Journal of Biochemical and Molecular Toxicology最新文献

Subarachnoid hemorrhage (SAH) is a specific type of stroke. Dihydroquercetin (DHQ), a flavonoid, is known for its various pharmacological properties. This study aimed to explore the roles and mechanisms of DHQ in influencing the progression of SAH. A rat SAH model was established using the endovascular perforation technique. Following SAH induction, DHQ was administered orally 1 h later. Assessments included SAH scores, neurological function, brain swelling, blood-brain barrier (BBB) integrity, neuronal damage, apoptosis levels, inflammation, and indicators of ferroptosis using various treatments. The HT22 cells were exposed to hemin to simulate SAH-like conditions under in vitro settings. Cell counting kit-8 assays, flow cytometry, enzyme?linked immunosorbent assay, BODIPY 581/591 C11 staining, western blot analysis, and biochemical kits were employed to evaluate the potential effects of DHQ. Moreover, the mechanisms responsible for the protective effect of DHQ were examined by western blot analysis. The in vivo findings revealed that DHQ mitigated neurological impairments, brain swelling, BBB disruption, and neuronal injury at 24 h post-SAH. DHQ also reduced neuronal degeneration, inflammation, and ferroptosis following SAH. The in vitro findings revealed that DHQ enhanced cell survival and reduced ferroptosis at 24 h following hemin exposure. Mechanistically, DHQ activated phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling in SAH rats and hemin-treated HT22 cells to exert neuroprotective effects. In conclusion, this study reveals that DHQ can effectively decrease BBB permeability, brain edema, neurological dysfunctions, and ferroptosis post-SAH by activating the PI3K/AKT/Nrf2/HO-1 pathway.

Metastasis is a major cause of poor prognosis of pancreatic cancer. Exosomes (Exos) regulate cancer progression by modulating macrophage polarization. This study aimed to investigate the effects of cancer-associated fibroblast (CAF)-released Exos on macrophage polarization in pancreatic cancer and the molecular mechanisms. THP-1 cells or xenografted tumor mice were treated with Exos from CAFs, and macrophage polarization was analyzed using quantitative real-time PCR (qPCR) and flow cytometry. THP-1 cells were cocultured with BXPC-3 cells, and metastasis was analyzed using Transwell assay and scratch test. Exosomal PTGS2 was detected using qPCR, and the NOD1 pathway was evaluated using western blot analysis. The results showed that Exos promoted M2-type polarization and inhibited M1-type polarization, and then facilitated pancreatic cancer cell migration, invasion, and epithelial-mesenchymal transition. PTGS2 expression was increased in Exo-treated macrophages, and its knockdown in CAFs facilitated M2 to M1 macrophage polarization. Moreover, Exos promoted the NOD1 pathway via PTGS2, and inhibition of NOD1 reversed the polarization caused by Exos. Additionally, NOD1 was required in M1/M2 polarization in vivo mediated by Exos. In conclusion, CAF-secreted Exos facilitated M2 macrophage polarization by carrying PTGS2 to activate the NOD1 pathway, thereby promoting pancreatic cancer metastasis, providing evidence that CAF-Exos accelerating pancreatic cancer progression.

This study investigates the metabolic disruptions caused by nicotine (NIC) exposure, with a particular focus on amino acid and lipid metabolism, and evaluates resveratrol (RSV) as a potential protective agent. Mice were divided into four groups: control (CON), NIC-exposed, NIC + RSV-treated, and RSV-only. NIC exposure resulted in significant weight loss, elevated glucose levels, altered lipid profiles, and organ damage, particularly in the liver and kidneys. Increased inflammation was evidenced by elevated levels of IL-6 and CRP. In contrast, RSV treatment mitigated these effects by improving lipid profiles, glycemic indices, and reducing inflammatory markers. Histopathological analysis confirmed reduced tissue damage in the NIC + RSV group compared to the NIC-alone group. Metabolomics analysis using LC-MS/MS revealed significant dysregulation in lipid, amino acid, and nucleotide metabolism in NIC-exposed mice. Fold-change analysis identified altered metabolites, including sphingomyelin 36:1;02 (p < 0.001), valine (p < 0.001), triacylglycerol 4:0–18:1 (p < 0.001), and ceramide 32:1;02 (p < 0.001). Amino acids such as arginine, phenylalanine, glutamic acid, tyrosine, and lysine, as well as NIC metabolites like nornicotine and cotinine, were identified, underscoring molecular fragmentation analysis findings. RSV treatment partially restored metabolic balance, highlighting its role as a metabolic modulator. This study underscores the therapeutic potential of RSV in alleviating NIC-induced metabolic dysfunctions by restoring lipid homeostasis and reducing inflammation. Additionally, it emphasizes the importance of RSV in addressing NIC-related metabolic impairments and the need for noninvasive biomarkers for early disease detection.

The eye is considered to be an immune-privileged region. However, several parts of the eye have distinct mechanisms for delivering immune cells to the injury sites or even in response to aging. Although these immune responses are intended to be protective, the visual acuity can be compromised by the release of pro-inflammatory cytokines by immune cells, which induce chronic inflammation and fibrosis. Age-related eye diseases (AREDs) are the primary cause of vision impairment (VI) in the elderly, with a poor comprehension of their pathophysiology. Age-related eye diseases affect both the anterior and posterior segments, resulting in diminished quality of life and risk of irreversible blindness. Immune system dysregulation and the upregulation of pro-inflammatory cytokines have been linked to AREDs, underscoring the need to comprehend inflammation's impact on ocular disorders to enhance patient symptom management. In this framework, the PubMed database was searched using the medical subject headings (MeSH) terms “Age-related eye diseases,” “dry eye syndrome,” “glaucoma,” “cataract,” “diabetic retinopathy,” “inflammation,” “interleukin,” and “cytokine” with the aim of overview the role of cytokines in AREDs and discuss their potential therapeutic approaches.

