after stroke, providing an important evidence for propofol as an effective strategy for neuroprotection in stroke.

    Graphical Abstract Fullsize Image
  • Xu-meng Han, Feng Huang, Ming-li Jiao, Hui-ru Liu, Zheng-hang Zhao, He ...
    2020 年 43 巻 10 号 p. 1490-1500
    発行日: 2020/10/01
    公開日: 2020/10/01
    [早期公開] 公開日: 2020/08/13
    ジャーナル フリー HTML
    電子付録

    Depression is the most significant risk factor for suicide, yet the causes are complex and disease mechanism remains unclear. The incidence and disability rate of depression are very high and the efficacy of some traditional antidepressants is not completely satisfactory. Recently, some studies have found that benzofurans have anti-oxidation and anti-monoamine oxidase properties, which are related to depression. Euparin is a monomer compound of benzofuran, previous work by our team found that it improves the behavior of depressed mice. However, additional antidepressant effects and mechanisms of Euparin have not been reported. In this study, the Chronic Unpredictable Mild Stress (CUMS) model of mice was used to further investigate the effect and mechanism of Euparin on depression. Results showed that Euparin (8, 16 and 32 mg/kg) reduced depression-like behavior in mice compared with the model group. Meanwhile, all doses of Euparin were found to increase the contents of monoamine neurotransmitter and decrease monoamine oxidase and reactive oxygen species (ROS) levels in brain of depression mice. Additionally, Euparin restored CUMS-induced decrease of Spermidine/Spermine N1-Acetyltransferase 1 (SAT1), N-methyl-D-aspartate receptor subtype 2B (NMDAR2B) and brain derived neurotrophic factor (BDNF) expression. These findings demonstrate that Euparin has antidepressant properties, and its mechanism involves the SAT1/NMDAR2B/BDNF signaling pathway.

    Graphical Abstract Fullsize Image
  • Tomoharu Takeuchi, Yasuhiro Horimoto, Midori Oyama, Sachie Nakatani, K ...
    2020 年 43 巻 10 号 p. 1501-1505
    発行日: 2020/10/01
    公開日: 2020/10/01
    ジャーナル フリー HTML

    Osteoclasts are the only bone-resorbing cells in organisms and understanding their differentiation mechanism is crucial for the treatment of osteoporosis. In the present study, we investigated the effect of Thiamet G, an O-GlcNAcase specific inhibitor, on osteoclastogenic differentiation. Thiamet G treatment increased global O-GlcNAcylation in murine RAW264 cells and suppressed receptor activator of nuclear factor-κB ligand (RANKL)-dependent formation in tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells, thereby suppressing the upregulation of osteoclast specific genes. Meanwhile, knockdown of O-linked N-acetylglucosamine (O-GlcNAc) transferase promoted the formation TRAP-positive multinuclear cells. Thiamet G treatment also suppressed RANKL and macrophage colony-stimulating factor (M-CSF) dependent osteoclast formation and bone-resorbing activity in mouse primary bone marrow cells and human peripheral blood mononuclear cells. These results indicate that the promotion of O-GlcNAc modification specifically suppresses osteoclast formation and its activity and suggest that chemicals affecting O-GlcNAc modification might potentially be useful in the prevention or treatment of osteoporosis in future.

    Graphical Abstract Fullsize Image
  • Katsuyuki Nakamura, Toshiaki Tanaka, Naoya Masumori, Atsushi Miyamoto, ...
    2020 年 43 巻 10 号 p. 1506-1510
    発行日: 2020/10/01
    公開日: 2020/10/01
    ジャーナル フリー HTML

    The usefulness of the urine protein : creatine ratio (UPCR) in management of molecular targeted therapy and immunotherapy has not been studied, although urine protein dipstick testing (uPr) is widely used in the clinical setting. The aim of this study was to investigate the usefulness of UPCR as compared to uPr in patients undergoing molecular targeted therapy for advanced renal cell carcinoma (RCC). A total of 25 patients (median age 68 years) with advanced RCC were included. Sunitinib, pazopanib, axitinib, sorefenib, everolimus, and nivolumab were administered to 15, 9, 16, 3, 7, and 13 patients, respectively, with duplication. Proteinuria was managed according to the grade determined by UPCR. Data at every treatment visit were retrospectively collected and uPr and UPCR were compared. The overall incidences of any grade of proteinuria associated with sunitinib, pazopanib, axitinib, sorafenib and everolimus were 86.7, 88.9, 93.8, 100, and 85.7%, respectively. There were discordances between the uPr-based grade and UPCR-based grade. UPCR did not meet the criteria of Grade 3 in 70.6, 100, 83.3, and 83.3% at visits in cases with uPr 3+ for sunitinib, pazopanib, sorafenib, and everolimus, respectively. In axitinib treatment, UPCR did not meet the criteria for withholding in 46.2% of the cases of uPr 2+ and more. Our study suggests that UPCR may be useful tool in management of adverse events associated with tyrosine kinase inhibitors, everolimus and can provide patients with optimal opportunities for receiving treatment.

