Biological and Pharmaceutical Bulletin
Online ISSN : 1347-5215
Print ISSN : 0918-6158
ISSN-L : 0918-6158
  • 44 巻 (2021) 6 号 p. 747-761
    Chrono-Drug Discovery and Development Based on Circadian Rhythm of Molecular, Cellular and Organ Level もっと読む

    This review describes the chronotherapeutic strategies based on molecular clock system of chronopharmacokinetic, chronopharmacodynamic and cancer chronopathological factors in the xenobiotic detoxification, transporter, receptor and molecular target. Chronotherapeutic strategies focus on the monitoring of rhythm, overcoming rhythm disruption, manipulation of rhythm, chrono-therapeutic drug monitoring, chrono-drug delivery system and chrono-drug discovery. The screening for small molecules targeting the clock genes is now in progress to stabilize circadian phase and enhance circadian amplitude, thereby consolidating and coordinating circadian organization,. The academic research along with a combination of chemical and biological information is essential to promote the research and development of new modality drug discovery such as clock genes.

  • 44 巻 (2021) 6 号 p. 789-797
    Acute Ramelteon Treatment Maintains the Cardiac Rhythms of Rats during Non-REM Sleep もっと読む

    Ramelteon, a melatonin receptor agonist, has a sleep-promoting effect by modulating sleep-wake rhythms. To examine the effect of ramelteon on cardiac function, authors simultaneously recorded electrocardiograms, electromyograms, and electrocorticograms in the frontal cortex and the olfactory bulb of unrestrained rats treated with ramelteon. Authors demonstrated that during non-REM sleep, heartrate variability was maintained by ramelteon treatment. Analysis of the electromyograms confirmed that neither microarousal during non-REM sleep nor the occupancy of phasic periods during REM sleep was altered by ramelteon. Thus, authors propose a remedial effect of ramelteon on cardiac activity by keeping the heartrate variability.

  • 44 巻 (2021) 6 号 p. 804-815
    Identification and Validation of Combination Plasma Biomarker of Afamin, Fibronectin and Sex Hormone-Binding Globulin to Predict Pre-eclampsia もっと読む

    Numerous studies have confirmed that the sFlt1/PlGF ratio is a good predictor of the signs and symptoms of Pre-Eclampsia. However, its usefulness is limited to diagnosis after 20 weeks of gestation. To address this issue, in the present study the authors used plasma samples collected at gestational weeks 14-24 weeks from subjects who were subsequently diagnosed as Pre-Eclampsia. By employing SWATH-based proteomics for comprehensive discovery and SRM-based target quantification using in silico peptide selection criteria for validation, the authors were able to identify a 3-protein combination biomarker (AFAM, FINC and SHBG) that can predict effectively during gestational weeks 14-24 whether pregnant women would subsequently develop Pre-Eclampsia.

  • 44 巻 (2021) 6 号 p. 830-837
    Protective Effect of Panduratin A on Cisplatin-Induced Apoptosis of Human Renal Proximal Tubular Cells and Acute Kidney Injury in Mice もっと読む

    Cisplatin is an effective anti-cancer drug. A serious major side effect of cisplatin is an acute kidney injury. The authors demonstrated that panduratin A, a bioactive flavonoid, ameliorates cisplatin-induced nephrotoxicity by inhibition of cell apoptosis. The renoprotective effect of panduratin A is mediated by reducing oxidative stress and inhibiting ERK1/2 and caspase 3 activations. The protective effect of panduratin A did not impair the anti-cancer activity of cisplatin in cancer cells. Panduratin A might be a good candidate agent to alleviate cisplatin’s nephrotoxicity.

  • 44 巻 (2021) 6 号 p. 869-874
    Assessment of Adherence to Post-exposure Prophylaxis with Oseltamivir in Healthcare Workers: A Retrospective Questionnaire-Based Study もっと読む

    Influenza causes nosocomial outbreaks in healthcare settings. Post-exposure prophylaxis (PEP) for healthcare workers is one of the effective strategies for preventing outbreaks of influenza. However, PEP adherence in healthcare workers is rarely analysed. This retrospective questionnaire-based study showed that the adherence to PEP among healthcare workers was low, especially among physicians, and that the primary factor for preventing PEP adherence was misguided self-decision that continuation of PEP was unnecessary. This study emphasized that medication education should be provided to ensure treatment compliance and maximize the therapeutic benefits of PEP when PEP is administered.

