The Regulation and Modification of GSDMD Signaling in Diseases

Cordeiro

et al. 2023

IJMS

Gestational diseases such as preeclampsia and gestational diabetes cause inflammasome activation and pyroptosis in the placenta and changes in placental kisspeptin levels. Although maternal hypothyroidism also reduces the kisspeptin/Kiss1R system at the maternal-fetal interface, there is still no information on whether this dysfunction causes inflammasome activation and pyroptosis in the placenta or influences the modulatory role of kisspeptin in these processes. This study aimed to evaluate whether hypothyroidism activates the inflammasome-NLRP3 pathway and pyroptosis at the maternal-fetal interface of rats and whether kisspeptin can modulate these processes. Hypothyroidism was induced in Wistar rats by the administration of propylthiouracil. Kisspeptin-10 (Kp10) treatment began on the 8th day of gestation (DG). Gene and/or protein expressions of NLRP3, Caspase 1, IL-1β, IL-18, and Gasdermin D (Gsmd) were evaluated in the deciduae and placentae at the 18th DG. Hypothyroidism increased the decidual and placental stainings of NLRP3, IL-1β, and Gasdermin D, and increased the gene expressions of Nlrp3, Ilβ, and Il18 in the placenta and of Gsmd in the decidua. Treatment with Kp10 suppressed the increase in NLRP3/Nlrp3, IL-1β, Il18, and Gasdermin D/Gsmd caused by hypothyroidism at the maternal-fetal interface. However, Kp10 increased the placental gene expressions of Casp1 and Il1β. The findings demonstrated that maternal hypothyroidism activated the inflammasome-NLRP3 pathway and pyroptosis at the maternal-fetal interface of rats and that treatment with Kp10 was able to block these processes, thus suggesting that kisspeptin analogues may be promising in the treatment of gestational diseases that involve inflammasome activation and pyroptosis.

Section: Resultsmentioning

confidence: 99%

Kisspeptin Suppresses Inflammasome-NLRP3 Activation and Pyroptosis Caused by Hypothyroidism at the Maternal-Fetal Interface of Rats

Cordeiro

et al. 2023

IJMS

“…Elevated GSDM-D levels have been associated with unfavorable prognosis in lung cancer but favorable in skin cutaneous melanoma and its expression is regulated by the binding of Foxo1 on its promoter [109]. The hypermethylating activity of DNMT was also found at the GSDM-D promoter in lymphocytes natural killer, NK92 cells, in which it appears to be a critical checkpoint for the inhibition of the pyroptosis mechanism [110]. An indirect regulation occurs in colorectal cancer, where the rp1-85f18.6 knockout, a lncRNA highly expressed in CRC patients, leads to an increased pyroptosis through the cleavage of GSDM-D, suggesting a possible application of epigenetic modulators of inflammosomes for cancer therapy [111].…”

Section: Epigenetic Regulation In Pyroptosismentioning

confidence: 99%

Epi-Regulation of Cell Death in Cancer

Beato¹,

Torre²,

Capone³

et al. 2023

Biochemistry

How do organisms regulate the correct balance between the production of “new” cells and the elimination of the “old” ones, remains an important biology issue under investigation. Cell(s) death represents a fundamental process involved in organism development and cell homeostasis, whose alteration is considered one hallmark of cancer and lead to drug resistance and consequently treatment failure. The recent re-classification of cell death has identified new molecular programs in which several proteins have a pivotal role. Several studies have highlighted a direct link between epigenetic modifications and cell death mechanisms. Different epi-modifications have been described, capable of regulating diverse key players implicated in cell death, leading to uncontrolled proliferation of cancer cells. Scientific efforts are focused on the understanding the epigenetic regulation of cell death mechanisms by developing tools and/or new epi-molecules able to overcome cell death resistance. The development of new epi-molecular tools can overcome cell death deregulation thus potentially improving the sensitivity to the anti-tumor therapies. This chapter focuses on the main epigenetic deregulations in cell death mechanisms in cancer.

“…Owing to increased intestinal permeability, bacterial LPS can be carried to the liver via the portal vein, wherein it can bind to TLR4 on the surface of hepatic Kupffer cells and trigger an immunological response in the liver ( 98 ). The mechanism may be related to the fact that GSDMD knockdown inhibits pyroptosis but promotes apoptosis, indicating the tampering effect of GSDMD between different types of cell death ( 99 ). The role of GSDMD in AIH is significant and complex and worthy of further study.…”

Section: Inflammasomes and Pyroptosis In Aildsmentioning

confidence: 99%

Inflammasome and pyroptosis in autoimmune liver diseases

et al. 2023

Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and IgG4-related sclerosing cholangitis (IgG4-SC) are the four main forms of autoimmune liver diseases (AILDs), which are all defined by an aberrant immune system attack on the liver. Most previous studies have shown that apoptosis and necrosis are the two major modes of hepatocyte death in AILDs. Recent studies have reported that inflammasome-mediated pyroptosis is critical for the inflammatory response and severity of liver injury in AILDs. This review summarizes our present understanding of inflammasome activation and function, as well as the connections among inflammasomes, pyroptosis, and AILDs, thus highlighting the shared features across the four disease models and gaps in our knowledge. In addition, we summarize the correlation among NLRP3 inflammasome activation in the liver-gut axis, liver injury, and intestinal barrier disruption in PBC and PSC. We summarize the differences in microbial and metabolic characteristics between PSC and IgG4-SC, and highlight the uniqueness of IgG4-SC. We explore the different roles of NLRP3 in acute and chronic cholestatic liver injury, as well as the complex and controversial crosstalk between various types of cell death in AILDs. We also discuss the most up-to-date developments in inflammasome- and pyroptosis-targeted medicines for autoimmune liver disorders.