Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
Volume 43 , Issue 6
Showing 1-16 articles out of 16 articles from the selected issue
Communication to the Editor
  • Maki Saito, Nanae Ishida, Hidetoshi Yamada, Miho Ibi, Masamichi Hirose
    2020 Volume 43 Issue 6 Pages 919-924
    Published: June 01, 2020
    Released: June 01, 2020
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    Supplementary material

    Eicosapentaenoic acid (EPA), one of the N-3 polyunsaturated fatty acids (n-3 PUFAs), is a major active ingredient of fish that contributes to improve dyslipidemia. Recently, we demonstrated that 8-hydroxyeicosapentaenoic acid (8-HEPE) had a more positive effect on metabolic syndrome than EPA, and that 8-HEPE induced peroxisome proliferator-activated receptor (PPAR)α activation in the liver. We investigated the effects of 8-HEPE-concentrated materials from Pacific krill on dyslipidemia and hepatic steatosis in low-density lipoprotein (LDL) receptor-deficient (LDLR-KO) mice. Eight-week-old male LDLR-KO mice were fed a Western diet (0.15% cholesterol, WD), WD supplemented with 8-HEPE-concentrated materials from Pacific krill (8-HEPE included; WD +8-HEPE), or a standard diet (SD) for eighteen weeks, respectively. Murine J774.1 macrophages were incubated in the absence or presence of 8-HEPE (50 µM) or EPA (50 µM). 8-HEPE-concentrated materials significantly increased the plasma high-density lipoprotein (HDL)-cholesterol level, and decreased the plasma LDL-cholesterol and hepatic triglyceride levels in WD-fed LDLR-KO mice. Moreover, the rate of Oil Red O-positive staining was higher in the liver of WD-fed LDLR-KO mice than in that of 8-HEPE + WD-fed LDLR-KO mice. 8-HEPE but not EPA significantly increased gene expression levels of ABCA1, CD36, and interleukin 6 (IL-6) in murine J774.1 macrophages compared with those in the control. These results suggest that 8-HEPE-concentrated materials improve dyslipidemia and hepatic steatosis increasing ABCA1, CD36, and IL-6 gene expressions in macrophages.

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Regular Articles
  • Haruki Torii, Motozumi Ando, Hideaki Tomita, Tomoko Kobaru, Mahoko Tan ...
    2020 Volume 43 Issue 6 Pages 925-931
    Published: June 01, 2020
    Released: June 01, 2020
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    Supplementary material

    We investigated whether use of hypnotic drugs, including benzodiazepine receptor agonists, as well as ramelteon and suvorexant are associated with fall incidents in elderly inpatients aged no less than 75 years, who were hospitalized at an acute care general hospital in Japan, between November 1st, 2016 and October 31st, 2017. Multivariate analysis results were reported as odds ratio (OR) with 95% confidence interval (CI). Following to a case-crossover study protocol, the time windows of the case and the control days were assigned to the day or the days, which are one day or 2–8 d before the fall incidents, respectively. In the enrolled 111 patients, the accumulated total available numbers of the cases and the control days were 111 and 554 patient days, respectively. Hypnotic drug use was significantly associated with fall incidents (OR: 2.85, 95% CI: 1.03–7.90, p = 0.04). Especially benzodiazepine receptor agonists (OR: 5.79, 95% CI: 1.52–22.1, p = 0.01) showed statistically significant association with fall incidents. In contrast, neither ramelteon (OR: 7.95, 95% CI: 0.72–87.9, p = 0.09) nor suvorexant (OR: 0.25, 95% CI: 0.06–1.06, p = 0.06) were significantly associated with fall incidents. Thus, benzodiazepine receptor agonists, but not ramelteon or suvorexant, showed significant association with fall incidents. Therefore, special care should be taken especially when benzodiazepine receptor agonists are administrated to elderly subjects. In contrast, fall risk may be much less in patients treated with ramelteon or suvorexant. These results could help us to conduct safer drug treatment for insomnia patients aged no less than 75 years.

