Journal of Biochemical and Molecular Toxicology最新文献

Lung adenocarcinoma (LUAD) is a common type of lung cancer with complicated pathological mechanism. Transcription Factor AP-2 Alpha (TFAP2A) and Cysteine protease inhibitor 1 (CST1) are upregulated genes in LUAD samples, accordingly, we focused on clarifying the role of TFAP2A/CST1 axis in LUAD. Expression analysis was performed using real-time quantitative polymerase chain reaction and western blot. Cellular behaviors were detected by colony formation assay, EdU assay, wound healing assay and flow cytometry. Ferroptosis was assessed by oxidative indicators, Fe²⁺ level and related proteins. TFAP2A and CST1 interaction was analyzed via ChIP assay and dual-luciferase reporter assay. TFAP2A function in vivo was evaluated by xenograft tumor assay. CST1 was overexpressed in LUAD samples and cells. Downregulation of CST1 inhibited proliferation, migration but it promoted apoptosis and ferroptosis of LUAD cells. TFAP2A interacted with the promoter of CST1 to up-regulate CST1 expression. TFAP2A regulated the malignant behaviors and ferroptosis of LUAD cells by targeting CST1. TFAP2A affected LUAD tumor growth via mediating CST1. All these data proved that TFAP2A/CST1 axis contributed to proliferation, migration while it suppressed apoptosis and ferroptosis in LUAD.

Colorectal cancer (CRC) is the third most prevalent cancer worldwide. While chemotherapy remains the standard treatment approach, natural products have emerged as a promising alternative. Among these, apigenin, a natural flavonoid, has garnered significant attention due to its pro-oxidant and antioxidant properties in various types of cancer. This study aimed to assess the potential impact of apigenin in CRC treatment by targeting mitochondrial SIRT3, HMGB1, and beclin 1-mediated autophagy in a mouse model of CRC. We administered 20 mg/kg of dimethyl hydrazine (DMH) intraperitoneally once weekly for 20 weeks to induce CRC in C57BL/6 mice. After 6 weeks of initiating the study, apigenin was intragastrically co-administered by oral gavage at 25 and 50 mg/kg until the end of week 20. The results revealed significant weight loss, shortening of the colon, and diarrhea in DMH-induced CRC, which are considered the marks of CRC. In addition, histopathological examination revealed dysplastic changes in the DMH-treated group, while no dysplasia was found in the apigenin-treated CRC groups. Importantly, the administration of apigenin to DMH-treated animals has led to a significant reduction of SIRT3 and MnSOD expression levels with a significant increase in LC3-II at either dose and a significant dose-dependent increase in the levels of MDA, c-JNK, HMGB1, and beclin 1 compared to the DMH-treated group. In conclusion, apigenin may have a promising role in suppressing DMH-induced CRC. It elicits a pro-oxidant activity by suppressing the gene expression of SIRT3 and subsequently, its target MnSOD, resulting in increased reactive oxygen species (ROS) and lipid peroxidation. The released ROS, in turn, activates JNK-mediated autophagy by enhancing HMGB1, beclin 1, and LC3-II protein levels.

