Journal of Biochemical and Molecular Toxicology最新文献

Niosomal formulations of phytocompounds represent a promising approach in nanomedicine for enhancing anticancer therapeutics. This study investigated the efficacy of a niosomal formulation of cubebin against 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer in a rat model. The cubebin-loaded niosomes were prepared using the thin-film hydration method and characterized for their key physicochemical properties. The formulation demonstrated a mean particle size of 97.6 nm, a zeta potential of −20.1 mV, and achieved a sustained in vitro drug release of 98.89% over 8 h. In vivo assessment in DMBA-induced rats revealed that treatment with the niosomal cubebin suspension significantly attenuated tumor growth. The therapeutic effects were correlated with a modulation of key biochemical parameters. Specifically, the treatment restored levels of oxidative markers, mitigated inflammatory cytokine markers, and normalized hormonal profiles. Histopathological analysis further confirmed the anticancer activity, reducing mammary gland hyperplasia and neoplastic lesions. The collective findings indicate that the niosomal formulation of cubebin possesses significant chemopreventive and antitumor potential against experimental breast cancer.

Rifampicin (RF) is a primary anti-tuberculosis medication utilized in tuberculosis treatment, and its concurrent administration with other medications, as well as the duration of therapy, may result in adverse effects. While the hepatotoxicity of RF is established, its impact on the spleen remains unexamined. Thus, our study aimed to investigate the impact of RF on the spleen and the protective role of Linalool (LN), a monoterpene, through the Heme oxygenase-1 (HO-1) enzyme pathway, with biochemical analyses, oxidative stress parameters, protein levels, and histopathological assessments. In the study, thirty healthy adult male Sprague-Dawley rats were randomly allocated into five groups: control, solvent control (dimethyl sulfoxide - DMSO), RF, LN, and RF + LN. Spleen tissues and blood specimens were collected from the rats for examination. RF markedly elevated total and indirect bilirubin, Fe²⁺, HO-1, and MDA levels, while diminishing GSH levels. Conversely, in the RF + LN group, total and indirect bilirubin, Fe²⁺, HO-1, and MDA levels were dramatically reduced, whereas GSH levels were elevated. Histopathologically, RF-induced defects were ameliorated in the LN-treated cohorts. In conclusion, rifampicin exhibited toxic effects on the spleen, which were mitigated by LN.

Traumatic brain injury (TBI) is a leading cause of death and disability. This study aims to reveal the molecular mechanism of TBI through bioinformatics and explore the neuroprotective role of anisodamine (ANI). Three TBI-related microarray datasets (GSE59645, GSE111452 and GSE58484) were downloaded, and analyzed for obtaining differentially expressed genes (DEGs). The genes in the intersection were analyzed with gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and a protein-protein interaction (PPI) network was constructed. Cytoscape was used to construct pharmacological networks and identify hub genes. Molecular docking was applied to evaluate the ability of an active ingredient to bind to a target, and the binding ability between ANI and HMOX1 were further validated by molecular dynamics simulation and cellular thermal shift assay. Lipopolysaccharide (LPS) induced microglia activation was used to simulate TBI conditions in vitro, and then the effects of ANI were tested. Cell viability was assessed by cell counting Kit 8, levels of inflammatory cytokines and NO were detected by qRT-PCR and Griess reagent, and apoptosis levels were detected by flow cytometry. TBI mouse models were constructed by controlled cortical impact (CCI), and after ANI treatment, the neurological injury was evaluated by mNSS, TTC staining, wet-dry method, HE staining, Nissl staining and TUNEL staining. 248 TBI-related DEGs were identified. These genes were significantly associated with inflammatory response. 6 core genes were further identified, including CCL2, CD44, TIMP1, SERPINE1, HMOX1 and CCNA2. Both scoparone and anisodamine (ANI) had good binding activity with these 6 proteins. In vitro experiments confirmed that ANI inhibited the activation of microglia and reduce neuroinflammation and apoptosis, partly via modulating HMOX1. In vivo experiments validated that ANI could significantly improve neurological function and suppressed neuronal apoptosis in TBI model. ANI exerts neuroprotective function in the secondary injury of TBI, suggesting it is an option to treat TBI, and the treatment time window and safety requires further exploration in the following work.