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  • Xiaolan Chen, Li Liu, Wei Chen, Feng Qin, Fang Zhou, Haifeng Yang
    2020 Volume 43 Issue 6 Pages 932-937
    Published: June 01, 2020
    Released: June 01, 2020
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    Rotavirus (RV) induced diarrhea has been a major reason affecting children healthy under 5 years old especially in developing countries. Although specific vaccines have preventive effects, antiviral therapy is essential for the diarrhea patients. Ziyuglycoside II is a traditional Chinese herb which has been proven to possess anti-virus effects. This study aimed to investigate the roles of Ziyuglycoside II in rotavirus-induced diarrhea and the underlying molecular mechanism. We found that normal MA104 cells treated with RV became swollen and gather together. However, Ziyuglycoside II treatment inhibited cell growth in a dose- and time dependent manner and suppressed RV replication. Moreover, Ziyuglycoside II reversed RV-induced downregulation of anti-inflammatory cytokine interleukin (IL)-10 and upregulation of pro-inflammatory factors, such as interferon-γ (IFN-γ), IL-1β, IL-6, and tumor necrosis factor (TNF-α). Moreover, Ziyuglycoside II administration and ribavirin blocked toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signaling pathway both in mRNA and protein level, which was paralleled with immunohistochemical assay. Additionally, Ziyuglycoside II administration improved diarrhea symptoms and decreased diarrhea scores. Ziyuglycoside II and ribavirin inhibited the apoptosis of small intestine epithelial cells induced by RV. Taken together, RV treatment induced diarrhea. Ziyuglycoside II administration inhibited TLR4/NF-κB pathway and inflammatory response and improved RV-induced diarrhea. The inhibitory effects of Ziyuglycoside II on RV-induced diarrhea predicted Ziyuglycoside II may be a promising drug for diarrhea.

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    Editor’s picks

    In the present study, Ziyuglycoside II inhibits rotavirus (RV) induced diarrhea via toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signaling pathway. Ziyuglycoside II inhibited the proliferation of MA104 cells infected with RV via suppressing RV duplication. The combination of Ziyuglycoside II and Ribavirin protected against RV-induced diarrhea through regulating TLR4/NF-κB signaling pathway. Moreover, the combined treatment suppressed the level of pro-inflammation cytokines and overexpressed anti-inflammation cytokine. Moreover, the combined therapy improved the lesion changes and inhibited the cell apoptosis in vivo. Thus Ziyuglycoside II may function as protective role in RV-induced diarrhea.

  • Yong Chen, Fang Lian, Qiang Lu, Shengliang Peng, Jiahao Li, Song Huang ...
    2020 Volume 43 Issue 6 Pages 938-945
    Published: June 01, 2020
    Released: June 01, 2020
    [Advance publication] Released: March 19, 2020
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    The neurodevelopmental toxicity of isoflurane has been proved by many studies, which makes it essential to explore the underline mechanisms and search for protective agents to attenuate its neurotoxcity. Accumulating evidence showed that L-theanine had neuroprotective effects on injured neurons and the developing brain. The present study was designed to investigate whether L-theanine could attenuate isoflurane-induced damage in neural stem cells and cognitive impairment in young mice, and to discuss the role of protein kinase B (Akt)–glycogen synthase kinase 3β (GSK-3β) signaling pathway in this process. Multipotential neural stem cells (NSCs) and C57BL/6J mice were treated with either gas mixture, isoflurane, or L-theanine 30 min prior to isoflurane exposure, respectively. NSC viability was detected by CCK-8 assay. NSC proliferation and apoptosis were assessed by immunofluorescence and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay, respectively. The levels of cleaved caspase-3 and phosphorylated (p)-Akt and p-GSK-3β in NSCs were tested by Western blotting. Cognitive function of mice was tested by Morris Water Maze at postnatal day (P) 30–35. The results indicated that isoflurane exposure inhibited NSC viability and proliferation, promoted NSC apoptosis as well as increased caspase-3 activation and down-regulated the expressions of p-Akt and p-GSK-3β in NSCs, and that isoflurane exposure on neonatal mice would induce late cognitive impairment. Pretreatment with L-theanine could attenuate isoflurane-caused damage in NSCs and cognitive deficits in young mice. Addinonally, the protective effects of L-theanine on isoflurane-injured NSCs could be reversed by Akt inhibitor Triciribine. Our data showed that pretreatment with L-theanine eliminated the NSC damage and cognitive impairment induced by isoflurane exposure, and that the neuroprotective effect of L-theanine was associated with the Akt–GSK-3β signaling pathway.

