Hypermethylation of PPARG-encoding gene promoter mediates fine particulate matter-induced pulmonary fibrosis by regulating the HMGB1/NLRP3 axis.

The inflammatory response induced by fine particulate matter (PM2.5), a common class of air pollutants, is an important trigger for the development of pulmonary fibrosis. However, the specific mechanisms responsible for this phenomenon are yet to be fully understood. To investigate the mechanisms behind the onset and progression of lung fibrosis owing to PM2.5 exposure, both rats and human bronchial epithelial cells were subjected to varying concentrations of PM2.5. The involvement of the PPARG/HMGB1/NLRP3 signaling pathway in developing lung fibrosis caused by PM2.5 was validated through the utilization of a PPARG agonist (rosiglitazone), a PPARG inhibitor (GW9662), and an HMGB1 inhibitor (glycyrrhizin). These outcomes highlighted the downregulation of PPARG expression and activation of the HMGB1/NLRP3 signaling pathway triggered by PM2.5, thereby eliciting inflammatory responses and promoting pulmonary fibrosis. Additionally, PM2.5 exposure-induced DNA hypermethylation of PPARG-encoding gene promoter downregulated PPARG expression. Moreover, the DNA methyltransferase inhibitor 5-azacytidine mitigated the hypermethylation of the PPARG-encoding gene promoter triggered by PM2.5. In conclusion, the HMGB1/NLRP3 signaling pathway was activated in pulmonary fibrosis triggered by PM2.5 through the hypermethylation of the PPARG-encoding gene promoter.

α-LA attenuates microcystin-LR-induced hepatocellular oxidative stress in mice through Nrf2-mediated antioxidant and detoxifying enzymes.

Microcystins constitute a class of toxins synthesized by cyanobacteria and are known to inflict significant damage on the antioxidant defense system of living organisms, primarily targeting the liver. α-Lipoic acid (α-LA) is universally recognized as a potent antioxidant in biological systems. It exerts its beneficial effects through multiple mechanisms-directly neutralizing reactive oxygen species (ROS) and free radicals, and indirectly enhancing antioxidant defenses by facilitating the regeneration of glutathione (GSH). However, the precise modus operandi of α-LA's protective effect against Microcystin-LR-induced hepatotoxicity remains incompletely elucidated. The present study, therefore, employed α-LA to explore its protective role against Microcystin-LR exposure in mice. A model of Microcystin-LR-induced hepatic injury was established by administering Microcystin-LR into the peritoneal cavity of BALB/c mice daily over a two-week period. Thereafter, BALB/c mice were pre-treated with varying concentrations of α-LA via oral gavage for a duration of 7 days, followed by a 7-day exposure to Microcystin-LR. Our findings reveal that α-LA pre-treatment significantly mitigated hepatic pathologies in Microcystin-LR-exposed mice. Furthermore, α-LA administration led to a notable elevation in the activities and expression levels of nuclear factor erythroid 2-related factor 2, superoxide dismutase, glutathione peroxidase, glutathione S-transferase, and glutathione-indicative of its antioxidative capacity. Concurrently, a significant decrease was observed in the activities and expression levels of malondialdehyde and cytochrome P450 2E1. Consequently, α-LA emerges as a promising therapeutic candidate for the amelioration of liver oxidative damage subsequent to Microcystin-LR exposure.

Effect of Grain Refinement on the Comprehensive Mechanical Performance of W-Cu Composites.

W-Cu composites are commonly subjected to coupled multiple fields in service, which imposes high requirements on their overall performance. In this study, the ultrafine-grained W-Cu composite was fabricated using the combination of electroless plating and spark plasma sintering. The wear resistance and high-temperature compressive properties of the ultrafine-grained W-Cu composite were investigated and compared with those of the commercial coarse-grained counterpart. Moreover, the underlying strengthening and wear mechanisms were also discussed. Here we show that the ultrafine-grained W-Cu composite exhibits superior integrated mechanical performance, making it a potential alternative to commercial W-Cu composites.

