Effect of Simvastatin on the Intestinal Rho/ROCK Signaling Pathway in Rats With Sepsis

Wang, Yu; Wang, Xiaofeng; Yang, Wenping; Zhao, Xin; Zhang, Rong

doi:10.1016/j.jss.2018.07.016

Cited by 17 publications

(9 citation statements)

References 27 publications

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“…In addition, the degree of intestinal injury, levels of tight junction proteins, and markers of the inflammatory response were all improved in CLP-subjected mice treated with the flavanone glycoside naringin, an effect associated with the inhibition of RhoA and ROCK activities in the ileum [170]. Moreover, pleiotropic actions of simvastatin include the downregulation of both RhoA and ROCK in the intestinal tissue of CLP-subjected rats, and this effect may explain, at least in part, how simvastatin prevents the intestinal barrier disruption in septic animals [171].…”

Section: Rho Proteins and Their Impact On Sepsis Outside The Cardiovascular Systemmentioning

confidence: 96%

Rho-Proteins and Downstream Pathways as Potential Targets in Sepsis and Septic Shock: What Have We Learned from Basic Research

Hahmeyer

Silva-Santos

2021

Cells

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Sepsis and septic shock are associated with acute and sustained impairment in the function of the cardiovascular system, kidneys, lungs, liver, and brain, among others. Despite the significant advances in prevention and treatment, sepsis and septic shock sepsis remain global health problems with elevated mortality rates. Rho proteins can interact with a considerable number of targets, directly affecting cellular contractility, actin filament assembly and growing, cell motility and migration, cytoskeleton rearrangement, and actin polymerization, physiological functions that are intensively impaired during inflammatory conditions, such as the one that occurs in sepsis. In the last few decades, Rho proteins and their downstream pathways have been investigated in sepsis-associated experimental models. The most frequently used experimental design included the exposure to bacterial lipopolysaccharide (LPS), in both in vitro and in vivo approaches, but experiments using the cecal ligation and puncture (CLP) model of sepsis have also been performed. The findings described in this review indicate that Rho proteins, mainly RhoA and Rac1, are associated with the development of crucial sepsis-associated dysfunction in different systems and cells, including the endothelium, vessels, and heart. Notably, the data found in the literature suggest that either the inhibition or activation of Rho proteins and associated pathways might be desirable in sepsis and septic shock, accordingly with the cellular system evaluated. This review included the main findings, relevance, and limitations of the current knowledge connecting Rho proteins and sepsis-associated experimental models.

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Section: Rho Proteins and Their Impact On Sepsis Outside The Cardiovascular Systemmentioning

confidence: 96%

Rho-Proteins and Downstream Pathways as Potential Targets in Sepsis and Septic Shock: What Have We Learned from Basic Research

Hahmeyer

Silva-Santos

2021

Cells

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“…The increasing evidence showed that targeting inflammation and apoptosis might be effective strategies for the treatment of sepsis-induced organ disorders. For example, Wang et al investigated the effect of simvastatin on sepsis-induced intestinal injury, and it was found that simvastatin could ameliorate the intestinal injury caused by sepsis partly by reducing the levels of inflammatory cytokines [ 30 ]; Guo et al showed that Esmolol played a protective role in the early stage sepsis rats by inhibiting inflammation and apoptosis in the intestinal tissue [ 31 ]. In the present study, the apoptotic cells in the intestine of septic mice and the intestinal epithelial cells stimulated by LPS were markedly increased, which were partly abolished by the administration of FK866.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of visfatin alleviates sepsis-induced intestinal damage by inhibiting Hippo signaling pathway