Although gemcitabine (GEM) is the cornerstone of the treatment of pancreatic cancer (PC), GEM resistance frequently arises. Circular RNA (circRNA) circ_0075829 is highly expressed in PC. However, whether circ_0075829 contributes to GEM resistance of PC is largely unknown. To generate GEM-resistant PC cells (BxPC-3/GR and SW1990/GR), we exposed GEM-sensitive PC cells to GEM. Circ_0075829, microRNA (miR)-326, and glutamic-oxaloacetic transaminase 1 (GOT1) were quantified by a qRT-PCR or western blot method. Cell survival and viability were gauged by MTS assay. Cell proliferation, apoptosis, invasion, and migration were assessed by EdU, flow cytometry, transwell, and wound-healing assays, respectively. Dual-luciferase reporter assays were used to verify the relationship between miR-326 and circ_0075829 or GOT1. Mouse xenografts were performed to evaluate the role of circ_0075829 in vivo. Our data showed that circ_0075829 was upregulated in GEM-resistant PC tissues and cells. Knockdown of circ_0075829 impeded the proliferation, invasion, migration, and glutamine metabolism, and promoted cell apoptosis and GEM sensitivity of GEM-resistant PC cells. Moreover, circ_0075829 silencing suppressed the tumorigenicity of SW1990/GR cells and sensitized them to the cytotoxic effect of GME in vivo. Mechanistically, circ_0075829 bound miR-326 and exerted regulatory effects by affecting miR-326 expression. GOT1 was a direct miR-326 target and a key downstream effector of miR-326. Furthermore, circ_0075829 modulated GOT1 expression via miR-326. Our findings establish a novel regulatory network, the circ_0075829/miR-326/GOT1 competing endogenous RNA (ceRNA) crosstalk, in the regulation of GEM resistance in PC.

With the gradual emergence of xylazine as a street drug, incidents of xylazine poisoning are now occurring worldwide. However, it remains unknown whether long-term exposure to xylazine causes nonalcoholic fatty liver disease (NAFLD). In the present study, the rats were injected with xylazine intraperitoneally for 28 consecutive days, and then serum and liver tissues were collected for analysis. Weight loss was observed in the 40 mg/kg group and elevated levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were observed. Histopathologic examination showed hepatic steatosis, necrosis, and fibrosis. By mRNA sequencing, 192 upregulated genes and 277 downregulated genes were found in the 40 mg/kg group, and the PPAR signaling pathway was ranked first in the KEGG pathway analysis. Four genes in the PPAR signaling pathway, Fabp5, Acox2, and Cpt2, were also verified in the 40 mg/kg group by RT-qPCR analysis and western blot. Our results demonstrated that long-term injection of xylazine causes NAFLD and the PPAR signaling pathway plays a core role in the process of xylazine-associated liver injury.

Breast cancer has seriously affected women's physical and mental health. This investigation aims at screening differentially expressed genes (DEGs) in breast cancer and illuminating the potential biological functions of Leiomodin 1 (LMOD1) and its behind mechanisms against breast cancer. The common DEGs (co-DEGs) between the GSE22820 and GSE29431 data sets and pivotal genes were screened out using bioinformatics methods. The biological roles of LMOD1 overexpression on malignant phenotypes were validated by functional assays and the impact on fatty acid synthesis was also elucidated in breast cancer cell lines. Additionally, colivelin, a STAT3 activator, was applied for further investigating the role of LMOD1 on the JAK2/STAT3 pathway in vitro. A total of 208 co-DEGs and 5 focal genes were screened through bioinformatics analysis, and 5 focal genes were downregulated in breast cancer cell lines. LMOD1 overexpression retarded proliferative, migratory, invasive capabilities of breast cancer cells. LMOD1 overexpression suppressed fatty acid synthesis. Furthermore, the inhibitory effects on malignant phenotypes of breast cancer cells with LMOD1 overexpression were partially abolished after colivelin treatment. Additionally, LMOD1 could impede fatty acid synthesis in breast cancer cells. Our study highlighted LMOD1 exerted as a tumor-suppressive role in breast cancer, which was correlated with restraining the JAK2/STAT3 pathway activation.

Hepatocellular carcinoma (HCC) is one of the most common cancers and a worldwide health concern that requires novel treatment approaches. Tyrosine kinase inhibitors (TKIs) and immune checkpoint blockades (ICBs) are the current standard of care; however, their clinical benefits are limited in some advanced and metastatic patients. With the help of gene engineering techniques, a novel adoptive cellular therapy (ACT) called chimeric antigen receptor (CAR)-T cells was recently introduced for treating HCC. A plethora of current clinical and preclinical studies are attempting to improve the efficacy of CAR-T cells by dominating the immunosuppressive environment of HCC and finding the best tumor-specific antigens (TSAs). The future of care for HCC patients might be drastically improved due to the convergence of novel therapeutic methods and the continuous progress in ACT research. However, the clinical application of CAR-T cells in solid tumors is still facing several challenges. In this study, we provide an overview of the advancement and prospects of CAR-T cell immunotherapy in HCC, as well as an investigation of how cutting-edge engineering could improve CAR-T cell efficacy and safety profile.

