花尻 瑠理

ABSTRACT Aim This study aimed to identify and establish novel biomarkers for human drug‐induced liver injury (DILI). Methods Patients with DILI ( N  = 52) or other liver diseases ( N  = 486) and healthy participants ( N  = 60) were recruited from the hospitals enrolled in this study. Metabolomics was conducted using serum samples from patients with DILI and healthy participants to screen for candidate DILI biomarkers. Subsequently, the serum concentrations of the candidate biomarkers were determined using a validated assay to characterize their properties and evaluate their ability to differentiate the patients with DILI from those who recovered from DILI and those with other liver diseases. Results Three metabolites, pyroglutamylglycine (pyroGluGly), phenylalanine (Phe), and phenylalanyltryptophan (PheTrp), were identified as candidate DILI biomarkers. The serum concentrations of pyroGluGly, Phe, and PheTrp demonstrated a high and similar differentiating ability (area under the receiver‐operating characteristic curve [ROC‐AUC] > 0.9) in patients with mixed and cholestatic DILI compared with those in patients who recovered from DILI, suggesting that these three metabolites are biomarkers for mixed/cholestatic DILI. All or some of them demonstrated a substantially high differentiating ability (ROC‐AUC > 0.8) in patients with mixed/cholestatic DILI compared with patients with other liver diseases, except for obstructive jaundice. Conclusions We identified novel DILI biomarkers that can be used to clinically assess patients with mixed/cholestatic DILI and to differentiate these patients from recovered patients and those with other liver diseases.

ABSTRACT Since around 2021, products such as e‐cigarette liquid cartridges, herbal products, and gummy products, claiming to contain tetrahydrocannabinol (THC) analogues, have been seen for sale on the internet. Recently, products claiming to contain other THC derivatives have appeared. In this study, we identified the ingredients in products distributed on the internet that claim to contain THC derivatives. The e‐cigarette cartridge product analyzed in this study was obtained from Japan in September 2024. One milligram of the oil product was treated with 1 mL of acetonitrile under ultrasonication. The resulting solutions were used for gas chromatography–mass spectrometry (GC – MS) and liquid chromatography–photodiode array–mass spectrometry (LC – PDA – MS) measurements. After isolating and purifying unknown components from the product, structural analysis was performed by measuring ¹ H, ¹³ C nuclear magnetic resonance (NMR) and various two‐dimensional NMR (COSY, HMQC, HMBC, and NOESY) and LC with hybrid quadrupole time‐of‐flight MS. The analysis revealed that chlorinated HHCs (i.e., (9R)‐2‐chloro‐HHC, (9S)‐2‐chloro‐HHC, (9R)‐4‐chloro‐HHC, (9S)‐4‐chloro‐HHC, (9R)‐2,4‐dichloro‐HHC, and (9S)‐2,4‐dichloro‐HHC) were the major components, and chlorinated dihydro‐ iso ‐THCs (i.e., 10‐chloro‐dihydro‐ iso ‐THC, 8‐chloro‐dihydro‐ iso ‐THC, and 8,10‐dichloro‐ iso ‐THC) were the minor components isolated and identified from the product. Furthermore, Δ ⁹ ‐THCB‐ O ‐butanoate, a compound in which the hydroxyl group at the C1 position of Δ ⁹ THCB was butanoylated, was detected.

Diffuse alveolar damage (DAD) is a pathological hallmark of severe interstitial lung diseases, such as acute respiratory distress syndrome (ARDS), and is linked to poor prognosis. Previously, we identified 14-3-3σ/stratifin (SFN) as a serum biomarker candidate for diagnosing DAD. To clarify the time-dependent relationship between SFN expression and DAD, we here investigated pathological and molecular changes in serum, bronchoalveolar lavage fluid (BALF), and lung tissue in an oleic acid (OA)-induced ARDS rat model. Acute alveolar edema was observed after OA administration, followed by alveolar epithelial cell proliferation and increased BALF and serum SFN levels. Proteomic analysis of lung tissue extracts revealed that proteins related to "inflammatory response" and "HIF-1 signaling," including plasminogen activator inhibitor-1, were markedly increased 3 h after acute lung injury, followed by a gradual decrease. Conversely, proteins associated with "cell cycle" and "p53 pathway," including SFN, showed a persistent increase starting at 3 h and peaking at 48 h. Western blotting and immunohistochemistry confirmed that SFN was expressed in a part of proliferated alveolar type-II cells, accompanied by p53 activation, an important event for differentiation into type-I cells. SFN may be a biomarker closely related to alveolar remodeling during the repair process after lung injury.