Journal of Biochemical and Molecular Toxicology最新文献

Melatonin exhibits various biological functions, including regulation of circadian and endocrine rhythms, anti-inflammatory, and antioxidant effects. Aging and damaged mitochondria are major sources of oxidative stress (OS), and mitochondrial quality control (MQC) is crucial for maintaining normal mitochondrial function. Myocardial ischemia-reperfusion injury is a major complication that can arise during reperfusion therapy for coronary heart disease. However, effective intervention strategies are currently lacking. Mitochondrial dysfunction and OS are considered central mechanisms of myocardial reperfusion injury, with mitochondrial-targeted interventions being a potential treatment direction. Recent studies have shown that melatonin improves mitochondrial structure and function through multiple pathways. This review discusses the mechanisms by which melatonin ameliorates myocardial ischemia-reperfusion injury, focusing on MQC, and explores its potential applications in the prevention and treatment of myocardial ischemia-reperfusion injury.

Posterior capsular opacification (PCO) is the most common complication after cataract surgery characterized by hyperproliferation, migration and epithelial-mesenchymal transition (EMT) in residual lens epithelial cells (LECs). Curcumin is a polyphenol compound possessing diverse pharmacological properties. Here, we investigated the functions and its potential mechanisms of curcumin in PCO using transforming growth factor beta2 (TGF-β2)-treated LECs. Cell phenotypes were analyzed using MTT, 5-thynyl-2′-deoxyuridine (EdU), transwell, and scratch assays, respectively. Levels of FGF7 (Fibroblast Growth Factor 7), ZEB1 (Zinc finger E-box binding homeobox 1), and EMT-related proteins were detected by qRT-PCR and western blot analysis. The protein interaction between FGF7 and ZEB1 was validated using Co-immunoprecipitation assay. Curcumin treatment weakened TGF-β2-induced proliferation, migration, invasion and EMT progression in LECs. The expression of FGF7 was boosted by curcumin in LECs. Functionally, FGF7 deficiency suppressed TGF-β2-induced proliferation, migration, invasion and EMT progression in LECs, and could reverse the suppressing action of curcumin on TGF-β2-induced LEC dysfunction. Mechanistically, FGF7 directly interacted with ZEB1, and curcumin could regulate ZEB1 expression via FGF7. Moreover, ZEB1 overexpression could abolish the protective effects of curcumin or FGF7 deficiency on LECs under TGF-β2 stimulation. In conclusion, curcumin protected LECs against TGF-β2-induced enhancement on the proliferation, migration, invasion and EMT process by regulating FGF7/ZEB1 axis, suggesting a new insight into the application of curcumin in PCO therapy.

Cyclophosphamide (CYP) is an effective chemotherapeutic and immunosuppressive agent; however, its clinical application is limited by a variety of toxic side effects. Mitochondrial dysfunction has been associated with the pathogenesis of chemotherapy-induced cardiotoxicity. This work aimed to evaluate the possible protective effect of galangin (Gal) on CYP-induced cardiotoxicity, pointing to its ability to promote mitochondrial biogenesis. Thirty two male rats were allocated equally into four groups: control; Gal-treated; CYP-treated; and Gal + CYP-treated groups. Markers of cardiac injury, oxidative/antioxidant status, inflammation, apoptosis, and mitochondrial function were assessed in addition to histopathological and electrocardiographic (ECG) evaluation. The current results revealed that Gal treatment significantly attenuated the cardiac injury and retrieved the alterations in cardiac histopathology and ECG changes. Also, it restored redox balance, as evidenced by the alleviation of malondialdehyde (MDA) levels and increased glutathione peroxidase (GPx) activity. Gal activated the sirtuin (SIRT) 1/nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated signaling pathway, as indicated by upregulation of SIRT1, Nrf2, SIRT3, and mitochondrial transcription factor (TFAM), in addition to increased levels of superoxide dismutase 2 (SOD)2 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), together with increased activity of citrate synthase (CS), pointing to improved mitochondrial function. It ameliorated the inflammation and apoptosis-associated markers supported by biochemical and immunostaining data. Our study provided novel insights elucidating the mitigative potential of against CYP-induced cardiac oxidative damage, inflammation, apoptosis, and mitochondrial dysfunction by upregulating the SIRT1/Nrf2/SIRT3/PGC-1α/TFAM survival pathway.

