Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
Volume 47, Issue 3
Displaying 1-23 of 23 articles from this issue
Review
  • Yoshiaki Okada
    2024 Volume 47 Issue 3 Pages 549-555
    Published: March 01, 2024
    Released on J-STAGE: March 01, 2024
    JOURNAL OPEN ACCESS FULL-TEXT HTML

    Severe infection pathogenicity is induced by processes such as pathogen exposure, immune cell activation, inflammatory cytokine production, and vascular hyperpermeability. Highly effective drugs, such as antipathogenic agents, steroids, and antibodies that suppress cytokine function, have been developed to treat the first three processes. However, these drugs cannot completely suppress severe infectious diseases, such as coronavirus disease 2019 (COVID-19). Therefore, developing novel drugs that inhibit vascular hyperpermeability is crucial. This review summarizes the mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–induced vascular hyperpermeability and identifies inhibitors that increase endothelial cell (EC) junction–related proteins and determines their efficacy in COVID-19 and endotoxemia models. Analyzing the effects of SARS-CoV-2 on vascular permeability revealed that SARS-CoV-2 suppresses Claudin-5 (CLDN5) expression, which is responsible for adhesion between ECs, thereby increasing vascular permeability. Inhibiting CLDN5 function in mice induced vascular hyperpermeability and pulmonary edema. In contrast, Enhancing CLDN5 expression suppressed SARS-CoV-2–induced endothelial hyperpermeability, suggesting that SARS-CoV-2–induced vascular hyperpermeability contributes to pathological progression, which can be suppressed by upregulating EC junction proteins. Based on these results, we focused on Roundabout4 (Robo4), another EC-specific protein that stabilizes EC junctions. EC-specific Robo4 overexpression suppressed vascular hyperpermeability and mortality in lipopolysaccharide-treated mice. An ALK1 inhibitor (a molecule that increases Robo4 expression), suppressed vascular hyperpermeability and mortality in lipopolysaccharide- and SARS-CoV-2–treated mice. These results indicate that Robo4 expression–increasing drugs suppress vascular permeability and pathological phenotype in COVID-19 and endotoxemia models.

  • Kazuki Nagayasu
    2024 Volume 47 Issue 3 Pages 556-561
    Published: March 01, 2024
    Released on J-STAGE: March 01, 2024
    JOURNAL FREE ACCESS FULL-TEXT HTML

    Mental illness poses a huge social burden, accounting for approximately 14% of all deaths. Depression, a major component of mental illness, affects approximately 300 million people worldwide, mainly in developed countries, and is not only a major social burden but also a cause of suicide. The social burden of depression is estimated to increase further in developing countries, and overcoming it is a pressing issue for all countries, including Japan. Although clinical evidence has demonstrated the efficacy of serotonergic neurotransmission enhancers in the treatment of depression, the full picture of their therapeutic effects has not yet been fully elucidated. In this review, we show that the hyperactivity of serotonin neurons, especially those in the dorsal raphe nucleus, is commonly induced by various antidepressants within a period corresponding to the onset of their clinical efficacy. We established quantitative prediction methods for pharmacological activity using only chemical structures to translate the biological understanding of mental disorders, including major depressive disorders, into clinically effective therapeutics. Our method exhibited better performance than the previously reported methods of quantitative prediction, while targeting a larger number of proteins. Our article suggests the importance of integrative neuropharmacology and informatics-based pharmacology studies to understand the biological basis of mental disorders and facilitate drug development for these disorders.

  • Masumi Katane, Hiroshi Homma
    2024 Volume 47 Issue 3 Pages 562-579
    Published: March 01, 2024
    Released on J-STAGE: March 01, 2024
    JOURNAL FREE ACCESS FULL-TEXT HTML

    It was long believed that D-amino acids were either unnatural isomers or laboratory artifacts, and that the important functions of amino acids were exerted only by L-amino acids. However, recent investigations have revealed a variety of D-amino acids in mammals that play important roles in physiological functions, including free D-serine and D-aspartate that are crucial in the central nervous system. The functions of several D-amino acids in the periphery and endocrine glands are also receiving increasing attention. Here, we present an overview of recent advances in elucidating the physiological roles of D-amino acids, especially in the periphery and endocrine glands.

  • Ryoichi Hashida, Takeshi Kawabata
    2024 Volume 47 Issue 3 Pages 580-590
    Published: March 01, 2024
    Released on J-STAGE: March 01, 2024
    JOURNAL FREE ACCESS FULL-TEXT HTML
    Supplementary material

    There are 48 nuclear receptors in the human genome, and many members of this superfamily have been implicated in human diseases. The NR4A nuclear receptor family consisting of three members, NR4A1, NR4A2, and NR4A3 (formerly annotated as Nur77, Nurr1, and NOR1, respectively), are still orphan receptors but exert pathological effects on immune-related and neurological diseases. We previously reported that prostaglandin A1 (PGA1) and prostaglandin A2 (PGA2) are potent activators of NR4A3, which bind directly to the ligand-binding domain (LBD) of the receptor. Recently, the co-crystallographic structures of NR4A2-LBD bound to PGA1 and PGA2 were reported, followed by reports of the neuroprotective effects of these possible endogenous ligands in mouse models of Parkinson’s disease. Based on these structures, we modeled the binding structures of the other two members (NR4A1 and NR4A3) with these potential endogenous ligands using a template-based modeling method, and reviewed the similarity and diversity of ligand-binding mechanisms in the nuclear receptor family.

