Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
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Review
  • Jing Wang, Naoki Takemura, Tatsuya Saitoh
    2021 Volume 44 Issue 5 Pages 599-604
    Published: May 01, 2021
    Released: May 01, 2021
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    The purine nucleotide ATP is a fundamental unit in cellular energy metabolism. Extracellular ATP and its metabolites are also ligands for a family of receptors, known as purinergic receptors, which are expressed ubiquitously in almost every cell type. In the immune system, extracellular ATP and its signals regulate the migration and activation of immune cells to orchestrate the induction and resolution of inflammation. In this review, we provide an overview of purinergic receptors and their downstream signaling related to macrophage activation. We also discuss the roles of purinergic signaling for macrophage functions in physiological and pathological conditions.

Regular Articles
  • Kazumasa Kotake, Takashi Hongo, Akihiro Tahira, Nana Niimi, Ikue Haisa ...
    2021 Volume 44 Issue 5 Pages 605-610
    Published: May 01, 2021
    Released: May 01, 2021
    [Advance publication] Released: February 20, 2021
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    Recombinant human thrombomodulin (rhTM) is an anti-coagulant used to treat disseminated intravascular coagulation (DIC). The efficacy of rhTM in patients with sepsis-induced DIC has been proved in some clinical trials, but the determining factors are not known. The aim of this study was to identify patients for whom rhTM will be effective and the factors that determine rhTM efficacy in alleviating DIC. A single-center, retrospective, observational study was conducted in patients with sepsis-induced DIC who were treated with rhTM in Okayama Saiseikai General Hospital (Okayama, Japan) between January 2010 and December 2019. Among 67 patients who were treated with rhTM, DIC was resolved in 24 patients. The multivariate logistic regression analysis revealed that age (odds ratio (OR) 1.05; 95% confidence interval (CI) 1.00–1.10; p < 0.05) and acute physiology and chronic health evaluation II scores (OR 0.88; 95% CI 0.78–0.98; p < 0.05) were factors that determined rhTM efficacy in alleviating DIC. Overall, our study provides valuable information on factors that should be considered before rhTM administration to patients with sepsis-induced DIC for a better management of healthcare costs.

  • Yohei Kawano, Masashi Nagata, Saeko Nakamura, Yuuki Akagi, Tatsunori S ...
    2021 Volume 44 Issue 5 Pages 611-619
    Published: May 01, 2021
    Released: May 01, 2021
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    Oral anticoagulants (OACs) pose a major bleeding risk, which may be increased or decreased by concomitant medications. To explore medications that affect the bleeding risk of OACs, we conducted a nested case-control study including 554 bleeding cases (warfarin, n = 327; direct OACs [DOACs], n = 227) and 1337 non-bleeding controls (warfarin, n = 814; DOACs, n = 523), using a Japanese health insurance database from January 2005 to June 2017. Major bleeding risk associated with exposure to concomitant medications within 30 d of the event/index date was evaluated, and adjusted odds ratios (aORs) were calculated using logistic regression analysis. Several antihypertensive drugs, such as amlodipine and bisoprolol, were associated with a decreased risk of bleeding (warfarin + amlodipine [aOR, 0.64; 95% confidence interval (CI): 0.41–0.98], DOACs + bisoprolol [aOR, 0.51; 95% CI, 0.33–0.80]). As hypertension is considered a significant risk factor for intracranial bleeding in antithrombotic therapy, antihypertensive drugs may suppress intracranial bleeding. In contrast, telmisartan, a widely used antihypertensive drug, was associated with an increased risk of bleeding [DOACs + telmisartan (aOR, 4.87; 95% CI, 1.84–12.91)]. Since telmisartan is an inhibitor of P-glycoprotein (P-gp), the elimination of rivaroxaban and apixaban, which are substrates of P-gp, is hindered, resulting in increased blood levels of both drugs, thereby increasing the risk of hemorrhage. In conclusion, antihypertensive drugs may improve the safety of OACs, and the pharmacokinetic-based drug interactions of DOACs must be considered.

