Jiucui Li

Bio: Jiucui Li is an academic researcher from Qingdao University. The author has contributed to research in topics: Medicine & Binding site. The author has an hindex of 1, co-authored 1 publications receiving 13 citations.

Panaxydol attenuates ferroptosis against LPS-induced acute lung injury in mice by Keap1-Nrf2/HO-1 pathway.

Abstract: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) induces uncontrolled and self-amplified pulmonary inflammation, and has high morbidity and mortality rates in critically ill patients. In recent years, many bioactive ingredients extracted from herbs have been reported to effectively ameliorate ALI/ARDS via different mechanisms. Ferroptosis, categorized as regulated necrosis, is more immunogenic than apoptosis and contributes to the progression of ALI. In this study, we examined the impact of panaxydol (PX), isolated from the roots of Panax ginseng, on lipopolysaccharide (LPS)-induced ALI in mice. In vivo, the role of PX on LPS-induced ALI in mice was tested by determination of LPS-induced pulmonary inflammation, pulmonary edema and ferroptosis. In vitro, BEAS-2B cells were used to investigate the molecular mechanisms by which PX functions via determination of inflammation, ferroptosis and their relationship. Administration of PX protected mice against LPS-induced ALI, including significantly ameliorated lung pathological changes, and decreased the extent of lung edema, inflammation, and ferroptosis. In vitro, PX inhibited LPS-induced ferroptosis and inflammation in bronchial epithelial cell line BEAS-2B cells. The relationship between ferroptosis and inflammation was investigated. The results showed that ferroptosis mediated inflammation in LPS-treated BEAS-2B cells, and PX might ameliorate LPS-induced inflammation via inhibiting ferroptosis. Meanwhile, PX could upregulate Keap1-Nrf2/HO-1 pathway, and selective inhibition of Keap1-Nrf2/HO-1 pathway significantly abolished the anti-ferroptotic and anti-inflammatory functions of PX in LPS-treated cells. PX attenuates ferroptosis against LPS-induced ALI via Keap1-Nrf2/HO-1 pathway, and is a promising novel therapeutic candidate for ALI.

Elucidation of the binding mechanism of astragaloside IV derivative with human serum albumin and its cardiotoxicity in zebrafish embryos

Abstract: LS-102 is a new derivative of astragaloside IV (AGS IV) that has been shown to possess potentially significant cardioprotective effects. However, there are no reports concerning its interaction with human serum albumin (HSA) and toxicology in vertebrates. The present investigation was undertaken to characterize the interaction of AGS IV and LS-102 with HSA using equilibrium dialysis and UHPLC-MS/MS methods, along with computational methods. Notably, the effects of AGS IV and LS-102 were studied in vivo using the zebrafish embryo model. Markers related to embryonic cardiotoxicity and thrombosis were evaluated. We showed that the plasma protein binding rate of AGS IV (94.04%–97.42%) was significantly higher than that of LS-102 (66.90%–69.35%). Through site marker competitive experiments and molecular docking, we found that AGS IV and LS-102 were located at the interface of subdomains IIA and IIIA, but the site I might be the primary binding site. Molecular dynamics revealed that AGS IV showed a higher binding free energy mainly due to the stronger hydrophobic and hydrogen bonding interactions. Moreover, the secondary structure implied no obvious effect on the protein structure and conformation during the binding of LS-102. LS-102 significantly ameliorated the astramizole-induced heart rate slowing, increased SV-BA spacing, and prevented arachidonic acid-induced thrombosis in zebrafish. To our knowledge, we are the first to reveal that LS-102 binds to HSA with reversible and moderate affinity, indicating its easy diffusion from the circulatory system to the target tissue, thereby providing significant insights into its pharmacokinetic and pharmacodynamic properties when spread in the human body. Our results also provide a reference for the rational clinical application of LS-102 in the cardiovascular field.

SIRT3-mediated mitochondrial autophagy in refeeding syndrome-related myocardial injury in sepsis rats

