Elaidic acid (EA, C18:1 trans) is a kind of principal Trans fatty acid (TFA) and is widely found in processed food. Pyroptosis is a form of programmed cell death, distinct from apoptosis and traditional necrosis. Excessive pyroptosis could induce body injury and serious inflammation. However, the effect of EA on pyroptosis has not been reported. In the study, we found that EA exposure caused liver damage and hepatocyte pyroptosis by testing GSDMD-N, Caspase 1, IL-18, and IL-1β in mice and HepG2 cells. Further exploring the mechanisms, we found that EA-induced pyroptosis depended on Cathepsin B (CTSB)-mediated NLRP3 inflammasome activation. Cell autophagy was closely related to lysosomes. Our study revealed that EA promoted hepatocyte autophagy, and activated autophagy induced lysosomal membrane permeabilization (LMP) and CTSB leakage. Inhibition of autophagy by 3-MA mitigated the CTSB leak, reduced the activation of the NLRP3 inflammasome, and then attenuated the EA-induced pyroptosis. In summary, these results indicated that EA induced hepatocyte pyroptosis via autophagy-CTSB-NLRP3 inflammasome pathway. The study revealed new insights into the toxicity mechanism of EA.
Copyright © 2023 Elsevier Ltd. All rights reserved.

Apigenin is considered the most-known natural flavonoid and is abundant in a wide variety of fruits and vegetables. A high fat diet (HFD) can induce liver injury and hepatocyte death in multiple ways. Pyroptosis is an innovative type of programmed cell death. Moreover, excessive pyroptosis of hepatocytes leads to liver injury. We used HFD to induce liver cell pyroptosis in C57BL/6J mice in this work. After gavage of apigenin, apigenin can significantly reduce the level of lactate dehydrogenase (LDH) in liver tissue ignited by HFD and reduce the levels of NLRP3 (NOD-like receptor family pyrin domain containing 3), the N-terminal domain of GSDMD (GSDMD-N), cleaved-caspase 1, cathepsin B (CTSB), interleukin-1β (IL-1β) and interleukin-18 (IL-18) protein expression and the colocalization of NLRP3 and CTSB and increase the level of lysosomal associated membrane protein-1 (LAMP-1) protein expression, thus alleviating cell pyroptosis. In a further in vitro mechanism study, we find that palmitic acid (PA) can induce pyroptosis in AML12 cells. After adding apigenin, apigenin can clear the damaged mitochondria through mitophagy and reduce the generation of intracellular reactive oxygen species (ROS), thus alleviating CTSB release caused by lysosomal membrane permeabilization (LMP), reducing the LDH release caused by PA and reducing the levels of NLRP3, GSDMD-N, cleaved-caspase 1, CTSB, IL-1β, and IL-18 protein expression. By adding the mitophagy inhibitor cyclosporin A (CsA), LC3-siRNA, the CTSB inhibitor CA-074 methyl ester (CA-074 Me), and the NLRP3 inhibitor MCC950, the aforementioned results were further confirmed. Therefore, our results show that HFD-fed and PA can damage mitochondria, promote the production of intracellular ROS, enhance the lysosomal membrane permeabilization (LMP), and cause the leakage of CTSB, thus activating the NLRP3 inflammatory body and inducing pyroptosis in C57BL/6J mice and AML12 cells, while apigenin alleviates this phenomenon through the mitophagy-ROS-CTSB-NLRP3 pathway.

Pyroptosis is characterized as gasdermin-mediated programmed death and has received substantial attention in recent years. Excessive hepatocyte pyroptosis could induce acute liver injury, and there is a lack of efficient natural compounds to alleviate it. Ginsenoside Rb1 is the most prevalent ginsenoside in ginseng with a variety of biological activities and is usually added to functional foods. In spite of the numerous beneficial effects ginsenoside Rb1 exerts, its role in hepatocyte pyroptosis is yet unknown. In this study, we found that ginsenoside Rb1 alleviated concanavalin A-induced hepatocyte pyroptosis and inhibited NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation, which is critical for the process of pyroptosis. Furthermore, with the addition of the mitophagy inhibitor cyclosporin A, we proved that ginsenoside Rb1 promoted PINK1/Parkin-mediated mitophagy to alleviate hepatocyte pyroptosis. The further mechanism was that ginsenoside Rb1 activated mitophagy to eliminate damaged mitochondria. With the clearance of damaged mitochondria, reactive oxygen species production decreased, and then NLRP3 inflammasome expression was inhibited. Our finding demonstrated that ginsenoside Rb1 could alleviate hepatocyte pyroptosis by activating mitophagy, which could provide a basis for formulating effective dietary therapy or dietary recommendation.

Endothelial cell (EC) dysfunction is one of the initiating factors of atherosclerosis. EC dysfunction is primarily caused by oxidative damage and inflammation. As a classic non‑specific antioxidant and anti‑inflammatory drug, curcumin has been widely used in studies of lipid metabolism disorders. However, whether curcumin is able to alleviate H2O2‑induced EC damage and its related mechanisms has remained to be elucidated. The present study confirmed the protective effects of curcumin on human umbilical vein endothelial cells (HUVECs). A HUVEC injury model was established using H2O2 and the optimal concentrations and time of curcumin to achieve therapeutic effects were explored. Curcumin was observed to inhibit H2O2‑induced pyroptosis by inhibiting the activation of NOD‑, LRR‑ and pyrin domain‑containing protein 3. In addition, curcumin improved HUVEC function by restoring αvβ3 and reducing endothelin‑1 expression. In conclusion, the results of the present study revealed the mechanism through which curcumin inhibits pyroptosis and indicated that curcumin may have a potential utility in treating diseases of EC dysfunction.

Aronia melanocarpa is a natural medicinal plant that has a variety of biological activities, its fruit is often used for food and medicine. Aronia melanocarpa polysaccharide (AMP) is the main component of the Aronia melanocarpa fruit. This research evaluated the delay and protection of AMP obtained from Aronia melanocarpa fruit on aging mice by D-Galactose (D-Gal) induction and explored the effect of supplementing AMP on the metabolism of the intestinal flora of aging mice. The aging model was established by intraperitoneal injection of D-Gal (200 mg/kg to 1000 mg/kg) once per 3 days for 12 weeks. AMP (100 and 200 mg/kg) was given daily by oral gavage after 6 weeks of D-Gal-induced. The results showed that AMP treatment significantly improved the spatial learning and memory impairment of aging mice determined by the eight-arm maze test. H&E staining showed that AMP significantly reversed brain tissue pathological damage and structural disorders. AMP alleviated inflammation and oxidative stress injury in aging brain tissue by regulating the AMPK/SIRT1/NF-κB and Nrf2/HO-1 signaling pathways. Particularly, AMP reduced brain cell apoptosis and neurological deficits by activating the PI3K/AKT/mTOR signaling pathway and its downstream apoptotic protein family. Importantly, 16S rDNA analysis indicated the AMP treatment significantly retarded the aging process by improving the composition of intestinal flora and abundance of beneficial bacteria. In summary, this study found that AMP delayed brain aging in mice by inhibiting inflammation and regulating intestinal microbes, which providing the possibility for the amelioration and treatment of aging and related metabolic diseases.
© 2021. The Author(s).