Journal of Biochemical and Molecular Toxicology最新文献

With the large range of applications for plastic products, the potential hazards of polystyrene microplastics (PS-MPs) as a hazardous substance have been widely concerned. Mesenchymal stem cells (MSCs) are important cells in the body with high self-renewal ability, multidirectional differentiation potential and low immunogenicity. Growth hormone (GH) has important biological regulatory effects on MSCs. However, the toxicological effects of PS-MPs on the role of GH in hMSCs are unclear yet. In this work, we explored the effects of PS-MPs on the biological activity of GH in hMSCs. Initially, we conducted experiments to investigate the cellular behavior of GH in hMSCs. It is noteworthy that poststimulation with PS-MPs, there was a significant reduction in the quantity of GH entering the cytoplasm, with almost negligible distribution observed in the cell nucleus. Consequently, we proceeded to examine the GH/GHR-mediated signaling pathways. The data revealed that poststimulation with PS-MPs, the downstream signaling pathways, including JAK2-STATs1/3/5, were significantly downregulated. To elucidate this intriguing finding, we delved further into the molecular mechanisms underlying the desensitization of GH/GHR signaling induced by PS-MPs. Experimental data demonstrated that the entry of PS-MPs into the cells resulted in a significant increase in intracellular reactive oxygen species (ROS), leading to cellular senescence. In summary, PS-MPs may induce desensitization of GH signaling in hMSCs through the ROS-induced cellular senescence. This study provides crucial insights into the biological effects of PS-MPs on the GH bioactivity in hMSCs.

Sepsis induces severe multiorgan dysfunction, with the lungs being particularly susceptible to damage. This study reveals that Hmox1 inhibitors effectively activate the FSP1/CoQ10/NADPH pathway, significantly enhancing autophagic activity while suppressing ferroptosis in alveolar epithelial cells, thereby alleviating lung injury in septic mice. To identify key gene modules and regulatory factors associated with sepsis-induced lung injury, we analyzed public transcriptomic data, including bulk RNA-seq datasets (GSE236391 and GSE263867) and a single-cell RNA-seq (scRNA-seq) data set (GSE207651). In vitro experiments were conducted using an LPS-induced alveolar epithelial cell injury model to evaluate the effects of Hmox1 inhibitors on cell viability, autophagy markers (LC3-II/LC3-I and p62), ROS levels, and intracellular iron content. Transmission electron microscopy was used to observe mitochondrial structural changes. In vivo, a cecal ligation and puncture (CLP)-induced sepsis mouse model was established to assess the therapeutic effects of Hmox1 inhibitors. This included evaluating survival rates, lung histopathological scores, lung wet-to-dry weight ratios, myeloperoxidase (MPO) activity, inflammatory cytokine levels, and changes in autophagy and ferroptosis markers. The results demonstrated that Hmox1 inhibitors effectively mitigate lung injury by modulating the autophagy-ferroptosis pathway, highlighting their potential as a therapeutic strategy for sepsis-induced lung damage.

Ulcerative colitis is a chronic inflammatory disease characterized by oxidative stress and the production of pro-inflammatory cytokines. Ferulic acid and quinic acid, two phenolic compounds, are thought to have potent antioxidant and anti-inflammatory properties. This study aimed to investigate the anti-inflammatory and antioxidant effects of ferulic acid and quinic acid in rats with acetic acid (AA)-induced ulcerative colitis. To this end, 64 Wistar rats were randomly divided into eight groups, each consisting of eight rats. AA was administered intrarectally to induce ulcerative colitis. Ferulic acid (20, 40, and 60 mg/kg), quinic acid (10, 30, 60, and 100 mg/kg), and dexamethasone (2 mg/kg) were received daily for five consecutive days. Then, the macroscopic and histopathological changes in the colon tissue were examined. Finally, the tissue levels of heme oxygenase 1 (HO1), nuclear factor erythroid 2-related factor 2 (NRF2), and NAD(P)H quinone dehydrogenase 1 (NQO1) mRNA expression and pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) were measured using the quantitative real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) methods, respectively. AA-induced ulcerative colitis in rats was associated with edema and severe damage to the epithelium, infiltration of inflammatory cells, and the presence of ulcers in the colon tissue. The results showed that rats who were administered AA showed a decrease in the expression of HO-1, Nrf2, and NQO1 and increased protein levels of TNF-α and IL-1β than the control group. Rats were administered ferulic acid, quinic acid and, dexamethasone significantly improved histopathological indices. The expression of HO-1, Nrf2, and NQO1 were upregulated by 60 mg/kg of ferulic acid, 60 and100 mg/kg of quinic acid and, 2 mg/kg of dexamethasone treatment compared to the ulcerative colitis group. The protein levels of TNF-α and IL-1β dose-dependently decreased by ferulic acid and quinic acid treatment compared to the ulcerative colitis group. Ferulic acid and quinic acid effectively reduce inflammation and mucosal damage in rats with ulcerative colitis, especially when administered in high doses. The possible mechanism of anti-inflammatory response by ferulic acid and quinic acid may involve the activating of the Nrf2/HO-1 pathway.

