Nitrous oxide (N 2 O) induces rapid and durable antidepressant effects in patients suffering from treatment-resistant depression 1,2 . The cellular and circuit mechanisms mediating this process are not known. Here we find that a single dose of inhaled N 2 O induces rapid and specific activation of layer V (L5) pyramidal neurons in the prefrontal cortex of rodents exposed to chronic stress conditions. N 2 O-induced L5 activation rescues a stress-associated hypoactivity state, persists following N 2 O exposure, and is necessary for its antidepressant action. While NMDA-receptor (NMDA-R) antagonism has been N 2 O’s purported mechanism of action, L5 neurons activate independently from NMDA-R function and synaptic activity. By examining different molecular targets controlling excitability and cortical circuit elements, we identify N 2 O-induced inhibition of calcium-sensitive potassium (SK2) channels as a primary molecular interaction responsible for driving both rapid and persistent L5 activity along with its ensuing antidepressant-like effects. These results suggest that N 2 O-induced L5 activation is crucial for its fast antidepressant action and this effect involves novel and specific molecular actions with SK2 channels expressed in specific L5 cell types.

The intestine is responsible for nutrient absorption and orchestrates metabolism in different organs during feeding, a process which is partly controlled by intestine-derived hormones. However, it is unclear whether the intestine plays an important role in metabolism during fasting. Here we have identified a novel hormone, famsin, which is secreted from the intestine and promotes metabolic adaptations to fasting. Mechanistically, famsin is shed from a single-pass transmembrane protein, Gm11437, during fasting and then binds OLFR796, an olfactory receptor, to activate intracellular calcium mobilization. This famsin-OLFR796 signaling axis promotes gluconeogenesis and ketogenesis for energy mobilization, and torpor for energy conservation during fasting. In addition, neutralization of famsin by an antibody improves blood glucose profiles in diabetic models, which identifies famsin as a potential therapeutic target for treating diabetes. Therefore, our results demonstrate that communication between the intestine and other organs by a famsin-OLFR796 signaling axis is critical for metabolic adaptations to fasting.
© 2023. The Author(s) under exclusive licence to Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences.

Nerolidol is a naturally occurring sesquiterpene alcohol with multiple properties, including antioxidant, antibacterial, and antiparasitic activities. A few studies investigating the antitumor properties of nerolidol have shown positive results in both cell culture and mouse models. In this study, we investigated the antitumor mechanism of cis-nerolidol in bladder carcinoma cell lines. The results of our experiments on two bladder carcinoma cell lines revealed that nerolidol inhibited cell proliferation and induced two distinct cell death pathways. We confirmed that cis-nerolidol induces DNA damage and ER stress. A mechanistic study identified a common cAMP, Ca2+, and MAPK axis involved in signal propagation and amplification, leading to ER stress. Inhibition of any part of this signaling cascade prevented both cell death pathways. The two cell death mechanisms can be distinguished by the involvement of caspases. The early occurring cell death pathway is characterized by membrane blebbing and cell swelling followed by membrane rupture, which can be prevented by the inhibition of caspase activation. In the late cell death pathway, which was found to be caspase-independent, cytoplasmic vacuolization and changes in cell shape were observed. cis-Nerolidol shows promising antitumor activity through an unorthodox mechanism of action that could help target resistant forms of malignancies, such as bladder cancer.

The ongoing metabolic and microbicidal pathways that support and protect cellular life generate potentially damaging reactive oxygen species (ROS). To counteract damage, cells express peroxidases, antioxidant enzymes that catalyze the reduction of oxidized biomolecules. Glutathione peroxidase 4 (GPX4) is the major hydroperoxidase specifically responsible for reducing lipid peroxides; this homeostatic mechanism is essential and its inhibition causes a unique type of lytic cell death, ferroptosis. The mechanism(s) that lead to cell lysis in ferroptosis, however, are unclear. We report that the lipid peroxides formed during ferroptosis accumulate preferentially at the plasma membrane. Oxidation of surface membrane lipids increased tension on the plasma membrane and led to the activation of Piezo1 and TRP channels. Oxidized membranes thus became permeable to cations, ultimately leading to gain of cellular Na + and Ca 2+ concomitant with loss of K + . These effects were reduced by deletion of Piezo1 and completely inhibited by blocking cation channel conductance with ruthenium red or 2-aminoethoxydiphenyl borate (2-APB). We also found that the oxidation of lipids depressed the activity of the Na + /K + -ATPase, exacerbating the dissipation of monovalent cation gradients. Preventing the changes in cation content attenuated ferroptosis. Together, our study establishes that increased membrane permeability to cations is a critical step in the execution of ferroptosis and identifies Piezo1, TRP channels and the Na + /K + -ATPase as targets/effectors of this type of cell death.

Mitochondrial DNA (mtDNA) escaping stressed mitochondria provokes inflammation via cGAS-STING pathway activation and, when oxidized (Ox-mtDNA), it binds cytosolic NLRP3, thereby triggering inflammasome activation. However, it is unknown how and in which form Ox-mtDNA exits stressed mitochondria in non-apoptotic macrophages. We found that diverse NLRP3 inflammasome activators rapidly stimulated uniporter-mediated calcium uptake to open mitochondrial permeability transition pores (mPTP) and trigger VDAC oligomerization. This occurred independently of mtDNA or reactive oxygen species, which induce Ox-mtDNA generation. Within mitochondria, Ox-mtDNA was either repaired by DNA glycosylase OGG1 or cleaved by the endonuclease FEN1 to 500-650 bp fragments that exited mitochondria via mPTP- and VDAC-dependent channels to initiate cytosolic NLRP3 inflammasome activation. Ox-mtDNA fragments also activated cGAS-STING signaling and gave rise to pro-inflammatory extracellular DNA. Understanding this process will advance the development of potential treatments for chronic inflammatory diseases, exemplified by FEN1 inhibitors that suppressed interleukin-1β (IL-1β) production and mtDNA release in mice.Copyright © 2022 Elsevier Inc. All rights reserved.