Melittin alleviates sepsis-induced acute kidney injury by promoting GPX4 expression to inhibit ferroptosis.

OBJECTIVES: Melittin, the main component of bee venom, is a natural anti-inflammatory substance, in addition to its ability to fight cancer, antiviral, and useful in diabetes treatment. This study seeks to determine whether melittin can protect renal tissue from sepsis-induced damage by preventing ferroptosis and explore the protective mechanism. METHODS: In this study, we investigated the specific protective mechanism of melittin against sepsis-induced renal injury by screening renal injury indicators and ferroptosis -related molecules and markers in animal and cellular models of sepsis. RESULTS: Our results showed that treatment with melittin attenuated the pathological changes in mice with lipopolysaccharide-induced acute kidney injury. Additionally, we found that melittin attenuated ferroptosis in kidney tissue by enhancing GPX4 expression, which ultimately led to the reduction of kidney tissue injury. Furthermore, we observed that melittin enhanced NRF2 nuclear translocation, which consequently upregulated GPX4 expression. our findings suggest that melittin may be a potential therapeutic agent for the treatment of sepsis-associated acute kidney injury by inhibiting ferroptosis through the GPX4/NRF2 pathway. CONCLUSIONS: Our study reveals the protective mechanism of melittin in septic kidney injury and provides a new therapeutic direction for Sepsis-AKI.

Ferroptosis in Macrophage Impairment in Sepsis.

Sepsis is a clinical syndrome with high mortality, which can lead to multiple organ dysfunction syndrome. Nonspecific immune dysfunction and immune imbalance are its important pathological features. Macrophages are important immune cells and one of the important components of innate and adaptive immunity. Regulating the function of macrophages may be a potential method for the treatment of sepsis. Up to now, ferroptosis has been proved to be involved in the pathophysiological mechanism of many diseases, such as Alzheimer's disease, cancer, Parkinson's disease, and renal degeneration. At present, relevant studies have reported that ferroptosis may be involved in the occurrence of sepsis This paper reviews the existing mechanisms of iron ptosis in macrophages in sepsis, with a view to providing si'l for future studies on sepsis.

LCZ696 Ameliorates Isoproterenol-Induced Acute Heart Failure in Rats by Activating the Nrf2 Signaling Pathway.

Objective: LCZ696 (sacubitril/valsartan) is an angiotensin II (Ang II) type 1 receptor-neprilysin inhibitor, with effects of immunosuppression, anti-inflammation, antiapoptosis, and antioxidation. The present study was aimed at determining whether LCZ696 has a protective effect against isoproterenol-induced acute heart failure (AHF) in rats. Methods: SD rats were randomly divided into four groups: control group, HF group, LCZ696 group, and enalapril group. The cardiac function of rats was evaluated using echocardiographic parameters, heart weight (HW), serum levels of cardiac troponin I (cTnI), and lactate dehydrogenase (LDH). HE is staining, which was used to determine the pathological damage of rat myocardial tissue. Also, we measured oxidative stress markers including reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT). Finally, the expression of Nrf2 signaling pathway-related proteins was determined using Western blot. Results: Compared with the HF group, LCZ696 could significantly improve cardiac function and myocardial injury in rats and reduce AHF-induced oxidative stress. In addition, the results of Western blot confirmed that LCZ696 could upregulate the expression of Nrf2 and HO-1 while decreasing Keap1 expression. Conclusion: LCZ696 ameliorates isoproterenol-induced AHF in rats by alleviating oxidative stress injury and activating the Nrf2 signaling pathway.

PM2.5 promotes replication of VSV by ubiquitination degradation of phospho-IRF3 in A549 cells.

Both PM2.5 and respiratory viruses are part of the atmospheric constituents. Respiratory viruses are often associated with PM2.5 exposure, but the mechanism of toxicity remains to be explored. The vitro models that adequately reproduce healthy cells or diseased cells exposing to PM2.5 and infecting VSV can provide a useful tool for studying innate immune mechanisms and investigating new therapeutic focus. In the environment of PM2.5, an infection model in which VSV infected A549 cells was established, that mimics the state in which the antiviral innate immune pathways are activated after the respiratory system is infected with RNA viruses. Subsequently, the model was exposed to PM2.5 for 24 h. PM2.5 could be ingested by A549 cells and synergize with VSV to inhibit cell viability and promote apoptosis. The expression of VSV-G were more abundant after VSV-infected A549 cells were exposed to PM2.5. Furthermore, PM2.5 inhibits VSV-induced IFN-ß expression in A549 cells. ISG15, CCL-5, and CXCL-10 had the same expression tendency with IFN-ß mRNA, consistently. Interestingly, when MG132 was applied, the expression of p-IRF-3 and IFN-ß proteins reduced by PM2.5 were refreshed. Conversely, the expression of VSV-G proteins were decreased. PM2.5 could degrade p-IRF-3 proteins by ubiquitination pathway to inhibit VSV-induced IFN-ß expression in A549 cells. Therefore, replication of the VSV viruses was promoted.

Toxoplasma gondii Cathepsin C1 inhibits NF-κB signalling through the positive regulation of the HIF-1α/EPO axis.

Toxoplasma gondii has evolved many successful strategies for immune evasion. However, the parasite-derived effectors involved in modulating NF-κB signalling pathway are largely unknown. T. gondii Cathepsin C1 (CPC1) is widely conserved among T. gondii strains and is important for T. gondii intracellular growth and proliferation. Our study showed that CPC1 protein could abrogate NF-κB activation after screening dense granule proteins. CPC1 suppressed NF-κB activation at or downstream of p65 and decreased the production of IL-1, IL-8, IL-6, IL-12, and TNF-α. Western blot analysis revealed that CPC1 inhibited phospho-p65 and CPC1 proteins primarily settled in cytoplasm. RNA sequencing analysis revealed that overexpression of CPC1 significantly upregulated erythropoietin (EPO), which can be induced by the hypoxia-inducible factor -1α (HIF-1α) during hypoxia. Furthermore, dual-luciferase reporter assays confirmed that CPC1 upregulated HIF-1α. Finally, both the knockdown of EPO and restriction of HIF-1α partially eliminated the suppression impact of CPC1 on the NF-κB signalling pathway. Our study identified a previously unrecognized role of CPC1 in the negative regulation of NF-κB activation through positive regulation of the HIF-1α/EPO axis. For the first time, CPC1 was shown to play an important role in immune evasion during T. gondii infection.