Emerging evidence suggests that astrocyte loss is one of the most important pathological features in the hippocampus of patients with major depressive disorder (MDD) and depressive mice. Pyroptosis is a recently discovered form of programmed cell death depending on Caspase–gasdermin D (Casp-GSDMD), which is involved in multiple neuropsychiatric diseases. However, the involvement of pyroptosis in the onset of MDD and glial pathological injury remains obscure. Here, we observed that depressive mice showed astrocytic pyroptosis, which was responsible for astrocyte loss, and selective serotonin reuptake inhibitor (SSRI) treatment could attenuate the pyroptosis induced by the chronic mild stress (CMS) model. Genetic KO of GSDMD, Casp-1, and astrocytic NOD-like receptor protein 3 (NLRP3) inflammasome in mice alleviated depression-like behaviors and inhibited the pyroptosis-associated protein expression. In contrast, overexpression of astrocytic GSDMD–N-terminal domain (GSDMD-N) in the hippocampus could abolish the improvement of behavioral alterations in GSDMD-deficient mice. This work illustrates that targeting the NLRP3/Casp-1/GSDMD–mediated pyroptosis may provide potential therapeutic benefits to stress-related astrocyte loss in the pathogenesis of depression.

Lung cancer is one of the most aggressive cancers with poor prognosis and high resistance rate. The family of signal transducer and activator of transcriptions (STATs) appears to modulate resistance in non-small cell lung cancer (NSCLC). In this work, we demonstrated that STAT3/ZEB1 is a critical axis in gefitinib resistance. STAT3-targeted inhibition therefore is a new potential therapeutic strategy for gefitinib resistance in lung cancer. Our small molecule screening identified a relatively specific STAT3-targeted inhibitor, LL1. Pharmacological and biochemical studies indicated that LL1 block the activation of STAT3 via inhibiting its phosphorylation. Further in vitro and in vivo studies elucidated that LL1 sensitizes the resistance cells to gefitinib through depleting STAT3 activity and blocking STAT3/ZEB1 signaling pathways. Little toxicity of LL1 was observed in animal models. All these favorable results indicated that LL1 is a chemotherapeutic adjuvant for gefitinib resistance in NSCLC.

Shikonin is the main component of the traditional Chinese medicine comfrey, which can inhibit the activity of PKM2 by regulating glycolysis and ATP production. Rheumatoid arthritis synovial cells (RA-FLSs) have been reported to increase glycolytic activity and have other similar hallmarks of metabolic activity. In this study, we investigated the effects of shikonin on glycolysis, mitochondrial function, and cell death in RA-FLSs. The results showed that shikonin induced apoptosis and autophagy in RA-FLSs by activating the production of reactive oxygen species (ROS) and inhibiting intracellular ATP levels, glycolysis-related proteins, and the PI3K-AKT-mTOR signaling pathway. Shikonin can significantly reduce the expression of apoptosis-related proteins, paw swelling in rat arthritic tissues, and the levels of inflammatory factors in peripheral blood, such as TNF-α, IL-6, IL-8, IL-10, IL-17A, and IL-1β while showing less toxicity to the liver and kidney.

Aims: To explore the neuroprotective effect of Ginsenoside Rg3 in a mouse model of depression induced by chronic restraint, and to elaborate whether it exerts a protective effect by inhibiting the upregulation of complement factor C1q and related microglial cell‐mediated synaptic injury. Methods: The mouse chronic restraint model of depression was prepared from male C57BL/6 mice. The depression‐like behaviors of mice were detected by sugar water preference, forced swimming test and tail suspension test. The neuronal phenotypes of mice were detected by Nissl staining, HE and Golgi staining. The expression of complement‐related pathway proteins was detected by Western Blot. The corticosterone content in the peripheral blood of mice in each group was detected by corticosterone kit. Molecular simulation and MST were used to detect the binding of Rg3 and C1q. Establish a co‐culture model of microglia and neurons; corticosterone stimulation and Rg3 pre‐protection were given to detect the damaging effect of microglial activation on neurons and the protective effect of Rg3. Results: In vivo experiments show that as depression progresses, the levels of complement factor C1q significantly increase, which is similar to the manifestations observed in depressed patients. Moreover, microglial cells in the hippocampus of depressed mice are significantly activated, while the number of neuronal synapses is significantly reduced, displaying apoptotic features. Ginsenoside Rg3, a drug with neuroprotective effects, reduces complement C1q levels and inhibits microglial activation, thereby protecting neurons and improving depression‐like behaviors. In vitro experiments show that CORT can induce microglial cells to secrete complement factor C1q, which may trigger neuronal apoptosis. Ginsenoside Rg3 may protect HT22 neurons by regulating microglial activation, reducing the secretion of complement factors, and inhibiting neuronal apoptosis. Conclusion: These results suggest that inhibiting excessive microglial activation and complement factor levels could be a potential strategy for treating depression.