Hydrogen sulfide alleviates particulate matter-induced emphysema and airway inflammation by suppressing ferroptosis.
Redox imbalance is an vital mechanism for COPD. At present, insufficient researches have been conducted on the protective effect of hydrogen sulfide (H2S) on PM-induced COPD. However, whether H2S exerts the anti-injury role by blocking ferroptosis and restoring redox equilibrium remain to be investigated.
Human lung tissue samples were collected for IHC staining, and the expressions of Nrf2, ferritinophagy- and ferroptosis-related proteins were observed. The WT C57BL/6 and Nrf2 knockout mice models were established with PM(200 μg per mouse). NaHS(Exogenous H2S) was injected intraperitoneally 30 min in advance. Twenty-nine days later, mice lung tissues were evaluated by HE's and PERLS-DAB's staining. Meanwhile, inflammation and oxidative stress indicators and iron levels were assessed by corresponding ELISA kit. Related protein expressions were detected through Western blot. BEAS-2B cells with or without H2S were exposed to PM2.5 for 36 h. Cell viability, mitochondrial morphology, inflammatory cytokines, antioxidant factors, iron levels, autophagic flux and the levels of ROS, LIP ROS, MitoROS, MMP, as well as related protein expressions were detected by specific methods, respectively. In addition, V5-Nrf2, Nrf2 siRNA, Nrf2 inhibitor ML385, PPAR-γ inhibitor GW9662, autophagy inhibitor CQ, iron chelator DFO and ferroptosis inhibitor Fer-1 were used to verify the target signaling pathways.
We found that the expressions of LIP ROS, ROS, COX2, MDA and other oxidative factors increased, while the antioxidant markers GPX4, GSH and GSH-Px significantly decreased, as well as active iron accumulation in COPD patients, PM-exposured WT and Nrf2-KO mice models and PM2.5-mediated cell models. NaHS pretreatment markedly inhibited PM-induced emphysema and airway inflammation by alleviating ferroptotic changes in vivo and vitro. With the use of V5-Nrf2 overexpression plasmid, Nrf2 siRNA and pathway inhibitors, we found NaHS activates the expressions of Nrf2 and PPAR-γ, and inhibites ferritinophagy makers LC3B, NCOA4 and FTH1 in BEAS-2B cells. Moreover, the anti-ferroptotic effect of NaHS was further verified to be related to the activation of Nrf2 signal in MEF cells.
This research suggested that H2S alleviated PM-induced emphysema and airway inflammation via restoring redox balance and inhibiting ferroptosis through regulating Nrf2-PPAR-ferritinophagy signaling pathway.
Wang Y
，Liao S
，Pan Z
，Jiang S
，Fan J
，Yu S
，Xue L
，Yang J
，Ma S
，Liu T
，Zhang J
，Chen Y
... -
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PM2.5 induces ferroptosis in human endothelial cells through iron overload and redox imbalance.
PM2.5 is becoming a worldwide environmental problem, which profoundly endangers public health, thus progressively capturing public attention this decade. As a fragile target of PM2.5, the underlying mechanisms of endothelial cell damage are still obscure. According to the previous microarray data and signaling pathway analysis, a new form of cell death termed ferroptosis in the current study is proposed following PM2.5 exposure. In order to verify the vital role of ferroptosis in PM2.5-induced endothelial lesion and further understand the potential mechanism involved, intracellular iron content, ROS release and lipid peroxidation, as well as biomarkers of ferroptosis were detected, respectively. As a result, uptake of particles increases cellular iron content and ROS production. Meanwhile, GSH depletion, and the decrease of GSH-Px and NADPH play significant roles in PM2.5-induced endothelial cell ferroptosis. Moreover, significantly changed expression of TFRC, FTL and FTH1 hinted that dysfunction of iron uptake and storage is a major inducer of ferroptosis. Importantly, index monitored above can be partially rescued by lipid peroxidation inhibitor ferrostatin-1 and iron chelator deferoxamine mesylate, which mediated antiferroptosis activity mainly depends on the restoration of antioxidant activity and iron metabolism. In conclusion, our data basically show that PM2.5 enhances ferroptosis sensitivity with increased ferroptotic events in endothelial cells, in which iron overload, lipid peroxidation and redox imbalance act pivotal roles.
