Myricanol attenuates sepsis-induced inflammatory responses by nuclear factor erythroid 2-related factor 2 signaling and nuclear factor kappa B/mitogen-activated protein kinase pathway via upregulating Sirtuin 1.

Sepsis, a life-threatening condition characterized by dysregulated immune responses, remains a significant clinical challenge. Myricanol, a natural compound, plays a variety of roles in regulating lipid metabolism, anti-cancer, anti-neurodegeneration, and it could act as an Sirtuin 1 (SIRT1) activator. This study aimed to explore the therapeutic potential and underlying mechanism of myricanol in the lipopolysaccharide (LPS)-induced sepsis model. In vivo studies revealed that myricanol administration significantly improved the survival rate of LPS-treated mice, effectively mitigating LPS-induced inflammatory responses in lung tissue. Furthermore, in vitro studies demonstrated that myricanol treatment inhibited the expression of pro-inflammatory cytokines, attenuated signal pathway activation, and reduced oxidative stress in macrophages. In addition, we demonstrated that myricanol selectively enhances SIRT1 activation in LPS-stimulated macrophages, and all of the protective effect of myricanol were reversed through SIRT1 silencing. Remarkably, the beneficial effects of myricanol against LPS-induced sepsis were abolished in SIRT1 myeloid-specific knockout mice, underpinning the critical role of SIRT1 in mediating myricanol's therapeutic efficacy. In summary, this study provides significant evidence that myricanol acts as a potent SIRT1 activator, targeting inflammatory signal pathways and oxidative stress to suppress excessive inflammatory responses. Our findings highlight the potential of myricanol as a novel therapeutic agent for the treatment of LPS-induced sepsis.

Pimpinellin ameliorates macrophage inflammation by promoting RNF146-mediated PARP1 ubiquitination.

Macrophage inflammation plays a central role during the development and progression of sepsis, while the regulation of macrophages by parthanatos has been recently identified as a novel strategy for anti-inflammatory therapies. This study was designed to investigate the therapeutic potential and mechanism of pimpinellin against LPS-induced sepsis. PARP1 and PAR activation were detected by western blot or immunohistochemistry. Cell death was assessed by flow cytometry and western blot. Cell metabolism was measured with a Seahorse XFe24 extracellular flux analyzer. C57, PARP1 knockout, and PARP1 conditional knock-in mice were used in a model of sepsis caused by LPS to assess the effect of pimpinellin. Here, we found that pimpinellin can specifically inhibit LPS-induced macrophage PARP1 and PAR activation. In vitro studies showed that pimpinellin could inhibit the expression of inflammatory cytokines and signal pathway activation in macrophages by inhibiting overexpression of PARP1. In addition, pimpinellin increased the survival rate of LPS-treated mice, thereby preventing LPS-induced sepsis. Further research confirmed that LPS-induced sepsis in PARP1 overexpressing mice was attenuated by pimpinellin, and PARP1 knockdown abolished the protective effect of pimpinellin against LPS-induced sepsis. Further study found that pimpinellin can promote ubiquitin-mediated degradation of PARP1 through RNF146. This is the first study to demonstrate that pimpinellin inhibits excessive inflammatory responses by promoting the ubiquitin-mediated degradation of PARP1.

Targeting tumor vascularization: promising strategies for vascular normalization.

Tumor recurrence after the clinical cure of tumor often results from the presence of an abnormal microenvironment, including an aberrant vasculature. The tumor microenvironment is rich in pro-angiogenic factors but lacks pro-maturation factors. Pro-angiogenic conditions in the tumor microenvironment, such as hypoxia, are double-edged swords, promoting both the repair of normal tissues and the development of an abnormal blood vessel network. The coexistence of perfusion and hypoxic zones and uneven blood vessel distribution in tumor tissues profoundly influence tumor deterioration, recurrence, and metastasis. Traditional anti-angiogenic therapies have shown limited efficacy, and promote drug resistance, and even metastasis. In contrast, vascular normalization therapy induces a more physiological-like state, leading to better outcomes and fewer side effects. Vascular normalization entails modifying the tumor vascular system to improve tumor oxygenation and substance transport, thereby contributing to improving the efficacy of radiotherapy, chemotherapy, and immunotherapy. This review mainly focuses on the process of tumor vascularization; potential therapeutic targets, including cells, metabolism, signaling pathways, and angiogenesis-related genes; and possible strategies to normalize blood vessels through regulating tumor vessel generation, the development of tumor vessels, and blood vessel fusion and pruning.