    Graphical Abstract Fullsize Image
    Editor’s picks

    The usefulness of the urine protein:creatine ratio (UPCR) in management of molecular targeted therapy has not been studied, although urine protein dipstick testing (uPr) is widely used. The authors investigated the usefulness of UPCR as compared to uPr in patients undergoing molecular targeted therapy for advanced renal cell carcinoma (RCC). They found that uPr-based grade tends to be higher than UPCR-based grade, which may lead to overestimate of proteinuria and unnecessary interruption of treatment. UPCR may be a better tool for evaluation of proteinuria in RCC patients receiving molecular targeted therapy.

  • Liqian Xuan, Jiajun Zhang, Jianmei Ji, Jun Hu, Fu Li
    2020 年 43 巻 10 号 p. 1511-1518
    発行日: 2020/10/01
    公開日: 2020/10/01
    ジャーナル フリー HTML

    Gallbladder carcinoma (GBC) is one of the most common carcinomas of the biliary tract and is associated with aggressive malignancy and poor prognosis. Current therapeutic strategies, including surgery, radiotherapy, and chemotherapy, are not sufficient for the treatment of GBC, and new therapeutic strategies are urgently needed. The antitumor effects of oroxylin A (OrA), a natural flavonoid extracted from the dried roots of medicinal plants such as Scutellariae species (Radix Scutellariae), have been widely reported in various cancers. In this study, we first evaluated the antitumor activity and the underlying mechanism of action of OrA on GBC cells in vitro. Our results revealed that OrA significantly attenuated the proliferation, migration, and invasion of GBC cells, simultaneously promoting their apoptosis. Suppression of the phosphate on and tension homology deleted chromosome ten (PTEN)/phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT) signaling pathway was found to be the underlying mechanism involved in the antitumor activity of OrA. In addition, experiments using a tumor xenograft mouse model confirmed the antitumor effects of OrA in vivo. Taken together, our findings indicate that OrA could be a potential antitumor agent for the prospective treatment of GBC.

    Graphical Abstract Fullsize Image
  • Shungo Imai, Kenji Momo, Hitoshi Kashiwagi, Takayuki Miyai, Mitsuru Su ...
    2020 年 43 巻 10 号 p. 1519-1525
    発行日: 2020/10/01
    公開日: 2020/10/01
    ジャーナル フリー HTML

    The anti-inflammatory agent colchicine may cause toxic effects such as rhabdomyolysis, pancytopenia, and acute respiratory distress syndrome in cases of overdose and when patients have renal or liver impairment. As colchicine is a substrate for CYP3A4 and P-glycoprotein (P-gp), drug–drug interactions are important factors that cause fatal colchicine-related side effects. Thus, we conducted a nation-wide survey to determine the status of inappropriate colchicine prescriptions in Japan. Patients prescribed the regular use of colchicine from April 2014 to March 2017 were identified using the Japanese large health insurance claims database. As the primary endpoint, we evaluated the concomitant prescription proportions of strong CYP3A4 and/or P-gp inhibitors classified as “contraindications for co-administration” with colchicine in patients with renal or liver impairment. We defined these cases as “inappropriate colchicine prescriptions.” Additionally, factors affecting inappropriate colchicine prescriptions were analyzed. Among the 3302 enrolled patients, 43 (1.30%) were inappropriately prescribed colchicine. Of these 43 patients, 11 had baseline renal and/or liver impairment. By multiple regression analysis, the primary diseases “gout” and “Behçet’s disease” were extracted as independent factors for inappropriate colchicine prescriptions with odds ratios of 0.40 (95% confidence interval: 0.19–0.84) and 4.93 (95% confidence interval: 2.12–11.5), respectively. We found that approximately 1% of patients had important colchicine interactions. Particularly, Behçet’s disease was a risk factor for inappropriate prescriptions, with approximately 25% of patients showing renal and/or liver impairment (classified as “contraindications for co-administration”). These findings may be useful for medical professionals who prescribe colchicine therapy.

