The involvement of metabolism by myeloperoxidase (MPO) has been reported in drug-induced agranulocytosis (AG). In this study, we investigated whether MPO metabolic reactions could be nonenzymatically mimicked using hypochlorous acid (HClO) and HL-60 cells to generate the reactive metabolite of vesnarinone, a drug known to cause AG, and to detect its cytotoxicity. First, HClO is a strong radical agent and has a direct cytotoxic effect on cells. We tried to reduce its cytotoxicity by using dimethyl sulfoxide (DMSO), which is a solvent but also has the characteristics of a radical scavenger. Thus, the cytotoxicity disappeared when ≥ 20% DMSO was added against HClO. When vesnarinone was reacted under this condition, we observed its concentration-dependent cytotoxicity and converting vesnarinone into two metabolites (metabolite 1 and 2). Next, the presence of reduced glutathione protected its cytotoxicity and converted metabolite 2 into metabolite 1, which were consistent with the MPO reaction. Furthermore, we performed the assessment using this assay system utilizing 12 drugs with different AG incidences. The correlation diagram created between the clinical maximum plasma/serum concentration (C_max) and the reciprocal concentration of 50% cell viability (1/CV₅₀) was suggested that drugs with high C_max (≥ 0.062 μg/mL) and strong cytotoxicity (CV₅₀ ≤ 40.9 µM) were related to a clear probability incidence of AG. In conclusion, it was suggested that the constructed HClO test system can be applied to drugs with a clear probability incidence of AG.

Target Safety Review (TSR) is a document that triggers the Target Safety Assessment and is designed to predict and identify on-target safety risks. However, with regard to the anticipated on-target risks extracted by TSR, nonclinical toxicity studies sometimes have limitations in predicting clinical safety risks. In this study, we investigated whether nonclinical toxicity studies could predict clinical infection risks expected in TSR. Using the OFF-X database, we identified 942 targets and 1323 drugs associated with infection risks. Through successive filters, i.e., applying “drug alert”, “on-target”, “causality with severity”, “class score”, and “evidence levels”, biologics became the focus, resulting in six targets and 17 drugs approved by PMDA. From PMDA reports, package inserts, and interview forms, we extracted immune-related findings in nonclinical toxicity studies and infection risks in clinical settings to analyze predictivity by target. Our survey shows clear immune-related toxicity in nonclinical studies of CD20 inhibitors (obinutuzumab, ofatumumab, rituximab), TNF-alpha inhibitors (adalimumab, golimumab), and IL-6R antagonists (sarilumab, tocilizumab). Indicators included B cell depletion, thymus atrophy, and decreased neutrophils. For IL-17, IL-23, and IL-1beta inhibitors, nonclinical studies did not always predict the infection risks observed in clinical settings. Although nonclinical toxicity studies sometimes provided insights into potential infection risks which can be anticipated by its target, their predictive power for specific mechanism of actions and infections appeared limited. Understanding the MOAs and biological background of the drug through the TSR and identifying and mitigating risks early in the project are essential for the safe development of new therapeutic agents.

Methylmercury (MeHg) is a well-established environmental neurotoxicant and the primary cause of Minamata disease. Recently, α-mercuri-acetaldehyde (HgCH₂CHO) and α-mercuri-acetic acid (HgCH₂COOH) have been proposed to be relevant to the Minamata tragedy. However, their in vivo toxicity has not been compared with that of MeHg under identical conditions. We conducted a comparative in vivo toxicity study of HgCH₂CHO and HgCH₂COOH using the dosing regimen previously established for MeHg. Male Wistar rats were orally administered MeHg, HgCH₂CHO, or HgCH₂COOH (26.6 µmol/kg/day) for 5 days, which was followed by a 2-day drug-free period and a single repeat of this cycle. Systemic toxicity was evaluated using the change in body mass, neurobehavioral effects were assessed using the hindlimb crossing test, and the total mercury accumulation in blood and organs was quantified. MeHg exposure resulted in marked weight loss and significant neurobehavioral impairment. In contrast, rats exposed to HgCH₂CHO or HgCH₂COOH exhibited only mild weight loss and substantially attenuated hindlimb crossing responses. The total mercury levels in the blood, liver, brain, muscle, and spleen were considerably lower in the HgCH₂CHO- and HgCH₂COOH-treated groups than in the MeHg group. The renal accumulation of mercury did not differ among the groups, despite the blood mercury levels in the HgCH₂CHO and HgCH₂COOH groups being extremely low, suggesting distinct toxicokinetic properties. Overall, HgCH₂CHO and HgCH₂COOH demonstrated much lower in vivo toxicity and systemic mercury burden than MeHg under equivalent dosing conditions. These findings do not challenge the established role of MeHg as the primary causative agent of Minamata disease.

Hydrogen sulfide (H₂S) is a novel gasotransmitter produced in mammalian cells and is known to various regulate physiological functions. Previous study reported that an imbalance in H₂S metabolism is associated with defective bone homeostasis. However, the detailed mechanism of how H₂S affect osteoclast differentiation remains unclear. In the present study, we demonstrated that the effect of H₂S donor GYY4137 on osteoclast differentiation and multi-nucleation. Treatment of GYY4137 significantly decreased the number of receptor activator of nuclear factor kappa-B ligand (RANKL)-induced tartrate-resistant acid phosphatase (TRAP)-positive cells and inhibited the expression of osteoclast-related genes, nuclear factor of activated T-cells 1 (NFATc1) and Cathepsin K(Ctsk). Additionally, the increased gene expression of dendritic cell-specific transmembrane protein (DC-STAMP), osteoclast stimulatory transmembrane protein (OC-STAMP), and v-ATPase V0 subunit d2 (Atp6v0d2), which are cell-cell fusion-related molecules by RANKL treatment, was attenuated by GYY4137. Furthermore, GYY4137 suppressed the phosphorylation of mitogen-activated protein kinases (MAPKs), including ERK1/2, JNK1/2, and p38MAPK, compared to RANKL-treated cells. Thus, our data suggested that H₂S donor GYY4137 as a novel osteoclast genesis inhibitor, significantly decreases osteoclast differentiation and multi-nucleation by inhibiting the expression of the cell-cell fusion molecules.

Over the past five decades, air pollution has posed a growing threat to human health, particularly affecting the respiratory system. This study aims to investigate the potential molecular mechanisms underlying the relationship between exposure to air pollutants and the development of COPD and to identify potential gene targets that may play a key role in this process. In this study, researchers used several publicly available databases to obtain target genes related to air pollutants and COPD, determine the overlapping genes between them and performed GO and KEGG enrichment analyses to elucidate the underlying mechanisms. Cross-validation was performed using multiple datasets from the Gene Expression Omnibus (GEO) database to screen out candidate targets, and molecular docking techniques were utilized to investigated molecular interactions between candidate targets and air pollutants. Candidate targets were subsequently validated and analyzed using immune cell infiltration analysis, single-cell transcriptome data, risk prediction model construction and clinical data to further elucidate their relationship with COPD. Findings suggest that HDAC9, DPP9 and KCNN4 are candidate targets of air pollutants that are potentially involved in COPD development. These results offer new insights into the potential molecular mechanisms linking air pollution exposure to COPD and underscore the need for further in-depth research on air pollution issues.