Chemico-biological interactions最新文献

Sepantronium bromide (YM155) emerged as one of the earliest small molecules designed to selectively suppress survivin (BIRC5), a key regulator of apoptosis and cell-cycle progression in cancer. Over the past two decades, YM155 has provided a unique translational framework to investigate the molecular crosstalk between survivin, cellular stress responses, and therapy resistance that shape cell-death outcomes. This mini-review integrates preclinical and clinical data to delineate how YM155 modulates transcriptional networks, mitochondrial integrity, DNA damage signaling, and autophagy. Particular attention is given to adaptive redox and metabolic programs that limit its efficacy in solid and hematological tumors. The article also revisits the outcomes of early clinical trials, highlighting both the safety profile and the challenges that hindered durable patient responses. Beyond oncology, emerging findings have repositioned YM155 as a probe to interrogate survivin-regulated processes in vascular and immune pathologies. By bridging molecular and clinical evidence, this review contextualizes YM155 within the broader landscape of targeted small molecules, emphasizing its value as a model for developing next-generation survivin modulators and precision-based therapeutic strategies.

Diisocyanates are intermediates required for the production of polyurethane, a foam and coating material with widespread use across many industries. Knowledge regarding the potential health hazards associated with exposure to the two most widely used diisocyanates, 4,4'-Methylene diphenyl diisocyanate (MDI) and toluene diisocyanate (TDI), has evolved since their popularization in the early 20th century. Both compounds have been used in industry for polyurethane manufacturing for many decades. As new studies have been published, it has been shown that MDI has a similar toxicological profile to TDI. This review provides an overview of the general body of literature on the potential health hazards resulting from exposure to diisocyanates, including MDI and TDI, in the occupational environment. This review provides an understanding of what was known, by decade, about the animal and human health effects identified through laboratory and epidemiological studies, and action taken by regulatory agencies to protect workers' health as knowledge on their sensitizing effects evolved over time. The findings of this historical review indicate that the incidence of adverse health effects resulting from diisocyanate exposure has been declining since the 1950s; improved industrial controls and increased efforts by regulatory agencies and stakeholders to protect worker health are responsible for the decline.

Abnormal activity level of human butyrylcholinesterase (BChE) was detected in patients with cardiovascular disease and neurodegenerative disorders, however, the specific role of BChE in the pathology of these diseases are not known yet. Homocysteine thiolactone (HTL) is a toxic thioester metabolite of homocysteine in conditions of hyperhomocysteinemia (HHcy). Experimental evidences suggest that HTL and resultant N-Hcy proteins that disrupt normal protein function, are associated with the pathology of HHcy-related complications such as cardiovascular diseases. Given the abundance of BChE in the blood and its esterase capacity, it is worthy to investigate the hydrolytic ability of BChE and its genetic polymorphism effects towards the endogenous toxic HTL in order to delineate its function in the complex disease network. In this study, human BChE and acetylcholinesterase were examined for their ability in HTL hydrolysis, and BChE demonstrates higher catalytic efficiency than reported serum paraoxonase 1. Furthermore, the catalytic mechanism uncovered by Quantum mechanics/Molecular mechanics molecular dynamics method helps to understand and substantiate the function of BChE in HTL metabolism. Six frequent BChE nonsynonymous coding single nucleotide polymorphisms (SNPs) variants were recombinantly produced and their catalytic activity was assessed. Differential catalytic efficiency toward HTL was observed among these variants, suggesting their distinct metabolic capability in vivo. These findings highlight the potential protection role of BChE against HTL-induced toxicity, and pave a way for future investigation into BChE's contribution in HTL metabolism and the possible correlation between specific BChE SNPs and susceptibility for developing HTL-associated diseases.