    Graphical Abstract Fullsize Image
  • Xin-Yi Wang, Gui-Bin Sun, Ya-Jing Wang, Fang Yan
    2020 年 43 巻 10 号 p. 1526-1533
    発行日: 2020/10/01
    公開日: 2020/10/01
    ジャーナル フリー HTML
    電子付録

    Imatinib-resistance is a significant concern for Bcr-Abl-positive chronic myelogenous leukemia (CML) treatment. Emodin, the predominant compound of traditional medicine rhubarb, was reported to inhibit the multidrug resistance by downregulating P-glycoprotein of K562/ADM cells with overexpression of P-glycoprotein in our previous studies. In the present study, we found that emodin can be a potential inhibitor for the imatinib-resistance in K562/G01 cells which are the imatinib-resistant subcellular line of human chronic myelogenous leukemia cells with overexpression of breakpoint cluster region-abelson (Bcr-Abl) oncoprotein. Emodin greatly enhanced cell sensitivity to imatinib, suppressed resistant cell proliferation and increased potentiated apoptosis induced by imatinib in K562/G01 cells. After treatment of emodin and imatinib together, the levels of p-Bcr-Abl and Bcr-Abl were significantly downregulated. Moreover, Bcr-Abl important downstream target, STAT5 and its phosphorylation were affected. Furthermore, the expression of Bcr-Abl and signal transducers and activators of transcription 5 (STAT5) related molecules, including c-MYC, MCL-1, poly(ADP-ribose)polymerase (PARP), Bcl-2 and caspase-3, were changed. Emodin also decreased Src expression and its phosphorylation. More importantly, emodin simultaneously targeted both the ATP-binding and allosteric sites on Bcr-Abl by molecular docking, with higher affinity with the myristoyl-binding site for enhanced Bcr-Abl kinase inhibition. Overall, these data indicated emodin might be an effective therapeutic agent for inhibiting resistance to imatinib in CML treatment.

    Graphical Abstract Fullsize Image
  • Guo-Min Liu, Tian-Cheng Lu, Mao-Lei Sun, Wen-Yuan Jia, Xuan Ji, Yun-Ga ...
    2020 年 43 巻 10 号 p. 1534-1541
    発行日: 2020/10/01
    公開日: 2020/10/01
    ジャーナル フリー HTML

    miR-144-5p exhibits anti-tumor activities in various cancers. Although treatment for glioblastoma has progressed rapidly, novel targets for glioblastoma are insufficient, particularly those used in precision medicine. In the current study, we found that ginsenoside Rd reduced the proliferation and migration of glioblastoma cells. Ginsenoside Rd up-regulated the tumor-suppressive miR-144-5p in glioblastoma cells. Moreover, Toll-like receptor 2, which is a target of miR-144-5p, was down-regulated. After inhibition of miR-144-5p, the effect of Ginsenoside Rd on proliferation inhibition and down-regulation of Toll-like receptor 2 was reduced. These data demonstrated the ginsenoside Rd/miR-144-5p/Toll-like receptor 2 regulatory nexus that controls the glioblastoma pathogenesis of glioblastoma. Our work provided novel targets for glioblastoma diagnosis and treatment.

    Graphical Abstract Fullsize Image
  • Shilin Yuan, Yanna Pan, Zeng Zhang, Yanming He, Yilong Teng, Haohui Li ...
    2020 年 43 巻 10 号 p. 1542-1550
    発行日: 2020/10/01
    公開日: 2020/10/01
    [早期公開] 公開日: 2020/08/05
    ジャーナル フリー HTML

    The steatosis and resultant oxidative stress and apoptosis play the important roles in the progression of nonalcoholic fatty liver disease (NAFLD), therefore, searching for the effective drugs against NAFLD has been a hot topic. In this work, we investigated a hyperbranched proteoglycan, namely FYGL extracted from Ganoderma lucidum, inhibiting the palmitic acid (PA)-induced steatosis in HepG2 hepatocytes. FYGL compose of hydrophilic polysaccharide and lipophilic protein. Both moieties conclude the reductive residues, such as glucose and cystine, making FYGL capable of anti-oxidation. Herein, we demonstrated that FYGL can significantly inhibit the steatosis, i.e., decrease the contents of triglycerides (TG) and total cholesterol (TC) in hepatic cells on the mechanism of increasing the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), therefore inhibiting the expressions of sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FASN), furthermore leading to the carnitine palmitoyl transferase-1 (CPT-1) expression increased against steatosis induced by fatty acids oxidation. Meanwhile, FYGL can alleviate reactive oxygen species (ROS) and malondialdehyde (MDA), promote superoxide dismutase (SOD) and total antioxidant capacity (T-AOC). Moreover, FYGL can prevent the cells from apoptosis by regulating the apoptosis-related protein expressions and alleviating oxidative stress. Notably, FYGL could significantly recover the cells activity and inhibit lactate dehydrogenase (LDH) release which were negatively induced by high concentration PA. These results demonstrated that FYGL has the potential functions to prevent the hepatocytes from lipid accumulation, oxidative stress and apoptosis, therefore against NAFLD.

