Fisetin Alleviates Lipopolysaccharide-Induced Acute Lung Injury via TLR4-Mediated NF-κB Signaling Pathway in Rats

Abstract

Conclusion: In human infection with H7N9 virus, ALI/ARDS was an important cause of its fatal prognosis. The low expression of cIAP2 inhibited its combination with RIPK1, which caused the combination of RIPK1 and RIPK3.Necroptosis was then induced with the recruitment and activation of MLKL, which destructed the airway epithelium cells followed with ALI/ARDS and triggered the deaths of patients. Background and Objective: We investigated the effect of induced pluripotent stem cells (iPSCs) in moderating pulmonary endothelial leakage in endotoxin-induced acute lung injury (ALI). Methods: Male C57BL/6 mice at 8 to 12 weeks of age were studied. Murine iPSCs were delivered through the tail veins of mice 4 hours after intratracheal instillation of lipopolysaccharide (LPS). Lung histopathologi-cal findings, proteins level and proinflammatory cytokines in peripheral blood and bronchoalveolar lavage fluid (BALF), expression of junctional proteins, and regulatory signaling pathways were analyzed after 24 hours. Human umbilical vein endothelial cells (HUVECs) were cultured as a relevant model as cells expressed major junctional proteins to be responsible for maintaining vascular integrity in vivo. Results: iPSCs significantly diminished the histopathological changes of ALI mice compared to treatment with control cells. Proteins leakage, IL-6 and MIP-2 levels in BALF were significantly reduced in iPSC-treated ALI mice. The iPSC therapy restored VE-cadherin expression in the lung of ALI mice. iPSC reduced the permeability of HUVECs monolayer increased by LPS or VEGF. In HUVECs, the iPSCs restored the expression of VE-cadherin in response to LPS or VEGF via reducing Snail expression and phosphorylation of focal adhesion kinase (FAK) in Tyr397 (pFAK-Tyr397). We found conditioned medium of iPSCs (iPSC-CM) contained TIMP-1, an antiangiogenic factor. Pharmacological TIMP-1 inhibition significantly reduced the histopathological benefit and the change of VE-cadherin and pFAK-Tyr397 expression from iPSC-CM in ALI mice. Conclusion: iPSCs attenuate endothelial cell leakage in endotoxin-induced ALI. These effects are mediated, at least in part, by the enhancement of TIMP-1 activity and reduction of FAK/Snail pathway. Background and Aim: Recent studies have showed that progranu-lin (PGRN) plays essential roles in inflammation and apoptosis. We previously found down-regulation of PGRN during acute lung injury (ALI). However, the roles of PGRN and its miRNAs regulatory mechanisms has not been well studied in ALI. This study was to investigate the roles of PGRN-targeting miRNAs and whether PGRN involved in during ALI. Methods: PGRN knockout/overexpression and wild-type mice via locally instilling recombinant adenovirus containing the mouse PGRN gene and the mouse PGRN shRNA, were subjected to lipopolysaccharide for assessing the roles of PGRN in ALI. The bioinformatics method was used to screen potential miRNAs targeting PGRN in ALI, and determined the exact roles of miR-34b-5p and the mechanism involved in ALI through gain-and loss-of-func...

The plant flavonoid, fisetin alleviates cigarette smoke‐induced oxidative stress, and inflammation in Wistar rat lungs

“…In addition, the CS-induced inflammatory cell population in BALF was markedly reduced in fisetin-treated rats supporting the preventive effects of fisetin against CS-induced lung tissue damage. Supporting our findings, fisetin has been shown to rescue different organs from inflammation-induced tissue damage (Feng, Jiang, Sun, Fu, & Li, 2016;Prasath, Sundaram, & Subramanian, 2013;Sahu et al, 2014).…”

Protective effects of hesperetin on lipopolysaccharide-induced acute lung injury in a rat model

“…[32,33] In the LPSstimulated ALI model, it is well-known that toll-like receptor-4 (TLR4)-mediated Nf-kβ activation increases the expression of TNF-α and IL-6 proinflammatory cytokines, and both these cytokines activate Nf-kβ. [31,34] In our study, administration of hesperetin was shown to reduce Nf-kβ immunoreactivity in the LPS+hesperetin group, leading to a significant reduction in TNF-α, IL-6, and IL-1β expression, compared to the LPS group. Also, hesperetin caused a non-significant increase in the anti-inflammatory IL-10 level compared to the LPS group (p= 0.15).…”

“…[29,30] The Nf-kβ is an important transcription factor which plays a central role in the regulation of immune responses, including the expression of genes of many inflammatory cytokines. [31] Previous studies have demonstrated that Nf-kβ regulates the inflammatory and immune response to extracellular stimuli and plays a pivotal role in ALI development. [32,33] In the LPSstimulated ALI model, it is well-known that toll-like receptor-4 (TLR4)-mediated Nf-kβ activation increases the expression of TNF-α and IL-6 proinflammatory cytokines, and both these cytokines activate Nf-kβ.…”

Exploring the molecular targets of dietary flavonoid fisetin in cancer

“…Also, fisetin was found to activate Nrf2 mediated induction of hemeoxygenase-1 (HO-1) important for cell survival under oxidative stress conditions [23]. More recent studies have found that fisetin attenuates oxidant-driven activation of c-Jun N-terminal protein kinase (JNK) and nuclear factor-kappa B (NF-κB) signaling pathways [24,25]. These data suggest a possible use of fisetin as a potent anti-oxidant in a wide variety of biological conditions.…”