Wang Y
，Tang M
《-》
PM(2.5)-induced iron homeostasis imbalance triggers cardiac hypertrophy through ferroptosis in a selective autophagy crosstalk manner.
Exposure to PM2.5 is correlated with cardiac remodeling, of which cardiac hypertrophy is one of the main clinical manifestations. Ferroptosis plays an important role in cardiac hypertrophy. However, the potential mechanism of PM2.5-induced cardiac hypertrophy through ferroptosis remains unclear. This study aimed to explore the molecular mechanism of cardiac hypertrophy caused by PM2.5 and the intervention role of MitoQ involved in this process. The results showed that PM2.5 could induce cardiac hypertrophy and dysfunction in mice. Meanwhile, the characteristics of ferroptosis were observed, such as iron homeostasis imbalance, lipid peroxidation, mitochondrial damage and abnormal expression of key molecules. MitoQ treatment could effectively mitigate these alternations. After treating human cardiomyocyte AC16 with PM2.5, ferroptosis activator (Erastin) and inhibitor (Fer-1), it was found that PM2.5 could promote ferritinophagy and lead to lipid peroxidation, mitochondrial dysfunction as well as the accumulation of intracellular and mitochondrial labile iron. Subsequently, mitophagy was activated and provided an additional source of labile iron, enhancing the sensitivity of AC16 cells to ferroptosis. Furthermore, Fer-1 alleviated PM2.5-induced cytotoxicity and iron overload in the cytoplasm and mitochondria of AC16 cells. It was worth noting that during the process of PM2.5 caused ferroptosis, abnormal iron metabolism mediated the activation of ferritinophagy and mitophagy in a temporal order. In addition, NCOA4 knockdown reversed the iron homeostasis imbalance and lipid peroxidation caused by PM2.5, thereby alleviating ferroptosis. In summary, our study found that iron homeostasis imbalance-mediated the crosstalk of ferritinophagy and mitophagy played an important role in PM2.5-induced ferroptosis and cardiac hypertrophy.
Li T
，Sun M
，Sun Q
，Ren X
，Xu Q
，Sun Z
，Duan J
... -
《Redox Biology》
Silver nanoparticles induce iron accumulation-associated cognitive impairment via modulating neuronal ferroptosis.
Silver nanoparticles (AgNPs) are widely used in daily life and medical fields owing to their unique physicochemical properties. Daily exposure to AgNPs has become a great concern regarding their potential toxicity to human beings, especially to the central nervous system. Ferroptosis, a newly recognized programmed cell death, was recently reported to be associated with the neurodegenerative process. However, whether and how ferroptosis contributes to AgNPs-induced neurotoxicity remain unclear. In this study, we investigated the role of ferroptosis in neurotoxic effects induced by AgNPs using in vitro and in vivo models. Our results showed that AgNPs induced a notable dose-dependent cytotoxic effect on HT-22 cells and cognitive impairment in mice as indicated by a decline in learning and memory and brain tissue injuries. These findings were accompanied by iron overload caused by the disruption of the iron transport system and activation of NCOA4-mediated autophagic degradation of ferritin. The excessive free iron subsequently induced GSH depletion, loss of GPX and SOD activities, differential expression of Nrf2 signaling pathway elements, down-regulation of GPX4 protein and production of lipid peroxides, initiating ferroptosis cascades. The mitigating effects of ferrostatin-1 and deferoxamine on iron overload, redox imbalance, neuronal cell death, impairment of mice learning and memory, Aβ deposition and synaptic plasticity reduction suggested ferroptosis as a potential molecular mechanism in AgNPs-induced neurotoxicity. Taken together, these results demonstrated that AgNPs induced neuronal cell death and cognitive impairment with Aβ deposition and reduction of synaptic plasticity, which were mediated by ferroptosis caused by iron-mediated lipid peroxidation. Our study provides new insights into the underlying mechanisms of AgNPs-induced neurotoxicity and predicts potential preventive strategies.
Zhai X
，Yan W
，Liu S
，Tian L
，Zhang Y
，Zhao Y
，Ni Y
，Shen H
，Wang J
，Wan Z
，Jiang F
，Xin L
... -
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ResearchGate
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钛学术
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