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Gallein is known as an inhibitor of Gβγ subunits, but roles of gallein in bone metabolism have not been reported. Fibroblast growth factor 2 (FGF-2) increases angiogenesis and promotes bone regeneration during the early stages of fracture healing. Osteoprotegerin (OPG) secreted by osteoblasts, binds to the receptor activator of nuclear factor-κB (RANK) ligand (RANKL) as a decoy receptor and prevents RANKL from binding to RANK, resulting in the suppression of bone resorption. Our previous report demonstrated that FGF-2 activates the phosphorylation of p38 mitogen-activated protein kinase (MAPK), stress-activated protein kinase/c-Jun N-terminal kinase (JNK), and p44/p42 MAPK in osteoblast-like MC3T3-E1 cells. Additionally, FGF-2-activated phosphorylation of p38 MAPK and JNK but not p44/p42 MAPK is positively involved in OPG synthesis in these cells. This work aimed to investigate the effects of gallein on the FGF-2-elicited OPG synthesis in osteoblast-like MC3T3-E1 cells and the mechanism. Our findings demonstrated that gallein significantly increased the FGF-2-elicited OPG synthesis in MC3T3-E1 cells. By contrast, fluorescein, gallein-like compound that does not bind Gβγ, did not affect the FGF-2-elicited OPG synthesis. Gallein significantly enhanced the FGF-2-induced OPG mRNA expression levels. Gallein did not affect the FGF-2-activated phosphorylation of p38 MAPK and p44/p42 MAPK, but significantly increased the FGF-2-activated phosphorylation of JNK, while fluorescein did not affect JNK phosphorylation. SP600125, a specific JNK inhibitor, strongly inhibited gallein-induced enhancement of FGF-2-induced OPG synthesis and mRNA expression levels. Our results indicated that gallein increases the FGF-2-induced OPG synthesis due to the JNK activation in the osteoblast., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: We investigated whether the initial voriconazole (VRCZ) dosing design, as determined using simulation software with a population pharmacokinetic model of Japanese patients, impacts the effectiveness and safety when compared with VRCZ initiation according to the package insert., Methods: In this single-center retrospective observational study, we employed records from Tosei General Hospital (a 633-bed hospital), dated April 2017 to September 2023. Eligible patients were divided into the software-based simulation group, comprising patients administered initial VRCZ dosage adjustment by pharmacists using software-based simulation, and the standard therapy group, whose dosage was administered by a physician following the package insert recommendations without simulation. The primary objective of this study was to determine the efficacy of VRCZ first-dose design in reducing the incidence of hepatotoxicity and visual symptoms., Results: The median ages of enrolled participants (n = 93) were 75 (68-79) and 72 (65-78) years in the software-based simulation and standard therapy groups, respectively. Regardless of formulation, initial trough concentrations were lower in the VRCZ software-based first dosage adjustment group and higher rate within the appropriate range (1-4 μg/mL). The incidence of all-grade hepatotoxicity or visual symptoms was significantly lower in the software-based simulation group. The log-rank test revealed a significant impact on the occurrence of ≥grade 2 hepatotoxicity in the software-based first dosage adjustment group compared to that in the standard therapy group., Conclusions: The initial VRCZ dosing design using simulation software improved the achievement of appropriate initial trough concentrations and resulted in fewer occurrences of hepatotoxicity (≥grade 2) when compared with the standard therapy., Competing Interests: Declaration of Competing interest Y. M. received travel funding and lecture fee from Pfizer Japan Inc. H. M. received honorarium from Pfizer R&D Japan G.K. The other authors declare no conflict of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Introduction: The Direct Peptide Reactivity Assay (DPRA) was developed as an alternative simple and versatile method for predicting skin sensitization. Here, we describe a novel Amino acid Derivative Reactivity Assay (ADRA) involving 2 amino acid derivatives: N-(2-(1-naphthyl)acetyl)-l-cysteine (NAC) and α-N-(2-(1-naphthyl)acetyl)-l-lysine (NAL), in which each amino-terminal residue is introduced into a naphthalene ring. ADRA measurements were conducted at 281nm, which improved baseline stability, and were less influenced by other substances in the reaction solutions than DPRA measurements that are conducted at 220nm., Methods: Chemically synthesized NAC and NAL were dissolved in phosphate buffers of pH9.5 and 12.0, respectively. Each solution, test chemical solution, and phosphate buffer, were mixed in 96-well microplates and incubated in the dark for 24h at 25°C. Following incubation, samples were diluted 10 times with a mixed solution of 25% acetonitrile/0.5% trifluoroacetic acid (TFA) in water, and NAC and NAL levels were quantified in each sample and control using a high-performance liquid chromatography (HPLC) system. The reactivity of NAC/NAL was calculated as the percent depletion based on the decrease in the non-reacted NAC/NAL concentration in the samples relative to the average concentration in the control; the average NAC/NAL reduction score was calculated. A 2-class classification model was developed using ADMEWORKS/ModelBuilder, and an optimal average score that could discriminate between sensitizers and non-sensitizers was determined., Results: A total of 82 test chemicals were applied to ADRA for comparison against DPRA. The prediction accuracy of ADRA was 88%, which was similar to that of DPRA., Discussion: ADRA was used to quantify NAC/NAL at 281nm, which showed high accuracy for the prediction of skin sensitization, similar to that of DPRA. Therefore, ADRA could be used to expand the range of chemicals tested in skin sensitization analyses., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Hepatocyte nuclear factor-6 (HNF-6) is a liver-enriched transcription factor that contains a single cut domain and a novel type of homeodomain. Here we have studied the developmental expression pattern of HNF-6 in the mouse. In situ hybridization experiments showed that HNF-6 mRNA is detected in the liver at embryonic day (E) 9, at the onset of liver differentiation. HNF-6 mRNA disappeared transiently from the liver between E12.5 and E15. In transfection experiments HNF-6 stimulated the expression of HNF-4 and of HNF-3 beta, two transcription factors known to be involved in liver development and differentiation. HNF-6 was detected in the pancreas from E10.5 onward, where it was restricted to the exocrine cells. HNF-6 was also detected in the developing nervous system. Both the brain and the spinal cord started to express HNF-6 at E9-9.5 in postmitotic neuroblasts. Later on, HNF-6 was restricted to brain nuclei, to the retina, to the ventral horn of the spinal cord, and to dorsal root ganglia. Our observations that HNF-6 contributes to the control of the expression of transcription factors and is expressed at early stages of liver, pancreas, and neuronal differentiation suggest that HNF-6 regulates several developmental programs.