Journal of Biochemical and Molecular Toxicology最新文献

Alzheimer's disease (AD) affects millions of people and has limited treatment options, thus making it a global health concern. Amyloid β (Aβ), a disrupted cholinergic system with high acetylcholinesterase (AChE), oxidative stress (OS), reduced antioxidants, and neuroinflammation are key factors influencing AD progression. Prior research has shown that AChE can interact with Aβ and increase its accumulation and neurotoxicity, so targeting AChEs and Aβ could be a potential therapeutic approach for AD treatment. It has been known that nonsteroidal anti-inflammatory drugs (NSAIDs) can inhibit Aβ accumulation. Previously, TKM01, a derivative of 4-anilinoquinazoline, has demonstrated inhibitory effects against GSK-3β—a regulator in AD progression. The current research included molecular docking studies of NSAIDs and TKM01 with Aβ and AChEs as targets. TKM01 exhibited a higher binding affinity with Aβ among all tested compounds. Molecular dynamic (MD) simulations confirmed the stability of the protein-TKM01 complexes. TKM01 also exhibited favorable drug-likeness properties, and no hepatoxicity was visualized in comparison with other compounds. Further, in vitro assay showed an inhibitory action of TKM01 (50–1200 µg/mL) on AChEs. In the in vivo studies on zebrafish larvae brains, we found that TKM01 (120 and 240 µg/mL) reduced the levels of AChEs and lipid peroxidation (LPO) and increased antioxidant superoxide dismutase (SOD) and catalase (CAT) in AlCl₃(80 µM)-induced AD-like model. Additionally, TKM01 treatment was found to decrease pro-inflammatory cytokines TNF-α, IL-1β, and IL-6. The current study demonstrates that TKM01 can be used to treat AD. Nonetheless, experimental validation is needed to reveal the cellular, sub-cellular, and molecular mechanisms and possible implications at a clinical stage.

Glucolipotoxicity (GLT) has emerged as established mechanism in the progression of diabetes. Identifying compounds that mitigate GLT-induced deleterious effect on β-cells are considered important strategy to overcome diabetes. Hence, in the present study, astaxanthin-s-allyl cysteine (AST-SAC) diester was studied against GLT in β-cells. Mus musculus pancreatic β-cell line (βTC-tet) was treated with high glucose (25 mM; HG) and 95 μM palmitate (PA) for 24 h to induce GLT. AST-SAC at various concentrations (5, 10, and 15 μg/ml) were treated to understand the protective effect against HG + PA exposure in β-cells. Under HG + PA exposure conditions oxidative stress, deregulation of mTOR pathway and endoplasmic reticulum (ER) stress are witnessed. AST-SAC treatment eased oxidative stress, mitochondrial depolarization, DNA damage, calcium overload and accumulation of autophagosome against HG + PA exposure conditions thereby protected the cell viability of β-cells. AST-SAC maintained the level of proteins involved in mTOR pathway under HG + PA exposure conditions. Also, AST-SAC treatment has mitigated the increased expression of genes and proteins such as IRE1 and PERK involved in ER stress-mediated unfolded protein response (UPR) signaling pathways. In correspondence to it, the expression of genes involved in insulin secretion was preserved by AST-SAC. Due to these protective effects of AST-SAC the insulin secretion was well-maintained in β-cells under HG + PA exposure conditions. AST-SAC through normalizing antioxidant status and mTOR axis as well as preventing the harmful effect of ER-stress mediated UPR pathway has promoted the β-cell survival and insulin secretion against GLT. Simultaneously targeting oxidative stress/mTOR axis/ER stress is required to efficiently overcome GLT in β-cells.