    Graphical Abstract Fullsize Image
  • Qian Zheng, Qin Zhu, Cuiping Li, Shuang Hao, Jianguo Li, Xin Yu, Dengm ...
    2020 年 43 巻 10 号 p. 1551-1555
    発行日: 2020/10/01
    公開日: 2020/10/01
    [早期公開] 公開日: 2020/08/04
    ジャーナル フリー HTML

    Sinomenine was found to play anti-cancer functions in different type of cancers, while the mechanisms underlying the anticancer effects of sinomenine in retinoblastoma (RB) remains unclear. The present study was designed to explore the impacts of sinomenine on cell proliferation and invasion ability of RB cells and the related mechanism. Human retinoblastoma cell line WERI-RB-1 and Y79 cells were cultured and treated by different concentration of sinomenine, and then the proliferation ability of the cells was determined via performing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) proliferation assay. The cell apoptosis was examined via performing the flow cytometry assay. Then scratch wound healing analysis as well as and transwell invasion analysis have been performed to determine the effect of sinomenine on cell migration ability as well as invasion ability. The proteins level of phosphatidylinositol 3-kinase (PI3K)/AKT signaling molecules were determined with Western blot assay. We found that sinomenine was able to decrease the proliferation and promote the apoptosis of RB cells in a dose-dependent manner; moreover, sinomenine also significantly suppressed the migration as well as invasion ability of WERI-RB-1 and Y79 cells in vitro. Furthermore, sinomenine also de-activated PI3K/AKT signaling in WERI-RB-1 cells via inhibited the phosphorylation of PI3K and AKT proteins. Sinomenine can exert anti-tumor function on RB cells in vitro, therefore sinomenine might be a potential alterative medication for the treatment for RB.

    Graphical Abstract Fullsize Image
    Editor’s picks

    Introduction: The present study was designed to explore the impacts of sinomenine on cell proliferation and invasion ability of RB cells and the related mechanism. WERI-RB-1 and Y79 cells were cultured and treated by different concentration of sinomenine. The authors found that sinomenine was able to decrease the proliferation and promote the apoptosis of RB cells in a dose-dependent manner; and also significantly suppressed the migration as well as invasion ability of WERI-RB-1 and Y79 cells in vitro via regulating the PI3K/AKT signaling pathway, suggesting that sinomenine has the potential to become an alternative medication for the treatment of RB.

  • Takahiro Sugiura, Yasushi Hirasawa, Tohru Toyoshi, Yasuo Matsumura
    2020 年 43 巻 10 号 p. 1556-1561
    発行日: 2020/10/01
    公開日: 2020/10/01
    ジャーナル フリー HTML

    Renal insufficiency secondary to contrast administration remains a prevalent and debilitating complication of angiographic procedures. Contrast-induced nephropathy (CIN) is a common clinical problem for which there is no effective medical treatment. However, agmatine has been shown to be effective against ischemia/reperfusion-induced acute kidney injury in rats, a similar condition to CIN. Our aim was to examine the protective effects of agmatine in a rat model of CIN and, based on those results, in a rabbit model of CIN. CIN in the rat model was induced by intravenous administration of indomethacin (10 mg/kg), Nω-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg) and iopamidol (OYPALOMIN, 7.4 g iodine/kg) at 2 weeks after a unilateral nephrectomy. CIN in the rabbit model was induced by intrarenal arterial injection of only iopamidol (BYSTAGE, 4.8 g iodine/kg). Intravenous injection of agmatine (0.1 and 0.3 mmol/kg) did not attenuate the CIN-induced renal insufficiency in the rat model. Intravenous injection of agmatine (0.3 mmol/kg) attenuated the CIN-induced renal insufficiency in the rabbit model such as increases in blood urea nitrogen and plasma creatinine levels. Renal histological damage was also improved by the agmatine administration. The difference in effects of agmatine injection between CIN rats and CIN rabbits was caused by indomethacin and L-NAME administrations. These results indicate that agmatine prevents the development of CIN-induced renal insufficiency in rabbits, and the effect is accompanied by activation of nitric oxide synthase and subsequent increase of blood flow.

