Cardioprotective Effects of Phlorizin on Hyperlipidemia-induced Myocardial Injury: Involvement of Suppression in Pyroptosis via Regulating HK1/NLRP3/Caspase-1 Signaling Pathway.

Hyperlipidemia (HLP) is a prevalent and intricate condition that plays a pivotal role in impairing heart function. The primary objective of this study was to assess the lipid-lowering and cardioprotective properties of phlorizin (PHZ) and to investigate its potential molecular mechanisms in rats. In this investigation, Sprague-Dawley rats were subjected to a high-fat diet for a period of 28 days to induce an HLP model. Subsequently, the rats received oral doses of PHZ or metformin from day 14 to day 28. We assessed various parameters using commercially available kits, including serum lipid deposition, myocardial injury biomarkers, oxidative stress markers, and inflammatory cytokine levels. We also employed electron microscopy to examine myocardial ultrastructural changes and conducted Western blot analyses to assess apoptosis factors and pyroptosis markers. Comparing the PHZ group with the model group, we observed significant improvements in blood lipid deposition and heart injury biomarkers. Furthermore, PHZ demonstrated a clear reduction in myocardial tissue oxidative stress and inflammatory factors, as well as a suppression of cell apoptosis. Subsequent investigations indicated that PHZ treatment led to a decreased inflammatory response and lowered levels of hexokinase 1 (HK1), NOD-like receptor thermal protein domain associated protein 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and Caspase-1. In summary, PHZ proved to be an effective remedy for alleviating HLP-induced cardiac damage by reducing blood lipid levels, mitigating oxidative stress, curbing inflammation, and suppressing pyroptosis. The inhibition of pyroptosis by PHZ appears to be linked to the regulation of the HK1/NLRP3/Caspase-1 signaling pathway.

Malus toringoides (Rehd.) Hughes decoction alleviates isoproterenol-induced cardiac fibrosis by inhibiting cardiomyocyte inflammation and pyroptosis via the HK1/NLRP3 signaling pathway.

Malus toringoides (Rehd.) Hughes, called "Eseye (Ese)," is a traditional medicinal plant from the Tibet province of China that has proven effective in treating cardiac conditions due to its anti-inflammatory, antioxidative, and antiapoptotic properties. In this study, we explored the underlying protective mechanisms of Ese decoction in isoproterenol (ISO)-induced cardiac fibrosis (CF) and established the fact that treatment with an Ese decoction attenuated tissue injury, decreased the release of IL-1ß, IL-18, TNF-α, and caspase-3, and elevated the Bax/Bcl-2 ratio in CF mice. We also found that with Ese treatment damage to the mitochondrial ultrastructure of myocardium was alleviated, and the level of reactive oxygen species was markedly diminished. Ese inhibited the expression of proteins associated with pyroptosis by the HK1/NLRP3 signaling pathway and also improved CF. Due to the anti-inflammatory, antioxidative, and antiapoptotic characteristics of Ese decoction, we found that Ese protected against ISO-induced CF, by inhibiting inflammation and pyroptosis as mediated by the HK1/NLRP3 signaling pathway.

Cichoric acid improves isoproterenol-induced myocardial fibrosis via inhibition of HK1/NLRP3 inflammasome-mediated signaling pathways by reducing oxidative stress, inflammation, and apoptosis.

Cichoric acid (CA), a natural phenolic compound found in many plants, has been reported to have antioxidant, anti-inflammatory, hypoglycemic, and other effects. The aim of this study was to determine the potential role and underlying mechanisms of CA in isoproterenol (ISO)-induced myocardial fibrosis (MF). The MF model was induced by subcutaneous ISO injection in mice. Blood and heart tissue were collected for examination. Hematoxylin and eosin staining and Masson's trichrome staining were used to evaluate the histopathological changes and collagen deposition. The production of reactive oxygen species markers was observed by fluorescence microscopy, the degree of cardiomyocyte microstructure injury was observed by transmission electron microscope, and oxidative stress factors were detected by kit method, and the effect of CA on inflammatory factors was detected by ELISA. The expression levels of collagen proteins and signaling pathways were further investigated by western blotting. The results showed that CA inhibited the expression of ISO-induced proinflammatory factors (TNF-α, IL-1ß, and IL-18) and proteins (HK1, NLRP3, caspase-1, cleaved-caspase-1, and ASC), and regulated the expression of apoptotic factors (caspase-3, cleaved-caspase-3, Bax, and Bcl-2). The results indicated that CA may regulate the HK1/NLRP3 inflammasome pathway by inhibiting HK1 expression and play a protective role in MF.

