Biological & Pharmaceutical Bulletin

Myelosuppression, a side effect of anticancer drugs, makes people more susceptible to infectious diseases by compromising the immune system. When a cancer patient develops a contagious disease, treatment with an anticancer drug is suspended or postponed to treat the infectious disease. If there were a drug that suppresses the growth of cancer cells among antibacterial agents, it would be possible to treat both infectious diseases and cancer. Therefore, this study investigated the effect of antibacterial agents on cancer cell development...

Lactosylceramide (Lac-Cer) constitutes the backbone structure of various gangliosides whose abnormal expression is associated with malignancy of neuroblastoma. The understanding of the regulatory mechanism of Lac-Cer contributes to the development of neuroblastoma therapy. In this study, the transcriptional mechanism of mouse β4-galactosyltransferase (β4GalT) 6, which is one of Lac-Cer synthase, was analyzed using mouse neuroblastoma cell line Neuro-2a. The -226 to -13 region relative to the most downstream transcriptional start site was determined to be the promoter region by luciferase assay using the 5'-deletion constructs...

A cancer diagnosis is devastating for both patients and their caregivers. With high morbidity and mortality, cancer is a serious disease area with unmet medical needs. Thus, innovative anticancer drugs are in high demand worldwide but are unequally available. Our study focused on first-in-class (FIC) anticancer drugs and investigated their actual development situation in the United States (US), European Union (EU), and Japan over the last two decades to obtain fundamental information for understanding how the aforementioned demands are met, especially to eliminate drug lags among regions...

Serum response factor (SRF) is a transcription factor that plays essential roles in multiple brain functions in concert with SRF cofactors such as ternary complex factor (TCF) and megakaryoblastic leukemia (MKL)/myocardin-related transcription factor (MRTF), which comprises MKL1/MRTFA and MKL2/MRTFB. Here, we stimulated primary cultured rat cortical neurons with brain-derived neurotrophic factor (BDNF) and investigated the levels of SRF and SRF cofactor mRNA expression. We found that SRF mRNA was transiently induced by BDNF, whereas the levels of SRF cofactors were differentially regulated: mRNA expression of Elk1, a TCF family member, and MKL1/MRTFA were unchanged, while in contrast, mRNA expression of MKL2/MRTFB was transiently decreased...

CCL17 (C-C motif chemokine ligand 17), an important chemokine, plays a vital role in regulating immune balance in the central nervous system. In this study, we explored the potential roles of CCL17 in a rat postoperative pain model and that of blocking CCL17 in the prevention of postoperative pain in rats. A right plantar incision in rat was used as a model of postoperative pain. A behavioral change was measured preoperatively and postoperatively using mechanical withdrawal thresholds and thermal withdrawal latency...

This study investigated whether pretreatment with puerarin could alleviate myocardial ischemia/reperfusion (I/R) injury in a cardiomyocyte oxygen-glucose deprivation and reoxygenation (OGD/R) model and in a mouse I/R injury model. For in vitro experiments, H9C2 cells were divided into control, erastin, OGD/R, OGD/R + puerarin, and OGD/R + ferrostatin (Fer)-1 groups. Parameters related to ferroptosis included levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), ATP, reactive oxygen species (ROS), glutathione (GSH), prostaglandin endoperoxide synthase (Ptgs) 2 mRNA, glutathione peroxidase (GPX) 4 protein and iron...

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Parkinson's disease (PD) is an age-related disorder with selective dopaminergic (DA) neuronal degeneration in the substantia nigra pars compacta. The presence of mainly α-synuclein-composed Lewy bodies in DA neurons is among the disease hallmarks in the brain of patients with PD. Human induced pluripotent stem cells (hiPSCs) are powerful tools to investigate PD pathophysiology and understand its molecular and cellular mechanisms better. In this study, we generated an α-synuclein-null hiPSC line introducing a nonsense mutation in the α-synuclein-encoding SNCA alleles using clustered regularly interspaced short palindromic repeats CRISPR-associated protein 9 (CRISPR-Cas9)-mediated gene editing...

Pharmacogenetics (PGx) enhances personalized care, often reducing medical costs, and improving patients' QOL. Unlike single variant analysis, multiplex PGx panel tests can result in applying comprehensive PGx-guided medication to maximize drug efficacy and minimize adverse reactions. Among PGx genes, drug-metabolizing enzymes and drug transporters have significant roles in the efficacy and safety of various pharmacotherapies. In this study, a genotyping panel has been developed for the Japanese population called PGx_JPN panel comprising 36 variants in 14 genes for drug-metabolizing enzymes and drug transporters using a mass spectrometry-based genotyping method, in which all the variants could be analyzed in two wells for multiplex analysis...

Pharmaceutical consultation targeting outpatients at the Fujita Health University Hospital (Japan) provides support to patients undergoing anticancer drug treatment. This study aimed to explore factors that affect the comprehension of cancer chemotherapy among outpatients who received cancer treatment at our hospital. A questionnaire survey was conducted, and comprehension was scored on a scale of 1-5 (1, no comprehension; 5, full comprehension). When factors other than age and sex [the influence of which on comprehension has been reported in previous reports] were noted, differences in comprehension between the questionnaire items were comparatively analyzed according to the presence/absence of the relevant factors...