Nephrotoxicity is a prominent complication of methotrexate (MTX) therapy that limits clinicians in its extensive use. MTX triggers oxidative burden and inflammation, so the nephroprotective potential of the synthetic derivative of 1,3,4-oxadiazole (5b) was explored in this research. Male Wistar rats were divided into four groups i.e., control group, MTX group, 5b (5 mg/kg) + MTX group and 5b (10 mg/kg) + MTX group, respectively. All treatments were given, intraperitoneally (i.p.) during 12 days of the animal model. The MTX-induced nephrotoxicity was evaluated by renal function markers i.e., serum creatinine (Cret), blood urea nitrogen (BUN), and albumin (Alb). Furthermore, antioxidant markers, catalase (CAT), glutathione-S-transferase (GST), and reduced glutathione (GSH), and oxidative stress, markers lipid peroxidase (LPO) and nitric oxide (NO), were analyzed. Pro-inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), were also calculated. DNA damage was assessed by the comet assay. Histopathological staining (Hematoxylin and eosin, Masson's trichrome) was done and immunohistochemistry was performed against Caspase-3, Nrf2, HO-1, TLR-4, TNF-α, and NF-κB. A significant improvement in the serum Cret, BUN, and Alb was observed in (5b) treated groups. Antioxidant markers were elevated, oxidative stress markers and pro-inflammatory cytokines were reduced, moreover, histopathological analysis revealed less tissue damage in (5b) administered groups. Immunohistochemistry showed increased immune expression of Nrf2 and HO-1 and decreased expression of TLR-4, TNF-α, Caspase-3, and NF-κB in 5b (5 mg/kg) + MTX group and 5b (10 mg/kg) + MTX group as compared to the MTX group. Hence, the results of this study favor the use of (5b) against MTX-induced nephrotoxicity.

Acute kidney injury (AKI) is one of the leading causes of chronic kidney disease and accounts for 50%–75% of mortality following renal pathologies or organ transplantation. Ischemia‒reperfusion injury (IRI) involves an interrupted blood supply to organs and the kidney; IRI exacerbates AKI development. Owing to several pharmacological treatment methods, AKI still has a poor prognosis, and novel therapeutic options are needed. Agomelatine (AGM) is a melatonin receptor agonist (MT1 and MT2) with increased bioavailability and lipophilicity. In this study, we aimed to investigate the antioxidant and anti-inflammatory effects of AGM in experimental renal IRI via long-term and short-term applications. Sixty male Sprague–Dawley rats were randomly divided into six groups (n = 10): the control, I/R, AGM20S, AGM40S, AGM20L, and AGM40L groups. Following the establishment of the renal IRI model, the rats received agomelatine at 20 and 40 mg/kg orally, and agomelatine solvent (hydroxyethylcellulose) was used as a vehicle. At the end of the experiment, blood samples and renal tissues were harvested for histopathological and biochemical analysis. Urea, creatinine, tumor necrosis factor (TNF-α), and interleukin-1 beta (IL-1β) levels were measured in blood serum samples. Malondialdehyde (MDA) levels and increased superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSHPx), and total glutathione (GSH) levels were measured in renal tissue supernatants. Our biochemical results indicated that AGM reduced creatinine, TNF-α, IL-1β, and malondialdehyde levels and increased SOD, CAT, GSHPx, and total GSH levels. Agolematine reduced infiltration, intratubular hemorrhage, and intratubular cast formation histopathologically. Our results suggest that AGM could be a potential therapeutic adjuvant agent for ischemia‒reperfusion injury in the kidney and several other organs.