Radiotherapy is a cornerstone of lung cancer management, though its efficacy is frequently undermined by intrinsic and acquired radioresistance. This review examines the complexity of lung tumors, highlighting their potential as a reservoir of novel targets for radiosensitization. Ionizing radiation (IR) primarily exerts its effects through oxidative damage and DNA double-strand breaks (DSBs). Lung cancer cells, however, develop mutations that enhance DNA damage response (DDR) and suppress cell death pathways. Additionally, interactions between tumor cells and tumor microenvironment (TME) components—including immune cells, stromal cells, and molecular mediators such as cytokines, chemokines, and growth factors—contribute to resistance against IR. Understanding these intricate relationships reveals potential targets to improve radiotherapy outcomes. Promising targets include DDR pathways, immunosuppressive cells and molecules, hypoxia, proangiogenic mediators, and other key signaling pathways. This review discusses emerging strategies, such as combining radiotherapy with immunomodulators, hypoxia and proangiogenic inhibitors, DDR-targeting agents, and other innovative approaches. By offering a comprehensive analysis of the lung TME, this review underscores opportunities to enhance radiotherapy effectiveness through targeted radiosensitization strategies.

Doxorubicin is a crucial chemotherapy used in the treatment of triple-negative breast cancer (TNBC) patients, but elevated doxorubicin doses may induce therapeutic resistance. To overcome this limitation, we have previously established a photodynamic therapeutic (PDT)-like strategy that irradiates doxorubicin-treated cells with a low-power nonionizing blue LED device. This combined treatment increases the production of reactive oxygen species to promote cell death, consequently enabling reduced doxorubicin dosages. Yet, precisely determining the molecular mechanisms that drive this outcome is still required for advancing such PDT-like approach. Here, we aimed to correlate the expression of the inflammatory markers NF-κB, IL-8, IL-6, and IL-1β with the survival of TNBC cells submitted to our PDT-like protocol. Our results show that NF-κB/p65 nuclear levels were enhanced in MDA-MB-231 cells treated with doxorubicin and blue LED. Moreover, this PDT-like strategy increased IL-6 mRNA levels in MDA-MB-231 cells. IL-1β and IL-8 mRNA were upregulated in samples incubated with doxorubicin regardless of concomitant irradiation with blue LED. These results show that our PDT-like protocol is effective in elevating inflammatory signals, shedding light on the molecular mechanisms that underlie the efficacy of this innovative anticancer therapeutic approach.

Carbon tetrachloride (CCl₄), a volatile organic compound, is harmful to multi-organs, including the liver, lungs, muscles, and kidneys. Methyl donors, such as methionine, choline, betaine, and folic acid, are vital to one-carbon metabolism and have great potential to alleviate oxidative stress and inflammation, thus mitigating disease onset. Hence, the current study aims to examine the therapeutic effect of methyl donors against CCl₄-induced nephrotoxicity. Nephrotoxicity was developed in male Sprague Dawley rats using CCl₄ at a dose of 1 mL/kg (4-week model induction) twice a week via the intraperitoneal route. Thereafter, methyl donor treatments through oral gavage were given for the next 6 weeks with a continuation of CCl₄ administration. Biochemical, oxidative stress parameters, histopathological, and qRT-PCR analyses were done at the completion of the 10-week. Biochemical analyses revealed that CCl₄ induces nephrotoxicity, as evidenced by increased urea and creatinine levels and decreased albumin levels. These detrimental effects were significantly ameliorated by methyl donor treatment. Moreover, CCl₄ decreased the antioxidant enzyme activity (superoxide dismutase; SOD and catalase; CAT) while increasing oxidative stress markers (malondialdehyde; MDA and nitrite). Methyl donor treatment effectively mitigated these oxidative changes. Histopathological analysis demonstrated the nephroprotective effect of methyl donors against CCl₄-induced nephrotoxicity, showing reduced tissue damage and protection of renal architecture. At the molecular level, methyl donor treatment alleviated the CCl₄-induced increase in kidney injury biomarkers (Kidney injury molecule 1; KIM-1 and Neutrophil gelatinase-associated lipocalin; NGAL), as well as inflammatory (IL-6 and TNF-α) and fibrosis-related genes (Acta-2 and TGF-β). In conclusion, our findings suggest that methyl donors possess anti-inflammatory and anti-fibrotic properties. They protect against CCl₄-induced oxidative damage to renal cells, likely due to their reactive oxygen species scavenging capabilities and their ability to restore key early renal injury biomarkers (KIM-1 and NGAL). Methyl donors hold great promise as a cutting-edge therapy approach for preventing CCl₄-induced nephrotoxicity.

