Journal of Biochemical and Molecular Toxicology最新文献

As the most prevalent subtype of lung cancer, lung adenocarcinoma (LUAD) is closely associated with angiogenesis, which is fundamental to its progression. ADAM8 (A disintegrin and metalloproteinase 8) is an enzyme associated with tumor invasion, while its implications in LUAD angiogenesis are a field that awaits exploration. A thorough investigation into the impacts of ADAM8 on LUAD angiogenesis could contribute to the development of therapeutic drugs for LUAD. Bioinformatics delineated the expression profiles of TFAP2A and ADAM8 in LUAD tissues, focusing on ADAM8-enriched pathways. qRT-PCR confirmed their expression in LUAD cells. The CCK-8 assay was applied to gauge cell viability, and Western blot detected the presence of JAK2/STAT3 pathway proteins and VEGFR-2 and VEGF. Angiogenesis assays quantified the length of angiogenesis, and dual-luciferase and Chromatin immunoprecipitation assays verified the TFAP2A-ADAM8 binding. ADAM8 exhibited high expression in LUAD tissues and cells, with notable enrichment in the VEGF and JAK/STAT pathways. Cellular assays revealed that elevated ADAM8 expression enhanced cell viability, promoted the phosphorylation of JAK2 and STAT3, and boosted angiogenic capacity. The JAK inhibitor Peficitinib reversed the proangiogenic effects induced by ADAM8 overexpression. We also discovered overexpression of TFAP2A, an upstream transcription factor of ADAM8, in LUAD. Rescue experiments indicated that ADAM8 overexpression could counteract the inhibitory effects of TFAP2A knockdown on LUAD angiogenesis. This study reveals for the first time the critical role of ADAM8 in LUAD angiogenesis, demonstrating that TFAP2A promotes JAK/STAT pathway conduction by activating ADAM8. This finding not only provides a new perspective for understanding the pathogenesis of LUAD but also lays the foundation for the development of new therapies targeting ADAM8.

Abdominal aortic aneurysm (AAA) is a severe cardiovascular disease (CVD) that is partly attributable to endothelial dysfunction, inflammatory response, and angiogenesis.

G protein-coupled receptor 4 (GPR4), a proton-sensitive G protein-coupled receptor that is abundantly expressed in vascular endothelial cells, has been associated with numerous physiological functions. Nevertheless, its potential involvement in the development of AAA remains unexplored.

In this study, we examined the impact of GPR4 deletion on the development of AAA in ApoE-deficient mice. The mice were categorized into four distinct groups: the ApoE−/− with saline group, the ApoE−/−GPR4−/− with saline group, the ApoE−/− with Ang II group, and the ApoE−/−GPR4−/− with Ang II group. AAA were induced in the ApoE−/− mice through the perfusion of angiotensin II (Ang II). Notably, GPR4 was substantially elevated in the AAA tissues from both human subjects and experimental mice. The deletion of GPR4 substantially decreased the formation of Ang II-induced AAA, damages to elastin, and the expression of aortic inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), as well as vascular endothelial growth factor A/vascular endothelial growth factor receptor 2 (VEGF-A/VEGF-R2), in ApoE−/− mice. Human aortic endothelial cells (HAECs) were transfected with lenti-viral GPR4 shRNA and subsequently stimulated with Ang II. Our findings indicate that the knockout of GPR4 attenuated Ang II-induced angiogenic tube formation in HAECs by decreasing the expression of VEGF-A and VEGF-R2. Furthermore, GPR4 knockout also hindered the activation of specificity protein-1 (SP-1) by reducing its expression and transcriptional activity. Notably, the overexpression of SP-1 reversed the inhibitory effects of GPR4 knockout on angiogenic tube formation and the expression of VEGF-A/VEGF-R2. This suggests that the protective effects of GPR4 knockout are achieved through the inhibition of SP-1. In summary, the absence of GPR4 impeded AAA formation, indicating that GPR4 could potentially serve as a therapeutic target for AAA.

Bisphenol A (BPA), an environmental endocrine disrupting chemical, is one of the most widely used chemicals in the world and is widely distributed in the external environment, specifically in food, water, dust, and soil. BPA exposure is associated with abnormal cognitive behaviors. However, the underlying mechanism remains unclear. In this study, pregnant female Sprague Dawley rats were orally exposed to BPA at a low dose of 0, 0.04, 0.4, or 4 mg per kg·of body weight per day from embryonic Day 0 (ED 0) to postnatal Day 21 (PND 21). Spatial learning and memory were measured via a Morris water maze test on PND 22. PI3K/Akt/mTOR signaling pathway protein expression was detected in the hippocampi of male offspring using a western blot. The water maze test demonstrated that BPA exposure considerably reduced the learning and memory capacities of the male offspring exposure groups when compared to the control group. The male offspring rats' latency to escape increased significantly, the time taken to traverse a platform reduced, and latency to find a hidden platform showed an increasing trend. Meanwhile, maternal exposure to BPA downregulated the expression of PI3K/Akt/mTOR/p70S6K pathway in the hippocampi of the offspring. Moreover, BPA exposure improved the GSK3β and phosphorylated tau protein (T231) levels, increased malondialdehyde levels, and activated caspase-3 expression in the hippocampi of the male offspring rats. Taken together, these findings indicate that maternal exposure to BPA causes learning and memory impairment and that the PI3K/Akt/mTOR pathway participates in the mechanism of BPA-induced neurocognitive decline.