  • Yufang Xiang, Biqi Ren, Yue Chen, Minghuan Jiang, Ningsheng Wang, Rui ...
    2021 Volume 44 Issue 5 Pages 620-626
    Published: May 01, 2021
    Released: May 01, 2021
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    The prevalence of type 2 diabetes mellitus (T2DM) is increasing rapidly in China. Glycemic control is vital in this patient population. We designed a cross-sectional questionnaire to investigate glycemic control and associated factors in T2DM patients in Western China. The survey included patients’ medical history, blood glucose status, and therapeutic medications, as well as demographic data. The Chi-square test, Fisher’s exact test, and logistic regression were performed to analyze the data. The STROBE checklist was used to check the procedure. Among 510 T2DM patients included in this study, 47.5% of them had blood glucose control within the normal range, defined as glycated hemoglobin A1c (HbA1c) ≤7% or fasting plasma glucose (FPG) <7.0 mmol/L. The mean age of participants was 60.58 ± 11.20 years, with a male to female ratio of 1.02 : 1. Glycemic control was significantly associated with region (p < 0.001), comorbidities (p < 0.001), monitoring frequency (p = 0.002), treatment with insulin (p = 0.003), and medication compliance (p < 0.001). Logistic regression analysis showed that unsuccessful glycemic control was significantly related to wealthier residence (p < 0.001), more comorbidities (p = 0.017), monitoring frequency (p = 0.003), and medication incompliance (p < 0.001). These results suggested that the level of glycemic control among T2DM patients in Western China was poor. It is necessary to carry out health management and nursing of diabetic patients from community, family and patients jointly.

  • Takashi Omoto, Junichi Asaka, Takamasa Sakai, Fumihiko Sato, Nobuyuki ...
    2021 Volume 44 Issue 5 Pages 627-634
    Published: May 01, 2021
    Released: May 01, 2021
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    Opioids are widely used for the treatment of moderate/severe pain in cancer and noncancer patients. In this study, we searched for safety signals for a wide variety of opioid-related adverse events (AEs) in elderly patients by disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database. Data from the JADER database from April 2004 to May 2018 were obtained from the Pharmaceuticals and Medical Devices Agency website. Safety signal detection of opioid-related AEs in elderly patients was defined using the relative elderly reporting odds ratio (ROR). Among the analyzed AEs, opioid-induced neurotoxicity (OIN) was assessed based on the time to onset using the Weibull shape parameter. The following safety signals were detected in elderly patients: respiratory depression, somnolence, hallucinations, akathisia and OIN. Fentanyl, tramadol, oxycodone and morphine exhibited a large relative elderly ROR for OIN. The median time to onset of OIN of transdermal fentanyl, oral tramadol, oral oxycodone and oral morphine was 13.5, 6, 9, and 6 d, respectively. These opioids were classified as early failure types using the Weibull distribution. Our results showed that elderly patients who are administered opioids should be closely monitored for AEs, such as respiratory depression, OIN and akathisia.

  • Yuya Nakazono, Hiroshi Arakawa, Masafumi Nishino, Ikumi Yamaki, Takahi ...
    2021 Volume 44 Issue 5 Pages 635-641
    Published: May 01, 2021
    Released: May 01, 2021
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    Supplementary material

    In vitro transport studies across cells grown on culture inserts are widely used for evaluating pharmacokinetic characteristics such as intestinal membrane permeability. However, measurements of the apparent permeability coefficient of highly lipophilic compounds are often limited by transport across the membrane filters, not by transport across the cultured cells. To overcome this concern, we have investigated the utility of a high-porosity membrane honeycomb film (HCF) for transcellular transport studies. Using the HCF inserts, the apparent permeability coefficient (Papp) of the drugs tested in LLC-PK1 and Caco-2 cells tended to increase with an increase in lipophilicity, reaching a maximum Papp value at Log D higher than 2. In contrast, using the commercially available Track-Etched membrane (TEM) inserts, a maximum value was observed at Log D higher than 1. The basolateral to apical transport permeability Papp(BL→AP) of rhodamine 123 across LLC-PK1 cells that express P-glycoprotein (P-gp) cultured on HCF inserts and TEM inserts was 2.33 and 2.39 times higher than the reverse directional Papp(AP→BL) permeability, respectively. The efflux ratio (Papp(B-A)/Papp(A-B)) of rhodamine 123 in LLC-PK1 expressing P-gp cells using HCF inserts was comparable to that obtained using TEM inserts, whereas the transported amount in both directions was significantly higher when using the HCF inserts. Accordingly, due to the higher permeability and high porosity of HCF membranes, it is expected that transcellular transport of high lipophilic as well as hydrophilic compounds and substrate recognition of transporters can be evaluated more accurately by using HCF inserts.