Selenium (Se) is an essential trace element with well-documented health benefits, including antioxidative, anti-inflammatory, antiapoptotic, and anticarcinogenic properties. Selenium nanoparticles (nano-Se) represent an advanced Se delivery system characterized by superior bioavailability and a reduced risk of Se-related toxicity. This study investigates the protective efficacy of nano-Se against cadmium chloride (CdCl₂)-induced infertility in adult male Wistar rats. The experimental design involved random allocation of the rats into nine groups: a healthy control group, a vehicle control group, three groups receiving nano-Se alone at 0.05, 0.1, and 0.2 mg/kg b.w./day, a group exposed to CdCl₂ to induce infertility, and three CdCl₂-exposed groups treated with nano-Se. After 30 days of treatment, the animals were euthanized for biochemical and histopathological assessments. The findings revealed that nano-Se administration ameliorated the detrimental effects of treatment CdCl₂ on serum testosterone levels. Additionally, nano-Se significantly reduced malondialdehyde levels and enhanced the activity of antioxidant enzymes in testicular homogenates. Histological analyses further demonstrated that nano-Se preserved the structural integrity of testicular tissue in the CdCl₂-induced fertility model. Nano-Se modulated apoptotic pathways, as evidenced by the suppression of Bax expression and upregulation of Bcl₂ expression in testicular tissue. Furthermore, nano-Se mitigated the overexpression of aquaporin-9 in CdCl₂-exposed rats. Collectively, these results provide robust biochemical, histological, and biochemical evidence supporting the potential therapeutic utility of nano-Se in mitigating testicular dysfunction.

Exosomes are critical mediators of intercellular crosstalk and play significant roles in the progression of various diseases including acute lung injury (ALI). However, the specific role of exosomes in ALI remains largely unexplored. In investigation, we demonstrated that exosomes released from cigarette smoke extract (CSE)-exposed bronchial epithelial cells (BEAS-2B) facilitated M1 macrophage polarization. Notably, CSE exposure enhanced the production of miR-107 within these exosomes. Inhibition of miR-107 markedly reversed the M1 macrophage polarization and inflammatory responses in vitro and ameliorated lung injury in vivo. Furthermore, exosomal miR-107 was found to downregulate KLF4, thereby promoting M1 macrophage polarization and inflammation of macrophages. Collectively, these findings demonstrate that CSE-exposed BEAS-2B cells could induce M1 macrophage polarization via transmitting exosomal miR-107, and eventually ultimately contributing to the progression of ALI, indicating a potential therapeutic strategy for ALI.

Silicosis is a worldwide occupational disease characterized by irreversible pulmonary fibrosis. Recent studies have showed that microRNAs (miRNAs) may play a crucial role in silicosis progression by modulating fibrosis-related gene express. In this study, we selected miR-207 as our research subject because we found that miR-207 can be match with Smad3 using bioinformatic techniques, which might silence the key fibrosis-related TGF-β1/Smad3 signal pathway. In this study, the mice were given silica suspension (20 µg/µL, 80 µL) via nostril once a day for 16 days to establish silicosis models, and then were transfected with miR-207 mimic or inhibitor. The mice which were given phosphate-buffered saline (PBS) (80 µL) via nostril were used as control. All mice were killed on Day 45 after the first exposure to dust, after which their lungs were removed for pathological observation and to measure the hydroxyproline content. Then, real-time polymerase chain reaction and Western blot analysis were applied to detect the relative expression levels of TGF-β1/Smad3 signaling pathway indicators (TGF-β1, TGF-βR, and Smad3), and myofibroblast transformation indicators (α-SMA and Fn). Results showed that the lung pathological images of silicosis model group mice showed significant fibrosis, and TGF-β1, TGF-βR, Smad3, α-SMA, and Fn were all highly upregulated compared with the control group mice. Intervention with miR-207 mimics significantly inhibited pulmonary fibrosis in silicosis mice by downregulation of TGF-β1/Smad3 and inhibiting of myofibroblast formation. Whereas these phenomena were not observed in silicosis mice treated with miR-207 inhibitor. The results demonstrated that miR-207 can block the progression of SiO₂-induced pulmonary fibrosis by targeting the TGF-β/Smad3 signaling pathway.

