Fish gallbladder ingestion remains a traditional folk remedy in several Asian countries but may result in severe hepatorenal toxicity. We report three patients admitted to the Poison Control Center, Bach Mai Hospital, Hanoi, Vietnam, following ingestion of grass carp (Ctenopharyngodon idella) gallbladders. A 44-year-old man developed severe hepatocellular injury (peak AST 4442 U/L, ALT 5115 U/L), moderate acute kidney injury (AKI), and prolonged severe hypertension requiring intravenous nicardipine infusion for 88 hr. A 48-year-old man presented with severe AKI (peak creatinine 749 µmol/L) and toxic hepatitis and underwent intermittent hemodialysis because of rapidly progressive renal dysfunction despite preserved urine output. A 73-year-old woman developed severe acute hepatocellular injury with AST and ALT levels exceeding 7000 U/L and ferritin of 40,000 ng/mL but without clinically significant AKI. Peak total bilirubin concentrations were 83.6, 102, and 99 µmol/L in Cases 1, 2, and 3, respectively. Viral hepatitis investigations were negative in all patients. Despite variable clinical phenotypes, all patients recovered with supportive treatment. These cases further illustrate the variable patterns of hepatorenal involvement following grass carp gallbladder ingestion, ranging from dialysis-requiring acute kidney injury to predominant hepatocellular injury with preserved renal function. Because toxin exposure could not be quantified, the observed variability may reflect differences in ingested toxin dose, host susceptibility, or both. These findings highlight interindividual variability in patterns of hepatorenal involvement following grass carp gallbladder ingestion.

Arsenic exposure is a major public health concern due to its toxicity and carcinogenicity, largely mediated by oxidative stress, and activation of the Nrf2 signaling pathway is considered a promising strategy to mitigate such damage. In this study, a quantitative structure–activity relationship (QSAR) model was developed to identify potential Nrf2 activators from food-derived compounds. Machine learning algorithms, including Random Forest (RF), Support Vector Machine (SVM), Linear Discriminant Analysis (LDA), and a stacking model, were developed and optimized. The optimized RF, SVM, and LDA models were subsequently integrated into a stacking framework, which was selected as the final predictive model for virtual screening based on its robust and balanced predictive performance. The stacking model achieved the highest accuracy during five-fold cross-validation (0.77) and demonstrated competitive performance on the independent test set (0.742 ± 0.040), with balanced precision, sensitivity, and F-measure. Consequently, the stacking model was selected as the final model for virtual screening. A total of 70,926 compounds retrieved from a food-derived database were filtered based on physicochemical criteria, and QSAR-based virtual screening predicted 920 compounds as potential activators of the Nrf2 signaling pathway, from which 5,7-Dimethylchrysin (FooDB ID: FDB015537) and Demethylvestitol (FooDB ID: FDB012218) were selected for experimental validation. In vitro assays using HepG2 cells demonstrated that 5,7-Dimethylchrysin significantly enhanced cell viability against sodium arsenite (150 μM)-induced cytotoxicity, with an effective concentration (EC50) of 0.54 μM, whereas Demethylvestitol exhibited only limited protective effects. Furthermore, luciferase reporter assays confirmed that 5,7-Dimethylchrysin activated antioxidant response element (ARE)-driven transcription in a concentration-dependent manner, producing a 1.5 to 2.4-fold increase at concentrations ranging from 0.78 to 6.25 μM. Overall, these findings highlight the effectiveness of integrating QSAR modeling with experimental validation to identify food-derived compounds with protective potential against arsenic-induced toxicity, with 5,7-Dimethylchrysin emerging as a promising candidate for further investigation.