  • Daichi Nomura, Ryo Abe, Mitsutoshi Tsukimoto
    2021 Volume 44 Issue 5 Pages 642-652
    Published: May 01, 2021
    Released: May 01, 2021
    [Advance publication] Released: March 04, 2021
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    Radiation is an effective cancer treatment, but cancer cells can acquire radioresistance, which is associated with increased DNA damage response and enhanced proliferative capacity, and therefore, it is important to understand the intracellular biochemical responses to γ-irradiation. The transient receptor potential melastatin 8 (TRPM8) channel plays roles in the development and progression of tumors, but it is unclear whether it is involved in the DNA damage response induced by γ-irradiation. Here, we show that a TRPM8 channel inhibitor suppresses the DNA damage response (phosphorylated histone variant H2AX-p53-binding protein 1 (γH2AX-53BP1) focus formation) and colony formation of B16 melanoma cells. Furthermore, the TRPM8 channel-specific agonist WS-12 enhanced the DNA damage response and increased the survival fraction after γ-irradiation. We found that the TRPM8 channel inhibitor enhanced G2/M phase arrest after γ-irradiation. Phosphorylation of ataxia telangiectasia mutated and p53, which both contribute to the DNA damage response was also suppressed after γ-irradiation. In addition, the TRPM8 channel inhibitor enhanced the γ-irradiation-induced suppression of tumor growth in vivo. We conclude that the TRPM8 channel is involved in radiation-induced DNA damage repair and contributes to the radioresistance of B16 melanoma cells. TRPM8 channel inhibitors might be clinically useful as radiosensitizers to enhance radiation therapy of melanoma.

    Editor’s picks

    The article by Nomura et al. suggested a novel mechanism of radiation-induced DNA damage repair contributing to radioresistance in melanoma. Authors have shown that the transient receptor potential melastatin 8 (TRPM8) channel is involved in radiation-induced DNA damage response, cell death, and cell cycle regulation. Furthermore, TRPM8 channel inhibitor enhanced tumor growth-inhibitory effect by gamma-ray in vivo. These findings proposed that the TRPM8 channel contributes to the resistance of the growth-inhibitory effect of radiation in melanoma and could be a novel molecular target to improve the efficiency of radiation therapy for melanoma.

  • Kaori Morimoto, Momona Sasaki, Erika Oikawa, Maho Abe, Tatsuro Kikuchi ...
    2021 Volume 44 Issue 5 Pages 653-658
    Published: May 01, 2021
    Released: May 01, 2021
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    Supplementary material

    Alogliptin (ALG), an inhibitor of dipeptidylpeptidase-4, is used in the management of type 2 diabetes mellitus, and has a high absorption rate (>60–71%), despite its low lipophilicity (logP=−1.4). Here, we aimed to clarify the mechanism of its intestinal absorption. ALG uptake into Caco-2 cells was time-, temperature-, and concentration-dependent, but was not saturated at concentrations up to 10 mmol/L. The uptake was significantly inhibited by the organic anion transporting polypeptide (OATP) substrate fexofenadine and by the OATP inhibitor 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS), but was not inhibited by organic cation transporter (OCT)/organic cation/carnitine transporter (OCTN) or peptide transporter 1 (PEPT1) substrates. Grapefruit, orange, and apple juices and their constituents, which are known to strongly inhibit intestinal OATPs, significantly inhibited ALG uptake into Caco-2 cells. The pH dependence was bell-shaped, indicating the involvement of a pH-sensitive transporter. However, ALG uptake by HEK293 cells overexpressing OATP2B1, a key intestinal OATP transporter of amphiphilic drugs, was not different from that of mock cells. In a rat in vivo study, apple juice reduced systemic exposure to orally administered ALG without changing the terminal half-life. These observations suggest that intestinal absorption of ALG is carrier-mediated, and involves a fruit-juice-sensitive transporter other than OATP2B1.