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  • Yota Shimato, Tatsuhiko Hattori, Takamasa Ohno
    2020 Volume 43 Issue 6 Pages 946-950
    Published: June 01, 2020
    Released: June 01, 2020
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    Supplementary material

    The extract of Lycium bark (LBE), which is the root bark of Lycium chinense, has long been used in China for hypertension, inflammation, and diabetes. LBE has been reported to ameliorate hyperglycemia in mice with alloxan-induced type 1 diabetes, but evidence on the effect of LBE in diabetes had not been enough. Therefore, we investigated the effects of LBE on type 2 diabetes using db/db mice. Nine-week-old male db/db mice were orally administered LBE (425 mg/kg) for 10 weeks. Blood samples were collected under anesthesia for the determination of blood glucose and insulin levels. The blood glucose level was increased in the control group and was unchanged in the LBE group. The blood insulin level was increased in both groups within 4 weeks, but it decreased in the control group and was maintained at a relatively high level in the LBE group thereafter. Furthermore, LBE increased the glucose uptake, which was measured using C2C12 myotubes, in a concentration-dependent manner, independent of the addition of a phosphatidylinositol 3-kinase inhibitor (i.e., LY294002) and an AMP-activated kinase inhibitor (i.e., dorsomorphin). And LBE increased the mRNA expression of glucose transporter (GLUT) 1. These results suggested that LBE decreased the blood glucose level by additive effect such as improvement of the insulin secretion, promoting activity of glucose uptake. These findings suggested that LBE administration can be a novel therapeutic approach for type 2 diabetes.

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  • Taichi Ohshiro, Satoshi Imuta, Ichiro Hijikuro, Hiroaki Yagyu, Takashi ...
    2020 Volume 43 Issue 6 Pages 951-958
    Published: June 01, 2020
    Released: June 01, 2020
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    Supplementary material

    The fungal 13-membered cyclodepsipeptides, beauveriolides I and III, were previously reported to be atheroprotective activity in mouse models via inhibiting sterol O-acyltransferase (SOAT) activity. A total of 149 beauveriolide derivatives (BVDs) synthesized combinatorially were evaluated in in silico absorption, distribution, metabolism and excretion (ADME) analysis and inhibitory activity toward the two SOAT isozymes, SOAT1 and SOAT2. Hence, only 11 BVDs exhibited SOAT2-selective inhibition. Among these, we chose BVD327, which had the highest ADME score, for further evaluation. BVD327 administration (50 mg/kg/d, per os (p.o.)) significantly decreased atherosclerotic lesions in the aorta and heart (25.4 ± 6.9 and 20.6 ± 2.9%, respectively) in apolipoprotein E knockout (Apoe−/−) mice fed a cholesterol-enriched diet (0.2% cholesterol and 21% fat) for 12 weeks. These findings indicate that beauveriolide derivatives can be used as anti-atherosclerotic agents.

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  • Zhangbao Chen, Jiaojiao Liu, Xia Kong, Hui Li
    2020 Volume 43 Issue 6 Pages 959-967
    Published: June 01, 2020
    Released: June 01, 2020
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    In this study, we investigated the physicochemical properties and composition of monosaccharidex from Polygonatum sibiricum. Simultaneously, we explored the in vivo and in vitro immunomodulatory activity and mechanism of Polygonatum sibiricum polysaccharide (PSP) activity by monitoring changes in immune organs, immune cells, and cytokines. The average molecular weight (Mw) of PSP was 9.514 × 104 Da. The monosaccharide components of PSP were galactose, rhamnose, arabinose, mannose, and glucose at a molar ratio of 11.72 : 1.78 : 4.15 : 1.00 : 2.48. PSP increased thymus and spleen indices, enhance the proliferative responses of splenocytes, and increased the phagocytosis of mononuclear macrophages. Simultaneously, PSP could recover the body mass of immunosuppressed mice, and increased blood erythrocyte counts in the sera of cyclophosphamide (Cy)-treated and normal mice, whilst blood leukocytes and platelet counts of Cy-treated mice recovered. PSP elevated the CD4+/CD8+ ratio is a dose-dependent manner and increased the levels of interleukin-2 (IL-2) and tumor necrosis factor-α (TNF-α) in the sera of Cy-treated mice. PSP further enhanced the expression of IL-2 and TNF-α in spleen lymphocytes. Additionally, PSP treatment accelerated the recovery of natural killer cell activity in a dose-dependent manner. Taken together, PSP not only regulated the immune function of normal mice, but participated in the protection against immunosuppression in Cy-treated mice, highlighting its potential as an immunostimulant.