Regular Article
  • Tatsuya Ishikawa, Daisuke Uta, Hiroaki Okuda, Ilia Potapenko, Kiyomi H ...
    2024 Volume 47 Issue 3 Pages 591-599
    Published: March 05, 2024
    Released on J-STAGE: March 05, 2024
    JOURNAL FREE ACCESS FULL-TEXT HTML

    The pain matrix, which includes several brain regions that respond to pain sensation, contribute to the development of chronic pain. Thus, it is essential to understand the mechanism of causing chronic pain in the pain matrix such as anterior cingulate (ACC), or primary somatosensory (S1) cortex. Recently, combined experiment with the behavior tests and in vivo calcium imaging using fiber photometry revealed the interaction between the neuronal function in deep brain regions of the pain matrix including ACC and the phenotype of chronic pain. However, it remains unclear whether this combined experiment can identify the interaction between neuronal activity in S1, which receive pain sensation, and pain behaviors such as hyperalgesia or allodynia. In this study, to examine whether the interaction between change of neuronal activity in S1 and hyperalgesia in hind paw before and after causing inflammatory pain was detected from same animal, the combined experiment of in vivo fiber photometry system and von Frey hairs test was applied. This combined experiment detected that amplitude of calcium responses in S1 neurons increased and the mechanical threshold of hind paw decreased from same animals which have an inflammatory pain. Moreover, we found that the values between amplitude of calcium responses and mechanical thresholds were shifted to negative correlation after causing inflammatory pain. Thus, the combined experiment with fiber photometry and the behavior tests has a possibility that can simultaneously consider the interaction between neuronal activity in pain matrix and pain induced behaviors and the effects of analgesics or pain treatments.

Note
  • Xinyan Shao, Takahito Miyake, Yuichi Inoue, Emi Hasegawa, Masao Doi
    2024 Volume 47 Issue 3 Pages 600-605
    Published: March 05, 2024
    Released on J-STAGE: March 05, 2024
    JOURNAL FREE ACCESS FULL-TEXT HTML

    Temperature-dependent translational control of the core clock gene Per2 plays an important role in establishing entrainment of the circadian clock to physiological body temperature cycles. Previously, we found an involvement of the phosphatidylinositol 3-kinase (PI3K) in causing Per2 protein expression in response to a warm temperature shift (WTS) within a physiological range (from 35 to 38.5 °C). However, signaling pathway mediating the Per2 protein expression in response to WTS is only sparsely understood. Additional factor(s) other than PI3K remains unknown. Here we report the identification of eukaryotic initiation factor 2α (eIF2α) kinases, protein kinase R (PKR) and PKR-like endoplasmic reticulum kinase (PERK), as a novel mediator of WTS-dependent Per2 protein expression. Canonically, eIF2α has been regarded as a major downstream target of PERK and PKR. However, we found that PERK and PKR mediate WTS response of Per2 in a manner not involving eIF2α. We observed that PERK and PKR serve as an upstream regulator of PI3K rather than eIF2α in the context of WTS-dependent Per2 protein expression. There have been studies reporting PI3K activation occurring depending on PERK and PKR, while its physiological contribution has remained elusive. Our finding therefore not only helps to enrich the knowledge of how WTS affects Per2 protein expression but also extends the region of cellular biology involving the PERK/PKR-mediated PI3K activation to include entrainment-mechanism of the circadian clock.

  • Misaki Kojima, Masakuni Degawa
    2024 Volume 47 Issue 3 Pages 606-610
    Published: March 08, 2024
    Released on J-STAGE: March 08, 2024
    JOURNAL FREE ACCESS FULL-TEXT HTML

    To clarify the causes of sex differences (male < female) in the serum total cholesterol (TCHO) and triglyceride (TG) levels in Meishan pigs, we examined the sex differences in mRNA levels of key hepatic enzymes involved in the biosynthesis/metabolism of cholesterol and TG using real-time RT-PCR. There were no sex differences in mRNA levels of 3-hydroxy-3-methylglutaryl-CoA reductase and CYP51A1 for cholesterol biosynthesis, or of the rate-limiting enzyme CYP7A1 for bile acid synthesis from cholesterol. By contrast, sex differences (male < female) were observed in mRNA levels of glycerol-3-phosphate acyltransferase 1 (GPAT1), a rate-limiting enzyme for TG biosynthesis. However, the sex differences in mRNA levels of carnitine palmitoyltransferase 1A (CPT1A) and acyl-CoA dehydrogenase long chain (ACADL), key enzymes for the oxidation of the fatty acids that are structural components of TG, were the opposite (male > female). Castration of male pigs led to an increase in the mRNA level of GPAT1 and decreases in those of CPT1A and ACADL. Furthermore, testosterone propionate (TP)-treatment of castrated males and intact females restored and changed, respectively, these mRNA levels to those of intact males. Notably, castration and TP-treatment increased and decreased, respectively, serum and hepatic TG levels. These findings suggest that sex differences in the serum and hepatic TG levels in Meishan pigs are closely correlated with differences in testosterone-associated mRNA expression levels of the key enzymes (GPAT1, CPT1A, and ACADL) involved in the TG biosynthesis process, although no causes of sex differences in serum and hepatic TCHO levels could be found.