  • 44 巻 (2021) 5 号 p. 642-652
    Involvement of TRPM8 Channel in Radiation-Induced DNA Damage Repair Mechanism Contributing to Radioresistance of B16 Melanoma もっと読む

    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.

  • 44 巻 (2021) 5 号 p. 659-668
    Effects of KY-903, a Novel Tetrazole-Based Peroxisome Proliferator-Activated Receptor γ Modulator, in Male Diabetic Mice and Female Ovariectomized Rats もっと読む

    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.

  • 44 巻 (2021) 5 号 p. 669-677
    Rivaroxaban Attenuates Right Ventricular Remodeling in Rats with Pulmonary Arterial Hypertension もっと読む

    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.

  • 44 巻 (2021) 5 号 p. 678-685
    Protonation State of a Histidine Residue in Human Oligopeptide Transporter 1 (hPEPT1) Regulates hPEPT1-Mediated Efflux Activity もっと読む

    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.

  • 44 巻 (2021) 5 号 p. 707-713
    Effects of the L/N-Type Ca2+ Channel Blocker Cilnidipine on the Cardiac Histological Remodelling and Inducibility of Atrial Fibrillation in High-Salt-Fed Rats もっと読む

    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.

  • 44 巻 (2021) 4 号 p. 507-514
    Overexpressed Hsa_circ_0001326 Contributes to the Decreased Cell Viability in SWAN71 Cells by Regulating MiR-186-5p/p27 Kip1 Axis もっと読む
  • 44 巻 (2021) 4 号 p. 522-527
    Dietary Fructooligosaccharides Reduce Mercury Levels in the Brain of Mice Exposed to Methylmercury もっと読む

    Fructooligosaccharides (FOS), typical nondigestible oligosaccharides, change the composition and/or activity of microbiota in the large intestine. Intestinal microbiota has important roles in the decomposition and fecal excretion of methylmercury (MeHg). Fecal Hg excretion was markedly higher in FOS-fed mice than in controls after oral administration of MeHg, but urinary Hg excretion was not. FOS-fed mice had lower total Hg levels in all tissues (including the brain) than controls. The possible mechanism on function of FOS is accelerated MeHg demethylation by intestinal bacteria and reduced MeHg absorption in the large intestine.

  • 44 巻 (2021) 4 号 p. 528-534
    Topical Application of BMS-509744, a Selective Inhibitor of Interleukin-2-Inducible T Cell Kinase, Ameliorates Imiquimod-Induced Skin Inflammation in Mice もっと読む

    Psoriasis is an inflammatory skin disease characterized by red scaly papules or plaques. It has been suggested that activation of immune cells such as T cells and abnormal differentiation and proliferation of keratinocytes are involved in the pathogenesis of psoriasis. IL-2-inducible T cell kinase (ITK) is a tyrosine kinase expressed in T cells that regulates T cell activation. Authors showed that topical application of BMS-509744, a selective ITK inhibitor, ameliorates psoriasis-like inflammation in the skin of mice. This study suggests that ITK inhibition in skin lesion is a promising candidate treatment for psoriasis.

  • 44 巻 (2021) 4 号 p. 544-549
    Increase in Blood Pressure by Local Injection of Ketamine into the Amygdala in Rats もっと読む

    Ketamine is known as a dissociative anesthetic that suppresses the cerebral cortex and activates the limbic system, and is unique as an anesthetic, since it induces blood pressure increase. Author examined the effect of ketamine, applied directly to the amygdala, on blood pressure. The results showed that the blood pressure was increased by ketamine injection into the basolateral and central nuclei of the amygdala, endopiriform nucleus and piriform cortex. Elucidation of the mechanism of ketamine-induced blood pressure increase will lead to understanding of the mechanism of side effects of ketamine, and will contribute to its appropriate use.