Chronic obstructive pulmonary disease (COPD), a smoking-associated chronic inflammatory disorder, involves macrophage-mediated inflammation and cell death, yet the mechanisms linking cigarette smoke (CS) to macrophage ferroptosis remain unclear. Through integrated transcriptomic and metabolomic analyses of CS-exposed macrophages, we identified activation of the ferroptosis pathway accompanied by dysregulated glycerophospholipid metabolism. Notably, phosphatidylcholine species enriched in polyunsaturated fatty acids (PUFA-PC), particularly 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), were markedly elevated. Functional studies revealed that DLPC exacerbated lipid peroxidation and triggered ferroptosis in macrophages. Mechanistically, DLPC downregulated the deubiquitinase ubiquitin-specific peptidase 7 (USP7), which normally stabilizes glutathione peroxidase 4 (GPX4) through TRAF/CAT domain-mediated binding and deubiquitination activity. This suppression accelerated GPX4 ubiquitination and subsequent proteasomal degradation. Furthermore, CS upregulated glycerol-3-phosphate acyltransferase 3 (GPAT3), whose genetic ablation diminished PUFA-PC (including DLPC) synthesis, attenuated lipid reactive oxygen species (ROS) accumulation, and inhibited ferroptosis in CS-stimulated macrophages. In vivo, adeno-associated virus-mediated GPAT3 knockdown in murine lung tissues mitigated ROS production, ferroptosis, and emphysema in an experimental emphysema murine model. Collectively, our findings delineate a CS-GPAT3-DLPC axis that drives macrophage ferroptosis via USP7/GPX4 dysregulation, offering novel mechanistic insights into COPD pathogenesis and identifying DLPC and GPAT3 as potential therapeutic targets.

Tobacco smoking (TS) is an established etiological factor in the development of head and neck squamous cell carcinoma (HNSCC). We previously developed a mouse model using a select tobacco carcinogen, dibenzo[a,l]pyrene (DB[a,l]P, and its ultimate carcinogenic metabolite diol-epoxide (DB[a,l]PDE) to induce oral squamous cell carcinoma (OSCC) in mice; the molecular characteristics and histological changes observed in the mouse oral cavity mimic those found in human HNSCC. In the present study, using our mouse model, we examined for the first time the co-carcinogenic effects of TS with DB[a,l]PDE on DNA damage, histology, molecular targets, and immune cell regulation. We observed a non-significant increase of the levels of DB[a,l]PDE-DNA adduct in the oral cavity of mice exposed to TS as compared to those exposed to compressed air. Histologically, we observed significant increases in epithelial hyperplasia and epithelial single cell necrosis in TS treated mice. TS significantly enhanced protein expression of NF-κB and Ki67 while the enhancement of COX-2 did not reach significance but p53 expression was significantly decreased. We analyzed immune cell regulation in both spleen and tongue (target organ). No significant changes were observed in the spleen; however, in the tongue, we observed a significantly reduced frequency of CD3+T cells that included reductions of both CD4 and CD8 T cells and a corresponding increase was observed for multiple myeloid cell populations. While preliminary, our results offer the foundation for future research using this mouse model to explore the impact of co-carcinogens/tumor promotors other than TS on critical factors involved in the development of HNSCC.

Copper is a toxic heavy metal that causes various damage when it accumulates in the body beyond the physiological threshold. Wilson disease (WD) is an inherited disorder characterized by impaired copper metabolism. Reproductive damage in male patients with WD is gradually attracting attention. However, the underlying mechanisms of copper toxicity are unclear. In this study, we investigated the role of inflammation and PANoptosis in testicular damage and impaired spermatogenesis caused by copper deposition using the WD model toxic milk (TX) mice. Copper chelator-penicillamine and toll-like receptor 4 (TLR4) inhibitor-eritoran were used to intervene in TX mice in our animal experiment methods. Testis samples were collected from mice for further analysis. The results showed that the morphology and ultrastructure of the testis and epididymis in TX mice were damaged, and the sperm counts decreased significantly. The TLR4/nuclear factor kappa-B (NF-κB) signaling pathway was activated by copper deposition, which led to the upregulation of serum and testicular inflammatory factors in TX mice. Meanwhile, pyroptosis, apoptosis, and necroptosis were significant in the testis of TX mice. Both chelated copper or inhibited TLR4 expression markedly suppressed the TLR4/NF-κB signaling pathway, thereby reducing the expression of inflammatory factors. PANoptosis in the testis of TX mice was also reversed. Our study indicated that pathological copper exposure induces inflammation and PANoptosis through the TLR4/NF-κB signaling pathway, leading to toxic testicular damage and impaired spermatogenesis in WD.