Abstract: Background Myocardial injury induced by refeeding syndrome (RFS) is one of the important causes of deterioration in critically ill patients. Sirtuin-3 (SIRT3) has been shown to regulate mitochondrial autophagy in myocardial ischemia/reperfusion injury; however, the role of mitochondrial autophagy on RFS-related myocardial injury in patients in critical condition has not been reported on. Methods Thirty Sprague-Dawley (SD) rats were divided into 3 groups (n=10 each group): the control group; the standard calorie refeeding (SCR) group; and the low calorie refeeding (LCR) group. The rats were weighed every third or four days from day 1 to day 14. On day 14, all rats were anesthetized and received an echocardiography test. Blood and bronchoalveolar lavage fluid (BALF) were collected and tested for arterial oxygen pressure (PaO2), phosphorus (P), and calcium (Ca), creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and cardiac troponin 1 (cTnI), myeloperoxidase (MPO), tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and IL-6. The histopathological change of hearts and lungs were evaluated, and lung injury score was calculated. Mitochondrial autophagy related proteins (including Beclin1, LC3, mitofusin-2, Mfn2, PINK1, Parkin, and SIRT3) were analyzed using a Western blot. To evaluate the effect of SIRT3, 20 rats were divided into 2 groups (n=10 each group): The adeno-associated virus 9 (AAV9-Nc) group; and the AAV9-SIRT3 overexpression (AAV9-SIRT3) group. The protocols for rats were the same as the SCR group since day 22 after injection of AAV9. The protein expressions of PINK1, Parkin, and SIRT3 were compared between the AAV9-Nc group and AAV9-SIRT3 group. Results SCR caused significant decline in cardiac contractility and increased inflammatory cell infiltration in myocardial tissue. Meanwhile, Beclin1, LC3, PINK1, Parkin, and SIRT3 levels decreased, while Mfn2 showed no significant change. Furthermore, significant positive correlations were also found between SIRT3 and P, PINK1, and Parkin, and significant negative correlations were found between SIRT3 and CK-MB, LDH, and cTnI. Overexpression of SIRT3 activated the PINK1/Parkin mediated mitochondrial autophagy. Conclusions SIRT3 has an essential role in RFS-related myocardial injury during LPS induced chronic sepsis in rats, probably via regulating mitochondrial autophagy.

Heme Oxygenase-1 Signaling and Redox Homeostasis in Physiopathological Conditions.

Abstract: Heme-oxygenase is the enzyme responsible for degradation of endogenous iron protoporphyirin heme; it catalyzes the reaction’s rate-limiting step, resulting in the release of carbon monoxide (CO), ferrous ions, and biliverdin (BV), which is successively reduced in bilirubin (BR) by biliverdin reductase. Several studies have drawn attention to the controversial role of HO-1, the enzyme inducible isoform, pointing out its implications in cancer and other diseases development, but also underlining the importance of its antioxidant activity. The contribution of HO-1 in redox homeostasis leads to a relevant decrease in cells oxidative damage, which can be reconducted to its cytoprotective effects explicated alongside other endogenous mechanisms involving genes like TIGAR (TP53-induced glycolysis and apoptosis regulator), but also to the therapeutic functions of heme main transformation products, especially carbon monoxide (CO), which has been shown to be effective on GSH levels implementation sustaining body’s antioxidant response to oxidative stress. The aim of this review was to collect most of the knowledge on HO-1 from literature, analyzing different perspectives to try and put forward a hypothesis on revealing yet unknown HO-1-involved pathways that could be useful to promote development of new therapeutical strategies, and lay the foundation for further investigation to fully understand this important antioxidant system.

Role of Ferroptosis in Lung Diseases

Abstract: Ferroptosis is a new type of programmed cell death characterized by intracellular iron accumulation and lipid peroxidation that leads to oxidative stress and cell death. The metabolism of iron, lipids, and amino acids and multiple signalling pathways precisely regulate the process of ferroptosis. Emerging evidence has demonstrated that ferroptosis participates in the occurrence and progression of various pathological conditions and diseases, such as infections, neurodegeneration, tissue ischaemia-reperfusion injury and immune diseases. Recent studies have also indicated that ferroptosis plays a critical role in the pathogenesis of acute lung injury, chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary infection and asthma. Herein, we summarize the latest knowledge on the regulatory mechanism of ferroptosis and its association with iron, lipid and amino acid metabolism as well as several signalling pathways. Furthermore, we review the contribution of ferroptosis to the pathogenesis of lung diseases and discuss ferroptosis as a novel therapeutic target for various lung diseases.