  • 44 巻 (2021) 4 号 p. 557-563
    Phosphorylation of Specificity Protein 3 Is Critical for Activation of β4-Galactosyltransferase 3 Gene Promoter in SH-SY5Y Human Neuroblastoma Cell Line もっと読む

    The malignant potential of neuroblastoma is associated with elevated expression of β4-galactosyltransferase (β4GalT) 3. The transcription of the β4GalT3 gene is regulated by transcription factor Sp3 in SH-SY5Y human neuroblastoma cell line, and Sp3 activates the β4GalT3 gene promoter. In this study, the authors demonstrated that the transcriptional activation of the β4GalT3 gene is mediated by the mitogen-activated protein kinase signaling, and the phosphorylation of the serine residues in Sp3 is important for the transcriptional activation. The findings propose a therapeutic strategy for the regulation of the β4GalT3 gene in neuroblastoma by controlling the phosphorylation of Sp3.

  • 44 巻 (2021) 3 号 p. 338-349
    Evaluation of Methods to Assess CYP3A Induction Risk in Clinical Practice Using in Vitro Induction Parameters もっと読む

    The authors evaluated the predictability of various methods used to assess clinical CYP3A induction risk based on various in vitro parameters, and demonstrated that correlation methods were better at predicting clinical induction risk than direct methods recommended in guidance/guidelines. Among correlation approaches, the Relative Factor (RF) and AUC/F2 methods showed an especially good correlation with clinical induction, and can be used to assess induction risk along with other correlation methods recommended in guidance/guidelines. These findings may allow researchers to more confidently determine whether or not a clinical induction study should be performed before clinical trials.

  • 44 巻 (2021) 3 号 p. 422-430
    Glucosyl Hesperidin Has an Anti-diabetic Effect in High-Fat Diet-Induced Obese Mice もっと読む

    Obese adipose tissue is characterized by increased immune cell infiltration. Adipocyte-immune cell interaction overproduces inflammatory adipokine, which contribute to the development of type 2 diabetes mellitus. The regulation of immune cells infiltration and inflammation in adipose tissue may exert preventive and therapeutic effects on obesity-related diseases. Flavonoids such as hesperidin have anti-inflammatory properties, but their low bioavailability limits their use as drugs and supplements. The authors report that glucosyl hesperidin (GH), a water-soluble derivative of hesperidin, ameliorated glucose intolerance and reduced macrophage infiltration into adipose tissue in high-fat diet-fed mice. These results suggest the usefulness of GH against obesity-related diseases.

  • 44 巻 (2021) 3 号 p. 431-436
    Deletion of TRPC3 or TRPC6 Fails to Attenuate the Formation of Inflammation and Fibrosis in Non-alcoholic Steatohepatitis もっと読む

    Two transient receptor potential canonical (TRPC) subfamily members, TRPC3 and TRPC6, reportedly participate in the development of fibrosis in cardiovascular and renal systems. This study is to investigate whether TRPC3 and TRPC6 channels also contribute to the formation of nonalcoholic steatohepatitis (NASH) which includes liver fibrosis, using TRPC3 or TRPC6 systemic knockout mice fed with the choline-deficient, L-amino acid-defined, high-fat diet. The authors found that systemic deletion of TRPC3 or TRPC6 gene alone failed to attenuate liver dysfunction and fibrosis in NASH model mice.

  • 44 巻 (2021) 3 号 p. 437-441
    Effects of Uremic Toxins on the Binding of Aripiprazole to Human Serum Albumin もっと読む

    Aripiprazole (ARP), an antipsychotic drug, binds strongly to site II on human serum albumin (HSA). In this study, the issue of how uremic toxins (indoxyl sulfate, indole acetic acid and p-cresyl sulfate) affect the binding of ARP to HSA were investigated. Authors demonstrated that these uremic toxins inhibit the binding of ARP to diazepam subsite within site II, and these inhibitory effects were more significant, comparing with those on the drug binding to arylpropionic acids subsite. These findings provide important information for considering the pharmacokinetics of ARP and the drugs that bind to site II during renal diseases.

  • 44 巻 (2021) 3 号 p. 442-447
    Altered Functional Connectivity of the Orbital Cortex and Striatum Associated with Catalepsy Induced by Dopamine D1 and D2 Antagonists もっと読む

    By combining whole-brain activation mapping of neurons activated in response to dopamine D1 and D2 receptor antagonists with non-bias analysis, Niu et al. provide the direct evidence that the orbital cortex in addition to the striatum are important brain areas associated with DA antagonists-induced movement abnormality.