Journal of Biochemical and Molecular Toxicology最新文献

Our earlier study demonstrated that metabolic disorders increase the expression of Syndecan-3 (Sdc-3), a heparan sulfate proteoglycan (HSPG) in erythrocytes, contributing to adhesion through the glycosaminoglycan chain. Reactive oxygen species (ROS) could be one of the factors for increased expression. This study aimed to determine whether quercetin, a bioactive antioxidant commonly found in food, could modulate Sdc-3 expression. Male Wistar rats were made dyslipidemic and diabetic, after which they were treated with quercetin at doses of 50 and 100 mg/kg body weight for a duration of 2 months. Sdc-3 expression in erythrocytes was assessed by Western blot, and erythrocyte adhesion to fibronectin was evaluated in-vitro. The quercetin-supplemented diet reduced circulating lipids, blood glucose, and MDA levels, mitigated changes in Sdc-3 expression, and decreased erythrocyte adhesion to fibronectin. These effects may be attributed to quercetin′s antioxidant properties, as was seen by the positive correlation between MDA levels and Sdc-3 expression. Sdc-3 levels in erythrocytes could serve as a prognostic marker for assessing the impact of dietary compounds on complications linked to metabolic disorders.

Parkinson's disease (PD) is an idiopathic and age-related neurodegenerative disorder, marked by the selective loss of dopaminergic neurons in the SNpc and the formation of α-synuclein aggregates. Consequently, this leads to motor and non-motor complications in PD-like patients. Research on plant-based secondary metabolites, such as polyphenols, confirmed that they may slow the development and progression of PD. Flavonoids generated the peak of interest due to their medicinal properties, including mitigation of the risk of PD. Quercetin, a subclass of flavonol type of flavonoids, attracted attention as a potential neuroprotective agent. Quercetin has been demonstrated to have anti-oxidant, anti-inflammatory, anti-apoptotic, and neuroprotective properties, along with obstruction of α-synuclein accumulation and mitochondrial protection. Moreover, studies also revealed that quercetin ameliorates the striatal dopamine content and distinctly modulates the various signalling pathways, including PI3K/AKT, Nrf2, MAPK and NF-kB that are involved in the disruption of disease. Further, quercetin modulates oxidative stress through upregulation of anti-oxidant enzymes, inhibits neuroinflammation via suppression of pro-inflammatory cytokines, prevents Lewy bodies formation and regulates autophagy along with apoptosis. By exhibiting the aforementioned effects, quercetin protects against the neuronal toxicity induced by various neurotoxins through multiple mechanisms to improve motor and non-motor functions. This highlights quercetin as a potential multifaceted therapeutic candidate for PD intervention. We searched for the published data on quercetin related to PD and summarized them in the current review. This review aims to address the understanding of mechanisms, therapeutic effects of quercetin and various models using neurotoxins to induce PD. This review aims to elucidate the underlying cellular and molecular mechanisms and therapeutic effects of quercetin, as well as to explore the various neurotoxin-induced models of PD used to investigate its efficacy. The major part of this review article discusses the roles of quercetin in the management of PD in animals of several experimental models used by many research studies. Overall, quercetin represents a promising, safe, effective and potentially neuroprotective candidate for disease disease-modifying strategy to combat neurological disorders such as PD.

This study investigates the protective effects of galangin (GAL) against doxorubicin (Dox)-induced hepatorenal toxicity in a rat model, focusing on oxidative stress, inflammation, and key markers, including interleukin-6 (IL-6), 8-hydroxydeoxyguanosine (8-OHdG), and aquaporin-1 (AQP-1). Male Sprague-Dawley rats were divided into four groups: Control, Dox, Dox+GAL 50 mg/kg, and Dox+GAL 100 mg/kg. GAL significantly attenuated Dox-induced damage by reducing IL-6 and 8-OHdG levels, restoring AQP-1 expression, and improving histopathological profiles. Biochemical analysis demonstrated GAL's antioxidant activity, evidenced by elevated levels of glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT), alongside decreased levels of malondialdehyde (MDA). These findings suggest GAL as a potential therapeutic agent for mitigating Dox-induced organ toxicity, with broader implications for conditions involving oxidative stress and inflammation.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Accumulating evidence suggests that dysregulation of cystatin SA (CST2) plays a pivotal role in tumor progression. However, the underlying mechanisms and clinical significance of CST2 in NSCLC remain unexplored, highlighting the need for a comprehensive investigation to identify potential therapeutic targets. The study recruited 69 NSCLC patients and purchased NSCLC cell lines including A549, PC-9, and H1299 as well as human bronchial epithelial cells (16HBE) for the study. The mRNA levels of CST2 and transcription factor AP-2 alpha (TFAP2A) were quantified using quantitative reverse transcription polymerase chain reaction, while their protein expression was assessed by western blotting or immunohistochemistry assay. Cell proliferation, apoptosis, migration, and invasion were analyzed using the 5-Ethynyl-2'-deoxyuridine assay, flow cytometry, wound-healing assay, transwell migration and invasion assays, respectively. Reactive oxygen species (ROS) levels and Fe²⁺ concentrations were measured by flow cytometry and colorimetric assay, respectively. The chromatin immunoprecipitation (ChIP)assay and dual-luciferase reporter assay were employed to elucidate the relationship between TFAP2A and CST2. A xenograft mouse model assay was conducted to evaluate the effects of TFAP2A and CST2 on the malignant progression of H1299 and A549 cells. The results showed that CST2 expression was found to be upregulated in NSCLC tissues and cells. CST2 promoted the proliferation, migration and invasion of H1299 and A549 cells, while inhibiting apoptosis, oxidative stress, and ferroptosis. TFAP2A transcriptionally activated CST2 in both H1299 and A549 cells, leading to the promotion in tumor progression in vitro. Similarly, TFAP2A enhanced the malignant progression of NSCLC cells in vivo by upregulating CST2 expression. Therefore, TFAP2A transcriptionally activated CST2, contributing to the malignant progression of NSCLC. These findings underscored the potential clinical significance of targeting the TFAP2A/CST2 axis as a novel therapeutic strategy for the treatment of NSCLC.