  • Yuma Ito, Megumi Yamamoto, Shohei Furukawa, Masaki Fukui, Ko Morishita ...
    2021 Volume 44 Issue 5 Pages 659-668
    Published: May 01, 2021
    Released: May 01, 2021
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    Peroxisome proliferator-activated receptor γ (PPARγ) modulators are expected to exert anti-diabetic effects without PPARγ-related adverse effects, such as fluid retention, weight gain, and bone loss. The present study showed that the novel tetrazole derivative KY-903 exerted similar selective PPARγ partial agonist properties to INT-131, a known PPARγ modulator, in transactivation assays, and decreased plasma glucose and triglyceride levels with increases in adiponectin levels in diabetic KK-Ay mice. These effects were similar to those of pioglitazone. Pioglitazone, but not KY-903, increased adipose tissue and heart weights. In pre-adipocytes (3T3-L1), KY-903, in contrast to pioglitazone, increased adiponectin mRNA levels without adipocyte differentiation, indicating anti-diabetic effects via adiponectin without adipogenesis. In ovariectomized rats fed a high-fat diet (OVX/HFD), KY-903 and pioglitazone decreased plasma triglyceride and non-esterified fatty acid levels and increased adiponectin levels, indicating insulin sensitization via adiponectin. KY-903 reduced body weight gain and adipose tissue weight, while pioglitazone increased heart weight and markedly reduced bone mineral density. In mesenchymal stem cell-like ST2 cells, KY-903 slightly reduced osteoblast differentiation without adipocyte differentiation, while pioglitazone markedly reduced it with adipocyte differentiation. In conclusion, KY-903 is a novel PPARγ modulator that exerts anti-diabetic effects without body weight gain or cardiac hypertrophy in diabetic mice and anti-obesity effects with minor bone loss in OVX/HFD, possibly due to increases in adiponectin levels without adipogenesis.

    Editor’s picks

    Peroxisome proliferator-activated receptor ɤ (PPARɤ) agonists, such as pioglitazone, are anti-diabetic drugs, but they cause PPARɤ-related adverse effects such as body weight gain, cardiac hypertrophy, and bone loss. The authors found that a novel PPARɤ modulator, KY-903, has similar anti-diabetic effects without PPARɤ-related adverse effects in diabetic mice, possibly due to increases in adiponectin without adipogenesis. KY-903 also has anti-obesity effects with slight bone loss in obese rats, possibly by PPARɤ antagonism against endogenous or diet-derived PPARɤ ligands. These findings are useful for research on PPARɤ, and KY-903 is a potential candidate of anti-diabetic and/or anti-obesity drugs.

  • Hideki Imano, Ryuji Kato, Atsuo Nomura, Maki Tamura, Yudai Yamaguchi, ...
    2021 Volume 44 Issue 5 Pages 669-677
    Published: May 01, 2021
    Released: May 01, 2021
    [Advance publication] Released: February 20, 2021
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    Supplementary material

    Pulmonary arterial hypertension (PAH) is a progressive condition that frequently results in right ventricular (RV) remodeling. The objectives of this study are to investigate effects of rivaroxaban on RV remodeling in a rat model of PAH, created with Sugen5416 and chronic hypoxia, and the in vitro effects of rivaroxaban on human cardiac microvascular endothelial cells (HCMECs). To create the PAH model, male Sprague-Dawley rats were subcutaneously injected with Sugen5416 (20 mg/kg) and exposed to 2 weeks of hypoxia (10% O2), followed by 2 weeks of exposure to normoxia. The animals were then divided into 2 groups with or without administration of rivaroxaban (12 mg/kg/d) for a further 4 weeks. HCMECs were cultured under hypoxic conditions (37 °C, 1% O2, 5% CO2) with Sugen5416 and with or without rivaroxaban. In the model rats, RV systolic pressure and Fulton index increased by hypoxia with Sugen5416 were significantly decreased when treated with rivaroxaban. In HCMECs, hypoxia with Sugen5416 increased the expression of protease-activated receptor-2 (PAR-2) and the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and nuclear factor-kappa B (NF-κB), while treatment with rivaroxaban significantly suppressed the expression of these proteins. Rivaroxaban attenuated RV remodeling in a rat model of PAH by reducing ERK, JNK and NF-κB activation. Rivaroxaban has the possibility of providing additive effects on RV remodeling in patients with PAH.

    Editor’s picks

    The authors investigated the effects of rivaroxaban on right ventricular (RV) remodeling in a rat model of pulmonary arterial hypertension (PAH), created with Sugen5416 and chronic hypoxia (SuHx). The Fulton index, RV systolic pressure, and RV Tei index increased by SuHx were significantly decreased when treated with rivaroxaban. Rivaroxaban has the potential of improving RV remodeling in PAH model rats through the suppression of multiple signaling pathways, including ERK, JNK, and NF-kB, associated with protease-activated receptor-2. These findings suggest the additive effects that rivaroxaban may have on the RV remodeling in PAH.