Although the strategy in cancer vaccination is to provide a therapeutic effect against an established tumor, there is an urgent need to develop prophylactic vaccines for non-viral cancers. In this study, we prepared polyplex nanoparticles through electrostatic interactions between a positively-charged modified tumor associated antigen, namely human derived melanoma gp10025-33 peptide (KVPRNQDWL-RRRR), and a negatively charged cytosine-phosphate-guanosine motif (CpG-ODN) adjuvant. We previously demonstrated successful transdermal delivery of various hydrophilic macromolecules by iontophoresis (IP) using weak electricity...

Hepatic fibrosis, a primary feature of non-alcoholic steatohepatitis (NASH), develops with inflammation and subsequent activation of hepatic stellate cells (HSCs), the main extracellular matrix-producing cells. Currently, no approved pharmacotherapy is available to treat hepatic fibrosis, even under dietary intervention. The activation of cultured HSCs has been shown to be attenuated by pharmacological inhibition of group IVA phospholipase A2 (IVA-PLA2 ), an enzyme initiating the generation of lipid proinflammatory mediators...

We previously identified androgen-dependent sex differences in the mRNA expression of drug metabolizing enzymes (DMEs), including CYPs, sulfotransferases and uridine 5'-diphospho-glucuronosyltransferases, and drug transporters in the pig liver and kidney. To elucidate the mechanism for such sex differences in pigs, we herein focused on the key regulators cut-like homeobox 2 (Cux2), B-cell lymphoma 6 (Bcl6), and signal transducer and activator of transcription 5b (Stat5b), which are reported to be responsible for the sex-biased gene expression of Cyps in the mouse liver...

Macular edema causes vision loss in patients with retinal vein occlusion (RVO) and diabetic macular edema (DME). The intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents is used for treatment; however, this therapy is invasive, and recurrence occurs in some cases. The establishment of a non-invasive treatment would help to solve these problems. Here, we focused on arctigenin, a lignan polyphenol found in burdock sprout, and has effects on inflammatory and microcirculatory when taken orally...

CYP3A4, which contributes to the metabolism of more than 30% of clinically used drugs, exhibits high variation in its activity; therefore, predicting CYP3A4 activity before drug treatment is vital for determining the optimal dosage for each patient. We aimed to develop and validate an LC-tandem mass spectrometry (LC-MS/MS) method that simultaneously measures the levels of CYP3A4 activity-related predictive biomarkers (6β-hydroxycortisol (6β-OHC), cortisol (C), 1β-hydroxydeoxycholic acid (1β-OHDCA), and deoxycholic acid (DCA))...

The onset of Alzheimer's disease (AD) is characterized by accumulation of amyloid β peptide (Aβ) in the brain. Neprilysin (NEP) is one of the major Aβ-degrading enzymes. Given findings that NEP expression in the brain declines from the early stage of AD before apparent neuronal losses are observed, enhancement of NEP activity and expression may be a preventive and therapeutic strategy relevant to disease onset. We screened for compounds that could enhance the activity and expression of NEP using a polyphenol library previously constructed by our research group and investigated the structure-activity relationships of the identified polyphenols...

Patients in Japan often have difficulty in screening and selecting chronic-care and rehabilitation hospitals for transfer because of the high cost and unavailability of new antiseizure medications, such as perampanel and lacosamide. To investigate whether the requirement for perampanel and lacosamide interfered with patients' hospital transfer by comparing the number of days required for hospital transfer. Data were obtained from patients 1) who were diagnosed with intracerebral hemorrhage or cerebral infarction, 2) who were treated with antiseizure medications for epilepsy, and 3) who were transferred to another hospital...

Anaphylaxis is a serious allergic or hypersensitivity reaction with a sudden onset that can be life-threatening or fatal. Previous studies have highlighted two pathways of anaphylaxis in mice. One is the classical immunoglobulin E (IgE)-mediated pathway that involves mast cells and histamine. The other is an alternative IgG-mediated pathway that involves basophils, monocytes/macrophages, neutrophils, and the platelet-activating factor (PAF). However, little is known about the mechanism by which complement anaphylatoxins contribute to the induction of anaphylaxis...

Studies have reported an association between elevated neutrophil-to-lymphocyte ratio (NLR) and poor prognosis in patients with melanoma treated with ipilimumab. However, it remains unclear whether NLR is useful in Japanese patients with melanoma, and if so, what is the optimal cut-off value. We retrospectively examined 38 patients who received ipilimumab from August 2015 to November 2021 at Nagoya University Hospital. We divided patients into two groups: 1-2 versus 3-4 cycles of ipilimumab. In univariate analysis, baseline neutrophil count and NLR were significantly higher in patients who discontinued ipilimumab within 2 cycles...

Non-alcoholic fatty liver disease (NAFLD) has emerged as one of the most frequent types of liver disease in pediatric populations with obesity. Tilianin has multiple biological activities including anti-inflammatory and antioxidant. Here, we aim to explore the functions and possible mechanisms of tilianin on NAFLD in obese children. A high-fat high-carbohydrate (HFHC) diet was used to feed 21-d-old mice. Tilianin was administered at a dose of 10 or 20 mg/kg daily. HFHC-fed mice gained weight, increased liver index...