Nrf2 protects against seawater drowning-induced acute lung injury via inhibiting ferroptosis.

BACKGROUND: Ferroptosis is a new type of nonapoptotic cell death model that was closely related to reactive oxygen species (ROS) accumulation. Seawater drowning-induced acute lung injury (ALI) which is caused by severe oxidative stress injury, has been a major cause of accidental death worldwide. The latest evidences indicate nuclear factor (erythroid-derived 2)-like 2 (Nrf2) suppress ferroptosis and maintain cellular redox balance. Here, we test the hypothesis that activation of Nrf2 pathway attenuates seawater drowning-induced ALI via inhibiting ferroptosis. METHODS: we performed studies using Nrf2-specific agonist (dimethyl fumarate), Nrf2 inhibitor (ML385), Nrf2-knockout mice and ferroptosis inhibitor (Ferrostatin-1) to investigate the potential roles of Nrf2 on seawater drowning-induced ALI and the underlying mechanisms. RESULTS: Our data shows that Nrf2 activator dimethyl fumarate could increase cell viability, reduced the levels of intracellular ROS and lipid ROS, prevented glutathione depletion and lipid peroxide accumulation, increased FTH1 and GPX4 mRNA expression, and maintained mitochondrial membrane potential in MLE-12 cells. However, ML385 promoted cell death and lipid ROS production in MLE-12 cells. Furthermore, the lung injury became more aggravated in the Nrf2-knockout mice than that in WT mice after seawater drowning. CONCLUSIONS: These results suggested that Nrf2 can inhibit ferroptosis and therefore alleviate ALI induced by seawater drowning. The effectiveness of ferroptosis inhibition by Nrf2 provides a novel therapeutic target for seawater drowning-induced ALI.

[Atmospheric Influences Analysis on the Satellite Passive Microwave Remote Sensing].

Passive microwave remote sensing offers its all-weather work capabilities, but atmospheric influences on satellite microwave brightness temperature were different under different atmospheric conditions and environments. In order to clarify atmospheric influences on Advanced Microwave Scanning Radiometer-Earth Observing System (AMSR-E), atmospheric radiation were simulated based on AMSR-E configuration under clear sky and cloudy conditions, by using radiative transfer model and atmospheric conditions data. Results showed that atmospheric water vapor was the major factor for atmospheric radiation under clear sky condition. Atmospheric transmittances were almost above 0.98 at AMSR-E's low frequencies (< 18.7 GHz) and the microwave brightness temperature changes caused by atmosphere can be ignored in clear sky condition. Atmospheric transmittances at 36.5 and 89 GHz were 0.896 and 0.756 respectively. The effects of atmospheric water vapor needed to be corrected when using microwave high-frequency channels to inverse land surface parameters in clear sky condition. But under cloud cover or cloudy conditions, cloud liquid water was the key factor to cause atmospheric radiation. When sky was covered by typical stratus cloud, atmospheric transmittances at 10.7, 18.7 and 36.5 GHz were 0.942, 0.828 and 0.605 respectively. Comparing with the clear sky condition, the down-welling atmospheric radiation caused by cloud liquid water increased up to 75.365 K at 36.5 GHz. It showed that the atmospheric correction under different clouds covered condition was the primary work to improve the accuracy of land surface parameters inversion of passive microwave remote sensing. The results also provided the basis for microwave atmospheric correction algorithm development. Finally, the atmospheric sounding data was utilized to calculate the atmospheric transmittance of Hailaer Region, Inner Mongolia province, in July 2013. The results indicated that atmospheric transmittances were close to 1 at C-band and X-band. 89 GHz was greatly influenced by water vapor and its atmospheric transmittance was not more than 0.7. Atmospheric transmittances in Hailaer Region had a relatively stable value in summer, but had about 0.1 fluctuations with the local water vapor changes.

[Study of the microwave emissivity characteristics of vegetation over the Northern Hemisphere].

The microwave emissivity is a function of structure, water content, and surface roughness, and all these factors have obvious seasonal variations. In the present study, the half-month averaged emissivities in summer and winter of 2003 over the vegetation of Northern Hemisphere were estimated using Advanced Microwave Scanning Radiometer-Earth Observing System (AMSR-E) combined with IGBP (International Geosphere-Biosphere Project labels) land classification data. Then the emissivities of vegetation land covers at different frequencies, the polarization and their seasonal variations were analyzed respectively. The results show that the emissivities of vegetation increase with the increase in frequencies, and decline with the frequency increasing over snow region. In summer, the vegetation emissivity at V-polarization of 89 GHz is larger than 0.944, and all emissivities are relatively stable and the RMSE of time series emissivity variation is less than 0.007 2. In winter, emissivities decrease over snow covered area, especially for higher frequencies. Furthermore, with the increase in vegetation density, the emissivities increase and emissivity polarization difference decreases.