Enhanced glycolysis and elevated lactic acid (LA) production are observed during sudden death syndrome (SDS) in broilers. However, the mechanism underlying LA-induced cardiomyocyte damage and heart failure in fast-growing broilers remains unclear. In this study, chicken embryo cardiomyocytes (CECs) were cultured and treated with LA to investigate LA-induced CEC injury and its mechanism, aiming to develop strategies to prevent LA-induced SDS in broilers. Results showed that LA inhibited CEC proliferation and contraction whereas inducing apoptosis. Furthermore, LA disrupted mitochondrial ultrastructure, reduced mitochondrial membrane potential, activated mitophagy, and disturbed mitochondrial dynamics. Treatment with Mdivi-1, a selective Drp1 inhibitor, improved CEC viability, restored mitochondrial network integrity, reduced reactive oxygen species production, and inhibited LA-induced apoptosis. These findings suggest that LA-induced cardiomyocyte injury during SDS in broilers is associated with mitochondrial damage and increased mitochondrial fission. The inhibition of mitochondrial hyperfission by Mdivi-1 effectively preserves CEC morphology, structure, and function, playing a critical role in preventing LA-induced damage. This study provides a foundation for strategies to prevent and control SDS in broilers.

Colon cancer is one of the most common cancer-related deaths. Drug resistance is one of the biggest challenges in cancer treatment. Numerous pharmacological and biochemical investigations have documented the benzimidazole ring's anticancer, anti-inflammatory, and antioxidant properties. Within the scope of our project, the effect of newly synthesized benzimidazolium salt (BS) on cell proliferation was tested with MTT assay, and its effect on apoptosis and cell cycle was tested with annexin V and PI in the two different colon cancer cell lines (HT-29 and DLD-1). Our study examined the expressions of some genes related to apoptosis and, additionally, caspase activities with the multicaspase kit.

BS showed an antiproliferative effect at lower doses in HT-29 colon cancer cells. When HT-29 cells were exposed to a 20 µM dosage, they showed increased caspase activity and apoptosis compared to DLD-1 cells. HT-29 accumulated in the G2/M phase of the cell cycle, whereas DLD-1 cells accumulated more in the S phase. In HT-29 cells, colony formation was inhibited; however, in DLD-1 cells, this effect was insufficient.

Based on the apoptosis-death pathway, BS is expected to have anti-cancer effects. As a result of this work, this chemical was thoroughly examined in two different colon cancer cell lines, and additional, more comprehensive initiatives are being planned in light of the information obtained from this study.

Thymoquinone (TQ) has shown antitumorigenic effects in breast cancer; however, its detailed impact on cell signaling mechanisms requires further investigation. This study aims to elucidate the molecular mechanisms behind TQ's antiproliferative effects in breast cancer by analyzing proteome-level changes. MCF-7 cells were treated with 15 µM TQ, the inhibitory concentration (IC50), for 48 h. Proteins from treated and untreated (control) groups were isolated and subjected to liquid chromatography–tandem mass spectrometry (LC–MS/MS) proteomic analysis. Identified proteins were functionally annotated, with hub proteins identified using Cytoscape software, and verification conducted through Western blot analysis. Label-free quantitation identified 629 master proteins, with 104 upregulated and 477 downregulated in TQ-treated samples compared to controls. Among these, 150 proteins showed dramatic regulation, including 11 upregulated and 139 downregulated proteins, with ribosomal proteins emerging as central. The heatmap demonstrated robust clustering of replicates. Functional annotations indicated that TQ significantly impacts crucial mechanisms such as carbon metabolism, amino acid biosynthesis, protein synthesis, and the citrate cycle, essential for metabolic reprogramming. This study identifies novel molecular targets associated with metabolic reprogramming, previously underexplored in TQ's effects, highlighting their pivotal role in TQ's anticancer mechanisms in breast cancer. These findings could lay the groundwork for developing future TQ-based therapies.

Wilms tumor 1-associated protein (WTAP) has been validated to be a crucial regulator in the tumorigenesis and advancement of diverse malignancies. This study intended to probe the impacts of WTAP on colorectal cancer (CRC) progression from the perspective of N6-methyladenosine (m6A) modification. The differential expression patterns of WTAP in clinical CRC samples and cultured cell lines were validated via qRT-PCR and western blot. Cell function tests were conducted with colony formation, transwell, and CCK-8. MeRIP-qPCR was conducted to identify the WTAP-mediated SOD2 (Superoxide dismutase 2) mRNA modification in CRC cells. Animal experiments were adopted to evaluate the function of WTAP in vivo. WTAP exhibited high expression pattern in CRC samples along with cells. Silencing of WTAP potently restrained the growth of CRC tumorigenesis in virto and in vivo. Mechanically, SOD2 was identified as an m6A target of WTAP. WTAP-mediated m6A modification of SOD2 mRNA elevated its stability in an IGF2BP3-dependent manner. Meanwhile, SOD2 overexpression could reverse the tumor suppressive effect induced by WTAP silencing. Molecular therapy targeting WTAP-SOD2 may offer novel insights and perspectives for the treatment of CRC.

To investigate the role and mechanism of triptophenolide (TRI) in resisting rheumatoid arthritis (RA). Network pharmacology analysis results suggested that TRI was related to multiple inflammation-related signaling proteins, and possessed the stable structural configuration. In animal experiments, TRI suppressed RA in mice, inhibited tissue inflammation, and improved synovial injury. Moreover, TRI can suppress RA via multiple signaling pathways, and inhibiting pyroptosis is one of the feasible treatments for improving RA.