Journal of Biochemical and Molecular Toxicology最新文献

Statins retards intracellular biosynthesis of cholesterol by inhibiting HMG-CoA reductase, increases low density lipoprotein (LDL) receptor (LDLR) expression and enhances LDL clearance rate through LDLRs. This reduces atherosclerotic tenor within the blood vessels showing the beneficial effect of statin drugs. On the other hand, incessant import into cell cytoplasm promotes chances to saturate cholesterol in organ or organelle(s). This organ or organelle is presumed to be inclined to unprecedented pathological abnormalities like upset of cell cycle regulation in cell nucleus, cholesterol storage disorder in lysosome and mitochondria, and diabetic onset in pancreas. While within the blood vessel the action of statin is therapy friendly by reducing cholesterol level; statin may also be accountable in casting intracellular morbidities by creating an environment of non-stop cholesterol entry. The spectrum of these harmful side effects by different types of statins (lipophilic/hydrophilic) are still remained unexplored offering an open area for future therapeutic interests.

Chrysin (CHR), 5,7-dihydroxyflavone, is a natural flavonoid found in many plant extracts possessing multiple medicinal effects, including anti-inflammatory and antioxidant properties. The aim of this study was to verify the protective role of CHR on testicular and hepatic injury induced by cadmium (Cd). Adult male Sprague Dawley rats were given CdCl₂ (3 mg/kg, ip) for 5 days and CHR effect was evaluated using two doses (75 and 150 mg/kg/orally). Administration of CHR showed ameliorative effects against both testicular and hepatic injury. It increased sperm quality and testosterone levels, in addition to the improvement of the integrity of blood-testes barrier by decreasing Cathepsin-D and increasing the regenerated potentials of SDF-1. Moreover, administration of CHR significantly increased SOD activity and GSH contents as well as decreased lipid peroxidation (MDA) and attenuated NOx and MPO levels in both hepatic and testicular tissues. In addition, CHR significantly mitigated Cd-induced increase in pro-inflammatory transcriptional factor NF-κB, the inflammasome pathway NLRP3/IL-1β, ER stress (IRE-1) and caspase-3 apoptotic marker in both liver and testes. In conclusion, the results of this study specify that testicular and liver damage related to Cd toxicity could be improved by CHR administration.

The anticancer activity of a series of newly synthesized pyrrole derivatives was systematically evaluated in HeLa cervical cancer cells, focusing on their potential as tyrosine kinase inhibitors and modulators of the mTOR signaling pathway. This study builds on our previous synthetic work by investigating the biological effects of seven structurally characterized compounds (d1-d7). Among them, compounds d1 and d3 exhibited the most potent cytotoxicity, with IC₅₀ values of 140.6 μM and 366.4 μM, respectively, after 48 h of treatment. Both compounds significantly impaired cell cycle progression-d1 induced S-phase arrest, while d3 caused G1-phase arrest-and markedly suppressed cell migration in wound healing assays. Mechanistically, these effects were accompanied by reduced phosphorylation of p70S6K (Thr389, Ser421/424) and increased p-4EBP1, indicating inhibition of mTORC1 signaling. These findings suggest that d1 and d3 are promising lead compounds with dual antiproliferative and anti-migratory activity in cervical cancer, mediated through modulation of the PI3K/Akt/mTOR axis.

Although the effect of thymoquinone (TQ), the biologically active component of black cumin seeds, has been investigated in many types of cancer, its effects on molecular pathways of cancer cells further need to be elucidated. This study aimed to investigate the effects of TQ on genotoxicity, oxidative stress, apoptosis, and inflammatory pathways in SW620 cells treated with irinotecan (IR), celecoxib (Clx), individually or both. DNA damage, oxidative stress/inflammatory response, cell cycle, apoptosis, and expression of carcinogenesis-related genes were determined using the Comet assay, ELISA assay, flow cytometry, and RT-PCR techniques, respectively. TQ (8 µM) combination with IR (8 µM) + Clx (4 µM) significantly increased cytotoxicity and genotoxicity of IR with/without Clx, while decreasing oxidative stress and inflammatory responses. TQ upregulated p21 and Bax, while downregulating Bcl-2 and Bcl-XL, increasing Bax/Bcl-2 ratio, which indicates an induction of apoptotic pathways. TQ also increased the percentage of cells in G2/M phase and decreased those in G0/G1 phase, thereby affecting cell cycle checkpoints in IR-treated cells with or without Clx. In conclusion, this study shows that the combination of TQ with IR, Clx, or both exerts significant effects on SW620 colon cancer cells, such that by enhancing DNA damage, TQ may induce G2/M cell cycle arrest and apoptosis, while reducing inflammatory responses, oxidative stress, and G0/G1 cell cycle arrest. These in vitro findings indicate that TQ may enhance the chemotherapeutic effects of IR and act as a potential adjuvant therapy; however, further in vivo studies are required to verify its suggested effects.