Natural products with stunning chemical diversity have been extensively researched for their anticancer potential for more than fifty years. This study aimed to determine the effect of indole derivative 1H-indole-2-hydroxy-3-carboxylic acid (IHCA), isolated as a novel alkaloid from Capparis ovata, on selected tumor suppressor, apoptotic, and cell cycle regulatory genes, which are known to be important in cancer pathophysiology, on Caco-2 and LNCaP cells in comparison with Taxol. The molecular mechanism of IHCA's anticancer activity is essentially undefined. Different concentrations of IHCA increased the expression levels of apoptosis-related genes, including BCL-2 and TNF-α. In addition, the tumor suppressor genes PTEN, P53, and RB were increased in LNCaP and Caco-2 cells. KRAS, an oncogenic gene, was significantly downregulated by IHCA in LNCaP cells. Western blot results showed that the protein expression levels of P53 and PTEN in LNCaP cells were increased when treated with IHCA, whereas CDK4 and TNF-α were decreased. Finally, IHCA and doxorubicin significantly increased P53-driven luciferase activity compared to the control. The results strongly suggest that the novel natural compound IHCA has an anticancer effect involving the regulation of the P53 gene and its networks in vitro. The molecular docking and MD simulation analyses reveal that IHCA exhibits superior binding potential to the MDM2 protein compared to Nutlin-3a. MD simulations further confirm that IHCA maintains a more stable and consistent interaction with MDM2, as indicated by lower RMSD values and reduced ligand fluctuation. These results highlight IHCA's potential as a more effective MDM2 inhibitor, suggesting its promise as a lead compound for anticancer drug development.

Clinical Trial Registration: Not applicable.

Impaired osteogenic differentiation serves as a pivotal pathogenic mechanism underlying osteonecrosis of the femoral head (ONFH). This study systematically investigated the pro-osteogenic effects of exosomal miR-4787-3p derived from bone marrow mesenchymal stem cells (BMSCs) in the pathogenesis of ONFH. Bone marrow was collected from both healthy donors and patients with post-traumatic ONFH. BMSC and BMSC-derived exosomes were isolated and characterized. BMSCs were transfected with miR-4787-3p mimic and inhibitor to collect exosomes. These exosomes were used to treat BMSCs stimulated by dexamethasone (DEX). A dual luciferase reporter gene assay was employed to verify the binding of miR-4787-3p and programmed cell death 4 (PDCD4). BMSCs were transfected with PDCD4 shRNA and stimulated by DEX. BMSCs transfected by PDCD4 vectors were stimulated by exosomes and DEX. Cell counting kit-8 assay, Alizarin red staining, and ALP activity detection were performed on BMSCs. Molecular analyses included qRT-PCR and Western blot of osteogenic markers and PDCD4 signaling components. BMSC and BMSC-derived exosomes were successfully isolated. Relative to healthy donors, miR-4787-3p was downregulated in BMSC-derived exosomes from patients with traumatic ONFH. Exosomal miR-4787-3p enhanced BMSCs' viability and osteogenic differentiation, as evidenced by increased mineralization, ALP activity, and upregulation of ALP/OPN/Runx2. PDCD4 was a target of miR-4787-3p. PDCD4 was up-modulated in BMSCs from patients with traumatic ONFH. PDCD4 knockdown enhanced BMSCs' viability, Alizarin red staining, ALP activity, ALP, OPN and Runx2 expression. PDCD4 reversed BMSC-derived exosomal miR-4787-3p promotion on BMSCs' viability, Alizarin red staining, ALP activity, ALP, OPN and Runx2 expression. BMSC-derived exosomal miR-4787-3p promoted BMSCs' osteogenic differentiation through direct targeting of PDCD4. These findings suggest its potential therapeutic application for ONFH by reversing impaired osteogenesis.