    Graphical Abstract Fullsize Image
    Editor’s picks

    The rapid degradation in kidney function caused by contrast media usually is temporary, but it can result in chronic kidney disease or even end-stage renal disease. Contrast-induced nephropathy (CIN) is a common clinical problem for which there is no effective medical treatment. The aim of this study was to examine the protective effects of agmatine, which is a polyamine found in mammals, in a rat and a rabbit model of CIN. The results indicate that agmatine prevents the development of CIN-induced renal insufficiency in rabbits, and the effect is accompanied by activation of nitric oxide synthase and subsequent increase of blood flow.

  • Yusuke Hirata, Yuki Nada, Yuto Yamada, Takashi Toyama, Kohji Fukunaga, ...
    2020 年 43 巻 10 号 p. 1562-1569
    発行日: 2020/10/01
    公開日: 2020/10/01
    ジャーナル フリー HTML

    trans-Fatty acids (TFAs) are unsaturated fatty acids with at least one carbon–carbon double bond in trans configuration. TFA consumption has been epidemiologically associated with neurodegenerative diseases (NDs) including Alzheimer’s disease. However, the underlying mechanisms of TFA-related NDs remain unknown. Here, we show a novel microglial signaling pathway that induces inflammation and cell death, which is dramatically enhanced by elaidic acid (EA), the most abundant TFA derived from food. We found that extracellular ATP, one of the damage-associated molecular patterns (DAMPs) leaked from injured cells, induced activation of the apoptosis signal-regulating kinase 1 (ASK1)-p38 pathway, which is one of the major stress-responsive mitogen-activated protein (MAP) kinase signaling pathways, and subsequent caspase-3 cleavage and DNA ladder formation (hallmarks of apoptosis) in mouse microglial cell lines including BV2 and MG6 cells. Furthermore, we found that in these microglial cell lines, EA, but not its cis isomer oleic acid, facilitated extracellular ATP-induced ASK1/p38 activation and apoptosis, which was suppressed by pharmacological inhibition of either p38, reactive oxygen species (ROS) generation, P2X purinoceptor 7 (P2X7), or Ca2+/calmodulin-dependent kinase II (CaMKII). These results demonstrate that in microglial cells, extracellular ATP induces activation of the ASK1-p38 MAP kinase pathway and ultimately apoptosis downstream of P2X7 receptor and ROS generation, and that EA promotes ATP-induced apoptosis through CaMKII-dependent hyperactivation of the ASK1-p38 pathway, in the same manner as in macrophages. Our study may provide an insight into the pathogenesis of NDs associated with TFAs.

    Graphical Abstract Fullsize Image
    Editor’s picks

    Elaidic acid (EA) is the most abundant food-derived trans-fatty acid (TFA), whose intake is associated with neurodegenerative diseases (NDs) including Alzheimer’s disease. Hirata et al. provide evidence implicating a novel microglial apoptosis signaling pathway in TFA-related NDs. In microglial cell lines such as MG6 and BV2, extracellular ATP, a damage-associated molecular pattern (DAMP) leaked from injured cells, triggered reactive oxygen species (ROS)-dependent activation of the apoptosis signal-regulating kinase 1 (ASK1)-p38 MAP kinase pathway, and ultimately apoptosis. EA strongly enhanced activation of the microglial apoptosis pathway, which may account for the underlying pathological mechanisms of TFA-related NDs that are closely associated with neuronal cell death and inflammation.

