Small-molecule caspase-1 inhibitor CZL80 terminates refractory status epilepticus via inhibition of glutamatergic transmission.

Status epilepticus (SE), a serious and often life-threatening medical emergency, is characterized by abnormally prolonged seizures. It is not effectively managed by present first-line anti-seizure medications and could readily develop into drug resistance without timely treatment. In this study, we highlight the therapeutic potential of CZL80, a small molecule that inhibits caspase-1, in SE termination and its related mechanisms. We found that delayed treatment of diazepam (0.5 h) easily induces resistance in kainic acid (KA)-induced SE. CZL80 dose-dependently terminated diazepam-resistant SE, extending the therapeutic time window to 3 h following SE, and also protected against neuronal damage. Interestingly, the effect of CZL80 on SE termination was model-dependent, as evidenced by ineffectiveness in the pilocarpine-induced SE. Further, we found that CZL80 did not terminate KA-induced SE in Caspase-1-/- mice but partially terminated SE in IL1R1-/- mice, suggesting the SE termination effect of CZL80 was dependent on the caspase-1, but not entirely through the downstream IL-1ß pathway. Furthermore, in vivo calcium fiber photometry revealed that CZL80 completely reversed the neuroinflammation-augmented glutamatergic transmission in SE. Together, our results demonstrate that caspase-1 inhibitor CZL80 terminates diazepam-resistant SE by blocking glutamatergic transmission. This may be of great therapeutic significance for the clinical treatment of refractory SE.

Urban climate adaptability and green total-factor productivity: Evidence from double dual machine learning and differences-in-differences techniques.

Climate change has increasingly become a significant challenge to sustainable socio-economic development, and climate adaptation is a key issue that relevant research focuses on regional sustainable development models. By employing panel data between 2007 and 2020 from 284 Chinese prefecture-level cities, this study adopts quasi-experimental methods, including a difference-in-differences design and double dual machine learning model, to study the impact of climate adaptability on green regional sustainable development. Empirical results confirm that the pilot policy of building climate-resilient cities significantly improves urban green total-factor productivity. Difference-in-difference models (derived from entropy-weight and propensity score matching) and double dual learning models also support the improving effect of regional green total-factor productivity after policy intervention. The digital economy has strengthened the green development effect of pilot policies for building climate-adaptive cities. In addition, policy interventions to build climate-adaptive cities promote green urban development by optimizing industrial development structures and enhancing economic growth resilience. In addition, climate adaptability can also attract highly skilled talent and high-quality enterprises, facilitate science and technological progress in urban areas, and thus promoting the green development of cities in China. This study objectively evaluates the effects of climate policies and provides insights for global adaptation to climate change and optimization of public policies.

Melatonin Ameliorates Hepatic Ferroptosis in NAFLD by Inhibiting ER Stress via the MT2/cAMP/PKA/IRE1 Signaling Pathway.

Ferroptosis, an iron-dependent cell death form, has recently been observed in the development of non-alcoholic fatty liver disease (NAFLD). Melatonin (Mel) shows potential benefits for preventing and treating liver diseases. Whether and how Mel ameliorates hepatic ferroptosis in NAFLD is not fully understood. Here we established a mouse model of NAFLD induced by long-term high-fat diet (HFD) feeding. We found that Mel treatment ameliorated global metabolic abnormalities and inhibited the progression of NAFLD in mice. Most importantly, Mel supplementation significantly improved HFD-induced iron homeostasis disorders in the liver, including iron overload and ferritin transport disorders. For another, Mel ameliorated HFD-induced hepatic lipid peroxidation. The recuperative role of exogenous Mel on hepatocyte ferroptosis was also observed in PA- or Erastin-treated HepG2 cells. Mechanistically, MT2, but not MT1, was involved in the effect of Mel. Furthermore, Mel treatment inhibited HFD or Erastin-activated ER stress and activated the PKA/IRE1 signaling pathway. Co-expression of p-PKA and p-IRE1 was enhanced by the MT2 antagonist. Inhibitions of PKA and IRE1 respectively improved hepatocyte ferroptosis, and activations of cAMP/PKA reversed Mel's effect on ferroptosis. Collectively, these findings suggest that exogenous Mel inhibits hepatic ferroptosis in NAFLD by ameliorating ER stress through the MT2/cAMP/PKA/IRE1 pathway, proving that Mel is a promising candidate drug for the treatment of hepatic ferroptosis in NAFLD.