Cadmium (Cd) is a toxic heavy metal which induces vascular disorders. Previous studies suggest that Cd in the bloodstream affects vascular endothelial cells (ECs), potentially contributing to vascular-related diseases. However, the molecular mechanisms of effects of Cd on ECs remain poorly understood. Notch signaling pathway abnormalities have been implicated in ECs disruption. The present study aims to investigate the effect of low Cd concentrations on the Notch signaling pathway in ECs. Mice were treated with low concentration of Cd (2.28 mg/kg), and tissues were collected for examination of mRNA and protein levels of Notch pathway components and VE-cadherin, a major junctional protein in ECs. We found that Cd treatment increases expression of NICD1, Hes1, Hey1, Hey2 and decreases expression of VE-cadherin in brain and kidney tissues. In vitro, a low concentration of Cd (1 μM) also induces increase expression of NICD1, Hes1, Hey1, Hey2, and decrease expression of VE-cadherin in human umbilical vein endothelial cells (HUVECs). Low concentration of Cd increased the permeability of HUVECs. We also found that Notch signaling negatively regulates the expression of VE-cadherin. In addition, DAPT, a Notch pathway inhibitor, prevents Cd-induced reduction in VE-cadherin expression in HUVECs. In summary, these findings revealed that Cd exposure decreases VE-cadherin expression through activation of the Notch signaling pathway.

Mycobacterium tuberculosis (Mtb) complex, responsible for tuberculosis (TB) infection, continues to be a predominant global cause of mortality due to intricate host-pathogen interactions that affect disease progression. MicroRNAs (miRNAs), essential posttranscriptional regulators, have become pivotal modulators of these relationships. Recent findings indicate that miRNAs actively regulate immunological responses to Mtb complex by modulating autophagy, apoptosis, and immune cell activities. This has resulted in increased interest in miRNAs as prospective diagnostic indicators for TB, especially in differentiating active infection from latent or inactive stages. Variations in miRNA expression during Mtb infection indicate disease progression and offer insights into the immune response. Furthermore, miRNAs present potential as therapeutic targets in host-directed therapy (HDT) techniques for TB infection. This work examines the function of miRNAs in TB pathogenesis, with the objective of identifying particular miRNAs that regulate the immune response to the Mtb complex, evaluating their diagnostic value and exploring their therapeutic implications in host-directed therapy for TB infection. The objective is to enhance comprehension of how miRNAs can facilitate improved diagnosis and treatment of TB.

Researchers are actively looking for novel anticancer medications because cancer is one of the leading causes of mortality worldwide. A fascinating area of study in medicinal chemistry is the screening of antioxidants for novel anticancer medicines, as antioxidants have lately been used as therapeutic candidates to combat a variety of ailments in aerobic species. Additionally, pyrazole-based heterocycle synthesis is a productive approach to the drug development process. To ascertain the molecular geometry and frontier orbital analysis, a DFT simulation of the produced compounds was conducted. Compound 7 showed the lowest energy gap and hardness, while compound 7 had the maximum softness. Therefore, a few quinazoline, benzimidazole, and tetrazinethione derivatives based on pyrazoles that were synthesized in our earlier work and exhibited antioxidant qualities were tested for their in vitro antiproliferative activity against the MCF7 and HCT116 cancer cell lines. The two cancer cell lines were most effectively inhibited by derivatives of sulfonamide and tetrazinethione. The molecular docking simulation toward CDK2 protein specified the best docking score of tetrazinethione 7 followed by sulfonamide derivative 4, compared to doxorubicin and roscovitine (kinase inhibitor). Most of the amino acids interacting with these compounds were involved in that interaction with the co-crystallized ligand. Their favorable oral bioavailability and drug-likeness characteristics were demonstrated by a modeling pharmacokinetics investigation. This research could help create novel antiproliferative drugs that are both efficient and selective.