Regular Article
  • Takashi Watanabe, Kaori Ambe, Masahiro Tohkin
    2024 Volume 47 Issue 3 Pages 611-619
    Published: March 13, 2024
    Released on J-STAGE: March 13, 2024
    JOURNAL FREE ACCESS FULL-TEXT HTML
    Supplementary material

    The addition of clinically significant adverse reactions (CSARs) to Japanese package inserts (PIs) is an important safety measure that can be used to inform medical personnel of potential health risks; however, determining the necessity of their addition can be lengthy and complex. Therefore, we aimed to construct a machine learning-based model that can predict the addition of CSARs at an early stage due to the accumulation of both Japanese and overseas adverse drug reaction (ADR) cases. The target comprised CSARs added to PIs from August 2011 to March 2022. The control group consisted of drugs without the same CSARs in their PIs by March 2022. Features were generated using ADR case accumulation data obtained from the Japanese Adverse Drug Event Report and the U.S. Food and Drug Administration Adverse Event Reporting System databases. The model was constructed using DataRobot, and its performance evaluated using the Matthews correlation coefficient. The target for the addition of CSARs included 414 cases, comprising 302 due to domestic case accumulation, 22 due to both domestic and overseas case accumulation, 12 due to overseas case accumulation, and 78 due to revisions of the company core data sheet. The best model was a generalized linear model with informative features, achieving a cross-validation of 0.8754 and a holdout of 0.8995. In conclusion, the proposed model effectively predicted CSAR additions to PIs resulting from the accumulation of ADR cases using data from both Japan and the United States.

  • Koichi Kato, Tomoki Nakayoshi, Sho Hioki, Masahiro Hiratsuka, Yoshinob ...
    2024 Volume 47 Issue 3 Pages 620-628
    Published: March 13, 2024
    Released on J-STAGE: March 13, 2024
    JOURNAL FREE ACCESS FULL-TEXT HTML

    One of the members of CYP, a monooxygenase, CYP2A13 is involved in the metabolism of nicotine, coumarin, and tobacco-specific nitrosamine. Genetic polymorphisms have been identified in CYP2A13, with reported loss or reduction in enzymatic activity in CYP2A13 allelic variants. This study aimed to unravel the mechanism underlying the diminished enzymatic activity of CYP2A13 variants by investigating their three-dimensional structures through molecular dynamics (MD) simulations. For each variant, MD simulations of 1000 ns were performed, and the obtained results were compared with those of the wild type. The findings indicated alterations in the interaction with heme in CYP2A13.4, .6, .8, and .9. In the case of CYP2A13.5, observable effects on the helix structure related to the interaction with the redox partner were identified. These conformational changes were sufficient to cause a decrease in enzyme activity in the variants. Our findings provide valuable insights into the molecular mechanisms associated with the diminished activity in the CYP2A13 polymorphisms.

Note
  • Kei Eto, Masanori Ogata, Yoshitaka Toyooka, Toru Hayashi, Hitoshi Ishi ...
    2024 Volume 47 Issue 3 Pages 629-634
    Published: March 15, 2024
    Released on J-STAGE: March 15, 2024
    JOURNAL FREE ACCESS FULL-TEXT HTML

    Inflammation is involved in the induction of chronic inflammatory and neuropathic pain. Moreover, the ketogenic diet, a high-fat, low-carbohydrate, and adequate protein diet, has an anti-inflammatory effect. Thus, we hypothesized that a ketogenic diet has a therapeutic effect on both types of chronic pain. In the present study, we investigated the effect of a ketogenic diet on mechanical allodynia, a chronic pain symptom, in formalin-induced chronic inflammatory pain and nerve injury-induced neuropathic pain models using adult male mice. Formalin injection into the hind paw induced mechanical allodynia in both the injected and intact hind paws, and the ketogenic diet alleviated mechanical allodynia in both hind paws. In addition, the ketogenic diet prevented formalin-induced edema. Furthermore, the diet alleviated mechanical allodynia induced by peripheral nerve injury. Thus, these findings indicate that a ketogenic diet has a therapeutic effect on chronic pain induced by inflammation and nerve injury.

Regular Article
  • Koichiro Adachi, Katsuhiro Ohyama, Yoichi Tanaka, Yoshiro Saito, Makik ...
    2024 Volume 47 Issue 3 Pages 635-640
    Published: March 15, 2024
    Released on J-STAGE: March 15, 2024
    JOURNAL OPEN ACCESS FULL-TEXT HTML

