Titanium Dioxide Nanoparticles Induce Cell Cycle Arrest and Apoptosis through Inhibiting PI3K/AKT/mTOR Pathway in Spermatogonia.

Titanium dioxide nanoparticles (TiO2 NPs) can result in the reduction of sperm numbers, but the mechanisms have not been well elucidated. The purpose of this study was to investigate the effects of TiO2 NPs on cell cycle and apoptosis in spermatogonia and to explore the role of PI3K/AKT/mTOR signaling pathway in this process. The mouse spermatogonia cell line (GC-1) was treated with TiO2 NPs at different concentrations (0, 25, 50, 75 and 100 µg/mL) for 24 h to detect cell viability, cell cycle, apoptosis, and key proteins related to cell cycle and PI3K/AKT/mTOR signaling pathway. The agonist (IGF-1) and inhibitor (LY294002) of PI3K were used to verify the role of PI3K/AKT/mTOR signaling pathway in cell cycle and apoptosis. TiO2 NPs significantly inhibited cell proliferation, induced cell cycle arrest at G0/G1 phase and resulted in apoptosis. TiO2 NPs downregulated the levels of cyclin-dependent kinases (CDKs) and cyclins, including CDK4, CDK2, Cyclin D1 and Cyclin E1, while upregulated the levels of p21 and p53 proteins. Furthermore, TiO2 NPs inhibited the PI3K/AKT/mTOR signaling pathway by decreasing the levels of p-PI3K, p-AKT and p-mTOR. IGF-1 reversed the G0/G1 phase arrest and apoptosis caused by TiO2 NPs. However, LY294002 aggravated the G0/G1 phase arrest and apoptosis resulting from TiO2 NPs. Collectively, TiO2 NPs induced cell cycle arrest at G0/G1 phase and apoptosis through inhibiting the activation of PI3K/AKT/mTOR pathway, which could be the main reason for the reduction in sperm numbers caused by TiO2 NPs.

Protective effects of lycopene on TiO2 nanoparticle-induced damage in the liver of mice.

Titanium dioxide nanoparticles (nano-TiO2 ) is one of the most widely used and produced nanomaterials. Studies have demonstrated that nano-TiO2 could induce hepatotoxicity through oxidative stress, and lycopene has strong antioxidant capacity. The present study aimed to explore if lycopene protects the liver of mice from nano-TiO2 damage. Ninety-six ICR mice were randomly divided into eight groups. They were control group, nano-TiO2 -treated group (50 mg/kg BW), lycopene-treated groups (5, 20, and 40 mg/kg BW), and 50 mg/kg BW nano-TiO2 - and lycopene-co-treated groups (nano-TiO2 + 5 mg/kg BW of lycopene, nano-TiO2 + 20 mg/kg BW of lycopene, nano-TiO2 + 40 mg/kg BW of lycopene). After treated by gavage for 30 days, the histopathology of the liver was observed. Liver function was evaluated using changes in serum biochemical indicators of the liver (AST, ALT, ALP); and the level of ROS was indirectly reflected by the level of SOD, GSH-Px, MDA, GSH, and T-AOC. TUNEL assay was performed to examine the apoptosis of hepatocytes. Proteins of p53, cleaved-caspase 9, cleaved-caspase 3, Bcl-2, and Bax as well as p38 were detected. Results showed that lycopene alleviated the liver pathological damage and reduced the injury to liver function induced by nano-TiO2 , as well as decreased nano-TiO2 -induced ROS. Meanwhile, lycopene mitigated apoptosis resulting from nano-TiO2 , accompanied by the reversed expression of apoptosis-related proteins. Furthermore, lycopene significantly reversed the upregulation of p-p38 induced by nano-TiO2 . In conclusion, this study demonstrated that nano-TiO2 resulted in hepatocyte apoptosis through ROS/ROS-p38 MAPK pathway and led to liver function injury. Lycopene protected mice liver against the hepatotoxicity of nano-TiO2 through antioxidant property.

Effects of nano-titanium dioxide on calcium homeostasis in vivo and in vitro: a systematic review and meta-analysis.