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    Editor’s picks

    Polygonatum sibiricum first appeared in ancient Chinese medicine books around 1000 years ago and is used to tonify the spleen and nourish the lungs. The authors present here a kind of natural polysaccharides (PSP) extracted from Polygonatum sibiricum were purified, characterized and assayed both in vitro and in vivo for its immunomodulatory activity and mechanism. It is of interest to note that PSP not only regulated the immune function of normal mice, but participated in the protection against immunosuppression in cyclophosphamide-treated mice, highlighting its potential as an immunostimulant.

  • Yuanyuan Zhang, Gaohua Zhang, Yingran Liang, Hongfang Wang, Qian Wang, ...
    2020 Volume 43 Issue 6 Pages 968-975
    Published: June 01, 2020
    Released: June 01, 2020
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    The purpose of the present study was to investigate the protective effects and the underlying mechanisms of Danshensu on liver injury induced by iron overload. The mouse model was induced by injection of iron dextran intraperitoneally for 14 d. Danshensu significantly ameliorated liver injury by decreasing iron accumulation in the liver, possibly by down-regulating the expression of iron uptake-related proteins: divalent metal ion transporters-1 (DMT-1), transferrin receptor (TfR), and L-type calcium channel α1C subunit. Furthermore, Danshensu alleviated oxidative stress injury through potentiating glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities; Immunohistochemistry results demonstrated that Danshensu reduced the expression of inflammatory cytokines: interleukin-6 (IL-6) and transforming growth factor-beta (TGF-β). Moreover, Danshensu prominently inhibited hepatocyte apoptosis through decreasing Bax and Caspase-3 and increasing Bcl-2 expression levels. The present results suggest that Danshensu possess significant hepatic-protection at least partly through inhibition of iron uptake, oxidative stress, inflammatory, and apoptosis. Therefore, we believe that Danshensu could be used as a promising therapeutic agent for preventing and treating iron overload diseases.

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    Editor’s picks

    Danshensu (3-(3,4-dihydroxyphenyl)-(2R)-lactic acid) is one of the water-soluble active ingredients of Salvia miltiorrhizae, a traditional Chinese medicine for the treatment of cardiovascular diseases. This study investigated the protective effects of Danshensu on the acute liver injury induced by iron overload in mice. The results indicated that the underlying mechanisms at least partly involve anti-oxidation, anti-inflammation, anti-apoptosis, and decreasing hepatic iron deposition possibly through down-regulating the expression of iron uptake related proteins, such as DMT1, TfR, and L-type Ca2+ CP α1C. Therefore, they conclude Danshensu could be a promising prophylactic or therapeutic agent for iron overload diseases.

