Fenglian Yan

5-hydroxymethylfurfural (5-HMF) has been shown to exert neuroprotective effects in a global cerebral ischemia mouse model in our previous study, where it demonstrated antioxidant and anti-inflammatory properties. However, studies on its antidepressant mechanisms remain scarce. Since oxidative stress and neuroinflammation are closely associated with depression, this study investigated the antidepressant effects of 5-HMF, focusing on its potential inhibition of oxidative stress via the Nrf2 pathway and its role in microglial M1 polarization-mediated neuroinflammation. An acute depression mouse model induced by intraperitoneal injection of lipopolysaccharide (LPS) was utilized. Mice received 5-HMF (12 mg/kg) or an equal volume of vehicle via intraperitoneal injection 30 min prior to and 5 min after LPS administration. At 24 h post-modeling, behavioral tests (sucrose preference, forced swim, and open field tests) were conducted to evaluate the antidepressant effect of 5-HMF. Histological damage in the hypothalamus was assessed using Nissl staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining. Immunofluorescence was performed to evaluate M1 polarization of hypothalamic microglia. Oxidative stress damage was assessed by measuring malondialdehyde (MDA), carbonyl groups, and 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels. Nrf2 DNA-binding activity was examined using an ELISA-based assay. The expression of inflammatory cytokines, Nrf2, and downstream antioxidant proteins was analyzed by ELISA kits and Western blotting. 5-HMF significantly alleviated LPS-induced depression-like behaviors, reduced hypothalamic neuronal damage, decreased oxidative stress, and inhibited microglial M1 polarization. It also regulated the expression of inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-4, and IL-10) and activated the Nrf2 signaling pathway, enhancing nuclear translocation efficiency. Notably, these effects were significantly attenuated by the Nrf2 inhibitor brusatol. In conclusion, 5-HMF exerts neuroprotective effects by modulating Nrf2-mediated oxidative stress responses and suppressing microglial M1 polarization-driven neuroinflammation. These findings suggest that 5-HMF may provide therapeutic potential for alleviating depression symptoms induced by acute inflammation.

Acute liver failure (ALF) is a life-threatening clinical syndrome with a substantial risk of mortality. A murine model of lipopolysaccharide (LPS)- and D-galactosamine (D-GalN)-induced ALF is widely used to investigate the underlying mechanisms and potential therapeutic drugs for human liver failure. Atractylenolide I (ATR-I) is an active component of the Atractylodes macrocephala rhizome and possesses various pharmacological activities, including anti-tumor, anti-inflammatory, and anti-oxidant properties. Given the key role of oxidative stress and inflammation in ALF pathogenesis, this study investigates the protective effects of ATR-I on LPS/D-GalN-induced ALF in mice. The results suggest that ATR-I pretreatment significantly ameliorates ALF, as evidenced by decreased serum aminotransferase levels and prolonged mice survival. Additionally, ATR-I pretreatment inhibits oxidative stress. Furthermore, the ATR-I pretreatment markedly suppresses M1 macrophage activation in hepatic mononuclear cells. In vitro experiments with bone marrow-derived macrophages indicate that ATR-I regulates macrophage polarization through the mitogen-activated protein kinase (MAPK) and interferon regulatory factor (IRF) signaling pathways. Collectively, ATR-I pretreatment protects mice from LPS/D-GalN-induced ALF partially by regulating M1 macrophage polarization.

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Invasive breast cancer is highly regulated by tumor-derived cytokines in tumor microenvironment. The development of drugs that specifically target cytokines are promising in breast cancer treatment. In this study, we reported that arctigenin, a bioactive compound from Arctium lappa L., could decrease tumor-promoting cytokines GM-CSF, MMP-3, MMP-9 and TSLP in breast cancer cells. Arctigenin not only inhibited the proliferation, but also the invasion and stemness of breast cancer cells via decreasing GM-CSF and TSLP. Mechanistically, arctigenin decreased the promoter activities of GM-CSF and TSLP via reducing the nuclear translocation of NF-κB p65 which is crucial for the transcription of GM-CSF and TSLP. Furthermore, arctigenin-induced depletion of GM-CSF and TSLP inhibited STAT3 phosphorylation and β-catenin signaling resulting in decreased proliferation, invasion and stemness of breast cancer cells in vitro and in vivo. Our findings provide new insights into the mechanism by which tumor-promoting cytokines regulate breast cancer progression and suggest that arctigenin is a promising candidate for cytokine-targeted breast cancer therapy.