  • Akiko Omori, Yuki Fujisawa, Shotaro Sasaki, Kazumi Shimono, Takashi Ki ...
    2021 Volume 44 Issue 5 Pages 678-685
    Published: May 01, 2021
    Released: May 01, 2021
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    To clarify the role of an amino acid residue in the pH-dependent efflux process in Chinese hamster ovary (CHO) cells expressing the human oligopeptide transporter hPEPT1 (CHO/hPEPT1), we determined the effect of extracellular pH on the hPEPT1-mediated efflux process. The efflux of glycylsarcosine (Gly-Sar), a typical substrate for hPEPT1, was determined using an infinite dilution method after cells were preloaded with [3H]-Gly-Sar. The efflux of [3H]-Gly-Sar was stimulated by 5 mM unlabeled hPEPT1 substrates in the medium. This trans-stimulation phenomenon showed that hPEPT1 mediated the efflux of [3H]-Gly-Sar from CHO/hPEPT1 and that hPEPT1 is a bi-directional transporter. We then determined the effect of extracellular pH (varying from 8.0 to 3.5) on the efflux activity. The efflux activity by hPEPT1 decreased with the decrease in extracellular pH. The Henderson–Hasselbälch-type equation, which fitted well to the pH-profile of efflux activity, indicated that a single amino acid residue with a pKa value of approximately 5.7 regulates the efflux activity. The pH-profile of the efflux activity remained almost unchanged irrespective of the proton gradient across the plasma membrane. In addition, the chemical modification of the histidine residue with diethylpyrocarbonate completely abolished the efflux activity from cells, which could be prevented by the presence of 10 mM Gly-Sar. These data indicate that the efflux process of hPEPT1 is also regulated in a pH-dependent manner by the protonation state of a histidine residue located at or near the substrate recognition site facing the extracellular space.

    Editor’s picks

    The authors indicated that the protonation of the histidine residue at the extracellular site in human oligopeptide transporter (hPEPT1) results in a decrease in the efflux activity, which is distinct from the sites of proton coupling for transport operation and substrate binding. Furthermore, they found that the decrease in extracellular pH reduced the turnover rate of transporters; in other words, the number of available transporters in the cycle was reduced. The protonation/deprotonation state of histidine determines the transport activity; the deprotonated histidine residue can participate in the transport cycle, whereas the protonated histidine residue can cease the transport.

  • Min-Kyoung Shin, Fumito Sasaki, Dae-Won Ki, Nwet Nwet Win, Hiroyuki Mo ...
    2021 Volume 44 Issue 5 Pages 686-690
    Published: May 01, 2021
    Released: May 01, 2021
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    Although more than 400 species of Cordyceps s.l. have been identified, most have not been well explored regarding their potential for medicinal use. In this study, the profiles of constituents of ten different species of Ophiocordyceps, which is an unexplored species of Cordyceps, were analyzed and their anti-tumor effects were further examined. Although all Ophiocordyceps samples exhibited similar peak patterns, Ophiocordyceps gracilioides (O. grac) had a distinct constituent profile from the other samples. Furthermore, O. grac was the most active in suppressing the transcriptional activities of both nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription (STAT)3, and the production of interleukin (IL)-6 from breast cancer cells. This study demonstrated that O. grac is a relatively unexplored Cordyceps s.l. that may have medicinal potential to inhibit the NFκB-STAT3-IL-6 inflammatory pathway in cancer.

  • Tomoko Sanada, Naoko Yoshida, Kazuko Kimura, Hirohito Tsuboi
    2021 Volume 44 Issue 5 Pages 691-700
    Published: May 01, 2021
    Released: May 01, 2021
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    There are many reports of falsified medicines that may cause harm to patients. A rapid and simple method of identifying falsified medicines that could be used in the field is required. Although Raman scattering spectroscopy has become popular as a non-destructive analysis, few validation experiments on falsified medicines that are actually distributed on the market have been conducted. In this study, we validated a discriminant analysis using an ultra-compact, portable, and low-cost Raman scattering spectrometer combined with multivariate analysis. The medicines were three types of erectile dysfunction therapeutic tablet and one type of antifungal tablet: tadalafil (Cialis), vardenafil hydrochloride (Levitra), sildenafil citrate (Viagra), and fluconazole (Diflucan), which is sometimes advertised as female Viagra. For each medicine, the authentic standard product and products obtained by personal import via the internet (genuine or falsified) were used. Discriminant analyses were performed on the Raman spectra combined with soft independent modeling of class analogy (SIMCA) and partial least squares discriminant analysis (PLS-DA). It was possible to identify all falsified samples by SIMCA using the standard product model for all four products. Using the PLS-DA using the PLS models of the four standard products, falsified Levitra and Diflucan samples were classified correctly, although some falsified Cialis and all Viagra samples also belonged to the standard class. In this study, SIMCA might be more suitable than PLS-DA for identifying falsified medicines. A spectroscopic module that combines the low-cost Raman scattering spectroscopy with SIMCA might contribute to the rapid identification of falsified medicines in the field.