Endothelial dysfunction is a fundamental pathological process in atherosclerosis (AS), a leading cause of cardiovascular disease worldwide. The present study aimed to explore lncRNA ZEB2-AS1's expression, diagnostic value in AS, and its function on proliferation, inflammation, and potential mechanism in AS-related endothelial dysfunction. ZEB2-AS1 was detected in the specimens of 120 patients with AS and 115 control subjects, and the findings were validated using the GSE120521 dataset. An in vitro model of AS was established by inducing HUVECs with ox-LDL. In this model, ZEB2-AS1 expression was silenced. Assessment of cell viability was carried out with a CCK-8 kit. The secretion profiles of key inflammatory factors (TNF-α, IL-6, IL-1β), along with the chemokine MCP-1 and adhesion molecules (VCAM-1, ICAM-1), were analyzed by ELISA. Potential target miRNAs were predicted through LncRNASNP2 and miEAA databases, and miR-149-5p was verified using rescue experiments. Upregulation of ZEB2-AS1 was observed in the blood and tissues of individuals with AS, consistent with the data on unstable plaques from GSE120521. ZEB2-AS1 knockdown intensified the viability inhibition triggered by ox-LDL and decreased the secretion of inflammatory factors and adhesion molecules. miR-149-5p, a target molecule of ZEB2-AS1, exerted a reversing influence on these alterations. In conclusion, ZEB2-AS1 upregulation in AS promotes ox-LDL-induced endothelial dysfunction via miR-149-5p, acting as a potential AS biomarker/therapeutic target.

Brain aging is a multifactorial process driven by oxidative stress, chronic inflammation, and cellular senescence, culminating in neurodegeneration and cognitive decline. In this study, we established a robust aging model by synergistically combining d-galactose and acute gamma-irradiation (6 Gy), intensified senescence-associated phenotypes in rat brain tissue. Rats were divided into four groups: Group I: negative control; group II (naringin-treated): rats were given naringin (50 mg/kg; p.o.) for 1 week; group III (Rad+ D-galactose): rats were exposed to whole-body gamma radiation (6 Gy) and then received D-galactose (300 mg/kg b. wt. i.p.) for 7 days; group IV (Rad+ D-galactose+ naringin): as in group III, then naringin (50 mg/kg b. wt. p.o.) for 1 week. This model exhibited elevated levels in IL-6, TNF-α, p16^INK4A, p21^CIP1 and retinoblastoma protein (Rb) levels, as well as upregulated NF-κBp65 protein expression in brain tissue. Remarkably, naringin supplementation reversed the pathological signatures, restoring antioxidant balance, suppressing inflammatory mediators, and modulating apoptotic pathways. Histological hallmarks such as gliosis, neurophagia, and pyknosis, as well as immunohistological staining of caspase-3 and p53 expression, confirmed the aforementioned consequences. Collectively, these findings highlight naringin's therapeutic potential in mitigating brain aging by targeting oxidative stress, inflammation, and apoptosis. This study offers a robust experimental framework for investigating senescence and supports naringin as a promising candidate for intervention in age-related neurodegenerative disorders.

The ubiquitin-proteasome system (UPS) is the primary mechanism for intracellular protein degradation, crucial in oncogenesis and tumor progression. Proteasome inhibitors disrupt UPS-mediated proteolysis, effectively inhibiting neoplastic cell proliferation, and have become established therapeutic targets in oncology. Gynecologic malignant tumors pose a significant threat to women's reproductive health globally. Among proteasome inhibitors, MG132 has garnered extensive attention in gynecologic oncology due to its multifaceted mechanisms, including cell cycle regulation, NF-κB signaling inhibition, and modulation of p53 activity. This review consolidates recent research on the therapeutic potential of MG132 in gynecologic malignant tumors, with a focus on its molecular mechanisms of action.

