Human & Experimental Toxicology最新文献

Background: Kaempferol has important medicinal value in the treatment of asthma. However, its mechanism of action has not been fully understood and needs to be explored and studied.

Methods: A binding activity of kaempferol with nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) was analyzed by molecular docking. Human bronchial epithelial cells (BEAS-2B) were treated with different concentrations (0, 1, 5, 10, 20, 40 μg/mL) of kaempferol to select its suitable concentration. In the transforming growth factor (TGF)-β1-induced BEAS-2B, cells were treated with 20 μg/mL kaempferol or 20 μM GLX35132 (a NOX4 inhibitor) to analyze its effects on NOX4-mediated autophagy. In the ovalbumin (OVA)-induced mice, 20 mg/kg kaempferol or 3.8 mg/kg GLX351322 administration was performed to analyze the therapeutic effects of kaempferol on NOX4-mediated autophagy. An autophagy activator, rapamycin, was used to confirm the mechanism of kaempferol in treatment of allergic asthma.

Results: A good binding of kaempferol to NOX4 (score = -9.2 kcal/mol) was found. In the TGF-β1-induced BEAS-2B, the NOX4 expression was decreased with kaempferol dose increase. The secretions of IL-25 and IL-33, and the NOX4-mediated autophagy were significantly decreased by kaempferol treatment in the TGF-β1-induced BEAS-2B. In the OVA-challenged mice, kaempferol treatment improved airway inflammation and remodeling through suppressing NOX4-mediated autophagy. The rapamycin treatment clearly hampered the therapeutic effects of kaempferol in the TGF-β1-induced cells and OVA-induced mice.

Conclusions: This study identifies kaempferol binds NOX4 to perform its functions in the treatment of allergic asthma, providing an effective therapeutic strategy in the further treatment of asthma.

Background: The most common type of glomerulonephritis in China is mesangial proliferative glomerulonephritis (MPGN) featured with mesangial cell overproliferation and inflammation, as well as fibrosis. Albiflorin (AF) is an effective composition extracted from Paeonia Alba Radix and has been administrated for various diseases. Nevertheless, there is no research reporting the effect of AF on MPGN.Purpose: Our work aims to probe into the role and possible mechanism of AF on MPGN.Research Design: We investigated the effects of AF on mesangial cell overproliferation, inflammation, and fibrosis in vitro and in vivo and identified the related signaling pathways.Study Sample: human mesangial cells (HMCs) and male Sprague Dawley (SD) rats.Data Analysis: SPSS 18.0 was used to analyze the data.Results: AF attenuated the proliferation and inflammation both in vitro and in vivo. In detail, AF decreased the ki67 expression in lipopolysaccharides (LPS)-treated HMCs and MPGN rats, and the mRNA expression or contents of inflammatory cytokines were reduced after AF treatment. The fibrosis of LPS-treated HMCs and MPGN rats was also reduced by AF. Moreover, AF effectively restrained 24 h urinary protein, improved kidney function, and mitigated dyslipidemia and pathological injury of MPGN rats. Additionally, we found that the protective effects of AF were accompanied by the blocking of PI3K/AKT/NF-κB pathway, and the inhibitory effects of AF on MPGN were reversed by insulin-like growth factor (IGF-1), the PI3K agonist.Conclusions: AF alleviates MPGN via restraining mesangial cell overproliferation, inflammation, and fibrosis via PI3K/AKT/NF-κB signaling.

Background: A growing number of studies have focused on the regulatory role of circular RNAs (circRNAs) in a variety of cancers. The purpose of this study was to investigate the effect of circRNA Keratin 14 (circKRT14) on the progression of esophageal cancer (EC).

Methods: The levels of circKRT14, miR-1256 and E2F transcription factor 3 (E2F3) were analyzed by real-time quantitative polymerase chain reaction (qRT-PCR) and western blot. The circular structure of circKRT14 was confirmed by RNase R digestion assay. Cell apoptosis, migration and invasion were detected by flow cytometry and transwell assay. The protein levels of related factors were determined by western blot. The relationship between miR-1256 and circKRT14 or E2F3 was verified by dual-luciferase reporter assay. The in vivo function of circKRT14 was studied by xenograft tumor assay.

