Toxicological Research最新文献

Gastric cancer (GC) is the most common cancer worldwide and the third leading cause of cancer death, with the fifth highest incidence. The development of effective chemotherapeutic agents is needed to decrease GC mortality. Policosanol (PC) extracted from Cuban sugar cane wax is a healthy functional food ingredient that helps improve blood cholesterol levels and blood pressure. Its various physiological activities, such as antioxidant, anti-inflammatory, and anticancer activities, have been reported recently. Nevertheless, the therapeutic efficacy of PC in gastric xenograft models is unclear. We aimed to investigate the anticancer effect of PC on human GC SNU-16 cells and a xenograft mouse model. PC significantly inhibited GC cell viability and delayed tumor growth without toxicity in the SNU-16-derived xenograft model. Therefore, we investigated protein expression levels in tumor tissues; the expression levels of Ki-67, a proliferation marker, and cdc2 were decreased. In addition, we performed proteomic analysis and found thirteen differentially expressed proteins. Our results suggested that PC inhibited GC progression via cdc2 suppression and extracellular matrix protein regulation. Notably, our findings might contribute to the development of novel and effective therapeutic strategies for GC.

3-Caffeoyl-4-dicaffeoylquinic acid (CDCQ) is a natural chlorogenic acid isolated from Salicornia herbacea that protects against oxidative stress, inflammation, and cancer. Nitric oxide (NO) plays a physiologically beneficial role in the cardiovascular system, including vasodilation, protection of endothelial cell function, and anti-inflammation. However, the effect of CDCQ on NO production and eNOS phosphorylation in endothelial cells is unclear. We investigated the effect of CDCQ on eNOS phosphorylation and NO production in human endothelial cells, and the underlying signaling pathway. CDCQ significantly increased NO production and the phosphorylation of eNOS at Ser1177. Additionally, CDCQ induced phosphorylation of PKA, CaMKII, CaMKKβ, and AMPK. Interestingly, CDCQ increased the intracellular Ca²⁺ level, and L-type Ca²⁺ channel (LTCC) blockade significantly attenuated CDCQ-induced eNOS activity and NO production by inhibiting PKA, CaMKII, CaMKKβ, and AMPK phosphorylation. These results suggest that CDCQ increased eNOS phosphorylation and NO production by Ca²⁺-dependent phosphorylation of PKA, CaMKII, CaMKKβ, and AMPK. Our findings provide evidence that CDCQ plays a pivotal role in the activity of eNOS and NO production, which is involved in the protection of endothelial dysfunction.

Phosphodiesterase 11A (PDE11A), a 3',5'-cyclic nucleotide phosphodiesterase, is a key regulator of intracellular signaling that functions by degrading cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). However, the function of PDE11A in brain tumors is currently unclear. In this study, we found that PDE11A may be involved in glioblastoma development. The protein and mRNA levels of PDE11A were significantly higher in U87-MG, U251-MG and U343-MG glioblastoma cell lines. Gene expression analyses by deep-sequencing revealed that PDE11A mRNA levels were higher in U87-MG and U251-MG cells compared to other cells in the cerebral cortex. A comprehensive analysis of The Cancer Genome Atlas (TCGA) data revealed that PDE11A expression was also elevated in glioblastoma patients. Taken together, these data indicate that PDE11A expression was increased in glioblastoma cell lines and glioma patients, suggesting that PDE11A could be a putative diagnostic marker and therapeutic target for glioma.

Advanced glycation end products (AGEs) can induce inflammatory signaling pathways through the receptor for AGEs (RAGE). Targeting RAGE could be a therapeutic strategy for treating chronic inflammation mediated by the AGE-RAGE axis. This study aimed to investigate the effects of Fimbristylis ovata and Artemisia vulgaris extracts on AGE-RAGE signaling and AGE-mediated oxidative stress and inflammation in THP-1 cells. F. ovata and A. vulgaris were extracted by a Soxhlet extraction, and antioxidant capacity was evaluated using DPPH and ABTS assays. The human monocytic cell line THP-1 was treated with AGE (600 µg/ml) with and without F. ovata and A. vulgaris extracts (100 µg/ml). The mitochondria-targeting antioxidant MitoQ (2 μg/ml) was used as a positive control. Cell viability, ROS generation, RAGE, AGE-RAGE signaling pathway components, and inflammatory cytokine levels were analyzed. F. ovata and A. vulgaris extracts showed antioxidative effects in non-cell-based assays. Treatment of THP-1 cells with AGE significantly increased the protein levels of RAGE and significantly increased the mRNA expression of cytokines, including TNF-α, IL-1β, and IL-6. AGEs induced the generation of ROS and levels of signaling molecules downstream of RAGE, including phosphorylated and total Erk1/2, JNK, and p38 MAPK, although not significantly. F. ovata and A. vulgaris extracts significantly decreased the protein levels of RAGE and significantly decreased the mRNA levels of cytokines. In conclusion, this study revealed that F. ovata and A. vulgaris extracts exert anti-inflammatory effects through the AGE-RAGE axis. However, details on this anti-inflammatory effect through AGE-RAGE signaling should be further investigated.

