Regulation of Pyroptosis in Gastric Cancer by Traditional Chinese Medicine： A Review / 中国实验方剂学杂志

Pyroptosis， a new type of inflammatory programmed cell death， is different from apoptosis， necrosis， cytosis， ferroptosis， and autophagy. Pyroptosis is dependent on the activation of cysteine aspartate-specific protease （Caspase）， which cleaves key mediator proteins to form pores in the cell membrane and induces the maturation and release of the proinflammatory cytokines interleukin-1β and interleukin-18 into the extracellular environment， resulting in a cascade of inflammatory reactions. Gastric cancer as a malignant tumor of the digestive tract is refractory and has poor prognosis， and the chemoradiotherapy of this disease may lead to a variety of complications. At present， the pathogenesis of gastric cancer remains unclear. Studies have proved that pyroptosis is associated with the occurrence and development of gastric cancer， which has attracted wide attention. Pyroptosis is a double-edged sword for gastric cancer. On the one hand， it can release the contents of proinflammatory cells to amplify or maintain inflammation and induce the "inflammation-cancer" transformation of cells. On the other hand， pyroptosis can enhance the sensitivity of drugs for chemotherapy to improve the therapeutic effect and survival. In recent years， the anti-tumor mechanism of traditional Chinese medicine （TCM） has become a research hotspot as TCM has demonstrated significant effects in clinical application. Therefore， the regulation of pyroptosis by TCM may be a new direction for the treatment of gastric cancer in the future. Based on the available studies， this paper introduces the roles of pyroptosis-associated key proteins in the occurrence and development of gastric cancer. Furthermore， this paper summarizes the effects of TCM prescriptions and active ingredients on alleviating gastric mucosal damage， reducing the incidence of gastric cancer， and preventing tumor metastasis and recurrence by mediating pyroptosis pathways， aiming to provide new ideas for deciphering the mechanism of pyroptosis and exploring the TCM treatment of gastric cancer in the future.

Natural Medicinal Components Mediating Pyroptosis by GSDMs in Anti-tumor Therapy： A Review / 中国实验方剂学杂志

Pyroptosis， an atypical new cell death mode other than apoptosis and necrosis， has been discovered in recent years. Pyroptosis depends on the cleavage of gasdermins （GSDMs） by Caspases. The activated GSDMs act on the plasma membrane to form a perforation， which results in cell lysis and triggers inflammation and immune response. Pyroptosis can be induced by four distinct signaling pathways， including canonical and non-canonical inflammasome pathways， apoptosis-associated Caspases-mediated pathway， and granzyme pathway. In these signaling pathways， GSDMs are the executors of pyroptosis. Pyroptosis is associated with the death of tumor cells and the inflammatory damage of normal tissues. Recent studies have demonstrated that moderate pyroptosis can lead to tumor cell death to exert an anti-tumor effect， and meanwhile stimulate the tumor immune microenvironment， while it can promote tumor development. Despite the good performance， drug-based anti-tumor therapies such as tumor immunotherapy， chemotherapy， and targeted therapy have some shortcomings such as drug resistance， recurrence， and damage to normal tissues. The latest research shows that a variety of natural compounds have anti-tumor effects in the auxiliary treatment of tumors by mediating the pyroptosis pathways in a multi-target and multi-pathway manner， which provide new ideas for the study of anti-tumor therapy. We reviewed the molecular mechanism of pyroptosis and the regulatory role of pyroptosis in tumors and tumor immune microenvironment， and summarized the recent research progress in the natural medicinal components regulating pyroptosis in anti-tumor therapy， with a view to providing ideas for the research on the anti-tumor therapy based on pyroptosis.

Mechanism of Shenqi Yiliu Prescription Combined with Cisplatin on H22 Liver Cancer-bearing Mice Based on NLRP3/Caspase-1/GSDMD Pyroptosis Pathway / 中国实验方剂学杂志

