Lung ischemia-reperfusion (I/R) injury remains one of the most common complications after various cardiopulmonary surgeries. The inflammation response triggered by the released damage-associated molecular patterns (DAMPs) aggravates lung tissue damage. However, little is known about the role of autophagy in the pathogenesis of lung I/R injury. Here, we report that a variety of inflammation-related and autophagy-associated genes are rapidly upregulated, which facilitate the inflammation response in a minipig lung I/R injury model. Left lung I/R injury triggered inflammatory cytokine production and activated the autophagy flux as evidenced in crude lung tissues and alveolar macrophages. This was associated with the release of DAMPs, such as high mobility group protein B1 (HMGB1) and heat shock protein 60 (HSP60). Indeed, treatment with recombinant HMGB1 or HSP60 induced autophagy in alveolar macrophages, whereas autophagy inhibition by knockdown of ATG7 or BECN1 markedly reduced DAMPtriggered production of inflammatory cytokines including IL-1β, TNF and IL12 in alveolar macrophages. This appeared to be because of decreased activation of MAPK and NF-κB signaling. Furthermore, knockdown of ATG7 or BECN1 inhibited Lys63 (K63)-linked ubiquitination of TNF receptor-associated factor 6 (TRAF6) in DAMP-treated alveolar macrophages. Consistently, treatment with 3-MA inhibited K63-linked ubiquitination of TRAF6 in I/R-injured lung tissues in vivo. Collectively, these results indicate that autophagy triggered by DAMPs during lung I/R injury amplifies the inflammatory response through enhancing K63-linked ubiquitination of TRAF6 and activation of the downstream MAPK and NF-κB signaling.

SUMMARYDuring anther development the male gametophyte develops inside the locule and the tapetal cells provide all nutrients for its development. Magnesium Transporter 5 (MGT5) is a member of the MGT family and has dual functions of Mg export and import. Here, we show that male gametophyte mitosis and intine formation are defective in a mgt5 mutant. The transient expression of GFP-MGT5 revealed that MGT5 is localized in the plasma membrane. These findings suggest that in the male gametophyte MGT5 plays a role in importing Mg from the locule and that Mg is essential for male gametophyte development. The expression of MGT5 in the knockout ABORTED MICROSPORES (AMS) mutant (AMS being an essential regulator of tapetum) is tremendously reduced. Chromatin immunoprecipitation and mobility shift assay experiments demonstrated that AMS can directly bind the promoter of MGT5. An immunoelectron microscopy assay revealed that MGT5-His is localized to the plasma membrane of the tapetum. These findings suggest that AMS directly regulates MGT5 in the tapetum and thus induces export of Mg into the locule. The mgt5 plant exhibits severe male sterility while the expression of MGT5 under the tapetum-specific promoter A9 partly rescued mgt5 fertility. mgt5 fertility was restored under high-Mg conditions. These findings suggest that the mgt5 tapetum still has the ability to export Mg and that a sufficient supply of Mg from the tapetum can improve the importation of Mg in the mgt5 male gametophyte. Therefore, MGT5 plays an important role in Mg transport from the tapetum to the microspore.

Nanozyme catalytic therapy triggered by tumor‐specific endogenous stimuli is an emerging tumor therapy that attracts wide attention. However, the current therapeutic efficacy of nanozyme catalytic therapy is severely limited by the catalytic efficiency of nanozymes and the concentration of endogenous reaction substrates. Herein, a novel and efficient IrN5 single‐atom (IrN5 SA) nanozyme is developed with multiple enzyme‐like catalytic activities. Due to the synergistic effect of central Ir single‐atom and axial N coordination, IrN5 SA exhibits better enzymatic catalytic performance than IrN4 SA. At tumor sites, IrN5 SA can generate a large amount of reactive oxygen species (ROS) through oxidase (OXD)‐like and peroxidase (POD)‐like catalytic activities. Moreover, IrN5 SA can also generate O2 and hydrogen peroxide (H2O2) through catalase (CAT)‐like and nicotinamide adenine dinucleotide (NADH) oxidase (NOX)‐like catalytic activities, realizing the efficient nanozyme catalytic therapy in a substrate‐cycle manner. Additionally, IrN5 SA can effectively break the intracellular NADH/NAD+ cycle balance by mimicking NOX, and then cooperate with fatty acid synthase cerulenin (Cer) to interfere with the energy metabolism homeostasis of tumor cells. Consequently, the designed IrN5 SA/Cer nanoagent can disrupt redox and metabolic homeostasis in the tumor region through an enzyme‐mimicking cascade reaction, effectively overcoming the shortcomings of current nanozyme catalytic therapy.