The study aimed to investigate the neuroprotective effects of fenofibrate (FENO), a triglyceride-lowering drug, in rats with cerebral ischemia. An ischemic cerebral edema model was established in rats, and an oxygen–glucose deprivation/reoxygenation (OGD/R) model was created in astrocytes. Neurological deficits were quantified using a standardized deficit score. Protein expression levels were assessed through immunohistochemical staining, western blot analysis, and enzyme-linked immunosorbent assays (ELISA). Gene expression was determined using real-time polymerase chain reaction (RT-PCR), while luciferase activity was measured using a commercially available kit. We found that FENO significantly reduced infarct volume and neurological deficits in rats subjected to middle cerebral artery occlusion (MCAO). Additionally, FENO inhibited increased brain water content and upregulated the expression of aquaporin-4 (AQP4), a protein associated with cerebral edema, in the ischemic hemisphere. Furthermore, FENO suppressed the inflammatory response in cortical tissue by reducing the expression of cytokines such as interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-α). It also increased the expression of myeloperoxidase (MPO) and promoted activation of astrocytes by increasing glial fibrillary acidic protein (GFAP). In vitro experiments further demonstrated that FENO reduced the expression of AQP4 against OGD/R in primary rat astrocytes. FENO also inhibited the activation of p38 by reducing its phosphorylation. Correspondingly, FENO suppressed the activation of activator protein 1 (AP-1) by reducing the levels of c-Jun and c-Fos, as well as the luciferase activity of AP-1. These effects were enhanced by the p38 specific inhibitor SB203580. Notably, the presence of the AP-1 specific inhibitor T5224 further promoted the effects of FENO in suppressing the expression of AQP4, implicating that the inhibitory effects of FENO on AQP4 expression are mediated by the p38/AP-1 signaling pathway. These findings suggest that FENO may have potential therapeutic benefits in stroke by targeting the p38/AP-1 signaling pathway and reducing AQP4 expression, thereby alleviating cerebral edema and inflammation.

This systematic review and meta-analysis aimed to evaluate and summarize the therapeutic effects of naringin on various kidney diseases, based on preclinical research. A comprehensive literature search was performed using electronic databases such as PubMed/Medline and Google Scholar, concentrating on the impact of naringin in different experimental animal models of kidney disease. After applying the inclusion and exclusion criteria, 27 studies were chosen for analysis. The meta-analysis revealed that naringin treatment significantly improved body weight gain and markers of kidney function, as evidenced by decreased serum urea, creatinine, and blood urea nitrogen (BUN) levels. Additionally, naringin treatment normalized antioxidant parameters, restored enzymes like superoxide dismutase and catalase, and alleviated oxidative stress markers, comprising myeloperoxidase and reactive oxygen species. Besides, naringin also alleviated inflammation as indicated by reduced levels of markers such as NF-κB, IL-6, KIM-1, COX-2, and TNF-α. Furthermore, it regulated apoptosis by decreasing the Bax, caspase-3, and p53 levels while increasing Bcl-2. In summary, the meta-analysis demonstrated that naringin significantly mitigates nephrotoxicity induced by oxidative stress, chemotherapy, drugs, and chemicals. This nephroprotective effect is mediated through a combination of several mechanisms, including antioxidant, anti-inflammatory, and anti-apoptotic pathways. These cellular and molecular improvements were associated with enhanced kidney structure, function, and overall physiology following naringin treatment. Overall, this systematic review and meta-analysis provide strong scientific evidence supporting the therapeutic potential of naringin in managing kidney diseases.

Nuclear factor of activated T-cells 5 (NFAT5) is recognized as an oncogene in a variety of tumors. However, the role of NFAT5 in cervical cancer (CC) cell phenotypic alterations remains to be elucidated. Here, we demonstrated that NFAT5 expression was elevated in CC samples and cells using quantitative real-time reverse transcription PCR, Western blot analysis, and immunohistochemistry assays, and high NFAT5 expression showed a poor prognosis. After C-33A cells were transfected with pcDNA-NFAT5 or NFAT5-short hairpin RNA (shRNA), cell proliferation, invasion, and apoptosis were evaluated using CCK-8 and EdU assays, transwell assays, and flow cytometry, respectively. Biomarkers indicating mitochondrial function, including the expression of the d-loop, ATP levels, and mitochondrial membrane potential, were detected. NFAT5 knockdown restrained cell proliferation and invasion, impaired mitochondrial function, and increased the ratio of cell apoptosis; however, NFAT5 overexpression showed the opposite results. RNA immunoprecipitation (RIP) and methylated RIP (MeRIP) assays were performed to identify interactions among NFAT5, methyltransferase-like 3 (METTL3), and insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3). Chromatin immunoprecipitation and dual-luciferase reporter gene assays demonstrated that NFAT5 binds to the peroxiredoxin 1 (PRDX1) promoter to drive PRDX1 transcription. METTL3 enhanced NFAT5 mRNA stability through IGF2BP3-mediated N6-Methyladenosine (m⁶A) modification, and NFAT5 transcriptionally regulated PRDX1 expression. Moreover, the reintroduction of METTL3 or PRDX1 promoted cell growth and mitochondrial function damage in NFAT5-silenced cells. In vivo experiments further demonstrated that NFAT5 promotes CC tumor growth. Taken together, NFAT5 upregulation mediated by the METTL3/IGF2BP3 complex in an m⁶A-dependent manner facilitates CC cell growth by transcriptionally regulating PRDX1 expression, providing a novel target for CC therapy.