Intestinal epithelial cells (IECs) play a crucial role in forming a protective barrier and regulating the absorption of substances passing through the small intestine. Disrupting the epithelial barrier function can result in intestinal diseases such as inflammatory bowel disease. Glyceraldehyde (GA)-derived advanced glycation end-products (AGEs) (toxic AGEs, TAGE) are AGEs formed by the nonenzymatic Maillard reaction. Although AGEs have been implicated in intestinal barrier breakdown, the associated mechanism remains underexplored. In this study, the effects of accumulated TAGE in IECs were investigated by focusing on tight junctions using Caco-2 cells—a human colorectal epithelial adenocarcinoma cell line. While GA treatment induced the formation of intracellular TAGE in Caco-2 cells, resulting in cell death, the generated intracellular TAGE triggered increased paracellular permeability. In addition, immunofluorescence staining showed that GA treatment decreased the fluorescence intensities of ZO-1 and claudin-7, which are tight junction proteins attached to the plasma membrane. Furthermore, an evaluation of the mechanism behind intestinal barrier breakdown revealed excessive reactive oxygen species (ROS) production and increased expression of reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase subunit genes, a mechanism of ROS production, in the GA-treated group compared with the control group. Furthermore, GA treatment induced necrosis and caused cytotoxicity in this condition. Overall, these results suggest that TAGE induction can disrupt tight junctions in IECs via cell injury as a pathway.

Chronic kidney disease (CKD) is a serious chemotherapy-associated clinical condition. CKD complicates the pharmacokinetics of anticancer drugs, requiring personalized dosing strategies to minimize toxicity. S-1 and oxaliplatin (the SOX regimen) are widely used for gastrointestinal cancer treatment. However, the specific association between systemic drug exposure and renal biomarker levels in CKD remains unclear. This study evaluated the pharmacokinetics of S-1 and oxaliplatin in 2 CKD model rats (5/6 nephrectomy and adenine-induced) and examined their relationships with renal biomarkers. S-1 (2 mg/kg as tegafur) and oxaliplatin (5 mg/kg) were administered separately, and plasma levels of tegafur, 5-fluorouracil (5-FU), 5-chloro-2,4-dihydropyridine, oxaliplatin, and platinum were measured by LC-tandem MS. Systemic exposure to S-1 and oxaliplatin was higher in the CKD model rats than in the normal group, with 5-FU levels being particularly higher in the adenine-induced model than in the 5/6 nephrectomy model. The area under the curve values of 5-FU and platinum were strongly correlated with plasma creatinine (P_Cr) levels (r = 0.79 and 0.88, respectively). Population pharmacokinetic analysis identified P_Cr as a significant covariate of 5-FU clearance. A nomogram constructed using P_Cr-based simulations demonstrated the feasibility of individualized S-1 dosing. Overall, our findings suggest that P_Cr is a practical biomarker to guide S-1 dose optimization and highlight the importance of pharmacokinetics-based strategies for patients with cancer and CKD.

He-Wei-Decoction (HWD), a traditional Chinese medicine formula, emphasizes “strengthening the spleen and supplementing qi (Jianpi Yiqi),” and “resolving stasis and detoxifying (Huayu Jiedu).” This formula has been utilized in the treatment of chronic atrophic gastritis (CAG), however, its precise mechanisms of action remain to be elucidated. This study integrates network pharmacology with molecular dockings to identify the underlying mechanisms of HWD in the treatment of CAG. Then, immunohistochemistry assay analyzed the gastric mucosal lesions before and after treatment with HWD in CAG patients. The efficacy and mechanism of key active compounds in the treatment of CAG were validated using a 1-methyl-3-nitro-1-nitrosoguanidine (MNNG)-induced GES-1 cell in vitro model. A total of 165 active compounds from HWD were identified, along with 169 targets associated with CAG. Gene oncology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and Component-Target-Pathway network analysis revealed that the Toll-like receptor (TLRs) signaling pathway may play a role in HWD’s regulation of inflammation in gastric mucosa. Molecular docking identified that luteolin, quercetin, and hederagenin potentially interact with key target proteins TLR4 and nuclear factor-kappaB (NF-κB). Experimental results validated that HWD significantly improved atrophic mucosa and inhibited the expression of TLR4, NF-κB, and cyclooxygenase 2 (COX2) proteins. The active compounds, luteolin, quercetin, and hederagenin, inhibit cell viability, migration and invasion, and reduce the expression of TLR4, NF-κB, and COX2. In summary, luteolin, quercetin, and hederagenin, the primary active components of HWD, can ameliorate the CAG by regulating the TLR4/NF-κB signaling pathway.

We previously reported that CD8⁺ T cell activation via drug-induced altered self-presentation increases the tumor immunogenicity and cancer immunotherapy efficacy. Although the anti-human immunodeficiency virus drug abacavir (ABC) increases the tumor immunogenicity and induces CD8⁺ T cell anti-tumor immune responses in mice inoculated with tumor cells ectopically expressing the human leukocyte antigen (HLA)-B*57:01, whether such anti-tumor immunity is also triggered in hosts with high HLA-B*57:01 expression levels remain unclear. To verify this, we investigated the anti-tumor effects of ABC on HLA-B*57:01-expressing tumor and normal host cells using HLA-B*57:01 transgenic (B*57:01-Tg) mice in this study. ABC suppressed the HLA-B*57:01-expressing B16F10 tumor growth and increased the CD8⁺ T cell tumor infiltration in B*57:01-Tg mice. ABC also activated the tumor-infiltrating CD8⁺ T cells to secrete interferon-γ but did not promote their proliferation in the tumors of B*57:01-Tg mice. Moreover, ABC did not increase the effector CD8⁺ T cell proportions in the tumor-draining lymph nodes of B*57:01-Tg mice. Overall, CD8⁺ T cells preferentially recognized the ABC-induced altered self-antigen-presenting HLA-B*57:01-expressing tumor cells, but not host cells, to elicit anti-tumor immunity.

Resistance to thyroid hormone-β (RTHβ) is caused by mutations in thyroid hormone receptors (TRs), with palpitations, tachycardia, and/or goiter being the most frequently reported clinical features. In recent years, several synthetic thyromimetics have been developed to target mutations associated with RTHβ. Resmetirom, which was granted an accelerated approval by the U.S. Food and Drug Administration, is a TRβ-agonist for the first line therapy for metabolic dysfunction-associated steatohepatitis. This study aimed to evaluate the potential mechanisms of action of resmetirom on RTHβ through co-factors and association with clinical manifestations. We selected cases from 13 clinical records based on recently reported domestic cases in Japan. Based on these clinical reports, we conducted screenings using clinical symptoms, laboratory findings, and mutation data. We attempted to unveil the interaction between 26 RTHβ mutants and resmetirom focusing on recruitment of co-factors. Among the 26 probands, dominant-negative effects (DNE) were identified in 12 mutant TRs (48.5 ± 11.8%). Resmetirom was involved in the recruitment of the co-activators, steroid receptor coactivator-1 and glucocorticoid receptor-interacting protein-1, as well as the co-repressors (CoRs), nuclear-CoR and silencing mediator of retinoic acid and TR. Co-factor recruitment by resmetirom was detected in all mutants. In eight patients with DNE, an association between transcriptional activity and clinical symptoms was observed, which were the reasons for clinical investigation. Notably, in the helix-12 mutant-P453, mild induction of DNE was associated with the recruitment of CoRs, suggesting that resmetirom may be effective in alleviating subjective symptoms in mutants with attenuated DNE located in helix-12.