  • Fangmei Chen, Xiaoying Yin, Yanqing Wang, Yixin Lv, Si Sheng, Sheng Ou ...
    2020 Volume 43 Issue 6 Pages 976-984
    Published: June 01, 2020
    Released: June 01, 2020
    [Advance publication] Released: March 19, 2020
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    Cytisine N-methylene-(5,7-dihydroxy-4′-methoxy)-isoflavone (CNF2) is a new compound isolated from the Chinese herbal medicine Sophora alopecuroides. Preliminary pharmacodynamic studies demonstrated its activity in inhibiting breast cancer cell metastasis. This study examined the pharmacokinetics, absolute bioavailability, and tissue distribution of CNF2 in rats, and combined computer-aided technology to predict the druggability of CNF2. The binding site of CNF2 and the breast cancer target human epidermal growth factor receptor-2 (HER2) were examined with molecular docking technology. Next, ACD/Percepta software was used to predict the druggability of CNF2 based on the quantitative structure–activity relationship (QSAR). Finally, a simple and effective HPLC method was used to determine plasma pharmacokinetics and tissue distribution of CNF2 in rats. Prediction and experimental results show that compared with the positive control HER2 inhibitor SYR127063, CNF2 has a stronger binding affinity with HER2, suggesting that its efficacy is stronger; and the structure of CNF2 complies with the Lipinski’s Rule of Five and has good drug-likeness. The residence time of CNF2 in rats is less than 4 h, and the metabolic rate is relatively fast; But the absolute bioavailability of CNF2 in rats was 6.6%, mainly distributed in the stomach, intestine, and lung tissues, where the CNF2 contents were 401.20, 144.01, and 245.82 µg/g, respectively. This study constructed rapid screening and preliminary evaluation of active compounds, which provided important references for the development and further research of such compounds.

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  • Xiaoyu Zhang, Guang Xin, Shiyi Li, Zeliang Wei, Yue Ming, Jiyan Yuan, ...
    2020 Volume 43 Issue 6 Pages 985-993
    Published: June 01, 2020
    Released: June 01, 2020
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    Supplementary material

    Acute biliary pancreatitis (ABP) with a high mortality rate is an incurable digestive system disease induced by abnormal bile acid regurgitation due to the biliary obstruction. Dehydrocholic acid (DA) alleviates the severity of cholestatic hepatitis related to biliary inflammation, suggesting DA is potential to develop for the incurable ABP management. Here we identified DA potency and explored the underlying mechanism in ABP. Our data showed that DA administration not only reduced typically clinicopathological parameters including serum levels of amylase and lipase but also suppressed pancreatic tissue edema, necrosis and trypsin activation in ABP mice. We also found that DA significantly reduced the necrosis of pancreatic acinar cells induced by sodium taurocholate (NaT). Further experimental data showed the significant inhibitions of DA on mitochondrial membrane potential depolarization, ATP exhaustion, calcium overload and reactive oxygen species (ROS) erupted in acinar cells induced by NaT, indicating DA could avert acinar cell death through protecting the mitochondrial function, scavenging excessive oxidative stress and balancing calcium. The comprehensive study found DA elevated the expression of transcription factor EB (TFEB) in vitro thus to increase the functional lysosome content. Indeed, DA decreased the Microtubule-associated protein light chain 3 (LC3) II/I ratio as well as ubiquitin-binding protein p62 and Parkin expressions in vivo and in vitro, revealing autophagy restoration maybe through the improvement of TFEB-mediated lysosome biogenesis. These data indicate that DA improves ABP through the mitochondrial protection, antioxidant ability enhancement and autophagy recovery. In conclusion, our study proposes a potential therapy strategy for the incurable ABP.

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  • Yan Xu, Lina Wei, Yanbo Wang, Lizhong Ding, Yinan Guo, Xiaozhou Sun, Y ...
    2020 Volume 43 Issue 6 Pages 994-999
    Published: June 01, 2020
    Released: June 01, 2020
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    Streptococcus pneumoniae (S. pneumoniae) is an opportunistic pathogen that causes pneumonia, meningitis and bacteremia in humans and animals. Pneumolysin (PLY), a major pore-forming toxin that is important for S. pneumoniae pathogenicity, is a promising target for the development of anti-infective agents. Ephedra sinica granules (ESG) is one of the oldest medical preparation with multiple biological activities (such as a divergent wind and cold effect); however, the detailed mechanism remains unknown. In this study, we found that ESG treatment significantly inhibited the oligomerization of PLY and then reduced the activity of PLY without affecting S. pneumoniae growth and PLY production. In a PLY and A549 cell co-incubation system, the addition of ESG resulted in significant protection against PLY-mediated cell injury. Furthermore, S. pneumoniae-infected mice showed decreased mortality, and alleviated tissue damage and inflammatory reactions following treatment with ESG. Our results indicate that ESG is a potential candidate treatment for S. pneumoniae infection that targets PLY. This finding partially elucidates the mechanism of the Chinese herbal formula ESG in the treatment of pneumococcal disease.