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited treatment options and poor prognosis. This study aimed to identify novel prognostic markers within the tumor microenvironment, particularly focusing on lipid-associated macrophages (LAMs). Using single-cell RNA sequencing (scRNA-seq) and transcriptome analysis, LGALS3BP was identified as a key lipid-related macrophage marker with significant prognostic value in TNBC. Our findings demonstrate that LGALS3BP is strongly associated with immune infiltration, particularly in influencing T cells and macrophages, and correlates positively with immune checkpoint expression. Furthermore, high LGALS3BP expression is linked to enhanced sensitivity to chemotherapeutic agents and improved outcomes in immunotherapy. These results highlight LGALS3BP as a potential biomarker for predicting TNBC prognosis and guiding personalized therapeutic strategies.

Beryllium sulfate (BeSO₄) is one of the leading members of beryllium family that can exert toxic effects via disrupting key signaling pathways and redox profile. Coumestrol (CML) is a polyphenolic compound with exceptional biological properties. This pre-clinical investigation was performed to explore the cardioprotective ability of CML against BeSO₄ induced sub-chronic cardiotoxicity. Thirty-six male Sprague Dawley rats were categorized into distinct groups as follows: control, BeSO₄ (12 mg kg⁻¹), BeSO₄ (12 mg kg⁻¹) + CML (5 mg kg⁻¹), and CML (5 mg kg⁻¹) treated group. It was observed that BeSO₄ administration upregulated the expression of cyclooxygenase-2 (COX-2), interleukin-1 receptor-associated kinase1 (IRAK1), toll-like receptor4 (TLR4), myeloid differentiation primary response protein88 (MyD88), nuclear factor-kappa B (NF-κB), tumor necrosis factor receptor-associated factor6 (TRAF6), tumor necrosis factor-alpha (TNF-α), IκB kinase (IKK), and interleukin-1 beta (IL-1β), while suppressing the expression of inhibitor of nuclear factor kappa B alpha (IκBα). The redox profile was altered through a significant reduction in enzymatic activities of HO-1, GPx, CAT, GSR, GST, and SOD, while a sudden escalation in the levels of ROS and MDA after BeSO₄ intoxication. The levels of cardiac injury markers such as ProBNP, CK-MB, CPK, C-reactive protein, troponin-T, LDH, troponin-I and BNP were elevated following the administration of BeSO₄. Besides, BeSO₄ exposure increased the levels of Caspase-9, Bax, and Caspase-3 while reducing the levels of Bcl-2. Cardiac histology showed severe disruptions in BeSO₄ treated rats. Nonetheless, CML therapy alleviated aforementioned disruptions via regulating redox balance, inflammatory and apoptotic profile of cardiac tissues. These findings suggest that CML could be employed in clinical research to validate these findings in humans.

Methylmercury (MeHg) and manganese (Mn) are environmental contaminants widely distributed in the Earth's crust and are associated with neurotoxicity, particularly affecting dopaminergic function. While both metals are known to share common toxicity pathways, such as mitochondrial dysfunction and dopaminergic neurodegeneration, limited research has explored the combined effects of MeHg and Mn exposure. Using Caenorhabditis elegans (C. elegans) as a model, we assessed the effects of acute co-exposure to MeHg and Mn on survival, dopaminergic neuron integrity, behavior analysis and mitochondrial function via high-resolution respirometry. Our results show that co-exposure reduced worm survival and body size and caused dopaminergic neuron disruptions, impaired locomotion, reduced basal slowing response (BSR), and increased swimming-induced paralysis (SWIP). Mitochondrial dysfunction was also evident, with Mn-induced impairment of mitochondrial respiration, while co-exposure led to possible compensatory increases in several mitochondrial activities, including OXPHOS CI and citrate synthase activity. The differential sensitivity of these endpoints to the metal combination underscores the importance of evaluating co-exposure scenarios to capture a more comprehensive view of the potential neurotoxic risks associated with environmental contaminants upon real-life exposure scenarios. These findings highlight the need to assess combined exposures, particularly in environments with complex contamination profiles, as the neurotoxic risks may exceed those observed with individual toxicants.