Vitamin B complex blocks the dust fall PM2 .5 -induced acute lung injury through DNA methylation in rats.

This study aimed to explore whether vitamin B complex (folic acid, B6 , and B12 ) could avert DNA methylation changes associated with inflammation induced by acute PM2.5 exposure. Sprague-Dawley rats were administered by gavage with different concentrations of vitamin B complex once a day for 28 days, and then by intratracheal instillation with saline or PM2.5 once every 2 days for three times. Vitamin B continued to be taken during the PM2.5 exposure. Rats were sacrificed 24 h after the last exposure. The results showed that vitamin B complex could block the pathological changes and injury in lungs induced by PM2.5 . Meanwhile, vitamin B complex could prevent the abnormal DNA methylation of IL-4 and IFN-γ to antagonize the imbalance of IL-4/IFN-γ associated with inflammation. It was further found that vitamin B complex could regulate DNA methyltransferases (DNMTs) and increase the S-adenosylmethionine (SAM)/S-Adenosyl-L-homocysteine (SAH) ratio to reverse the hypomethylation of genomic DNA and the abnormal DNA methylation of IL-4 and IFN-γ. In conclusion, vitamin B complex has a protective effect on acute lung injury by attenuating abnormal DNA methylation induced by PM2.5 in rats. This study may provide a new insight into the physiological function of vitamin B to prevent the health effects induced by PM2.5 .

Dust fall PM2.5-induced lung inflammation in rats is associated with hypermethylation of the IFN-γ gene promoter via the PI3K-Akt-DNMT3b pathway.

Inflammation is one of the major adverse effects of fine particulate matter (PM2.5) on the lung system; however, its mechanisms remain unclear. Rats were exposed to different concentrations of PM2.5 to investigate the mechanism of short-term exposure-induced lung inflammation. The regulation of PI3K-Akt and DNA methyltransferase 3b (DNMT3b) was assessed by using a PI3K inhibitor and a DNA methyltransferase inhibitor. We found that PM2.5 could decrease interferon-γ (IFN-γ) levels and increase interleukin 4 (IL-4), IL-5 and IL-13 levels in bronchoalveolar lavage fluid (BALF) to promote eosinophil infiltration and eventually lead to allergic pulmonary inflammation. Moreover, the CpG island methylation rate of the IFN-γ promoter and the protein expression of DNMT3b, PI3K and p-Akt were increased in lung tissues after PM2.5 exposure. Both inhibitors reversed the CpG island hypermethylation of IFN-γ. In conclusion, in PM2.5-induced lung injury, the activated PI3K-Akt pathway, via an increase in DNMT3b expression, is involved in CpG hypermethylation of the IFN-γ gene promoter.

Long-term instillation to four natural representative chrysotile of China induce the inactivation of P53 and P16 and the activation of C-JUN and C-FOS in the lung tissues of Wistar rats.

Chrysotile is the only type of asbestos still widely exploited, and all kinds of asbestos including chrysotile was classified as a group I carcinogen by the IARC. There is a wealth of evidence that chrysotile can cause a range of cancers, including cancer of the lung, larynx, ovary, and mesothelioma. As the second largest chrysotile producer, China is at great risk of occupational exposure. Moreover, our previous experiment and some other studies have shown that the toxicity of mineral fibre from various mining areas may be different. To explore the oncogenic potential of chrysotile from different mining areas of China, Wistar rats were administered 0.5 mL chrysotile asbestos suspension of 2.0 mg/mL (from Akesai, Gansu; Mangnai, Qinghai; XinKang, Sichuan; and Shannan, Shaanxi) dissolved in saline by intratracheal instillation once-monthly and were sacrificed at 1 mo, 6 mo, and 12 mo. Our results found that chrysotile caused lung inflammation and lung tissue damage. Moreover, prolonged exposure of chrysotile can induce inactivation of the tumor suppressor gene P53 and P16 and activation of the protooncogene C-JUN and C-FOS both in the messenger RNA and protein level. In addition, chrysotile from Shannan and XinKang has a stronger effect which may link to cancer than that from Akesai and Mangnai.