    Fluvastatin is a 3-hydroxy-3-methylglutaryl CoA reductase inhibitor that competitively inhibits human cytochrome P450 (P450) 2C9 in vitro. Drug interactions between a variety of P450 2C9 substrates/inhibitors and fluvastatin can increase the incidence of fluvastatin-related hepatic or skeletal muscle toxicity in vivo. In this survey, the prescribed dosage of fluvastatin was reduced or discontinued in 133 of 164 patients receiving fluvastatin alone, as recorded in the Japanese Adverse Drug Event Report database of spontaneously reported events. The median days to onset of fluvastatin-related disorders were in the range 30–35 d in the 87 patients. Therefore, we aimed to focus on fluvastatin and, using the pharmacokinetic modeling technique, estimated the virtual plasma and hepatic exposures in subjects harboring the impaired CYP2C9*3 allele. The plasma concentrations of fluvastatin modeled after a virtual oral 20-mg dose increased in homozygotes with CYP2C9*3; the area under the plasma concentration curve was 4.9-fold higher than that in Japanese homozygotes for wild-type CYP2C9*1. The modeled hepatic concentrations of fluvastatin in patients with CYP2C9*3/*3 after virtual daily 20-mg doses for 7 d were 31-fold higher than those in subjects with CYP2C9*1/*1. However, heterozygous Chinese patients with CYP2C9*1/*3 reportedly have a limited elevation (1.2-fold) in plasma maximum concentrations. Virtual hepatic/plasma exposures in subjects harboring the impaired CYP2C9*3 allele estimated using pharmacokinetic modeling indicate that such exposure could be a causal factor for hepatic disorders induced by fluvastatin prescribed alone in a manner similar to that for interactions with a variety of co-administered drugs.

  • Manami Tomomatsu, Naoto Imamura, Hoshimi Izumi, Masatsugu Watanabe, Ma ...
    2024 Volume 47 Issue 3 Pages 641-651
    Published: March 19, 2024
    Released on J-STAGE: March 19, 2024
    JOURNAL FREE ACCESS FULL-TEXT HTML

    Recently, mitochondrial dysfunction has gained attention as a causative factor in the pathogenesis and progression of age-related macular degeneration (AMD). Mitochondrial damage plays a key role in metabolism and disrupts the balance of intracellular metabolic pathways, such as oxidative phosphorylation (OXPHOS) and glycolysis. In this study, we focused on oxidized low-density lipoprotein (ox-LDL), a major constituent of drusen that accumulates in the retina of patients with AMD, and investigated whether it could be a causative factor for metabolic alterations in retinal pigment epithelial (RPE) cells. We found that prolonged exposure to ox-LDL induced changes in fatty acid β-oxidation (FAO), OXPHOS, and glycolytic activity and increased the mitochondrial reactive oxygen species production in RPE cells. Notably, the effects on metabolic alterations varied with the concentration and duration of ox-LDL treatment. In addition, we addressed the limitations of using ARPE-19 cells for retinal disease research by highlighting their lower barrier function and FAO activity compared to those of induced pluripotent stem cell-derived RPE cells. Our findings can aid in the elucidation of mechanisms underlying the metabolic alterations in AMD.

    Editor's pick

    Mitochondrial dysfunction is recognized as a key factor in the pathological progression of age-related macular degeneration (AMD) and can disrupt the balance of intracellular metabolic pathways (e.g., oxidative phosphorylation and glycolysis). The authors focused on oxidized low-density lipoprotein (ox-LDL), reported to a primary component accumulated in the retina of AMD patients, and elucidated its effect on metabolic alterations with increased mitochondrial reactive oxygen species production in retinal pigment epithelial cells. It was discovered that prolonged exposure to ox-LDL is crucial for the induction of these metabolic alterations. These significantly contribute to understanding the mechanisms underlying AMD metabolic alterations.

  • Hitoshi Kashiwagi, Yuki Sato, Shunsuke Nashimoto, Shungo Imai, Yoh Tak ...
    2024 Volume 47 Issue 3 Pages 652-659
    Published: March 19, 2024
    Released on J-STAGE: March 19, 2024
    JOURNAL FREE ACCESS FULL-TEXT HTML

    Platelets have been reported to exert diverse actions besides hemostasis and thrombus formation in the body. However, whether platelets affect transporter activity remains to be determined. In this study, we examined the effects of platelets on the activity of amino acid transporter system A, which is known to be changed by various factors, and we clarified the mechanism by which platelets affect system A activity. Among system A subtypes, we found that sodium-coupled neutral amino acid transporter (SNAT) 4 played a central role in the transport activity of system A in HuH-7 human hepatoma cells. Interestingly, platelets showed a biphasic effect on system A activity: activated platelet supernatants (APS) including the granule contents released from platelets downregulated system A activity at lower concentrations and the downregulation was suppressed at higher concentrations. The downregulation was due to a decrease in the affinity of SNAT4 for its substrate and not a decrease in the SNAT4 abundance on the plasma membrane. In addition, APS did not decrease the expression level of SNAT4 mRNA. On the other hand, platelets did not affect system A activity when the platelet suspension was added to HuH-7 cells. These results indicate that platelets indirectly affect the transport activity of system A by releasing bioactive substances but do not directly affect it by binding to HuH-7 cells.