  • Kentaro Yano, Masaki Kimura, Yayoi Watanabe, Takuo Ogihara
    2021 Volume 44 Issue 5 Pages 701-706
    Published: May 01, 2021
    Released: May 01, 2021
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    We previously reported that exposure of human colon adenocarcinoma (Caco-2) cells to the bitter substance phenylthiocarbamide (PTC) rapidly enhanced the transport function of P-glycoprotein (P-gp). In this study, we investigated the short-term effect of etoposide, another bitter-tasting P-gp substrate, on P-gp transport function in the same cell line. We found that etoposide exposure significantly increased both the P-gp protein level in the plasma membrane fraction and the efflux rate of rhodamine123 (Rho123) in Caco-2 cells within 10 min. The efflux ratio (ratio of the apparent permeability coefficient in the basal-to-apical direction to that in the apical-to-basal direction) of Rho123 in etoposide-treated cells was also significantly increased compared with the control. These results indicated that etoposide rapidly enhances P-gp function in Caco-2 cells. In contrast, P-gp expression in whole cells at both the mRNA and protein level was unchanged by etoposide exposure, compared with the levels in non-treated cells. Furthermore, etoposide increased the level of phosphorylated ezrin, radixin and moesin (P-ERM) proteins in the plasma membrane fraction of Caco-2 cells within 10 min. P-gp functional changes were blocked by YM022, an inhibitor of cholecystokinin (CCK) receptor. These results suggest that etoposide induces release of CCK, causing activation of the CCK receptor followed by phosphorylation of ERM proteins, which recruit intracellular P-gp for trafficking to the gastrointestinal membrane, thereby increasing the functional activity of P-gp.

  • Eri Harada, Kazumi Sugino, Megumi Aimoto, Akira Takahara
    2021 Volume 44 Issue 5 Pages 707-713
    Published: May 01, 2021
    Released: May 01, 2021
    [Advance publication] Released: February 27, 2021
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    High salt intake has been shown to induce hypertrophy and fibrosis in the atria and ventricles, which could result in the development of atrial fibrillation (AF). Whereas the development of AF is suggested to be prevented by renin–angiotensin system (RAS) inhibitors, recent findings have indicated that this prevention is closely associated with their antihypertensive effects. In this study, we investigated whether the L/N-type Ca2+ channel blocker cilnidipine counteracts salt-induced atrial and ventricular remodelling and the inducibility of AF. Cilnidipine was orally administered to Dahl salt-sensitive rats fed with an 8% NaCl diet at 10 mg/kg for 5 weeks, and then electrophysiological evaluation and histological analyses were performed. The effects were compared with those of the L-type Ca2+ channel blocker amlodipine at 3 mg/kg. Following the intake of the 8% NaCl diet, the blood pressure (BP) increased, and fibrosis was induced in the atria and ventricles. Cilnidipine decreased BP, and the extent of the decrease in the cilnidipine group was similar to those in the amlodipine group. Cilnidipine produced a greater decrease in the fibrotic area in the atria and ventricles than amlodipine. The cilnidipine group shortened the AF duration from 7.43 ± 3.16 to 2.95 ± 1.73 s, which had been increased by NaCl intake. Plasma noradrenaline levels in the cilnidipine group were lower than those in the amlodipine group. Thus, the suppressive effects of cilnidipine on the salt-induced atrial and ventricular remodelling, fibrosis, and AF sustainability might be closely associated with its N-type Ca2+ channel-blocking actions.