  • Tomoaki Ishida, Kei Kawada, Shumpei Morisawa, Kohei Jobu, Yasuyo Morit ...
    2020 年 43 巻 10 号 p. 1570-1576
    発行日: 2020/10/01
    公開日: 2020/10/01
    ジャーナル フリー HTML

    Yokukansan is a Kampo formula that is commonly used by the elderly because it is expected to improve peripheral symptoms of dementia and delirium. However, side effects from its use are frequently reported in the elderly. In particular, pseudoaldosteronism caused by the licorice contained in yokukansan leads to hypertension, hypokalemia, and muscle weakness, which may result in death. This study aimed to identify the risk factors of pseudoaldosteronism with yokukansan use. Using cases reported in the Japanese Adverse Drug Report (JADER) database, the reporting odds ratio (ROR) was calculated and compared to assess the risk of pseudoaldosteronism for each licorice-containing Kampo formula. We also analyzed the risk factors for pseudoaldosteronism in patients taking yokukansan. Yokukansan (ROR 2.4, 95% confidence interval (CI) 1.9–2.8; p < 0.001) had a higher risk of pseudoaldosteronism than that of other licorice-containing Kampo formulas. Furthermore, the results of a logistic regression analysis in patients taking yokukansan showed that the licorice dose (OR 1.5, 95% CI 1.2–2.0; p < 0.01), older age (<70 years, OR 5.9, 95% CI 1.8–20; p < 0.01), dementia (OR 2.8, 95% CI 1.6–4.9; p < 0.001), low body weight (<50 kg, OR 2.2, 95% CI 1.1–3.5; p = 0.034) were risk factors for pseudoaldosteronism, Although not significant, treatment with loop diuretics (OR 1.8, 95% CI 0.98–3.5; p = 0.059) tended to increase the risk of pseudoaldosteronism. In summary, patients must understand the risk factors when considering taking yokukansan and reduce the licorice dose they consume.

    Graphical Abstract Fullsize Image
  • Mayako Uchida, Yasuhiro Mori, Kenta Akiba, Moena Miyasaka, Tatsuya Hir ...
    2020 年 43 巻 10 号 p. 1577-1582
    発行日: 2020/10/01
    公開日: 2020/10/01
    [早期公開] 公開日: 2020/08/14
    ジャーナル フリー HTML

    Bendamustine plays an especially important role as a treatment for non-Hodgkin lymphoma (NHL). However, patients administered bendamustine alone or in combination with rituximab (BR) may experience drug-associated skin toxicities that can profoundly impact their health-related QOL through both physical discomfort and psychological distress. Moreover, worsening skin symptoms may lead to dose reduction or termination in the management of cancer chemotherapy. We retrospectively investigated patient backgrounds and pretreatment characteristics from medical records of NHL patients treated with bendamustine alone or BR therapy and identified predictive factors for skin toxicities at the start of chemotherapy. Patients were eligible for the study if they were 20 years older, diagnosed with NHL, and received bendamustine alone or BR therapy at the Department of Hematology, Kobe City Medical Center General Hospital, between April 1, 2011, and March 31, 2018. This study included 95 patients with newly diagnosed or refractory or relapsed NHL. Multivariate stepwise logistic regression analysis with backward selection revealed that baseline non-prior chemotherapy (odds ratio (OR), 15.72; 95% confidence interval (CI), 4.24–83.13, p < 0.001) was a significant factor influencing the occurrence of skin toxicity. Our results demonstrated that non-prior chemotherapy was a significant risk factor for skin toxicities in patients with NHL receiving bendamustine alone or BR therapy. No patient experience serious side effects of grade 3 or higher and that bendamustine is very useful as a first-line treatment.

    Graphical Abstract Fullsize Image
  • Tadashi Imafuku, Motoko Tanaka, Koki Tokunaga, Shigeyuki Miyamura, Hir ...
    2020 年 43 巻 10 号 p. 1583-1590
    発行日: 2020/10/01
    公開日: 2020/10/01
    ジャーナル フリー HTML

    Chronic kidney disease (CKD) patients with secondary hyperparathyroidism (SHPT) have an increased risk of cardiovascular disease (CVD). Cinacalcet is a calcimimetic that permits impaired endothelial functions to be recovered via inhibiting parathyroid hormone (PTH) production in SHPT patients. However, the underlying mechanism for its action remains unknown. The purpose of this study was to examine the effect of cinacalcet on the redox state of human serum albumin (HSA), a reliable marker for assessing endothelial oxidative damage in SHPT patients who were receiving hemodialysis. Cinacalcet was administered to six SHPT patients for a period of 8 weeks. After 4 weeks of treatment, cinacalcet significantly decreased the oxidized albumin ratio which is a ratio of reduced and oxidized forms of HSA via increasing reduced form of HSA. Moreover, the radical scavenging abilities of HSA that was isolated from SHPT patients were increased by cinacalcet, suggesting the recovery of the impaired vascular anti-oxidant ability. Interestingly, the oxidized albumin ratio in SHPT patients was significantly higher than that in hemodialysis patients. In addition, the changes of intact PTH levels were significantly correlated with the oxidized albumin ratio. It therefore appears that PTH may induce oxidative stress in SHPT patients. In fact, an active analogue of PTH increased the production of reactive oxygen species in human endothelial cells. Thus, cinacalcet exhibits anti-oxidative activity through its pharmacological action. Additionally, cinacalcet itself showed radical scavenging activity. In conclusion, cinacalcet improves the redox status of HSA by inhibiting PTH production and partially by its radical scavenging action.