  • Yoko Amagase, Mari Hoshiyama, Shiho Hasegawa, Miwa Kanbara, Yumiko Miz ...
    2024 Volume 47 Issue 3 Pages 660-668
    Published: March 20, 2024
    Released on J-STAGE: March 20, 2024
    JOURNAL FREE ACCESS FULL-TEXT HTML

    Flopropione (Flo) has been used for gallstone and urolithiasis as a spasmolytic agent almost exclusively in Japan. According to the package insert, its main mechanism is catechol-O-methyltransferase (COMT) inhibition and anti-serotonergic effect. This is obviously contrary to pharmacological common sense, but it is described that way in pharmacology textbooks and occurs in questions in the National Examination for Pharmacists in Japan. As this is a serious problem in education, we re-examined the action of Flo. The guinea pig ureter was hardly contracted by serotonin, but noradrenaline (NA) elicited repetitive twitch contraction, which was inhibited by Flo. The sphincter of Oddi (SO) exhibited a spontaneous repetitive twitch contraction, which was inhibited by NA and Flo. The inhibitory effect of NA was reversed by α- and β-blockers, whereas that of Flo was not. Entacapone, a representative COMT inhibitor, did not affect the movement of the ureter and the SO. Nifedipine suppressed carbachol-induced contraction of the taenia coli, spontaneous movement of the SO, and NA-induced contraction of the ureter to almost the same extent, whereas Flo did not inhibit the taenia coli, but inhibited the contraction of the SO and the ureter. The inhibitory pattern of Flo resembled that of the ryanodine receptor agonist 4-chloro-m-cresol and the inositol 1,4,5-trisphosphate (IP3) receptor antagonist 2-aminoethoxydiphenyl borate. It is concluded that COMT inhibition or serotonin inhibition is not involved in the spasmolytic action of Flo. Flo might act on ryanodine receptors and/or IP3 receptors, which are responsible for periodic Ca release from Ca stores, to disrupt coordinated Ca dynamics.

  • Megumi Yamamoto, Yui Shibata, Yuma Ito, Masaki Fukui, Hikaru Kioka, Yo ...
    2024 Volume 47 Issue 3 Pages 669-679
    Published: March 21, 2024
    Released on J-STAGE: March 21, 2024
    JOURNAL FREE ACCESS FULL-TEXT HTML

    Osteoporosis is caused by imbalance between osteogenesis and bone resorption, thus, osteogenic drugs and resorption inhibitors are used for treatment of osteoporosis. The present study examined the effects of (R)-4-(1-hydroxyethyl)-3-{4-[2-(tetrahydropyran-4-yloxy)ethoxy]phenoxy}benzamide (KY-273), a diphenyl ether derivative, on CDK8/19 activity, osteoblast differentiation and femoral bone using micro-computed tomography in female rats. KY-273 potently inhibited CDK8/19 activity, promoted osteoblast differentiation with an increase in alkaline phosphatase (ALP) activity, and gene expression of type I collagen, ALP and BMP-4 in mesenchymal stem cells (ST2 cells). In female rat femur, ovariectomy decreased metaphyseal trabecular bone volume (Tb.BV), mineral content (Tb.BMC), yet had no effect on metaphyseal and diaphyseal cortical bone volume (Ct.BV), mineral content (Ct.BMC) and strength parameters (BSPs). In ovaries-intact and ovariectomized rats, oral administration of KY-273 (10 mg/kg/d) for 6 weeks increased metaphyseal and diaphyseal Ct.BV, Ct.BMC, and BSPs without affecting medullary volume (Med.V), but did not affect Tb.BV and Tb.BMC. In ovariectomized rats, alendronate (3 mg/kg/d) caused marked restoration of Tb.BV, Tb.BMC and structural parameters after ovariectomy, and increased metaphyseal but not diaphyseal Ct.BV, Ct.BMC, and BSPs. In ovaries-intact and ovariectomized rats, by the last week, KY-273 increased bone formation rate/bone surface at the periosteal but not the endocortical side. These findings indicate that KY-273 causes osteogenesis in cortical bone at the periosteal side without reducing Med.V. In conclusion, KY-273 has cortical-bone-selective osteogenic effects by osteoblastogenesis via CDK8/19 inhibition in ovaries-intact and ovariectomized rats, and is an orally active drug candidate for bone diseases such as osteoporosis in monotherapy and combination therapy.

  • Lin Zhou, Chu-Ling Zhang, Kun Jiang, Hong-Yu Cheng, Wen-Wen Xiong, Ji- ...
    2024 Volume 47 Issue 3 Pages 680-691
    Published: March 22, 2024
    Released on J-STAGE: March 22, 2024
    JOURNAL OPEN ACCESS FULL-TEXT HTML

    Cholelithiasis, commonly known as gallstones, represents a prevalent hepatobiliary disorder. This study aimed to elucidate the therapeutic role and mechanism of Danyankang capsulein treating cholelithiasis induced by a high-fat diet in C57BL/6 mice. The therapeutical potential of Danyankang was assessed through biochemical analyses, histopathological examinations, protein detection, and 16S rDNA sequencing. A high-fat diet resulted in cholelithiasis manifestation in mice, with discernable abnormal serum biochemical indices and disrupted biliary cholesterol homeostasis. Danyankang treatment notably ameliorated liver inflammation symptoms and rectified serum and liver biochemical abnormalities. Concurrently, it addressed biliary imbalances. Elevated expressions of toll-like receptor 4 (TLR4), nuclear factor-kappaB (NF-κB)/pNF-κB, HMGCR, CYP7A1, and CYP8B1 observed at the inception of cholelithiasis, were notably reduced upon Danyankang administration. Furthermore, 16S rDNA analysis revealed a decline in species number and diversity of the intestinal flora in cholelithiasis-treated mice, while the decline was reversed with Danyankang treatment. Danyankang capsules reduced the abundance of Verrucomicrobiota and increased the abundance of Actinobacteriota and Proteobacteria. In conclusion, the present study demonstrates that Danyankang exerts potent therapeutic efficacy against high-fat diet-induced cholelithiasis. This beneficial outcome is potentially linked to the inhibition of the TLR4/pNF-κB and SHP/CYP7A1/CYP8B1 signaling pathways, as well as the enhancement of intestinal flora species abundance.