Di-(2-ethylhexyl) phthalate (DEHP), a pervasive environmental plasticizer, is detected in humans through dietary intake, inhalation, and dermal contact. Epidemiological evidence links urinary DEHP metabolites (e.g., MEHHP and MEOHP) to cardiovascular dysfunction, including reduced heart rate variability and endothelial impairment, which are key risk factors for myocardial infarction (MI). However, the cell-type-specific molecular mechanisms underlying DEHP-aggravated MI pathogenesis in specific cell types remain poorly characterized. This study aims to identify and validate DEHP-specific molecular mechanisms in immune cells that link exposure to MI pathogenesis through integrated machine learning (ML), single-cell RNA sequencing (scRNA-seq), and molecular docking (MD) approaches. Transcriptomic data sets (GSE66360, GSE60993, GSE61144, GSE48060, and GSE141512) were integrated to screen for MI-related genes via weighted gene co-expression network analysis (WGCNA) and a combined differential expression analysis. Simultaneously, DEHP targets were predicted using ChEMBL, PharmMapper, and SwissTargetPrediction. Shared DEHP-MI targets were then identified via intersection analysis and prioritized via an ensemble of 11 ML algorithms. Subsequently, immune cell infiltration was profiled via CIBERSORT, and scRNA-seq data (GSE269269) spatially validated cell-type-specific expression patterns of core genes. Finally, DEHP-target binding stability was evaluated by MD simulations. Intersection analysis identified 56 DEHP-MI targets that are shared and implicated in innate immune activation and chemotaxis. Six core genes (SLC2A3, MMP9, AKR1C3, DAPK2, MAP3K8, and TRIB1) were prioritized as diagnostic biomarkers (AUC = 0.981), with SHAP indicating SLC2A3 and MMP9 as primary drivers of MI prediction. These genes correlated with pro-inflammatory neutrophil/M0 macrophage infiltration (*r* = 0.585–0.772), while suppressing adaptive immune cells. scRNA-seq revealed cell-type-specific pathogenic mechanisms: MMP9 and SLC2A3 were localized to inflammation-primed CD14⁺ monocytes, and AKR1C3 was enriched in cytotoxic NK cells. MD confirmed high-affinity DEHP binding to all core targets (ΔG < −5.0 kcal/mol), structurally supporting their role as disruptors. DEHP exacerbates MI by directly binding to SLC2A3 and MMP9. This activates a pro-inflammatory immune dysregulation potential through cell-type-specific pathogenic mechanisms. Monocyte-enriched SLC2A3/MMP9 drives neutrophil recruitment and M0 macrophage polarization (*r* = 0.585–0.772), while NK cell-localized AKR1C3 disrupts cytotoxic regulation. This study deciphers DEHP cardiotoxicity via spatially resolved inflammatory-immune networks and provides novel therapeutic targets for environmental cardiovascular intervention.

Nephrotoxicity refers to the damage caused to the kidneys by drugs and toxic substances, leading to acute and chronic kidney injury. Ferroptosis is a type of iron-driven cell death where oxidative stress causes lipid peroxide accumulation in cells, which is critical in the nephrotoxicity pathogenesis. Several studies have investigated the protective effects of natural compounds against nephrotoxicity, including curcumin, quercetin, and baicalein. This review highlights that natural compounds reduce ferroptosis in nephrotoxicity by enhancing protective pathways such as GPX4, Nrf2/GPX4, and SIRT1/p53, while suppressing harmful pathways including Hippo, HIF-2α/DUOX1/GPX4, ERK1/2, ALOX12, and ferritinophagy. Notably, ferroptosis mechanisms and pathway involvement may differ depending on the nephrotoxic agent; for example, cisplatin-induced injury prominently involves NCOA4-mediated ferritinophagy and iron dyshomeostasis, while adriamycin may activate distinct oxidative stress and lipid peroxidation pathways. Thus, natural compounds may target specific ferroptotic pathways depending on the nephrotoxicity model. Overall, natural compounds offer promising therapeutic strategies for kidney protection against nephrotoxic agents by mitigating ferroptosis.