Fisetin Attenuates Doxorubicin-Induced Cardiomyopathy In Vivo and In Vitro by Inhibiting Ferroptosis Through SIRT1/Nrf2 Signaling Pathway Activation

Abstract: Doxorubicin (DOX) is an anthracycline antibiotic that is used extensively for the management of carcinoma; however, its clinical application is limited due to its serious cardiotoxic side effects. Ferroptosis represents iron-dependent and reactive oxygen species (ROS)-related cell death and has been proven to contribute to the progression of DOX-induced cardiomyopathy. Fisetin is a natural flavonoid that is abundantly present in fruits and vegetables. It has been reported to exert cardioprotective effects against DOX-induced cardiotoxicity in experimental rats. However, the underlying mechanisms remain unknown. The present study investigated the cardioprotective role of fisetin and the underlying molecular mechanism through experiments in the DOX-induced cardiomyopathy rat and H9c2 cell models. The results revealed that fisetin treatment could markedly abate DOX-induced cardiotoxicity by alleviating cardiac dysfunction, ameliorating myocardial fibrosis, mitigating cardiac hypertrophy in rats, and attenuating ferroptosis of cardiomyocytes by reversing the decline in the GPX4 level. Mechanistically, fisetin exerted its antioxidant effect by reducing the MDA and lipid ROS levels and increasing the glutathione (GSH) level. Moreover, fisetin exerted its protective effect by increasing the SIRT1 expression and the Nrf2 mRNA and protein levels and its nuclear translocation, which resulted in the activation of its downstream genes such as HO-1 and FTH1. Selective inhibition of SIRT1 attenuated the protective effects of fisetin in the H9c2 cells, which in turn decreased the GSH and GPX4 levels, as well as Nrf2, HO-1, and FTH1 expressions. In conclusion, fisetin exerts its therapeutic effects against DOX-induced cardiomyopathy by inhibiting ferroptosis via SIRT1/Nrf2 signaling pathway activation.

Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury

Abstract: Itaconate, a metabolite produced during inflammatory macrophage activation, has been extensively described to be involved in immunoregulation, oxidative stress, and lipid peroxidation. As a form of iron and lipid hydroperoxide-dependent regulated cell death, ferroptosis plays a critical role in sepsis-induced acute lung injury (ALI). However, the relationship between itaconate and ferroptosis remains unclear. This study aims to explore the regulatory role of itaconate on ferroptosis in sepsis-induced ALI. In in vivo experiments, mice were injected with LPS (10 mg/kg) for 12 h to generate experimental sepsis models. Differential gene expression analysis indicated that genes associated with ferroptosis existed significant differences after itaconate pretreatment. 4-octyl itaconate (4-OI), a cell-permeable derivative of endogenous itaconate, can significantly alleviate lung injury, increase LPS-induced levels of glutathione peroxidase 4 (GPX4) and reduce prostaglandin-endoperoxide synthase 2 (PTGS2), malonaldehyde (MDA), and lipid ROS. In vitro experiments showed that both 4-OI and ferrostatin-1 inhibited LPS-induced lipid peroxidation and injury of THP-1 macrophage. Mechanistically, we identified that 4-OI inhibited the GPX4-dependent lipid peroxidation through increased accumulation and activation of Nrf2. The silence of Nrf2 abolished the inhibition of ferroptosis from 4-OI in THP-1 cells. Additionally, the protection of 4-OI for ALI was abolished in Nrf2-knockout mice. We concluded that ferroptosis was one of the critical mechanisms contributing to sepsis-induced ALI. Itaconate is promising as a therapeutic candidate against ALI through inhibiting ferroptosis.

Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury

Abstract: Itaconate, a metabolite produced during inflammatory macrophage activation, has been extensively described to be involved in immunoregulation, oxidative stress, and lipid peroxidation. As a form of iron and lipid hydroperoxide-dependent regulated cell death, ferroptosis plays a critical role in sepsis-induced acute lung injury (ALI). However, the relationship between itaconate and ferroptosis remains unclear. This study aims to explore the regulatory role of itaconate on ferroptosis in sepsis-induced ALI. In in vivo experiments, mice were injected with LPS (10 mg/kg) for 12 h to generate experimental sepsis models. Differential gene expression analysis indicated that genes associated with ferroptosis existed significant differences after itaconate pretreatment. 4-octyl itaconate (4-OI), a cell-permeable derivative of endogenous itaconate, can significantly alleviate lung injury, increase LPS-induced levels of glutathione peroxidase 4 (GPX4) and reduce prostaglandin-endoperoxide synthase 2 (PTGS2), malonaldehyde (MDA), and lipid ROS. In vitro experiments showed that both 4-OI and ferrostatin-1 inhibited LPS-induced lipid peroxidation and injury of THP-1 macrophage. Mechanistically, we identified that 4-OI inhibited the GPX4-dependent lipid peroxidation through increased accumulation and activation of Nrf2. The silence of Nrf2 abolished the inhibition of ferroptosis from 4-OI in THP-1 cells. Additionally, the protection of 4-OI for ALI was abolished in Nrf2-knockout mice. We concluded that ferroptosis was one of the critical mechanisms contributing to sepsis-induced ALI. Itaconate is promising as a therapeutic candidate against ALI through inhibiting ferroptosis.