  • Hiroshi Inano, Yoshihito Morimoto, Kanata Kitagawa, Akito Shibuya, Koz ...
    2024 Volume 47 Issue 3 Pages 692-697
    Published: March 25, 2024
    Released on J-STAGE: March 25, 2024
    Advance online publication: February 28, 2024
    JOURNAL FREE ACCESS FULL-TEXT HTML

    Existing antiemetic therapy against emetic-risk agents across malignancies 24 h post-dose in the acute period in cisplatin (CDDP)-based regimens yields a satisfactory complete response (CR) rate of ≥90%. However, the control rate after 24 h in the delayed period is unsatisfactory. This study compared the efficacy of fosnetupitant (F-NTP), a neurokinin 1 receptor antagonist, with that of fosaprepitant (F-APR) and aprepitant (APR) in the treatment of patients with cancer at high emetic risk due to chemotherapy. In this retrospective case-control study involving patients receiving cisplatin-containing regimens and neurokinin 1 receptor antagonists, patients were divided into three groups based on prophylactic antiemetic therapy: F-NTP, F-APR, and APR. The CR rate was evaluated for each period up to 168 h and further subdivided into acute (0–24 h), delayed (24–120 h), overall (0–120 h), and beyond-delayed (120–168 h) periods. Eighty-eight patients were included in the F-NTP group, 66 in the F-APR group, and 268 in the APR group. The CR rates at 0–168 and 120–168 h after cisplatin administration were significantly higher in the F-NTP group than in the F-APR and APR groups. After adjusting for confounding factors, F-NTP use was an independent factor in the multivariate analysis. Prophylactic antiemetic therapy, including F-NTP, was effective and well-tolerated during the delayed period. The efficacy of F-NTP in managing chemotherapy-induced nausea and vomiting was superior to those of F-APR and APR during the study period.

    Editor's pick

    Management of chemotherapy-induced nausea and vomiting (CINV) after delayed periods presents a significant challenge in cancer chemotherapy. This study represents the first attempt to compare the administration of fosnetupitant (F-NTP), fosaprepitant (F-APR), or aprepitant (APR) from 0 to 168 hours following the initial doses of cisplatin-based regimens. The authors demonstrated that F-NTP was significantly more effective than F-APR and APR in reducing CINV after anticancer drug administration from 0 to 168 hours, without significant side effects. The efficacy of F-NTP was particularly effective in the beyond-delayed periods (120-168 hours), which is the focus of attention of the revised Japanese antiemetic guidelines.

  • Yi Liu, Miho Suzuoki, Hiroki Tanaka, Yu Sakurai, Hiroto Hatakeyama, Hi ...
    2024 Volume 47 Issue 3 Pages 698-707
    Published: March 26, 2024
    Released on J-STAGE: March 26, 2024
    JOURNAL FREE ACCESS FULL-TEXT HTML
    Supplementary material

    RNA vaccines based on Lipid nanoparticles (LNP) were put into practical use within only one year after the global outbreak of the coronavirus disease 2019 (COVID-19). This success of RNA vaccine highlights the utility of an mRNA delivery system as a vaccination strategy. Potent immunostimulatory activity of LNPs (i.e., inflammation occurring at the injection site and the production of inflammatory cytokines) have recently been reported. However, we have only limited knowledge concerning which cells are responsible for responding to the LNPs. We report herein on in vitro chemokine production from non-immune cells in response to exposure to LNPs. In this study, SM-102, an ionizable lipid that is used in the approved RNA vaccine for the clinical usage of COVID-19 mRNA vaccine, was used. Immortalized mouse lymphatic endothelial cells (mLECs) or professional antigen presenting cells (APCs) such as RAW 264.7 monocyte/macrophage cells were incubated with LNPs that contained no mRNA. As a result, chemokines involved in the recruitment of monocytes/neutrophils were produced only by the mLECs following the LNP treatment. These findings indicate that LEC appear to serve as the cell that sends out initial signals to response LNPs.

    Editor's pick

    [Highlighted Paper selected by Editor-in-Chief]
    The study examined which cells are responsible for responding to the LNPs used in the approved COVID-19 mRNA vaccine. In this study, the authors incubated immortalized mouse lymphatic endothelial cells (mLECs) or professional antigen presenting cells (APCs) such as RAW 264.7 monocyte/macrophage cells with SM-102 LNPs that contained no mRNA. As a result, chemokines involved in the recruitment of monocytes/neutrophils were produced only by the mLECs following the empty LNP treatment. These findings indicate that LECs appear to serve as the cells that send out initial signals to response LNPs.