    Editor’s picks

    Atrial fibrillation (AF) is one of the most frequent arrhythmias in patients with hypertension. The authors found that an L/N-type calcium channel blocker cilnidipine exerts anti-AF effects in the remodeled atria of Dahl salt-sensitive rats more potently than amlodipine. Since plasma catecholamine levels is lower in the cilnidipine-treated animals than those in amlodipine-treated ones, blockade of N-type calcium channels presumably contributes to the superior cardioprotective effect of cilnidipine. These findings provide important information for considering treatment of hypertension complicating AF.

  • Rui-zhi Tan, Ying Yan, Yan Yu, Hui Diao, Xia Zhong, Xiao Lin, Yi-yi Li ...
    2021 Volume 44 Issue 5 Pages 714-723
    Published: May 01, 2021
    Released: May 01, 2021
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    Supplementary material

    Ischemia–reperfusion injury (IRI) is the major cause of acute kidney injury (AKI). The previous studies demonstrated that Oridonin can protect kidney against IRI-induced AKI, but the underlying molecular mechanism is unclear. In this study, it showed that Oridonin significantly improved kidney damage, and inhibited the expression of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α and MCP-1, as well as macrophage marker F4/80 in kidney and the secretion of inflammatory cytokins in serum of AKI mice in vivo. In addition, Oridonin also effectively reduced the expression and secretion of lipopolysaccharide (LPS)-induced inflammatory factors in macrophage cell line RAW264.7 in vitro. Notably, Oridonin strongly downregulated Mincle and AKT/nuclear factor-kappaB (NF-κB) signaling both in vivo and in vitro, and the results of cellular recovery experiments of overexpression of Mincle in macrophage suggested that Oridonin suppressed inflammatory response of macrophage through inhibiting Mincle, which may be the underlying mechanism of Oridonin improving injury in kidney of AKI mice. In summary, the above results indicated that Oridonin can protect kidney from IRI-induced inflammation and injury by inhibiting the expression of Mincle in macrophage.

  • Shoma Izumi, Masaki Domoto, Hirohito Esaki, Hitoki Sasase, Naoya Nishi ...
    2021 Volume 44 Issue 5 Pages 724-731
    Published: May 01, 2021
    Released: May 01, 2021
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    Nicotine enhances attention, working memory and recognition. One of the brain regions associated with these effects of nicotine is the medial prefrontal cortex (mPFC). However, cellular mechanisms that induce the enhancing effects of nicotine remain unclear. To address this issue, we performed whole-cell patch-clamp recordings from mPFC layer 5 pyramidal neurons in slices of C57BL/6J mice. Shortly (approx. 2 min) after bath application of nicotine, the number of action potentials, which were elicited by depolarizing current injection, was increased, and this increase persisted for over 5 min. The effect of nicotine was blocked by the α4β2 nicotinic acetylcholine receptor (nAChR) antagonist dihydro-β-erythroidine, α7 nAChR antagonist methyllycaconitine, or intracellular perfusion with the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA). Additionally, the voltage-dependent potassium 7 (Kv7) channel blocker, 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone dihydrochloride (XE-991), as well as nicotine, shortened the spike threshold latency and increased the spike numbers. By contrast, the Kv7 channel opener, retigabine reduced the number of firings, and the addition of nicotine did not increase the spike numbers. These results indicate that nicotine induces long-lasting enhancement of firing activity in mPFC layer 5 pyramidal neurons, which is mediated by the stimulation of the α4β2 and α7 nAChRs and subsequent increase in intracellular Ca2+ levels followed by the suppression of the Kv7 channels. The novel effect of nicotine might underlie the nicotine-induced enhancement of attention, working memory and recognition.

Notes
  • Kayoko Matsubara, Kazuaki Matsumoto, Yuta Yokoyama, Erika Watanabe, Yu ...
    2021 Volume 44 Issue 5 Pages 732-736
    Published: May 01, 2021
    Released: May 01, 2021
    JOURNALS FREE ACCESS FULL-TEXT HTML