With the extensive application of titanium dioxide nanoparticles (TiO2 NPs), their impacts on calcium homeostasis have aroused extensive attention from scholars. However, there are still some controversies in relevant reports. Therefore, a systematic review was performed followed by a meta-analysis to explore whether TiO2 NPs could induce the imbalance in calcium homeostasis in vivo and in vitro through Revman5.4 and Stata15.0 in this research. Fourteen studies were included through detailed database retrieval and literature screening. Results indicated that the calcium levels were significantly increased and the activity of Ca2+-ATPase was significantly decreased by TiO2 NPs in vivo and in vitro. Subgroup analysis of the studies in vivo showed that TiO2 NPs exposure caused a significant increase in calcium levels in rats, exposure to large-sized TiO2 NPs (>10 nm) and long-term (>30 days) exposure could significantly increase calcium levels, and the activity of Ca2+-ATPase showed a concentration-dependent downward trend. Subgroup analysis of the studies in vitro revealed that intracellular calcium levels increased significantly in animal cells, exposure to small-sized TiO2 NPs (≤10 nm) and high concentration (>10 µg/mL) exposure could induce a significant increase in Ca2+ concentration, and the activity of Ca2+-ATPase also showed a concentration-dependent downward trend. This research showed that the physicochemical properties of TiO2 NPs and the experimental scheme could affect calcium homeostasis.

The Key Technologies of Road Elevation Detection Based on Sensor Fusion.

The detection of long-distance pavement elevation undulation is the main data basis for pavement slope detection and flatness detection, and is also the data source for 3D modeling and quality evaluation of pavement surfaces. The traditional detection method is to use a level and manual coordination to measure; however, the detection accuracy is low and the detection speed is slow. In this paper, the high-speed non-contact vehicle-mounted road undulationelevation detection method is adopted, combined with the advantages of each sensor measurement; three methods are proposed to detect the road undulation elevation: rotary encoders, accelerometers, attitude sensor data fusion detection; GPS RTK detection; and Kalman filtering detection. Through modeling and experimental comparison, Kalman filter detection is not disturbed by the environment, and the detection accuracy is higher than the current international standard.

Effect of Titanium Dioxide Nanoparticles on Mammalian Cell Cycle In Vitro: A Systematic Review and Meta-Analysis.

Although most studies that explore the cytotoxicity of titanium dioxide nanoparticles (nano-TiO2) have focused on cell viability and oxidative stress, the cell cycle, a basic process of cell life, can also be affected. However, the results on the effects of nano-TiO2 on mammalian cell cycle are still inconsistent. A systematic review and meta-analysis were therefore performed in this research based on the effects of nano-TiO2 on the mammalian cell cycle in vitro to explore whether nano-TiO2 can induce cell cycle arrest. Meanwhile, the impact of physicochemical properties of nano-TiO2 on the cell cycle in vitro was investigated, and the response of normal cells and cancer cells was compared. A total of 33 articles met the eligibility criteria after screening. We used Review Manager 5.4 and Stata 15.1 for analysis. The results showed an increased percentage of cells in the sub-G1 phase and an upregulation of the p53 gene after being exposed to nano-TiO2. Nevertheless, nano-TiO2 had no effect on cell percentage in other phases of the cell cycle. Furthermore, subgroup analysis revealed that the cell percentage in both the sub-G1 phase of normal cells and S phase of cancer cells were significantly increased under anatase-form nano-TiO2 treatment. Moreover, nano-TiO2 with a particle size <25 nm or exposure duration of nano-TiO2 more than 24 h induced an increased percentage of normal cells in the sub-G1 phase. In addition, the cell cycle of cancer cells was arrested in the S phase no matter if the exposure duration of nano-TiO2 was more than 24 h or the exposure concentration was over 50 µg/mL. In conclusion, this study demonstrated that nano-TiO2 disrupted the cell cycle in vitro. The cell cycle arrest induced by nano-TiO2 varies with cell status and physicochemical properties of nano-TiO2.

Nanosized Titanium Dioxide Induced Apoptosis and Abnormal Expression of Blood-Testis Barrier Junction Proteins Through JNK Signaling Pathway in TM4 Cells.