et al. 2022

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Background The aim of this study is to investigate role of Visfatin, one of the pro-inflammatory adipokines, in sepsis-induced intestinal injury and to clarify the potential mechanism. Methods C57BL/6 mice underwent cecal ligation and puncture (CLP) surgery to establish sepsis model in vivo. Intestinal epithelial cells were stimulated with LPS to mimic sepsis-induced intestinal injury in vitro. FK866 (the inhibitor of Visfatin) with or without XMU-MP-1 (the inhibitor of Hippo signaling) was applied for treatment. The expression levels of Visfatin, NF-κB and Hippo signaling pathways-related proteins were detected by western blot or immunohistochemistry. The intestinal cell apoptosis and intestinal injury were investigated by TUNEL staining and H&E staining, respectively. ELISA was used to determine the production of inflammatory cytokines. Results The expression of Visfatin increased in CLP mice. FK866 reduced intestinal pathological injury, inflammatory cytokines production, and intestinal cell apoptosis in sepsis mice. Meanwhile, FK866 affected NF-κB and Hippo signaling pathways. Additionally, the effects of FK866 on inflammatory response, apoptosis, Hippo signaling and NF-κB signaling were partly abolished by XMU-MP-1, the inhibitor of Hippo signaling. In vitro experiments also revealed that FK866 exhibited a protective role against LPS-induced inflammatory response and apoptosis in intestinal cells, as well as regulating NF-κB and Hippo signaling, whereas addition of XMU-MP-1 weakened the protective effects of FK866. Conclusion In short, this study demonstrated that inhibition of Visfatin might alleviate sepsis-induced intestinal injury through Hippo signaling pathway, supporting a further research on Visfatin as a therapeutic target.

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“…Previous studies have shown that the Rho/ROCK signaling pathway plays a significant role in the pathogenesis of sepsis [ 32 ]. ROCK inhibitors obviously alleviated the leukocyte migration, systemic inflammation, vascular hyperpermeability and endothelial injury [ 33 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

ROCK inhibitor fasudil reduces the expression of inflammatory factors in LPS-induced rat pulmonary microvascular endothelial cells via ROS/NF-κB pathway

Liu

Pan

et al. 2022

BMC Pharmacol Toxicol

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Background Inflammation plays a major role in the pulmonary artery hypertension (PAH) and the acute lung injury (ALI) diseases. The common feature of these complications is the dysfunction of pulmonary microvascular endothelial cells (PMVECs). Fasudil, the only Rho kinase (ROCK) inhibitor used in clinic, has been proved to be the most promising new drug for the treatment of PAH, with some anti-inflammatory activity. Therefore, in the present study, the effect of fasudil on lipopolysaccharide (LPS)-induced inflammatory injury in rat PMVECs was investigated. Methods LPS was used to make inflammatory injury model of rat PMVECs. Thereafter, the mRNA and protein expression of pro-inflammatory factors was evaluated by reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) assay respectively. Intracellular reactive oxygen species (ROS) levels were measured by the confocal laser scanning system. The activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and the content of malondialdehyde (MDA) were determined by using commercial kits according to the manufacturer’s instructions. Western blot assay was used to detect the protein expression of nuclear factor kappa B (NF-κB) p65. Results Fasudil effectively prevented inflammatory injury induced by LPS, which is manifested by the decrease of pro-inflammatory cytokines interleukin-6 (IL-6) and monocyte chenotactic protein-1 (MCP-1). Meanwhile, fasudil dramatically reduced the levels of ROS and MDA, and also elevated the activities of SOD and GSH-Px. Furthermore, the nuclear translocation of NF-κB p65 induced by LPS was also suppressed by fasudil. Additionally, the ROS scavengers N-Acetylcysteine (N-Ace) was also found to inhibit the nuclear translocation of NF-κB and the mRNA expression of IL-6 and MCP-1 induced by LPS, which suggested that ROS was essential for the nuclear translocation of NF-κB. Conclusions The present study revealed that fasudil reduced the expression of inflammatory factors, alleviated the inflammatory and oxidative damage induced by LPS in rat PMVECs via ROS-NF-κB signaling pathway.

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Effect of Simvastatin on the Intestinal Rho/ROCK Signaling Pathway in Rats With Sepsis

Cited by 17 publications

References 27 publications

Rho-Proteins and Downstream Pathways as Potential Targets in Sepsis and Septic Shock: What Have We Learned from Basic Research

Rho-Proteins and Downstream Pathways as Potential Targets in Sepsis and Septic Shock: What Have We Learned from Basic Research

Inhibition of visfatin alleviates sepsis-induced intestinal damage by inhibiting Hippo signaling pathway

ROCK inhibitor fasudil reduces the expression of inflammatory factors in LPS-induced rat pulmonary microvascular endothelial cells via ROS/NF-κB pathway

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