Cisplatin (CIS) is a chemotherapeutic agent frequently used in cancer treatment. However, depending on the dosage and duration of use, CIS can lead to hepatotoxicity and nephrotoxicity. Iristectorin A (IRIS), a natural flavonoid, has been found to exhibit antioxidant and protective effects. In this paper, we scrutinized the effects and molecular mechanisms of the IRIS on CIS-induced liver and kidney damage in mice. IRIS administration alleviated CIS-induced elevations in AST, ALT, ALP, BUN, and creatinine levels by approximately 12%, 15%, 11%, 21%, and 15%, respectively. It also inhibited liver and kidney MDA levels by approximately 29% and 28%, while enhancing liver and kidney GSH, SOD, and CAT levels by 47%–60%, 85%–70%, and 90%–55%, respectively. IRIS enhanced liver and kidney mRNA expression levels of Nrf2 (by approximately 1.6- and 1.5-fold, respectively), HO-1 (by 1.5- and 1.5-fold, respectively), and Bcl-2 (by 1.5- and 1.4-fold, respectively). In addition, IRIS suppressed the mRNA expression levels of NF-κB (by 0.7- and 0.7-fold), TNF-α (by 0.7- and 0.7-fold), Bax (by 0.8- and 0.7-fold), and Cas-3 (by 0.9- and 0.7-fold). Protein expression analysis revealed that IRIS increased Nrf2 (by 1.5- to 1.2-fold) and Bcl-2 levels (by 1.3- to 1.7-fold), and reduced Bax (by 0.7- to 0.8-fold) and Cas-3 (by 0.8- and 0.8-fold) levels altered by CIS treatment. Moreover, IRIS administration prevented histopathological changes in the liver and kidney caused by CIS. Ultimately, IRIS was found to substantially mitigate CIS-induced hepatorenal injury by targeting oxidative stress, inflammation, and apoptosis through regulation of the Nrf2/HO-1 signaling pathway. Therefore, IRIS holds potential as a therapeutic adjuvant in the use of CIS.

The transient receptor potential ankyrin 1 (TRPA1) channels, characterized as nonselective cation channels with permeability to calcium ions (Ca^2 +), are part of the extensive family of transient receptor potential (TRP) channels. Research has demonstrated that TRPA1 channels function as sensors for oxidative stress in the renal tubules. Additionally, TRPA1 expression has increased in renal tissue following ischemia-reperfusion (IR). There is also a significant correlation between IR-induced renal injury and TRPA1 expression. This study investigated the effects of selective TRPA1 agonist ASP7663 and selective TRPA1 antagonist HC-030031 on renal IR injury. A total of 40 rats were divided into four groups: control, IR, IR+ASP7663, and IR + HC-030031. The rat kidneys were exposed to 45 min of ischemia, followed by 24 h of reperfusion. TRPA1 agonist ASP7663 and selective TRPA1 antagonist HC-030031 were administered intraperitoneally to the treatment groups with renal IR. HC-030031 administration reduced the elevated kidney injury molecule-1 (KIM-1), blood urea nitrogen (BUN), and creatinine (Cre) caused by renal IR. HC-030031 administration reduced the increased histopathological damage in renal tissue due to IR. It also reduced renal tissue interleukin-1beta (IL-1β), interleukin-6 (IL-6), toll-like receptor-4 (TLR-4), phosphorylated-NF-κB, phosphorylated-IκB-α, tumor necrosis factor-alpha (TNF-α), and caspase-3 levels. In this study, TRPA1 antagonist HC-030031 showed a protective behavior on renal IR injury by averting inflammation and apoptosis. After further studies, TRPA1 inhibition may be a new treatment strategy to prevent renal IR injury.

Sevoflurane (Sev) is a widely applied anesthetic in clinical practice; however, it could induce neurotoxicity and lead to postoperative cognitive dysfunction (POCD). This study aimed to investigate the role and underlying mechanism of circHOMER1 in Sev-induced neurotoxicity and POCD. Sev treated mouse hippocampal neuronal HT22 cells and SD rats. RT-qPCR was used to detect the levels of circHOMER1 and miR-217. ELISA was employed to measure the levels of inflammatory factors IL-6, IL-1β, and TNF-α. Commercially available kits assessed the concentration of MDA and measured the activities LDH and SOD. The CCK-8 assay assessed cell viability. Flow cytometry analyzed cell apoptosis. The Morris water maze test evaluated the learning and cognitive abilities of the rats. Dual luciferase reporter assays and RIP experiments validated the targeted binding of circHOMER1 to miR-217. Sev treatment significantly reduces cell viability, increases apoptosis, stimulates inflammatory responses and oxidative stress, and induces learning and memory impairments in SD rats. Following exposure to Sev, the expression of circHOMER1 is markedly decreased, while overexpression of circHOMER1 can alleviate Sev-induced neuroinflammation, oxidative stress, and learning and memory deficits in rats. CircHOMER1 targets miR-217, and transfection of miR-217 antagonizes the neuroprotective effects of circHOMER1. This study demonstrated that circHOMER1 negatively regulated miR-217, thereby inhibiting Sev-induced neurotoxicity and learning and memory disorders.