[Study of the microwave emissivity characteristics over different land cover types].

The microwave emissivity over land is very important for describing the characteristics of the lands, and it is also a key factor for retrieving the parameters of land and atmosphere. Different land covers have their emission behavior as a function of structure, water content, and surface roughness. In the present study the global land surface emissivities were calculated using six month (June, 2003-August, 2003, Dec, 2003-Feb, 2004) AMSR-E L2A brightness temperature, MODIS land surface temperature and the layered atmosphere temperature, and humidity and pressure profiles data retrieved from MODIS/Aqua under clear sky conditions. With the information of IGBP land cover types, "pure" pixels were used, which are defined when the fraction cover of each land type is larger than 85%. Then, the emissivity of sixteen land covers at different frequencies, polarization and their seasonal variation were analyzed respectively. The results show that the emissivity of vegetation including forests, grasslands and croplands is higher than that over bare soil, and the polarization difference of vegetation is smaller than that of bare soil. In summer, the emissivity of vegetation is relatively stable because it is in bloom, therefore the authors can use it as its emissivity in our microwave emissivity database over different land cover types. Furthermore, snow cover can heavily impact the change in land cover emissivity, especially in winter.

Sodium Propionate Attenuates the Lipopolysaccharide-Induced Epithelial-Mesenchymal Transition via the PI3K/Akt/mTOR Signaling Pathway.

Short-chain fatty acids (SCFAs), especially propionate, originate from the fermentation of dietary fiber in the gut and play a key role in inhibiting pulmonary inflammation. Chronic inflammation may induce an epithelial-mesenchymal transition (EMT) in alveolar epithelial cells and result in fibrotic disorders. This study was designed to investigate the beneficial effect of sodium propionate (SP) on lipopolysaccharide (LPS)-induced EMT. In cultured BEAS-2B cells, the protein expression levels of E-cadherin, α-smooth muscle actin (SMA), and vimentin were 0.66 ± 0.20, 1.44 ± 0.23, and 1.32 ± 0.21 in the LPS group vs 1.11 ± 0.36 (P < 0.05), 1.04 ± 0.30 (P < 0.05), and 0.96 ± 0.13 (P < 0.01) in the LPS + SP group (mean ± standard deviation), respectively. Meanwhile, LPS-triggered inflammatory cytokines and extracellular proteins were also reduced by SP administration in BEAS-2B cells. Moreover, SP treatment attenuated inflammation, EMT, extracellular matrix (ECM) deposition, and even fibrosis in a mouse EMT model. In terms of mechanism, LPS-treated BEAS-2B cells exhibited a higher level of phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) phosphorylation, which was interrupted by SP treatment. It is worth noting that the blockade of the PI3K/Akt/mTOR signaling cascade reduced the LPS-evoked EMT process in BEAS-2B cells. These results suggest that SP can block LPS-induced EMT via inhibition of the PI3K/Akt/mTOR signaling cascade, which provides a basis for possible clinical use of SP in airway and lung diseases.

Hyperoside suppresses hypoxia-induced A549 survival and proliferation through ferrous accumulation via AMPK/HO-1 axis.

BACKGROUND: Hypoxia is commonly existed in tumors and lead to cancer cell chemo/radio-resistance. It is well-recognized that tumor hypoxia is a major challenge for the treatment of various solid tumors. Hyperoside (quercetin-3-O-galactoside, Hy) possesses antioxidant effects and has been reported to protect against hypoxia/reoxygenation induced injury in cardiomyocytes. Therefore, Hy may be attractive compound applicable to hypoxia-related diseases. PURPOSE: This study was designed to determine the role of Hy in hypoxia-induced proliferation of non-small cell lung cancer cells and the underlying mechanism. STUDY DESIGN AND METHODS: A549, a human non-small cell lung cancer (NSCLC) cell line, was used in the present study. 1% O2 was used to mimic the in vivo hypoxic condition of NSCLC. The potential mechanisms of Hy on hypoxia-induced A549 survival and proliferation, as well as the involvement of AMPK/HO-1 pathway were studied via CCK-8 assay, EdU staining, flow cytometry, qRT-PCR and western blot. RESULTS: We showed that pretreatment with Hy suppressed hypoxia-induced A549 survival and proliferation in dose-dependent manner. In terms of mechanism, hypoxia-treated A549 showed the lower AMPK phosphorylation and the reduced HO-1 expression, which were reversed by Hy pretreatment. Both AMPK inhibitor (Compound C) and HO-1 activity inhibitor (Zinc protoporphyrin IX) abolished Hy-evoked A549 cell death under hypoxia stimuli. Of note, Ferrous iron contributed to Hy-induced A549 cell death under hypoxia, while Hy had no effect on lipid peroxidation under hypoxia. CONCLUSION: Taken together, our results highlighted the beneficial role of Hy against hypoxia-induced A549 survival and proliferation through ferrous accumulation via AMPK/HO-1 axis.