Note
  • Ayano Iwazaki, Tomomichi Sone, Shuji Okumura, Ryota Maki, Takeyuki Koh ...
    2024 Volume 47 Issue 3 Pages 708-712
    Published: March 26, 2024
    Released on J-STAGE: March 26, 2024
    JOURNAL FREE ACCESS FULL-TEXT HTML
    Supplementary material

    In 2020, the coronavirus disease 2019 (COVID-19) pandemic made social distancing compulsory. In patient lectures by hepatitis B patients (Patient Lectures)—a humanity education initiative that had traditionally been delivered face-to-face to assembled students—it was necessary to divide the students into two groups, one that attended the Patient Lectures in person (face-to-face group) and another that assembled in a separate room to view the delivered lecture simultaneously and remotely via a teleconferencing platform (remote group). To investigate possible changes in students’ awareness of hepatitis B patients before (pre-) and after (post-) the lecture that year, the face-to-face and remote-attendance groups were analyzed separately. The participants were 203 fourth-year students belonging to the Faculty of Pharmaceutical Sciences at Japan’s Setsunan University, whose pre-clinical education curriculum prior to pharmacy practice experience included a Patient Lecture. The students were divided into two groups based on their student-ID numbers. Survey questionnaires were completed anonymously before and after the Patient Lecture. The students’ awareness of hepatitis B patients’ experience changed significantly after attending the Patient Lectures; this change was similar in both the face-to-face and remote-attendance groups. Regarding the possibility of hepatitis B virus infection, the remote group selected fewer answers implying strong convictions than did the face-to-face group, and both groups perceived several issues incorrectly. Although slight differences were observed between the two groups, the changes before and after the lectures were similar, indicating that humanity-education lectures are worthwhile not only when delivered in face-to-face contexts but also when delivered and viewed remotely within a class setting.

Regular Article
  • Yoshiaki Tanaka, Rina Takagi, Shingen Mitou, Machiko Shimmura, Tetsuya ...
    2024 Volume 47 Issue 3 Pages 713-722
    Published: March 27, 2024
    Released on J-STAGE: March 27, 2024
    Advance online publication: March 01, 2024
    JOURNAL FREE ACCESS FULL-TEXT HTML

    Diabetic retinopathy (DR) can cause visual impairment and blindness, and the increasing global prevalence of diabetes underscores the need for effective therapies to prevent and treat DR. Therefore, this study aimed to evaluate the protective effect of pemafibrate treatment against DR, using a Spontaneously Diabetic Torii (SDT) fatty rat model of obese type 2 diabetes. SDT fatty rats were fed either a diet supplemented with pemafibrate (0.3 mg/kg/d) for 16 weeks, starting at 8 weeks of age (Pf SDT fatty: study group), or normal chow (SDT fatty: controls). Normal chow was provided to Sprague–Dawley (SD) rats (SD: normal controls). Electroretinography (ERG) was performed at 8 and 24 weeks of age to evaluate the retinal neural function. After sacrifice, retinal thickness, number of retinal folds, and choroidal thickness were evaluated, and immunostaining was performed for aquaporin-4 (AQP4). No significant differences were noted in food consumption, body weight, or blood glucose level after pemafibrate administration. Triglyceride levels were reduced, and high-density lipoprotein cholesterol levels were increased. Extension of oscillatory potential (OP)1 and OP3 waves on ERG was suppressed in the Pf SDT fatty group. Retinal thickness at 1500 microns from the optic disc improved in the Pf SDT fatty group. No significant improvements were noted in choroidal thickness or number of retinal folds. Quantitative analyses showed that AQP4-positive regions in the retinas were significantly larger in the Pf SDT fatty group than in the SDT fatty group. The findings suggest that pemafibrate treatment can exert protective effects against DR.

  • Ryoya Ibuki, Takashi Tokui, Masaya Kuriyama, Kanji Hosoda, Hiroshi Tom ...
    2024 Volume 47 Issue 3 Pages 723-731
    Published: March 28, 2024
    Released on J-STAGE: March 28, 2024
    JOURNAL FREE ACCESS FULL-TEXT HTML
    Supplementary material

    Recently, liposomal formulations that target macrophages have been used to treat lung diseases. However, the detailed mechanism of the cellular uptake must be elucidated to identify a formulation with excellent cellular uptake efficiency to treat non-tuberculous mycobacterial lung disease. We studied the effect of lipid composition on the cellular uptake of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)/cholesterol (Chol) liposomes with a size of approximately 200 nm into THP-1-derived macrophages. The amount of DPPC/Chol liposomes (80/20 mol%) was greater than that of DPPC/Chol (60/40 mol%) and DPPC/Chol (67/33 mol%) liposomes. The anisotropy of 1,6-diphenyl-1,3,5-hexatriene indicated that the membrane fluidity of the DPPC/Chol (80/20 mol%) liposomes was higher than that of the other two liposomes. DPPC/Chol (80/20 mol%) and DPPC/Chol (67/33 mol%) liposomes were taken up via clathrin- and caveolae-mediated endocytosis and phagocytosis. However, proteins involved in cellular uptake through ligand–receptor interactions were adsorbed to a greater extent on DPPC/Chol (80/20 mol%) liposomes than on DPPC/Chol (67/33 mol%) liposomes. Pretreatment of cells with antibodies against the low-density lipoprotein receptor and scavenger receptor type B1 largely inhibited the uptake efficiency of DPPC/Chol (80/20 mol%) liposomes. Our results indicate that the membrane fluidity of DPPC/Chol liposomes, which is controlled by the Chol ratio, is an important factor in controlling protein adsorption and the subsequent uptake efficiency of liposomes.