Nanosized titanium dioxide (nano-TiO2) has been widely used in consumer products. It can cross the blood-testis barrier (BTB), and it has adverse effects on the male reproductive system. However, the specific mechanism has not been fully elucidated. The purpose of this study was to understand the role of the JNK signaling pathway in the apoptosis and abnormal expression of BTB junction proteins induced by nano-TiO2 in TM4 cells. After different concentration of nano-TiO2 treatments, the cell viability, apoptosis, mitochondrial membrane potential (Δψm), BTB junction proteins (Claudin-11, ZO-1, ß-catenin), apoptosis-related proteins (Bax, Bcl-2, cleaved caspase-9, cleaved caspase-3), and phosphorylated (p)-JNK protein were examined. The results showed that cell viability, apoptosis rates, Δψm, and apoptosis-related protein levels changed in a concentration-dependent manner. Cell viability decreased significantly from 100 µg/mL nano-TiO2 group. Apoptosis rates increased significantly from 150 µg/mL nano-TiO2 group, and Δψm decreased significantly from 150 µg/mL nano-TiO2 group. The protein levels of Bax, cleaved caspase-9, and cleaved caspase-3 increased significantly from 150 µg/mL nano-TiO2 group, and the protein level of Bcl-2 decreased significantly from 100 µg/mL nano-TiO2 group. The protein level of p-JNK increased significantly from 100 µg/mL nano-TiO2 group. Abnormal expression of ZO-1 and ß-catenin started from 150 µg/mL nano-TiO2 group, and abnormal expression of Claudin-11 started from 100 µg/mL nano-TiO2 group. Cells were treated with JNK inhibitor SP100625 to determine whether the changes of the above indicators in the concentration of 150 µg/mL nano-TiO2 group can be reversed. We found that SP100625 at 20 µM significantly reversed these effects. These results highlighted that nano-TiO2 could activate the JNK signaling pathway to induce mitochondria-mediated apoptosis and abnormal expression of BTB junction proteins in TM4 cells.

Genotoxicity evaluation of silica nanoparticles in murine: a systematic review and meta-analysis.

Silica nanoparticles (SiNPs) have been widely used in nanotechnology, and more attention has been paid to their safety evaluation. However, there are still inconsistent conclusions about the genotoxicity of SiNPs. A systematic review was conducted to explore whether SiNPs have genotoxicity followed by a meta-analysis of in vivo and in vitro murine genotoxicity tests. A total of 26 eligible studies were identified in this meta-analysis through a detailed process of inclusion and exclusion, which included 9 in vivo studies, 15 in vitro studies, and 2 in both. The results of in vitro studies showed that SiNPs exposure significantly increased the indicators of the comet assay, such as tail DNA content (T DNA%), tail length (TL), and olive tail moment (OTM). Indicators of mutagenicity had not been affected in vitro studies, such as mutation frequency (MF) and micronucleus (MN) frequency. There was a significant increase in MN frequency, but there was no influence on T DNA% in vivo. Results of subgroup analysis indicated that size and treatment time of SiNPs were the associated factors in vitro genotoxicity. The size of SiNPs, <21 nm, induced more DNA damage than larger sized SiNPs. It could induce MN formation when the treatment time of SiNPs was <12 h, and even more DNA damage when the exposure time over 12 h. SiNPs can induce genotoxicity both in vivo and in vitro. Comet assay may be more sensitive to detect in vitro genotoxicity, and MN frequency may be more suitable to detect in vivo genotoxicity.

Design and synthesis of novel spirooxindole-indenoquinoxaline derivatives as novel tryptophanyl-tRNA synthetase inhibitors.

In the current study, we used an integrated approach combining bioinformatics, rational drug design, one-pot synthesis, and biological experiments in vitro for the potential discovery of novel tryptophanyl-tRNA synthetase (TrpRS) inhibitors. Atom economic and diastereoselective syntheses were used to generate several Spirooxindole-indenoquinoxaline derivatives in situ from isatin and amino acids viz. proline, phenylglycine, and sarcosine through targeting the 1,3-dipolar cycloaddition of azomethine ylides. These compounds were assayed by biochemical TrpRS inhibition, using in vitro experiments to test against various gram-positive and gram-negative strains, and using diffuse large B cell lymphoma (DLBCL) cell lines. Compound 6e was found to be the most active in vitro with IC50 values of 225 and 74 nM for tests against hmTrpRS and ecTrpRS, respectively. We also found a MIC90 value of 4 µg/mL for tests against S. aureus and IC50 values which ranged from 2.9 to 4.8 µM for tests against proliferation of DLBCL cell lines. Moreover, compound 6e was remarkably good at inducing bacterial autolysis in MRSA strains. Our results suggested that such an integrated approach could be an attractive and viable strategy for the discovery of novel TrpRS inhibitors as potential lead compounds for antibiotics and as novel anticancer agents. Discovery of novel spirooxindole-indenoquinoxaline TrpRS inhibitors as potential lead compounds with antibacterial and antitumor activities.