ObjectiveTo explore the anti-tumor effect and mechanism of Shenqi Yiliu prescription in the intervention of pyroptosis. MethodTen male BALB/c mice were randomly selected and assigned to the blank group. The remaining 40 mice underwent the induction of the liver cancer xenograft model. After 5 days of modeling， 40 surviving mice were randomly divided into model group， cisplatin group ［2.5×10-3 g·kg-1·（3 d）-1］， Shenqi Yiliu prescription group （27 g·kg-1·d-1）， and a combination group （Shenqi Yiliu prescription group + cisplatin）. The mice in the blank group and the model group were treated with an equal volume of normal saline for 10 days. The general conditions of mice in each group were observed. After the intervention， the tumor weight of the mice was weighed and the tumor inhibition rate was calculated. Hematoxylin-eosin （HE） staining was used to observe the pathological changes in tumor tissues. The levels of mouse liver function indicators， including alanine aminotransferase （ALT） and aspartate aminotransferase （AST） were detected. The TdT-mediated dUTP-biotin nick end labeling （TUNEL） assay was used to detect DNA damage in mouse tumor tissue cells. Immunohistochemistry （IHC）， immunofluorescence （IF）， and Western blot were used to detect the protein expression levels of NOD-like receptor protein 3 （NLRP3）， cysteinyl aspartate-specific protease-1 （Caspase-1）， and gasdermin D （GSDMD） in tumor tissues. The levels of interleukin-1β （IL-1β） and interleukin-18 （IL-18） in tumor tissues were detected by enzyme-linked immunosorbent assay （ELISA）. ResultCompared with the mice in the blank group， those in the model group were in a poor mental state， sleepy， and lazy， and their fur color was dull， with increased levels of serum ALT and AST in liver function tests （P<0.01）. Compared with the model group， the groups with drug intervention showed improved mental state， inhibited tumor growth to varying degrees， and decreased tumor weight， and the tumor inhibition rate in the combination group was the highest （P<0.01）. HE staining showed that the pathological and morphological lesions of the tumor tissues in the model group were significant， while those in all groups with drug intervention were improved to a certain extent. The karyolysis and nuclear rupture in the Shenqi Yiliu prescription group and the combination group were more significant. In the liver function test， the serum ALT and AST levels of mice in the Shenqi Yiliu prescription group and the combination group decreased （P<0.01）， and the inflammatory factors IL-1β and IL-18 in each group with drug intervention decreased （P<0.05， P<0.01）. Among them， the declining trend of IL-1β and IL-18 in the Shenqi Yiliu prescription group was the most significant （P<0.01）. TUNEL staining showed that the positive TUNEL staining in each group with drug intervention decreased after intervention （P<0.05， P<0.01）， especially the cisplatin group and Shenqi Yiliu prescription group （P<0.01）. Western blot， IHC， and IF found that the protein expression levels of NLRP3， Caspase-1， and GSDMD in each group with drug intervention decreased （P<0.05， P<0.01）. Compared with the mice in the cisplatin group， those in the Shenqi Yiliu prescription group and the combination group had better mental state and regular tumor morphology， and the tumor weight of the mice in the combination group decreased （P<0.05）. The levels of ALT and AST in the Shenqi Yiliu prescription group decreased （P<0.05）， and the levels of IL-1β and IL-18 in the Shenqi Yiliu prescription group and the combination group decreased （P<0.05， P<0.01）， especially in the combination group （P<0.01）. The results of IHC showed that the expression of GSDMD protein in the tumor tissues of mice in the combination group was reduced （P<0.01）. IF detection showed that the expression of NLRP3 in the tumor tissues of the Shenqi Yiliu prescription group was reduced （P<0.01）. The results of Western blot showed that the expression level of NLRP3 protein in the Shenqi Yiliu prescription group and the combination group decreased （P<0.01）， and the expression level of Caspase-1 protein in the combination group decreased （P<0.01）. The decrease in GSDMD protein expression was not significant， and the difference was not statistically significant. ConclusionShenqi Yiliu prescription combined with cisplatin has an obvious anti-tumor effect， which may be achieved by down-regulating the NLRP3/Caspase-1/GSDMD inflammatory pyroptosis pathway to inhibit cell pyroptosis， and relieve the inflammatory response in mice with liver cancer.

Research progress in Gasdermin family proteins and their association with diseases / 中华微生物学和免疫学杂志

Gasdermin family (GSDMs), consisting of six proteins (GSDMA, GSDMB, GSDMC, GSDMD, GSDME and DFNB59) in humans and ten proteins (GSDMA1-3, GSDMC1-4, GSDMD, GSDME and DFNB59) in mice, might be involved in multiple physiological and pathological processes, including epithelial cell development, apoptosis, inflammation, carcinogenesis and immune-related diseases. Recent studies confirmed GSDMD, which containing an N-terminal domain with pore-forming activity and a C-terminal domain with structural autoinhibition, as a crucial substrate of inflammatory caspases in pyroptosis, pioneering a new area for structural and functional research on Gasdermin family proteins. This review will summarize the latest progress in the structures, functions and association with diseases of several Gasdermin family proteins.

Research progress in Gasdermin family proteins and their association with diseases / 中华微生物学和免疫学杂志

Gasdermin family (GSDMs), consisting of six proteins (GSDMA, GSDMB, GSDMC, GSDMD, GSDME and DFNB59) in humans and ten proteins (GSDMA1-3, GSDMC1-4, GSDMD, GSDME and DFNB59) in mice, might be involved in multiple physiological and pathological processes, including ep-ithelial cell development, apoptosis, inflammation, carcinogenesis and immune-related diseases. Recent studies confirmed GSDMD, which containing an N-terminal domain with pore-forming activity and a C-termi-nal domain with structural autoinhibition, as a crucial substrate of inflammatory caspases in pyroptosis, pio-neering a new area for structural and functional research on Gasdermin family proteins. This review will sum-marize the latest progress in the structures, functions and association with diseases of several Gasdermin fam-ily proteins.