  • Ryosuke Matsukane, Risa Isshiki, Kimitaka Suetsugu, Haruna Minami, Koj ...
    2024 Volume 47 Issue 3 Pages 732-738
    Published: March 29, 2024
    Released on J-STAGE: March 29, 2024
    JOURNAL FREE ACCESS FULL-TEXT HTML
    Supplementary material

    Hypomagnesemia is a characteristic adverse event of cetuximab in patients with head and neck cancer (HNC). However, there is limited information about its prevalence, risk factors, and preventive strategies. This study aimed to investigate the risk factors of hypomagnesemia and examine the preventive effects of prophylactic magnesium (Mg) administration. We initially investigated HNC patients treated with cetuximab between 2013 and 2019. Our institute started prophylactic Mg treatment (20-mEq Mg sulfate administration before cetuximab) in practice during this period. We retrospectively assess the preventive efficacy by comparing patients before and after its implementation. In total, 109 patients were included. In 60 patients without prophylaxis, all-grade and grade ≥2 hypomagnesemia at 3 months occurred in 61.7 and 15.0% of patients. The incidence of hypomagnesemia was not affected by regimens and concomitant medications. In 49 patients treated with prophylactic Mg treatment, there was no significant decrease in the cumulative incidence of hypomagnesemia. However, the preventive Mg treatment eliminated the need for additional Mg repletion to maintain Mg levels in patients treated with paclitaxel + cetuximab. A risk factor in patients without prophylaxis was a low Mg level at pre-treatment (≤2.0 mg/dL) (odds ratio: 6.03, 95% confidence interval: 1.78–20.4, p = 0.004), whereas that in patients with prophylaxis was the number of cetuximab doses (≥10) (odds ratio: 5.50, 95% confidence interval: 1.52–19.87, p = 0.009). In conclusion, a low pre-treatment Mg level was the only risk factor that could be avoided by prophylactic Mg administration. This preventive intervention is recommended for managing cetuximab-induced hypomagnesemia.

    Editor's pick

    The authors mainly investigated the risk factors and preventive strategies of cetuximab-induced hypomagnesemia in head and neck cancer (HNC) patients. Their results indicated that a low pre-treatment serum magnesium level emerges as the only risk factor, and this risk can be effectively mitigated through intravenous prophylactic magnesium sulfate administration from initiating cetuximab treatment. This preventive intervention exhibits minimal adverse events and is thus recommended for managing cetuximab-induced hypomagnesemia. Given that cetuximab interruption due to adverse events directly impacts prognosis, the insights gleaned from their study hold significant relevance for the optimal care of HNC patients undergoing cetuximab treatment.

  • Utano Tanaka, Keisuke Mogi, Natsumi Fujita, Miho Moriwake, Katsuya Mor ...
    2024 Volume 47 Issue 3 Pages 739-749
    Published: March 30, 2024
    Released on J-STAGE: March 30, 2024
    JOURNAL FREE ACCESS FULL-TEXT HTML
    Supplementary material

    Patients with diabetes exhibit altered taste sensitivity, but its details have not been clarified yet. Here, we examined alteration of sweet taste sensitivity with development of glucose intolerance in Otsuka Long-Evans Tokushima Fatty (OLETF) rats as a model of non-insulin-dependent diabetes mellitus. Compared to the cases of Long Evans Tokushima Otsuka (LETO) rats as a control, glucose tolerance of OLETF rats decreased with aging, resulting in development of diabetes at 36-weeks-old. In brief-access tests with a mixture of sucrose and quinine hydrochloride, OLETF rats at 25 or more-weeks-old seemed to exhibit lower sweet taste sensitivity than age-matched LETO ones, but the lick ratios of LETO, but not OLETF, rats for the mixture and quinine hydrochloride solutions decreased and increased, respectively, aging-dependently. Expression of sweet taste receptors, T1R2 and T1R3, in circumvallate papillae (CP) was almost the same in LETO and OLETF rats at 10- and 40-weeks-old, while expression levels of a bitter taste receptor, T2R16, were greater in 40-weeks-old rats than in 10-weeks-old ones in both strains. There was no apparent morphological alteration in taste buds in CP between 10- and 40-weeks-old LETO and OLETF rats. Metagenomic analysis of gut microbiota revealed strain- and aging-dependent alteration of mucus layer-regulatory microbiota. Collectively, we concluded that the apparent higher sweet taste sensitivity in 25 or more-weeks-old OLETF rats than in age-matched LETO rats was due to the aging-dependent increase of bitter taste sensitivity in LETO rats with alteration of the gut microbiota.

    Editor's pick

    Diabetes patients are well-known to exhibit alteration of taste sensitivity, but the alteration profiles have not been clarified in detail yet. In brief-access tests with a mixture of sucrose and quinine hydrochloride, the lick ratios of control, but not non-insulin-dependent diabetes mellitus (NIDDM)-model, rats for the mixture and quinine hydrochloride solutions decreased aging-dependently. Metagenomic analysis of gut microbiota revealed strain- and aging-dependent alteration of mucus layer-regulatory microbiota. These findings suggested that control, but not NIDDM-model, rats exhibited an aging-dependent increase of bitter taste sensitivity with alteration of gut microbiota.

feedback
Top