In this work, advanced zinc oxide and graphene oxide-based nanocomposites were successfully synthesized, characterized, and studied for their antimicrobial capabilities for biomedical applications. Zinc nitrate hexahydrate and hexamethylenetetramine were used in a hydrothermal process at 90°C to synthesize the nanocomposites. Transmission electron microscopy confirmed ZnO nanoparticles dispersion on the GO sheets, indicating strong interfacial interactions, while X-ray diffraction analyzed the crystalline nature of the nanocomposite. The presence of functional groups was confirmed by Fourier-transform infrared spectroscopy. The thermal studies were carried out by differential scanning calorimetry, and antimicrobial tests revealed strong antifungal efficacy against Aspergillus niger and antibacterial activity against Escherichia coli and Staphylococcus aureus. The enhanced antimicrobial performance is due to the combined effects of GO and ZnO-induced reactive oxygen species generation. Thus, the results highlight the successful synthesis of ZnO-GO nanocomposites and a promising multifunctional antimicrobial material suitable for biomedical applications such as wound healing and protective coatings.

Phthalates are well-known emerging contaminants in the environment and food packaging, posing serious risks to human health as endocrine disruptors with significant neurotoxic potential. Epidemiological and experimental evidence have linked early-life phthalate exposure to neurodevelopmental disorders, including attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). However, the precise molecular mechanisms responsible for these associations remain poorly understood. This study aimed to comprehensively investigate the putative toxic targets and molecular pathways underlying phthalate-induced ADHD and ASD through integrated network toxicology and molecular docking approaches. Targets related to phthalates, ADHD, and ASD were extracted from various databases, yielding 21 potential targets associated with ADHD and ASD, which are common to the studied phthalates. Network analysis highlighted BDNF and ESR1 as the top two core targets. Functional enrichment analyses demonstrated that the core targets are involved in multiple pathways. Furthermore, the GEO database was queried to identify differentially expressed genes (DEGs) and gene modules through Weighted Gene Co-expression Network Analysis (WGCNA) using the R package. Moreover, molecular docking demonstrated high binding affinity between phthalates and core targets, with di(2-ethylhexyl) phthalate with BDNF and diisononyl phthalate with ESR1, emphasizing the potential role of phthalate exposure in neurodevelopmental disorders. The stability of these complexes was demonstrated through molecular dynamics simulations, which confirmed their binding interactions remained constant throughout the simulation. Our findings contribute to a deeper understanding of the intricate molecular mechanisms of phthalate-induced neurotoxicity, offering a valuable foundation for the development of future therapeutic strategies to mitigate their adverse effects on neurodevelopment.

Cardiovascular diseases are a threat to human health and are associated with increased mortality. Gallic acid (GA) (3,4,5-trihydroxybenzoic acid) is a naturally occurring polyphenolic compound with cardiovascular preventive properties. However, the precise mechanism underlying its cardioprotective effect is not fully understood. The Notch signaling system is essential in heart injury/repair mechanisms, and clarifying this mechanism in a Lipopolysaccharide (LPS) stimulated zebrafish embryo larvae (ZFEL) model for cardioprotective function. This study aimed to elucidate the cardioprotective activity of GA in LPS stimulated ZFEL via Notch signaling pathway. In this study, an in vivo cardiac injury model was developed in ZFEL using LPS induction. The GA cardioprotective property was investigated by LC_50, survival analysis, morphological assessment, heart rate assessment, cell death, and nitric oxide determination. Expression of Notch signaling and the cardiac biomarker protein were done by immunoblotting and in addition whole mount immunohistochemistry was performed for NICD, MMP 9, and MMP 13. GA protects LPS-induced ZFEL by increasing survival rates, normalizing morphological anomalies, restoring abnormal heart rate, preventing cell death, and inhibiting NO generation. It suppressed the Notch signaling pathway (Notch1, Delta1, Hey1, and Hes1) and cardiac biomarker proteins (MPO, MMP-9, MMP-13, and NO) in LPS-stimulated ZFEL, indicating cardioprotective property. Our findings showed that GA suppressed both molecular and cellular events during LPS-induced heart damage via the Notch signaling pathway.