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  • Masashi Homma, Hideya Kokubun, Kosuke Okuwaki, Chikatoshi Katada, Nori ...
    2020 Volume 43 Issue 6 Pages 1000-1006
    Published: June 01, 2020
    Released: June 01, 2020
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    In this study, we conducted a pharmacokinetic analysis of tapentadol (TP) in Japanese patients with cancer pain and identified covariates influencing pharmacokinetic parameters. In addition, the analgesic effects and adverse effects of TP were investigated. Data were collected from in-patients with cancer pain who had been administered TP as an extended-release formula. The median (range) estimated clearance (CL/F) and distribution volume (Vd/F) of TP were 86.7 (31.3–213.7) L/h and 1288 (189–6736) L, respectively. There was a strong negative correlation between CL/F and age, Child–Pugh score, and albumin-bilirubin (ALBI) score. The subjects were further divided into two groups according to the factors highly correlated with CL/F. The CL/F of patients in the Child–Pugh B group was 0.46-times that of patients in the Child–Pugh A group. In addition, the CL/F of patients with an ALBI score > −2.40 was 0.56-times that of patients with ALBI scores ≤−2.40, and both differences were statistically significant (p < 0.05). The mean intensity of pain over 24 h was investigated daily from before starting TP for the first 7 d of the treatment. TP reduced pain in six of nine patients; the mean pain visual analogue scale score decreased significantly from 59.2 mm before administration to 42.5 mm at days 5–7. Overall, the Child–Pugh and ALBI scores significantly affected the clearance of TP, which was reduced in patients with impaired liver function. These results suggest that TP is an opioid with a sufficient analgesic effect for cancer patients.

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  • Tomohiro Shirayanagi, Shigeki Aoki, Sota Fujimori, Kenji Watanabe, Tet ...
    2020 Volume 43 Issue 6 Pages 1007-1015
    Published: June 01, 2020
    Released: June 01, 2020
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    The interaction of human leukocyte antigen (HLA) with specific drugs is associated with delayed-type hypersensitivity reactions, which cause severe cutaneous toxicity. Such interactions induce structural alterations in HLA complexes via several different mechanisms such as the hapten theory, p-i concept, and altered peptide repertoire model, leading to the activation of cytotoxic T cells. To date, comprehensive detection of such structural alterations in preclinical studies has been difficult. Here, we evaluated structural alterations in HLA complexes focusing on the interaction between the HLA-B*57 : 01 allele and abacavir (an anti-human immunodeficiency virus drug), representing a model of abacavir hypersensitivity syndrome induced by changes in the peptide repertoire on the HLA molecule. We employed a phage display method using a commercially available antibody library to screen specific phage antibodies able to recognize HLA-B*57 : 01. The affinity of selected phage antibodies increased because of structural alterations in HLA-B*57 : 01 following exposure to abacavir, indicating that specific phage antibodies can identify drug-mediated structural changes in HLA complexes. We also identified an unreported structural change in HLA-B*57 : 01 using the phage display method, whereby abacavir increased the expression of peptide-deficient HLA-B*57 : 01 on the cell surface. These results suggest that phage display technology is a useful method for detecting structural changes in HLA complexes. This technology represents a potential novel strategy for predicting HLA-associated hypersensitivity reactions by drugs in pre-clinical studies.

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    Editor’s picks

    The interaction of human leukocyte antigen (HLA) with specific drugs induces structural alteration in HLA and delayed-type hypersensitivity reactions, which cause severe cutaneous toxicity. Shirayanagi et al. selected specific phage antibodies able to recognize HLA-B*57:01 and evaluated structural alterations in HLA-B*57:01 complexes induced by abacavir. The affinity of selected phage antibodies increased because of structural alterations in HLA-B*57:01 following exposure to abacavir, indicating that specific phage antibodies can identify drug-mediated structural changes in HLA complexes. These results suggest that phage display technology is a useful method for detecting structural changes in HLA complexes.