Results: CircKRT14 was significantly increased in EC tissues and cells. CircKRT14 silencing inhibited EC cell proliferation, migration, and invasion, but promoted EC cell apoptosis in vitro. CircKRT1 acted as a sponge for miR-1256 in EC, and in-miR-1256 abolished the inhibitory effect of circKRT14 suppression on EC cell progression. E2F3 was a target of miR-1256 and functioned as an oncogene in EC cells. MiR-1256 curbed EC progression by downregulating E2F3. CircKRT14 could affect E2F3 expression by targeting miR-1256. CircKRT14 regulated EC progression in vivo through miR-1256/E2F3 axis.

Conclusions: These results uncovered that circKRT14 up-regulated the expression of E2F3 and promoted the malignant development of EC through sponging miR-1256.

Sevoflurane is the most commonly used anesthetic in clinical practice and exerts a protective effect on cerebral ischemia-reperfusion (I/R) injury. This study aims to elucidate the molecular mechanism by which sevoflurane postconditioning protects against cerebral I/R injury. Oxygen-glucose deprivation/reperfusion (OGD/R) model in vitro and the middle cerebral artery occlusion (MCAO) model in vivo were established to simulate cerebral I/R injury. Sevoflurane postconditioning reduced neurological deficits, cerebral infarction, and ferroptosis after I/R injury. Interestingly, sevoflurane significantly inhibited specificity protein 1 (SP1) expression in MACO rats and HT22 cells exposed to OGD/R. SP1 overexpression attenuated the neuroprotective effects of sevoflurane on OGD/R-treated HT22 cells, evidenced by reduced cell viability, increased apoptosis, and cleaved caspase-3 expression. Furthermore, chromatin immunoprecipitation and luciferase experiments verified that SP1 bound directly to the ACSL4 promoter region to increase its expression. In addition, sevoflurane inhibited ferroptosis via SP1/ACSL4 axis. Generally, our study describes an anti-ferroptosis effect of sevoflurane against cerebral I/R injury via downregulating the SP1/ASCL4 axis. These findings suggest a novel sight for cerebral protection against cerebral I/R injury and indicate a potential therapeutic approach for a variety of cerebral diseases.

Iron is a necessary biological element and one of the richest in the human body, but it can cause changes in cell function and activity control. Iron is involved in a wide range of oxidation - reduction activities. Whenever iron exceeds the cellular metabolic needs, its excess causes changes in the products of cellular respiration, such as superoxide, hydrogen peroxide and hydroxyl. The formation of these compounds causes cellular toxicity. Lack of control over reactive oxygen species causes damages to DNA, proteins, and lipids. Conversely, superoxide, hydrogen peroxide and hydroxyl are reactive oxygen species, using antioxidants, restoring DNA function, and controlling iron stores lead to natural conditions. Iron poisoning causes clinical manifestations in the gastrointestinal tract, liver, heart, kidneys, and hematopoietic system. When serum iron is elevated, serum iron concentrations, total iron-binding capacity (TIBC) and ferritin will also increase. Supportive care is provided by whole bowel irrigation (WBI), esophagogastroduodenoscopy is required to evaluate mucosal injury and remove undissolved iron tablets. The use of chelator agents such as deferoxamine mesylate, deferasirox, deferiprone, deferitrin are very effective in removing excess iron. Of course, the combined treatment of these chelators plays an important role in increasing iron excretion, and reducing side effects.

Objective: The aim of this study was to examine the association between serum complement 1q (C1q) and the associated factors of acute ischemic stroke in patients with type 2 diabetes (T2DM).

Methods: The baseline clinical variables of the participants were collected, and the levels of blood lipids, blood sugar, inflammatory cytokines, and C1q in the three groups were then compared. The variables which affected the associated factors of acute ischemic stroke in T2DM cases were determined.

Results: The levels of C1q in the DAIS group were increased significantly compared with those in the T2DM group. Receiver operating characteristic curve analyses showed that the AUC for C1q and the combined diagnosis of acute ischemic stroke were 0.830 (95%CI 0.747-0.914), with a sensitivity of 0.854 and specificity of 0.780. The results of Pearson's correlation analyses demonstrated that C1q was associated positively with low-density lipoprotein cholesterol (LDL-C), fasting blood glucose (PBG), 2-h postprandial blood glucose (2h PG), and high-sensitive C reaction protein (hs-CRP) (all p < .05). Stratified analysis showed that there was a positive relationship between C1q and the associated factors of acute ischemic stroke for partial LDL-C, and hs-CRP strata. Logistic model analysis suggested that C1q was an independent risk factor for acute ischemic stroke in patients with T2DM. After adjusting for potential confounders, a one-standard deviation (SD) increase in C1q level was strongly related to an approximately 1.5-fold increased risk of acute ischemic stroke in cases with a hs-CRP ≥1.78 mg/L.

