Esketamine alleviates postoperative depression-like behavior through anti-inflammatory actions in mouse prefrontal cortex.

The rising incidence of postoperative depression (POD) in recent years has placed a heavy burden on patients' physical and mental health. At this point in time, however, POD pathogenesis remains poorly understood and novel therapeutic strategies are being sought. The present study aimed to clarify esketamine's protective effects and possible mechanisms of action in POD. To this avail, we used an animal model of postoperative depression to analyze behavioral, parameters, plus the inflammatory response in serum and in the medial prefrontal cortex (mPFC). Using immunofluorescence staining, we detected the number of microglia and parvalbumin (PV) in mPFC, and determined changes in neuronal dendritic spine density via Golgi staining. Expression of Iba1, PSD95 and NF-κB was examined by Western blot analysis. Our results show that esketamine can significantly improve depression-like symptoms caused by anesthesia and surgery. In addition, esketamine administration reversed the decrease in the density of PV neurons and restored synaptogenesis in mPFC which had been perturbed by inflammation. The evidence obtained suggests esketamine's anti-inflammatory effects may be mediated by the BDNF/TrkB signaling pathway and possibly by attenuation of the nuclear factor κB (NF-κB) pathway. These data warrant further investigations into the interplay of esketamine, and microglia in the modulation of POD symptomatology.

Chrysophanol Exerts Anti-inflammatory Activity by Targeting Histone Deacetylase 3 Through the High Mobility Group Protein 1-Nuclear Transcription Factor-Kappa B Signaling Pathway in vivo and in vitro.

Chrysophanol (Chr) is the main monomer isolated from Rheum rhabarbarum. This study aimed to identify the potential in vitro and in vivo cytoprotective effects of Chr on lipopolysaccharide (LPS)-triggered acute lung injury (ALI). We used an ALI-murine model and constructed an inflammatory macrophage in vitro cell model to determine the cellular mechanisms involved in Chr-mediated activity. To observe the vital role of histone deacetylase 3 (HDAC3) in abolishing inflammation action, HDAC3 was downregulated using small interfering RNA. Analysis of the expression of nuclear transcription factor-kappa B p65 (NF-κB p65) and molecules of its downstream signaling pathway were assessed in vitro and in lung tissue samples using the mouse model. Concentrations of tumor necrosis factor-α, interleukin-1ß, high mobility group protein 1 (HMGB1), and interleukin-16 in supernatants and the bronchoalveolar lavage fluid were measured using enzyme-linked immunosorbent assay. A reporter gene assay measured HMGB1 activity, and NF-κB p65 and HMGB1 intracellular localization was determined by immunofluorescence detection on histological lung samples from Chr-treated mice. The protein interactions between HMGB1, HDAC3, and NF-κB p65 were tested by co-immunoprecipitation. Chr treatment relieved LPS-induced lung lesions. Chr also enhanced superoxide dismutase levels in ALI mice. Chr reduced the LPS-induced protein expression of NF-κB and its related pathway molecules in both in vivo and in vitro models. Moreover, Chr downregulated LPS-enhanced HMGB1 expression, acetylation, and nuclear nucleocytoplasmic translocation. However, HDAC3 knockdown substantially reduced Chr-mediated HDAC3/NF-κB expression. Furthermore, Chr enhanced HMGB1/HDAC3/NF-κB p65 complex interaction, whereas HDAC3 knockdown reduced Chr-mediated HMGB1/HDAC3/NF-κB p65 formation. This study showed that the protective effects induced by Chr were associated with the regulation of the HMGB1/NF-κB pathway via HDAC3.

Rhein attenuates lipopolysaccharide-primed inflammation through NF-κB inhibition in RAW264.7 cells: targeting the PPAR-γ signal pathway.

Inflammation is a common inducer of numerous severe diseases such as sepsis. The NF-κB signaling pathway plays a key role in the inflammatory process. Its activation promotes the release of pro-inflammatory mediators like inducible nitric oxide synthase and tumor necrosis factor alpha. Peroxisome proliferator-activated receptor gamma (PPAR-γ) inactivates nuclear factor kappa B (NF-κB) and subsequently attenuates inflammation. Rhein, an agent isolated from rhubarb, has been known to have anti-inflammatory effects. However, its influence on PPAR-γ remains largely unknown. In this study, an inflammation model was constructed by stimulating RAW264.7 cells with lipopolysaccharide. Rhein was used as a therapeutic agent, while rosiglitazone (PPAR-γ activator) and GW9662 (PPAR-γ inhibitor) were used as disrupters for in depth studies. The results demonstrated that rhein inhibits NF-κB activation and inflammatory factor release. However, GW9662 significantly reduced this effect, indicating that PPAR-γ is a critical mediator in the rhein-mediated anti-inflammatory process. Additionally, positive modulation of PPAR-γ expression and activity by rosiglitazone correspondingly influenced the effects of rhein on inflammatory factors and NF-κB expression. We also found that rhein could enhance PPAR-γ, NF-κB, and histone deacetylase 3 (HDAC3) binding. These results indicate that rhein exerts its anti-inflammation function by regulating the PPAR-γ-NF-κB-HDAC3 axis.

Epimedium Polysaccharide Alleviates Polyglutamine-Induced Neurotoxicity in Caenorhabditis elegans by Reducing Oxidative Stress.

Epimedium has been traditionally used to treat a variety of medical conditions, including neurological disorders. In this study, an acidic polysaccharide EbPS-A1 is isolated from Epimedium brevicornum and found to contain mainly galacturonic acid, galactose, and rhamnose but also arabinose and glucuronic acid. Using Caenorhabditis elegans models, we show that EbPS-A1 is capable of inhibiting behavioral dysfunction mediated by polyglutamine (polyQ), which is implicated in several neurodegenerative disorders such as Huntington's disease. Interestingly, EbPS-A1 does not inhibit polyQ aggregation or extend lifespan in the nematodes; it does, however, improve the survival under increased oxidative stress of both polyQ and wild-type nematodes intoxicated by paraquat. Further studies reveal that EbPS-A1 is capable of not only scavenging free radicals in vitro but also reducing reactive oxygen species levels, enhancing antioxidant enzyme activities, and decreasing lipid peroxidation product in C. elegans models. Together, these results suggest that the protective effect of Epimedium polysaccharide against polyQ-mediated neurotoxicity is likely due to its antioxidant function.