    Ampicillin-sulbactam is a first-line therapy for pneumonia and is mainly excreted by the kidney. It is important to optimize the dose and dosing interval of ampicillin-sulbactam because in patients with decreased renal function and low skeletal muscle mass, such as the elderly, excess drug may burden renal function. In this study, we evaluated indices of renal function and optimized the dose and dosing interval of ampicillin-sulbactam based on pharmacokinetics (PK) and pharmacodynamics theory in elderly patients. The serum concentrations of ampicillin and sulbactam were measured by HPLC, and PK parameters were calculated. Correlations between the clearance of ampicillin or sulbactam and renal function were evaluated, and dosing optimization was calculated based on PK parameters. The PK parameters of ampicillin were CL = 6.5 ± 4.0 L/h, Vd = 19.3 ± 0.2 L, Ke = 0.4 ± 0.2, and t1/2 = 2.7 ± 1.6 h. The most correlated renal function index was estimated glomerular filtration rate (eGFRcys-c) calculated by serum cystatin-c (r = 0.7374, correlation formula; CL of ampicillin = 0.1937 × eGFRcys-c−0.6726). Based on this formula, we calculated the clearance of ampicillin and developed dosing regimens for the elderly. Serum cystatin-c concentration is an ideal index to optimize ampicillin-sulbactam antimicrobial therapy in elderly patients with pneumonia.

  • Ryota Tanaka, Daiki Eto, Koji Goto, Yoshifumi Ohchi, Norihisa Yasuda, ...
    2021 Volume 44 Issue 5 Pages 737-741
    Published: May 01, 2021
    Released: May 01, 2021
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    For intensive care unit (ICU) patients, injectable voriconazole (VRCZ) is difficult to use because the patients often develop acute kidney injury. Since many ICU patients have consciousness disturbance, oral ingestion of tablet formulation is also difficult, and administration of a suspension via enteral feeding tube is required when using VRCZ. In this study, we investigated the in vitro adsorption property of oral VRCZ to feeding tube and performed pharmacokinetic analysis of VRCZ prepared by powdering and simple suspension for ICU patients. VRCZ was tube-administered to five ICU patients at a loading dose of 300 mg and plasma VRCZ concentrations before and at 1, 2, 4, 8, 12 h after the first dose were measured using HPLC. Pharmacokinetic parameters were calculated by non-compartmental model analysis. The recovery rate of VRCZ after infusion of the suspension through feeding tube was 89.8 ± 8.3%, but the cumulative rates after the first and second re-infusion were 102.7 ± 20.7 and 99.3 ± 10.3%, respectively, suggesting almost no residual drug in the tube after re-infusion. Metabolic phenotype was extensive metabolizer (EM) in two patients and intermediate metabolizer (IM) in three patients. The values of total clearance (CLtot/F) calculated by moment analysis were 0.51 and 0.55 L/h/kg in two EM patients, and 0.09, 0.29 and 0.31 L/h/kg in three IM patients. The CLtot/F was apparently lower in IM patients compared to EM. In conclusion, powdered and suspended VRCZ administered via enteral feeding tube showed pharmacokinetics depending on CYP2C19 gene polymorphism, similar to that observed in usual oral administration.

  • Ryota Yamagata, Wataru Nemoto, Maho Fujita, Osamu Nakagawasai, Koichi ...
    2021 Volume 44 Issue 5 Pages 742-746
    Published: May 01, 2021
    Released: May 01, 2021
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    The intrathecal (i.t.) injection of substance P (SP) and N-methyl-D-aspartate (NMDA) induce transient nociceptive response by activating neurokinin (NK) 1 and NMDA receptors, respectively. We have recently reported that angiotensin (Ang) (1–7), an N-terminal fragment of Ang II, could alleviate several types of pain including neuropathic and inflammatory pain by activating spinal MAS1. Here, we investigated whether Ang (1–7) can inhibit the SP- and NMDA-induced nociceptive response. The nociceptive response induced by an i.t. injection of SP or NMDA was assessed by measuring the duration of hindlimb scratching directed toward the flank, biting and/or licking of the hindpaw or the tail for 5 min. Localization of MAS1 and either NK1 or NMDA receptors in the lumbar superficial dorsal horn was determined by immunohistochemical observation. The nociceptive response induced by SP and NMDA was attenuated by the i.t. co-administration of Ang (1–7) (0.03–3 pmol) in a dose-dependent manner. The inhibitory effects of Ang (1–7) (3 pmol) were attenuated by A779 (100 pmol), a MAS1 antagonist. Moreover, immunohistochemical analysis showed that spinal MAS1 co-localized with NK1 receptors and NMDA receptors on cells in the dorsal horn. Taken together, the i.t. injection of Ang (1–7) attenuated the nociceptive response induced by SP and NMDA via spinal MAS1, which co-localized with NK1 and NMDA receptors. Thus, the spinal Ang (1–7)/MAS1 pathway could represent a therapeutic target to effectively attenuate spinal pain transmission caused by the activation of NK1 or NMDA receptors.

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