Capmatinib and tepotinib are selective MET inhibitors for MET exon 14 skipping non-small cell lung cancer (NSCLC), yet comprehensive real-world safety profiles, particularly concerning respiratory and rare adverse events (AEs), remain limited. We conducted a disproportionality analysis of the FDA AE Reporting System (FAERS) database, utilizing four algorithms (ROR, PRR, BCPNN, MGPS) to identify AE signals from 1771 cases for capmatinib and 470 for tepotinib, standardized with MedDRA v26.0. Both inhibitors shared signals for systemic AEs, such as peripheral oedema and gastrointestinal disorders. However, their respiratory AE profiles diverged: capmatinib was associated with pleural effusion and pulmonary oedema, whereas tepotinib was linked to infectious complications, including interstitial lung disease and infectious pleural effusion. Importantly, we identified significant novel signals beyond current drug labels: sensory disturbances, and thrombosis for capmatinib; and fluid imbalance-related events for tepotinib. These distinct AE profiles highlight an infection-driven pulmonary risk for tepotinib requiring close monitoring, while capmatinib's association with sensory disorders warrants specific patient management considerations. Our findings underscore the need for individualized safety monitoring based on the unique AE profiles of each MET inhibitor.

Osteoarthritis (OA) is a chronic disorder involving pain and functional disturbance due to its impact on joint tissues. This study investigated the mechanism of the DEAD-box helicase 3 X-linked (DDX3X)/NOD-like receptor protein 3 (NLRP3)/gasdermin D (GSDMD) pathway in pyroptosis and inflammatory responses in OA chondrocytes. Mouse chondrocyte ATDC5 cells were cultured in vitro and induced for chondrogenic differentiation, followed by H₂O₂ treatment to simulate OA. Cells were transfected for 24 h with siRNA-DDX3X, pcDNA3.1-NLRP3, pcDNA3.1-GSDMD, and corresponding negative controls. Cell viability was evaluated by CCK-8. Reactive oxygen species (ROS), interleukin (IL)−6, tumor necrosis factor-α (TNF-α), IL-1β, and IL-18 levels in the supernatant, DDX3X, GSDMD, and NLRP3 mRNA and protein levels, and pyroptosis-related protein (Collagen II, Aggrecan, Cleave-Caspase-1, full-length GSDMD [GSDMD-FL], GSDMD-N-terminal domain [GSDMD-NT], apoptosis-associated spot-like protein [ASC]) levels were assessed by ELISA, RT-qPCR, and western blot. The NLRP3-DDX3X interaction was predicted and validated by the STRING database and Co-IP assay. H₂O₂-treated ATDC5 showed decreased cell viability, and Collagen II and Aggrecan levels, increased GSDMD-FL cleavage, supernatant ROS, IL-6, TNF-α, IL-1β, and IL-18 levels, DDX3X mRNA and protein expression, Cleave-Caspase-1, GSDMD-NT, NLRP3, and ASC levels, and an enhanced NLRP3-DDX3X interaction. However, DDX3X knockdown partially reversed the above phenomenon in H₂O₂-treated ATDC5, indicating that suppressing the DDX3X/GSDMD axis attenuated OA chondrocyte pyroptosis and inflammatory response in vitro. NLRP3 or GSDMD overexpression partly counteracted DDX3X knockdown-improved OA chondrocyte pyroptosis and inflammation. Inhibiting the DDX3X/NLRP3/GSDMD axis alleviated chondrocyte pyroptosis and inflammatory response in OA in vitro, thus ameliorating chondrocyte injury.

Delphinidin, a bioactive anthocyanidin found in pigmented fruits and vegetables, exhibits remarkable therapeutic potential due to its antioxidant, anti-inflammatory, and anti-cancer properties. This review synthesizes current knowledge on delphinidin's structure, dietary sources, stability challenges, and mechanisms of action. As a potent antioxidant, it scavenges reactive oxygen species (ROS) and upregulates endogenous defenses via the Nrf2 pathway, mitigating oxidative stress in chronic diseases. Delphinidin suppresses inflammation by inhibiting NF-κB and MAPK signaling, reducing pro-inflammatory cytokines like TNF-α and IL-6. Its anti-cancer effects include apoptosis induction, cell cycle arrest, and inhibition of angiogenesis and metastasis through modulation of VEGF, MMPs, and PI3K/Akt pathways. Additionally, delphinidin demonstrates cardioprotective effects by enhancing endothelial function and reducing LDL oxidation, while its neuroprotective actions involve attenuating neuroinflammation and amyloid-β aggregation in neurodegenerative disorders. The compound also improves metabolic health by enhancing insulin sensitivity and inhibiting α-glucosidase. However, delphinidin's pH and thermal instability limit its clinical application, prompting research into encapsulation and nano-delivery systems to enhance bioavailability. This review underscores delphinidin's promise as a nutraceutical or adjunctive therapy while highlighting the need for further studies to validate its efficacy in humans and optimize delivery methods.