Supplementary information: The online version contains supplementary material available at 10.1007/s43188-021-00114-0.

Alteration of redox status is one of the molecular pathways commonly associated with pesticide toxicity. Antioxidants, including those obtained from plant phenolics, have been shown to mitigate pesticide-induced cellular injury. The present study was aimed at evaluating the effect of daflon-500 ^® , a flavonoid compound on sub-chronic chlorpyriphos-evoked changes in antioxidant and biochemical parameters in the hypophysis and testes of adult male rats. Twenty-five male albino rats were randomly divided into 5 groups of 5 animals each. Group I (DW) received distilled water (2 ml/kg); group II (SO) was dosed with soya oil (2 ml/kg); Group III (DAF) received daflon-500 ^® at 1000 mg/kg ~ 1/5th of LD50 (≥ 5000 mg/kg); group IV (CP) was administered chlorpyriphos at 7.74 mg/kg ~ 1/10th of LD₅₀ (77.4 mg/kg) while group V (DAF + CP) was previously treated with daflon-500 ^® (1000 mg/kg) and then exposed to CP (7.74 mg/kg), 30 min later. Daily oral regimen administration was done for 60 days after which the animals were sacrificed by cervical venesection after light chloroform anesthesia. The hypophysis and testicular tissues were harvested, and their homogenates were analyzed for malondialdehyde, catalase and superoxide dismutase, and acetylcholinesterase levels. A significant increase in the hypophysis and testicular MDA concentrations, coupled with a decrease in the SOD, CAT, and AChE activities were observed in the CP group. The levels of these oxidative and biochemical parameters were alleviated in the group pretreated with Daflon-500 ^® . Results of this study demonstrated that pre-treatment with Daflon-500 ^® mitigated CP-induced alterations in oxidative and biochemical parameters apparently due to the antioxidant effect of the flavonoid compound.

In this study, the modulatory effects of anthracene (ANT) and benz[a]anthracene (BEN) on biochemical markers associated with neurodegeneration were assessed in mouse hippocampal neuronal cells (HT-22). Neuronal cells were cultured and exposed to ANT and BEN (25-125 µM) for 5 days, and the cell viability was determined via MTT assay. Morphological characteristics of the cells were assessed using a compound microscope. Biochemical parameters such as acetylcholinesterase (AChE), monoamine oxidase (MAO) and adenosine deaminase (ADA) activities as well as oxidative stress biomarkers (catalase [CAT], glutathione -S- transferase [GST] activities and Glutathione [GSH] levels) and nitric oxide [NO] levels were assessed after cells were treated with ANT and BEN for two days. The results showed that cell viability reduced with an increase in exposure time. After the fifth day of treatment, BEN and ANT (125 µM) reduced percentage viability to 41 and 38.1%, respectively. Light micrographs showed shrinkage of cells, neuronal injury and cell death in cells treated with higher concentrations of BEN and ANT (50 and 125 µM). Furthermore, AChE and MAO activities reduced significantly after treatment for 48 h with ANT and BEN. A significant decrease in CAT and GST activities and low GSH levels were observed after treatment with BEN and ANT. However, both polycyclic aromatic hydrocarbons caused a significant increase in ADA activity and NO levels. These results suggest that ANT and BEN may induce neurodegeneration in neuronal cells via oxidative stress-induced-neuronal injury, disruption of cholinergic, monoaminergic and purinergic transmission, and increased nitric oxide levels.

Vinyl chloride is a colorless gas with a pleasant odor capable of entering the body through oral or inhalation routes. Extensive studies on this compound indicated that it is a carcinogen, and Vinyl chloride exposure can result in a specific type of cancer in vinyl chloride workers. Whereas hemoglobin plays a vital role in oxygen transfer throughout the body, in a molecular aspect, the effect of vinyl chloride on human hemoglobin has not been studied. Furthermore, selenium as an antioxidant is a vital factor for the health of humans and animals. Then this research investigated the effect of the antioxidant capability of selenium at the same concentrations in blood on the interaction between vinyl chloride and hemoglobin. UV-visible, Fourier-transform infrared, chemiluminescence, and fluorescence spectroscopies were employed. The results indicated the destruction of hemoglobin structure in different concentrations of vinyl chloride. At the same time, the antioxidant effect of selenium inhibited the destructive impact of vinyl chloride on hemoglobin structure.