Notes
  • Yuki Shimba, Keigo Katayama, Noriyuki Miyoshi, Masahiko Ikeda, Akihito ...
    2020 Volume 43 Issue 6 Pages 1016-1019
    Published: June 01, 2020
    Released: June 01, 2020
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    Endurance exercise training has been shown to induce peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression in skeletal muscle. We recently reported that skeletal muscle-specific PGC-1α overexpression suppressed atherosclerosis in apolipoprotein E-knockout (ApoE−/−) mice. β-Aminoisobutyric acid (BAIBA) is a PGC-1α-dependent myokine secreted from myocytes that affects multiple organs. We have also reported that BAIBA suppresses tumor necrosis factor-alpha-induced vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) gene expression in endothelial cells. In the present study, we hypothesized that BAIBA suppresses atherosclerosis progression, and tested that hypothesis with ApoE−/− mice. The mice were administered water containing BAIBA for 14 weeks, and were then sacrificed at 20 weeks of age. Atherosclerotic plaque area, plasma BAIBA concentration, and plasma lipoprotein profiles were assessed. Immunohistochemical analyses of the plaque were performed to assess VCAM-1 and MCP-1 protein expression levels and macrophage infiltration. The results showed that BAIBA administration decreased atherosclerosis plaque area by 30%, concomitant with the elevation of plasma BAIBA levels. On the other hand, plasma lipoprotein profiles were not changed by the administration. Immunohistochemical analyses indicated reductions in VCAM-1, MCP-1, and Mac-2 protein expression levels in the plaque. These results suggest that BAIBA administration suppresses atherosclerosis progression without changing plasma lipoprotein profiles. We propose that the mechanisms of this suppression are reductions in both VCAM-1 and MCP-1 expression as well as macrophage infiltration into the plaque.

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  • Yoshimitsu Kiriyama, Anna Tani, Minako Kadoya, Ryoko Okamoto, Hiromi N ...
    2020 Volume 43 Issue 6 Pages 1020-1022
    Published: June 01, 2020
    Released: June 01, 2020
    [Advance publication] Released: March 20, 2020
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    Glioblastoma comprises 54% of all the gliomas derived from glial cells and are lethally malignant tumors of the central nervous system (CNS). Glioma cells disrupt the blood–brain barrier, leading to access of circulating immune cells to the CNS. Blocking the interaction between programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) enhances T-cell responses against tumor cells, and inhibition of the PD-1/PD-L1 pathway is used as immunotherapy for cancer, including glioblastoma. Nitric oxide (NO) has multiple physiological roles, such as immune modulation and neural transmission in the CNS. Moreover, it has both tumor-promoting and tumor-suppressive functions. We examined the effects of NOC-18, an NO donor, on the expression of PD-L1 in A172 glioblastoma cells. NOC-18 increased PD-L1 expression in A172 glioblastoma cells. Moreover, this increase is regulated via the c-Jun N-terminal kinase pathway.

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  • Keiki Sakurama, Koji Nishi, Victor Tuan Giam Chuang, Mai Hashimoto, Ke ...
    2020 Volume 43 Issue 6 Pages 1023-1026
    Published: June 01, 2020
    Released: June 01, 2020
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    Aripiprazole (ARP) is one of antipsychotics and binds to human serum albumin (HSA) with a high affinity. In this study, we investigated the binding characteristics of ARP to oxidized HSA as observed in chronic disease conditions. Oxidized HSAs were prepared using chloramine-T (CT-HSA) or metal-catalyzed oxidation system (MCO-HSA) in vitro, respectively. An increase in the carbonyl content was confirmed in oxidized HSAs. From the results of circular dichroism (CD) and tryptophan fluorescence spectra, no significant structural change of oxidized HSAs was observed. These results indicate that prepared HSAs are mildly oxidized and well reflects the status of HSA during chronic diseases. However, oxidized HSAs were observed to have a significant decrease in binding to ARP. The results of the induced CD spectrum suggested that ARP bound to oxidized HSAs with a similar orientation. These results suggest that oxidation of HSA during chronic disease state significantly affected the microenvironment of the binding site for ARP and binding capacity of HSA to ARP.

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