    Graphical Abstract Fullsize Image
    Editor’s picks

    Cinacalcet is a calcimimetic that permits impaired endothelial functions to be recovered via inhibiting parathyroid hormone (PTH) production in SHPT patients receiving hemodialysis. However, the underlying mechanism for its action remains unknown. The article by Imafuku et al. reported cinacalcet improves the redox status of human serum albumin (HSA) by inhibiting PTH production and partially by its radical scavenging action and increaed the anti-oxidant defense system in the blood circulation of SHPT patients. Such an anti-oxidative action of cinacalcet may, in part, explain the reduced risk for cardiovascular and all-cause mortality during cinacalcet treatment.

Notes
  • Shinobu Nakanishi, Kanna Kurihara, Mitsuhiro Denda
    2020 年 43 巻 10 号 p. 1591-1594
    発行日: 2020/10/01
    公開日: 2020/10/01
    ジャーナル フリー HTML
    電子付録

    Japanese cedar (Cryptomeria japonica) pollen allergen Cry j1 increases the intracellular calcium concentration in human keratinocytes, and also impairs the epidermal barrier function. Here, we show that reduced glutathione (GSH) blocks both thrombin activation and the Cry j1-induced intracellular calcium elevation in cultured human keratinocytes, and also prevents the Cry j1-induced decrease of barrier function in ex vivo human skin.

    Graphical Abstract Fullsize Image
  • Yutaro Azuma, Kenichi Suzuki, Koji Higai, Kojiro Matsumoto, Shusuke Ta ...
    2020 年 43 巻 10 号 p. 1595-1599
    発行日: 2020/10/01
    公開日: 2020/10/01
    [早期公開] 公開日: 2020/07/29
    ジャーナル フリー HTML
    電子付録

    Calreticulin (CRT) and calnexin (CNX), homologous major chaperones in the endoplasmic reticulum (ER), are known to translocate to the cell surface in response to chemotherapeutic agents, such as mitoxantrone (MIT), and cellular stresses, including apoptosis. Cell surface CRT (ecto-CRT) is relevant to the phagocytic uptake of cancer cells and dying cells, and pre-apoptotic exposure of CRT has been reported to result in enhanced immunogenicity of dying tumor cells, serving as a damage-associated molecular pattern (DAMP). In this study, HT-29 cells were treated with MIT to induce ER stress, and ecto-CRT and cell surface CNX were quantified by flow cytometry in the absence or presence of caspase inhibitors, a calpain inhibitor, or a scavenger of reactive oxygen species. The biphasic (early transient and late sustained) increase of ecto-CRT on HT-29 cells was observed after treatment with MIT. We confirmed that the early increase in ecto-CRT after 4 h of MIT treatment was not related to apoptosis, whereas the increase of ecto-CRT, as well as that of cell-surface CNX, during the later stage of treatment was caspase dependent and related to apoptosis. In addition, our results suggested that the early peak of ecto-CRT was mediated by activation of caspase 8 by ER stress. Thus, the physiological significance of the late increases in cell-surface CRT and/or CNX might be considered an “eat-me signal” for the removal of dead cells by phagocytosis, while the early increase in ecto-CRT caused by ER stress might enhance the immunogenicity of stressed tumor cells.

    Graphical Abstract Fullsize Image
  • Takanori Mei, Hiroshi Noguchi, Kimitaka Suetsugu, Yu Hisadome, Keizo K ...
    2020 年 43 巻 10 号 p. 1600-1603
    発行日: 2020/10/01
    公開日: 2020/10/01
    ジャーナル フリー HTML