Paeonol is a principle bioactive compound separated from the root bark of Cortex Moutan and has been shown to confer various biological functions, including antineuroinflammation and neuroprotection. Inflammation, blood–brain barrier (BBB), permeability, and apoptosis are three major underlying mechanisms involved in early brain injury (EBI) postsubarachnoid hemorrhage (SAH). This study aimed to detect the roles and mechanisms of paeonol in EBI following SAH. A SAH model was established by an endovascular perforation method in Sprague-Dawley rats. The localizations of HMGB1 and p65 were identified by immunofluorescence staining. Protein levels were measured by western blot analysis. The serum levels of HMGB1 and the levels of inflammatory cytokines in the brain cortex were evaluated by ELISA. Hematoxylin and eosin staining was conducted to detect neuronal degeneration. Brain water content and Evans blue extravasation were assessed to determine EBI. Neuronal apoptosis was examined by TUNEL. Paeonol deacetylated HMGB1 by upregulating SIRT1 level. SIRT1 inhibition attenuated the protective effects of paeonol against neurological dysfunctions, brain edema, and BBB disruption. SIRT1 inhibition rescued the paeonol-induced inhibition in inflammatory response. The paeonol-induced decrease in neuronal apoptosis was restored by SIRT1 inhibitor. The paeonol-mediated deactivated TLR4/MyD88/NF-κB pathway was activated by SIRT1 inhibitor. Paeonol alleviates the SAH injury in rats by upregulating SIRT1 to inactivate the HMGB1/TLR4/MyD88/NF-κB pathway.

Prostate cancer (PCa) is one of the leading causes of cancer death among men worldwide. Circular RNAs (circRNAs) have been implicated in the pathogenesis of PCa. However, the precise action of circ_0001326 in PCa malignant progression is still unknown. The levels of circ_0001326, miR-577 and voltage dependent anion channel 1 (VDAC1) were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Cell proliferation, colony formation, apoptosis, migration and invasion were evaluated by the Cell Counting Kit-8 (CCK-8), EdU staining, colony formation, flow cytometry, wound-healing and transwell assays, respectively. Targeted relationships among circ_0001326, miR-577 and VDAC1 were confirmed by dual-luciferase reporter assays. Xenograft experiments were performed to detect the role of circ_0001326 in tumor growth. Our data revealed that circ_0001326 was overexpressed in PCa tissues and cells. Circ_0001326 depletion repressed PCa cell proliferation, migration, and invasion and enhanced apoptosis in vitro, as well as hampered tumor growth in vivo. Mechanistically, circ_0001326 directly targeted miR-577, and VDAC1 was directly targeted and suppressed by miR-577. Moreover, the effects of circ_0001326 knockdown on PCa cell functional behaviors were mediated by miR-577. VDAC1 silencing phenocopied miR-577 overexpression in regulating PCa cell functional behaviors in vitro. Furthermore, circ_0001326 regulated VDAC1 expression through sponging miR-577. Our findings showed that circ_0001326 regulated PCa cell functional behaviors at least partly through targeting the miR-577/VDAC1 axis.

Triple-negative breast cancer (TNBC) poses a significant clinical challenge due to its aggressive nature, lack of specific therapeutic targets, and drug resistance. Chemotherapy resistance in TNBC is largely driven by the abnormal activation of epithelial-to-mesenchymal transition (EMT) and the associated cancer stem cell-like characteristics. The combination of multiple chemotherapeutic drugs has shown promise as a treatment approach for TNBC. This study evaluates the efficacy of a novel combination therapy involving the anti-inflammatory drug Budesonide and Salinomycin, which targets cancer stem cells. Co-administration of Budesonide and Salinomycin demonstrated a synergistic effect in inhibiting TNBC cell growth by activating the intrinsic apoptosis pathway. It induced a 2- to 3-fold increase in intracellular reactive oxygen species (ROS) generation and a 25%–30% rise in mitochondrial membrane depolarization. Additionally, extensive signaling studies revealed that the co-treatment specifically targeted multiple signaling nodes, limiting downstream crosstalk. The combination also enhanced autophagic activity by inhibiting the AKT/mTOR pathway and reduced cell migration and stemness by suppressing the EMT process. Therefore, the combination of Budesonide and Salinomycin offers a novel therapeutic approach for TNBC.