Cytochrome P450 2D6 (CYP2D6), a key enzyme involved in the metabolism of a wide range of pharmaceuticals, exhibits extensive genetic variants, including copy number variations (CNVs) and structural alterations. Hybrid alleles formed between CYP2D6 and its highly homologous pseudogene CYP2D7 frequently result in reduced or absent enzymatic activity and show marked interethnic variability. However, accurate characterization of CNVs and hybrid structures in the Japanese population remains technically challenging. In this study, we performed a comprehensive analysis of CYP2D6 genetic and structural variants in 1,287 Japanese patients with solid tumors using whole-genome sequencing (WGS). CNVs and diplotypes were inferred using Sequenza and Aldy, visually inspected with Integrative Genomics Viewer (IGV), and validated using quantitative PCR and Sanger sequencing. A total of 68 distinct diplotypes were identified. The most frequent diplotype was *1/36+*10 (0.2176), followed by *1/*1 (0.1919), *1/*2 (0.0940), *1/*10 (0.0653), *2/*36+*10 (0.0645), and *36/*36+*10 (0.0513). Complete gene deletion (*5/*5) was detected in three cases, and heterozygous deletion (*5/–) in 86 cases. Given that functional annotations for CYP2D6 alleles are well established, WGS-based comprehensive detection represents a practical and scalable strategy for pharmacogenomic profiling. This approach is expected to support optimized drug selection and advance personalized medicine.

S-allyl-L-cysteine (SAC) is a major bioactive compound in aged black garlic with multiple pharmacological benefits, including antioxidant and neuroprotective effects; however, the underlying molecular mechanisms of these benefits remain unclear. In our previous study, we demonstrated that cystathionine γ-lyase (CSE), a sulfur-containing amino acid-metabolizing enzyme involved in the transsulfuration pathway, metabolizes S-nitroso-L-cysteine via a C-S lyase reaction. In this study, we investigated whether CSE-mediated metabolism is involved in the physiological effects of various cysteine derivatives, including SAC. We evaluated the potential of a series of S-alkylcysteine derivatives with varying alkyl chain lengths and degrees of unsaturation as CSE substrates. Recombinant CSE experiments revealed that thiol compounds were produced from propyl derivatives, whereas supersulfides were generated from ethyl, propyl, and allyl derivatives. Kinetic analysis demonstrated that the allyl derivative exhibited a stronger substrate affinity than the propyl derivative, similar to that of the endogenous substrate cystathionine. This study suggests a novel molecular basis for CSE-mediated metabolism and subsequent supersulfide production, which contributes to the diverse health-promoting effects of SAC in mammalian tissues.

Glyoxalase I (GLO I) detoxifies the reactive glycolytic byproduct methylglyoxal (MG) and is frequently overexpressed in cancer cells. High GLO I expression is closely associated with resistance to anticancer drugs, including doxorubicin (DOX). However, the functional relationship between GLO I activity and DOX-induced cell death remains unclear. In this study, we investigated whether inhibition of GLO I enhances cellular sensitivity to DOX. Using non-small cell lung cancer cell lines with low (NCI-H460 cells) or high (NCI-H522 cells) GLO I expression, we found that NCI-H522 cells, which we previously reported to be highly sensitive to the GLO I inhibitor TLSC702 and to accumulate MG following GLO I inhibition, were more resistant to DOX than NCI-H460 cells. Cotreatment with exogenous MG significantly potentiated DOX-induced cytotoxicity through multiple cell death pathways, supporting a role for MG-related processes in modulating DOX responses. While simultaneous treatment with TLSC702 and DOX showed limited enhancement, pretreatment with TLSC702 followed by DOX markedly increased cell death in GLO I-high cells, suggesting that prior disruption of MG detoxification may sensitize cells to subsequent DOX exposure. This effect was accompanied by enhanced poly(ADP-ribose) polymerase (PARP) cleavage and was partially suppressed by caspase and autophagy inhibitors, indicating enhanced apoptosis with contributions from additional cell death pathways. Collectively, these results demonstrate that GLO I inhibition primes cancer cells for enhanced DOX-induced apoptosis, providing mechanistic insights into GLO I-associated chemoresistance.