Dysregulation of m6A modification has emerged as a vital factor in the development of esophageal squamous cell carcinoma (ESCC). Here, we sought to explore the critical role of m6A methylation mediated by the m6A methyltransferase METTL3 in ESCC. Protein expression analysis was performed by immunohistochemistry and immunoblot assays. The mRNA levels of METTL3 and IFI27 were detected by quantitative PCR. Cell sphere formation potential, migration, invasiveness, apoptosis, proliferation and viability were assessed by standard sphere formation, wound healing, transwell, flow cytometry, EdU and CCK-8 assays, respectively. The impact of METTL3 or IGF2BP2 on IFI27 mRNA was evaluated by methylated RNA immunoprecipitation (MeRIP), RIP or mRNA stability analysis. Xenograft assays were used to detect the in vivo function of METTL3. Elevated levels of METTL3 were observed in ESCC tumors and cells, and these increased levels were associated with the declined prognosis of ESCC. MELLT3 depletion impeded ESCC cell growth, invasiveness, migration, and sphere formation, and induced cell apoptosis in vitro. Elevated IFI27 expression was positively correlated with METTL3 levels in ESCC. Moreover, METTL3 mediated m6A methylation of IFI27 mRNA to stabilize the mRNA. The m6A reader IGF2BP2 also affected m6A methylation and expression of IFI27 mRNA. Additionally, IFI27 re-expression had a counteracting impact on the effects of METTL3 deficiency on in vitro ESCC cell behaviors and in vivo KYSE30 xenograft growth. Our findings demonstrate that METTL3-mediated IFI27 mRNA m6A methylation drives ESCC development through an IGF2BP2-dependent mechanism. Blocking the METTL3/IFI27 axis may be effective for preventing ESCC.

Pesticide exposure can cause many skin diseases such as hypopigmentation and contact dermatitis, but the underlying mechanisms remain unclear. Furthermore, Organophosphate pesticides (OPs) including Diazinon (DZN) can affect cellular pathways like ATPase, leading to mitochondrial energy deficit and even apoptosis in the cell's functions. Following cell exposure to the OP pesticide DZN through treatment, we evaluated alteration in gene expression and DNA damage. Bioinformatic analysis was performed based on the AutoDock, Protein Data Bank, STRING, Way2Drug, and Comparative Toxicogenomics databases and tools. The MTT assay, wound healing, DAPI staining, flow cytometry, and real-time PCR were applied in the current study. The results showed that the viability and migration capacity of HFFF2 cells decreased, and the apoptosis rate increased in the DZN-treated group. These findings revealed that DZN regulated the expression of the apoptotic genes in DZN cells.

This study focused on the role of the microRNA (miR)-373-3p/LATS2 axis in the prognosis and metastasis of thyroid cancer patients. miR-373-3p and LATS2 expression were assessed in thyroid cancer tissues and cells. The relationship between miR-373-3p and clinicopathological characteristics of patients with thyroid cancer and the impact of miR-373-3p and LATS2 expression levels on the survival and prognosis of thyroid cancer patients were analyzed. The targeting relationship between miR-373-3p and LATS2 was predicted and verified, and their impact on the malignant cell phenotype was assessed. Compared with adjacent normal tissues and normal human thyroid cells, miR-373-3p was highly expressed, while LATS2 was expressed at low levels in thyroid cancer tissues and cells (both p < 0.001). miR-373-3p expression was independent of age (p = 0.201) and gender (p = 0.516), and it was correlated with lymph node metastasis and TNM stage of thyroid cancer (both p < 0.001). Moreover, high miR-373-3p expression was associated with poor patient prognosis (p = 0.034). Interference with miR-373-3p or overexpression of LATS2 repressed KMH-2 cell malignant phenotypes (all p < 0.05). miR-373-3p targeted and suppressed LATS2 expression. Interference with miR-373-3p blocked its inhibition on LATS2, thereby repressing thyroid cancer progression and metastasis.