[Effects of curcumin on liver fibrosis induced by cholestasis in mice].

OBJECTIVE: To investigate the protective effects of curcumin on bile duct ligation(BDL)-induced liver cholestasis in mice, so as to provide a new treatment strategy for liver fibrosis. METHODS: Forty-two healthy adult male BALB/c mice were randomly divided into sham group (n =6), sham+curcumin group (n=6), BDL treatment group (n=10), BDL+curcumin group(n=10), BDL+curcumin+ZnPP group (n=10). Seven days after BDL operation, the sham operation + curcumin group and the BDL+ curcumin group were treated with curcumin at the dose of 30 mg/kg by intraperitoneal injection once a day for 7 days.The mice in BDL+ curcumin +ZnPP group were treated with curcumin (30 mg/kg) and ZnPP (50 µmol/kg) by intraperitoneal injection once a day for 7 days. For the sham group and the BDL group, mice were treated with equal-volume saline daily by intraperitoneal injection. After 14 days of BDL, the plasma and liver tissues were collected, the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured. The pathological changes of liver tissue and liver fibrosis were observed, and the protein expression of HO-1 in liver tissue was detected. RESULTS: Compared with the sham group, mice in the BDL group had enlarged liver gallbladder and the serum levels of ALT and AST were increased significantly (P＜0.05). Meanwhile, the results of Sirius red staining and qRT-PCR of pro-fibrosis related genes showed collagen deposition in the liver, and immunohistochemistry of macrophages and neutrophils showed inflammatory cell infiltration in the liver. Compared with the BDL group, the serum levels of ALT and AST in the curcumin treatment group were decreased significantly (P＜0.05), collagen deposition and inflammatory cell infiltration were improved, and HO-1 expression was increased (P＜0.05) after curcumin treatement. In the curcumin treatment group, the protective effect of curcumin on liver injury could be reversed by HO-1 active inhibitor ZnPP. CONCLUSION: Curcumin can improve liver inflammation and fibrosis caused by BDL, and this protective effect is related to the regulation of HO-1 activity by curcumin.

Heme oxygenase-1 attenuates seawater drowning-induced acute lung injury through a reduction in inflammation and oxidative stress.

OBJECTIVE: Heme oxygenase-1 (HO-1) plays a critical protective role in various insults-induced acute lung injury (ALI) through its strong anti-inflammatory, anti-oxidant, and anti-apoptotic properties, but its protective role and mechanism on seawater aspiration-induced acute lung injury remains unclear. This study aimed to explore the therapeutic potential and mechanism of HO-1 to attenuate seawater aspiration-induced ALI in vivo and in vitro. METHODS: The viability and invasion of A549 cell were analyzed through cell counting kit-8 and lactate dehydrogenase release assay; the transcriptional level of inflammatory cytokines (TNF-α, IL-6, IL-8 and MCP-1) and cell proliferation-related cytokines (FoxM1, Ccnb1 and Cdc25C) in seawater-treated A549 cell were tested by qPCR; apoptotic cells were analyzed by flow cytometryd; HO-1mRNA and protein were determined by qPCR and western blotting; the fluorescent indicators (DCFH-DA, dihydroethidium, MitoSox Red and Fluo-4) were used to monitor generation of ROS and mitochondrial function. The lung wet/dry weight radio and lactate dehydrogenase activity, Sirius red staining, TUNEL assay and immunohistochemical staining with anti-pan Cytokeratin antibody were analyzed in seawater-drowning mice. The role of HO-1 on seawater-drowning pulmonary injury was explored via HO-1 activity inhibitors (Zinc protoporphyrin) in vitro and in vivo. RESULTS: Seawater exposure decreased the cellular viability, increased the production of pro-inflammatory cytokines (IL-6, IL-8 and TNF-α), induced cellular apoptosis and inhibited the expression of cell proliferation-related cytokines (FoxM1, Ccnb1 and Cdc25C). Moreover, seawater exposure led to mitochondrial dysfunction in A549 cells. Supplement of HO-1 sepcific inducer (heme) or its catalytic product (biliverdin) significantly attenuated seawater-induced A549 damage and promoted cell proliferation. However, Zinc protoporphyrin abolished the beneficial effects of HO-1 on seawater drowning-induced pulmonary tissue injury. CONCLUSION: HO-1 attenuates seawater drowning-induced lung injury by its anti-inflammatory, anti-oxidative, and anti-apoptosis function.