Phlorizin ameliorates myocardial fibrosis by inhibiting pyroptosis through restraining HK1-mediated NLRP3 inflammasome activation.

The specific role of phlorizin (PHL), which has antioxidant, anti-inflammatory, hypoglycemic, antiarrhythmic and antiaging effects, on myocardial fibrosis (MF) and the related pharmacological mechanisms remain unknown. The objective of this study was to determine the protective actions of PHL on isoprenaline (ISO)-induced MF and its molecular mechanisms in mice. PHL was administered at 100 and 200 mg/kg for 15 consecutive days with a subcutaneous injection of ISO (10 mg/kg). MF was induced by ISO and alleviated by treatment with PHL, as shown by reduced fibrin accumulation in the myocardial interstitium and decreased levels of myocardial enzymes, such as creatinine kinase-MB, lactate dehydrogenase, and aspartate transaminase. In addition, PHL significantly decreased the expression of the fibrosis-related factors alpha smooth muscle actin, collagen I, and collagen III induced by ISO. The generation of intracellular reactive oxygen species induced by ISO was attenuated after PHL treatment. The malondialdehyde level was reduced, whereas the levels of superoxide dismutase, catalase, and glutathione were elevated with PHL administration. Moreover, compared to ISO, the level of Bcl-2 was increased and the level of Bax protein was decreased in the PHL groups. PHL relieved elevated TNF-α, IL-1ß, and IL-18 levels as well as cardiac mitochondrial damage resulting from ISO. Further studies showed that PHL downregulated the high expression of hexokinase 1 (HK1), NLRP3, ASC, Caspase-1, and GSDMD-N caused by ISO. In conclusion, our findings suggest that PHL protects against ISO-induced MF due to its antioxidant, anti-apoptotic, and anti-inflammatory activities and via inhibition of pyroptosis mediated by the HK1/NLRP3 signaling pathway in vivo.

Hesperidin protects against cisplatin-induced cardiotoxicity in mice by regulating the p62-Keap1-Nrf2 pathway.

Hesperidin (HES) is an abundant and economical dietary bioflavonoid, and it has several pharmacological properties such as antioxidant activity and powerful cardiac protection. However, HES protection against cisplatin (CP)-induced cardiotoxicity and its mechanism have not been fully clarified. The current study was performed to further elucidate the mechanism of HES against CP-induced cardiotoxicity. Mice were orally administered HES (100 or 300 mg kg-1 day-1) for 7 consecutive days and then injected intraperitoneally (i.p.) with CP (5 mg kg-1) on days 3 and 6. On day 8, mice were anaesthetised with sodium pentobarbital (50 mg kg-1, i.p.), and blood and heart samples were collected for analysis. HES treatment reduced CP-induced cardiac pathologic damage and leakage of the myocardial markers cardiac troponin I (cTnI), creatine kinase (CK), and lactate dehydrogenase (LDH). HES treatment reduced levels of reactive oxygen species (ROS) and malondialdehyde (MDA), which is an oxidative product, and increased antioxidant marker levels including superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). HES also reduced the CP-induced release of the inflammatory factors tumour necrosis factor (TNF)-α and interleukin (IL)-6. Additionally, HES treatment up-regulated the expression of anti-apoptotic protein Bcl-2 and down-regulated the expression of pro-apoptotic proteins Bax and Caspase-3. HES treatment also improved the expression of pathway proteins p62 and Nrf2 and inhibited the increase in CP-induced Keap1 expression. Thus, HES may provide protection against CP cardiotoxicity through inhibiting oxidative stress, inflammation, and apoptosis, which may contribute to activation of the p62-Keap1-Nrf2 signalling pathway. These findings suggest that HES may be a promising protective agent against CP cardiotoxicity in future anticancer clinical practice.