Natural killer (NK) cells are a part of the innate immune system and represent the first line of defense against infections and tumors. NK cells can eliminate tumor cells without major histocompatibility restriction and are independent of the expression of tumor-associated antigens. Therefore, they are considered an emerging tool for cancer immunotherapy. However, the general toxicity and biodistribution of NK cells after transplantation remain to be understood. This study was conducted to evaluate the general toxicity and biodistribution of human NK cells after single or repeated intravenous dosing in severely combined immunodeficient (SCID) mice. There were no test item-related toxicological changes in single and repeated administration groups. The no observed adverse effect level of human NK cells was 2 × 10⁷ cells/head for both male and female SCID mice. Results from the biodistribution study showed that human NK cells were mainly distributed in the lungs, and a small number of the cells were detected in the liver, heart, spleen, and kidney of SCID mice, in both the single and repeated dose groups. Additionally, human NK cells were completely eliminated from all organs of the mice in the single dose group on day 7, while the cells persisted in mice in the repeated dose group until day 64. In conclusion, transplantation of human NK cells in SCID mice had no toxic effects. The cells were mainly distributed in the lungs and completely disappeared from the body over time after single or repeated intravenous administration.

Skin sensitization is induced when certain chemicals bind to skin proteins. Direct peptide reactivity assay (DPRA) has been adopted by the OECD as an alternative method to evaluate skin sensitization by assessing a substance's reaction to two model peptides. A modified spectrophotometric method, Spectro-DPRA, can evaluate skin sensitization, in a high throughput fashion, to obviate some limitations of DPRA. Pre-validation studies for Spectro-DPRA were conducted to determine transferability and proficiency, within- and between-laboratory reproducibility, and predictive ability based on GLP principles at three laboratories (AP, KTR, and KCL). All laboratories confirmed high (> 90%) concordance for evaluating the sensitivity induced by ten chemical substances. The concordance among the three tests performed by each laboratory was 90% for AP, 100% for KTR, and 100% for KCL. The mean accuracy of the laboratories was 93.3% [compared to the standard operating procedure (SOP)]. The reproducibility among the three laboratories was as high as 86.7%; the accuracy was 86.7% for AP, 100% for KTR, and 86.7% for KCL (compared to the SOP). An additional 54 substances were assessed in 3 separate labs to verify the prediction rate. Based on the result, 29 out of 33 substances were classified as sensitizers, and 19 out of 21 identified as non-sensitizers; the corresponding sensitivity, specificity, and accuracy values were 87.9%, 90.5%, and 88.9%, respectively. These findings indicate that the Spectro-DPRA can address the molecular initiating event with improved predictability and reproducibility, while saving time and cost compared to DPRA or ADRA.

The present aimed to characterize the toxicity of silica nanoparticles in Sprague Dawley rats and determine the dose levels for a repeated-dose toxicity study. Silica nanoparticles (SiO₂, 20 nm and 50 nm) were administered as a single intratracheal instillation of standardized SiO₂ 20 nm (low dose, 200 µg/mL; high dose, 400 µg/mL) and 50 nm (low dose, 200 µg/mL; high dose, 400 µg/mL). Each group consisted of five male rats. We documented the mortality rate, clinical signs, body weight, bronchoalveolar lavage fluid analysis, hematological values, serum chemistry values, organ weight, gross findings at necropsy, and histopathological assessments. Rats treated with 200 µg/mL and 400 µg/mL SiO₂ 50 nm exhibited a decreased mean corpuscular volume, while those treated with 400 µg/mL of SiO₂ 50 nm showed increases in absolute monocyte and absolute lymphocyte count as well as prothrombin time. In addition, rats treated with 400 µg/mL SiO₂ 20 nm and 50 nm presented reduced creatinine, alanine aminotransferase, and sodium levels. Therefore, a single intratracheal instillation of SiO₂ 20 nm and 50 nm elicited no toxicity up to a dose of 400 µg/mL, and the approximate lethal dose of this test substance exceeded 400 µg/mL in male Sprague Dawley rats under the present experimental conditions.