    Vonoprazan fumarate (vonoprazan) is a new kind of acid suppressant with potent acid inhibitory effects. Therefore, it has been administered to kidney transplant recipients for treatment or prophylaxis of steroid ulcers, refractory peptic ulcers, and gastroesophageal reflux disease. Because tacrolimus, which is a well-established immunosuppressant for kidney transplantation, and vonoprazan share the CYP3A4 system for metabolism, drug interactions are anticipated upon simultaneous administration. We retrospectively analyzed 52 kidney transplant recipients who were converted from rabeprazole, which has a small effect on the tacrolimus trough blood concentration (C0), to vonoprazan between August 2016 and July 2019. We compared the tacrolimus C0/tacrolimus dose (C0/D) before and after conversion and serum liver enzymes, serum total bilirubin, and the estimated glomerular filtration rate (eGFR). As a result, mean tacrolimus C0/D before and after conversion was 1.98 ± 1.02 and 2.19 ± 1.15 (ng/mL)/(mg/d), respectively, (p < 0.001). Additionally, mean aspartate transaminase (AST) before and after conversion was 18.6 ± 4.2 and 19.6 ± 5.2 IU/L, respectively, (p = 0.037). Mean alanine transaminase (ALT) before and after conversion was 15.8 ± 5.5 and 17.6 ± 7.1 IU/L, respectively, (p = 0.007). Mean eGFR before and after conversion was 50.6 ± 14.4 and 51.4 ± 14.7 mL/min/1.73 m2, respectively (p = 0.021). Mean AST, ALT, and eGFR were slightly but significantly elevated within normal ranges after conversion. In conclusion, our study suggests that the mean tacrolimus C0/D was elevated significantly by converting from rabeprazole to vonoprazan, but it had little clinical significance. Vonoprazan can be administered safely to kidney transplant recipients receiving tacrolimus.

    Graphical Abstract Fullsize Image
  • Takeo Yamaguchi, Toshihiro Ishimatu
    2020 年 43 巻 10 号 p. 1604-1608
    発行日: 2020/10/01
    公開日: 2020/10/01
    ジャーナル フリー HTML

    Human erythrocytes contain abundant cholesterol as membrane lipids. Cholesterol contributes to the stability and function of the membrane. Membrane stability of the erythrocyte has been mainly examined under hypotonic conditions, but not under high hydrostatic pressure. So, the effect of cholesterol on the membrane stability of human erythrocyte was examined under a pressure of 200 MPa. As with hypotonic hemolysis, the pressure-induced hemolysis was enhanced by depletion of cholesterol from the intact erythrocyte membrane, whereas suppressed by cholesterol loading to the intact one. Enhancement of such hemolysis was associated with the suppression of fragmentation, whereas the hemolysis was suppressed by the facilitation of vesiculation. Cholesterol induced the tight linkage of the lipid bilayer with cytoskeleton. Taken together, these results suggest that the erythrocyte membrane stability is affected by such tight linkage by cholesterol.

    Graphical Abstract Fullsize Image
  • Daisuke Nakano, Kenji Ishitsuka, Maya Takashima, Rie Arima, Aya Satou, ...
    2020 年 43 巻 10 号 p. 1609-1614
    発行日: 2020/10/01
    公開日: 2020/10/01
    ジャーナル フリー HTML

    In the course of our screening program for novel chemotherapeutic candidates from plants against adult T-cell leukemia/lymphoma, the extracts of Asclepias curassavica L. showed potent activity against MT-1 and MT-2 cells. Therefore, we attempted to isolate their active components. We identified a new cardenolide, 19-dihydrocalactinic acid methyl ester (1), along with 16 known cardenolides (217). Their structures were determined on the basis of spectroscopic data. Almost all of the isolated cardenolides inhibited the growth of both tumor cell lines. All the doubly linked cardenolides (1117) except for 14 showed more potent activity than the other cardenolides. A comparison of the activities of 11, 14 and 16 revealed that the presence of hydroxy or acetoxy functional groups at C-16 led to a decrease in the activity. The 50% effective concentration (EC50) value of calotropin (11) against MT-2 cells was comparable to the potency of the clinical antineoplastic drug doxorubicin. The cytotoxic effect of 11 toward normal mononuclear cells obtained from the peripheral blood (PB-MNCs) was observed at a concentration 6 to 12 times higher than that used to induce growth inhibition against MT-1 and MT-2 cells. The proportions of annexin V-positive cells after 72 h of treatment with 11 were increased, indicating that it significantly induced apoptosis in MT-1 and MT-2 cells in a concentration-dependent manner. Cell cycle experiments demonstrated that 11 arrested MT-1 and MT-2 cells at the G2/M phase. Therefore, compound 11 may be a promising candidate for the treatment of adult T-cell leukemia/lymphoma.

    Graphical Abstract Fullsize Image
Notice of Withdrawal
feedback
Top