Conclusion: In DAIS patients, the levels of C1q were increased significantly and were an independent associated factor which affected the occurrence of acute ischemic stroke.

Except for clinical value, borneol is routinely used in food and cosmetics with seldom safety evaluation. To investigate its hepatoxicity, we exposed 3 dpf (days post fertilization) larval zebrafish to borneol at a gradient of concentrations (200-500 μM) for 3 days. Herein, our results revealed that high doses of borneol (300-500 μM) caused liver size decrease or lateral lobe absence. Borneol also seriously disturbed the hepatic protein metabolism presented with the increased activity of alanine aminotransferase (ALT) and lipid metabolism shown with the increased level of triglycerides (TG) and total cholesterol (TC). The lipid accumulation (oil red staining) was detected as well. Additionally, significant upregulation of genes was detected that related to oxidative stress, lipid anabolism, endoplasmic reticulum stress (ERS), and autophagy. Conversely, the lipid metabolism-related genes were markedly downregulated. Moreover, the changes in the superoxide dismutase activity and the level of glutathione and malondialdehyde raised the likelihood of lipid peroxidation. The outcomes indicated the involvement of oxidative stress, ERS, lipid metabolism, and autophagy in borneol-induced lipid metabolic disorder and hepatic injury. This study will provide a more comprehensive understanding of borneol hepatoxicity and the theoretical basis for the safe use of this compound.

Corynetoxins, members of the tunicamycin group of antibiotics, are produced by the bacterium, Rathayibacter toxicus. They cause a severe neurologic disorder in domestic livestock, are hepatotoxins, and can damage retinal photoreceptors. For these toxins to be ingested by livestock, the bacterium must first be transported onto host plants by adhering to nematode larvae. In the infected seed heads, bacterial galls (gumma) then form. While corynetoxicity occurs most commonly in Australia, it has occurred sporadically in other countries and, due to the widespread global distribution of the bacterium, nematode, and host plants, there is great potential for further spread, particularly as the range of host plant species and nematode vectors identified for R. toxicus is increasing. Since many animal species are susceptible to corynetoxins poisoning, it is likely that humans would also be vulnerable if exposed to these potent, lethal toxins.

Intervertebral disc degeneration (IDD) is a complex degradative disorder associated with inflammation. Emodin, an anthraquinone derivative, possesses strong anti-inflammatory activity. This study focused on the in vitro therapeutic action of emodin in a cellular model of IDD. Human nucleus pulposus cells (NPCs) were stimulated with interleukin-1β (IL-1β) to induce inflammation. Cell Counting Kit-8 and terminal deoxynucleotidyl transferase dUTP nick end labeling staining assays were performed to evaluate the viability and apoptosis of NPCs, respectively. Caspase-3 activity was measured to indirectly assess cell apoptosis. Western blot analysis was performed to detect protein expression levels. Reverse transcription-polymerase chain reaction was performed for the detection of relative mRNA levels of tumor necrosis factor-α (TNF-α) and IL-6. Enzyme-linked immunosorbent assay was performed to analyze TNF-α and IL-6 secretion. Our results showed that emodin treatment mitigated IL-1β-induced reduction of cell viability in NPCs. Moreover, the increase in reactive oxygen species (ROS) production, apoptotic rate, and caspase-3 activity in IL-1β-stimulated NPCs was reduced by emodin treatment. Treatment with emodin also abolished IL-1β-induced inflammation in NPCs, as indicated by reduced secretion of IL-6 and TNF-α. Besides, the increase in expression levels of phosphorylated p65 and nuclear p65 in IL-1β-stimulated NPCs was suppressed by emodin treatment. Furthermore, inhibition of nuclear factor kappa B (NF-κB) activation with pyrrolidine dithiocarbamate aggravated the protective effects of emodin. These results suggested that emodin protected NPCs against IL-1β-induced apoptosis and inflammation via inhibiting ROS-mediated activation of NF-κB.