Evaluation of the effect of intraperitoneal etanercept administration on oxidative stress and inflammation indicators in the kidney and blood of experimental sepsis-induced rats

Aydın, Emre; Yildirim, Y.; Aydin, Fatma; Bahadır, Mehmet Veysi; Kaplan, İbrahim; Kadiroğlu, Berfin; Ketani, M. Aydın; Yılmaz, Zülfükar; Kadiroglu, Ali Kemal; Yılmaz, Mehmet Emin

doi:10.1590/0037-8682-0016-2020

Cited by 8 publications

(6 citation statements)

References 34 publications

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“…Sepsis brings about a large proportion of mortality and morbidity all over the globe, with inflammation and oxidative stress playing crucial roles (Aydin et al 2020).…”

Section: Discussionmentioning

confidence: 99%

Omega-3 fatty acids impair miR-1-3p-dependent Notch3 down-regulation and alleviate sepsis-induced intestinal injury

Chen

Xie

Liu

et al. 2022

Mol Med

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Background Sepsis is a troublesome syndrome that can cause intestinal injury and even high mortality rates. Omega-3 fatty acids (FAs) are known to protect against intestinal damage. Accordingly, the current study set out to explore if omega-3 FAs could affect sepsis-induced intestinal injury with the involvement of the microRNA (miR)-1-3p/Notch3-Smad axis. Methods First, cecal ligation and perforation (CLP) was performed to establish septic mouse models in C57BL/6J mice, and mouse intestinal epithelial MODE-K cells were induced by lipopolysaccharide (LPS) to establish sepsis cell models. The CLP-induced septic mice or LPS-exposed cells were subjected to treatment with Omega-3 FAs and activin (Smad signaling activator), miR-1-3p inhibitor and over-expressed/short hairpin RNA (oe-/sh)-Notch3 to explore their roles in inflammation, intestinal oxidative stress and cell apoptosis. A dual-luciferase reporter gene assay was further performed to verify the regulatory relationship between miR-1-3p and Notch3. Results Omega-3 FAs inhibited CLP-induced intestinal injury and ameliorated LPS-induced intestinal epithelial cell injury by down-regulating miR-1-3p, as evidenced by decreased levels of tumor necrosis factor-α, interleukin-1β (IL-1β) and IL-6, in addition to diminished levels of reactive oxygen species, malondialdehyde levels and superoxide dismutase activity. Furthermore, miR-1-3p could down-regulate Notch3, which inactivated the Smad pathway. Conclusion Collectively, our findings indicated that omega-3 FAs elevate the expression of Notch3 by down-regulating miR-1-3p, and then blocking the Smad pathway to alleviate intestinal epithelial inflammation and oxidative stress injury caused by sepsis.

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“…Sepsis brings about a large proportion of mortality and morbidity all over the globe, with inflammation and oxidative stress playing crucial roles (Aydin et al 2020).…”

Section: Discussionmentioning

confidence: 99%

Omega-3 fatty acids impair miR-1-3p-dependent Notch3 down-regulation and alleviate sepsis-induced intestinal injury

Chen

Xie

Liu

et al. 2022

Mol Med

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“…An imbalance of the oxidant-antioxidant system leaning towards the dominance of oxidants during inflammation will lead to oxidative stress. Accumulating evidence has revealed that oxidative stress is as important as inflammation with respect to the pathophysiology of sepsis, as numerous drug candidates exert their protective effects on septic AKI via the suppression of inflammation as well as oxidative stress, and these drugs include etanercept, honokiol and glycyrrhizic acid (23)(24)(25). In the present study, the results also illustrated that PINO could significantly attenuate oxidative stress by reducing MDA production and increasing the level of GSH in LPS-challenged HK-2 cells, further affirming the protective role of PINO in septic AKI.…”

Section: Discussionmentioning

confidence: 99%

Pinocembrin ameliorates lipopolysaccharide‑induced HK‑2 cell apoptosis and inflammation by regulating endoplasmic reticulum stress

Feng

2022

Exp Ther Med

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Pinocembrin (PINO) is a natural flavonoid drug that possesses a range of biological activities, including antimicrobial, antioxidant and anti-inflammatory activities. The specific aim of the present study was to examine the pharmacological role of PINO in sepsis-mediated acute kidney injury (AKI), as well as to investigate the potential underlying mechanism. Human renal tubular epithelial cells (of the HK-2 cell line) were stimulated with lipopolysaccharide (LPS) for 24 h to simulate septic AKI in vitro , after which the experiments were repeated and the cells were pretreated with increasing concentrations of PINO (0, 50, 100 and 200 µg/ml). Using an MTT cell viability assay, PINO was revealed to be non-toxic to HK-2 cells. In LPS-treated HK-2 cells, PINO alleviated the loss of cell viability. Western blotting was used to analyze the expression levels of pro-inflammatory cytokines, including IL-1β, IL-6 and TNF-α, and the results revealed that PINO decreased the expression levels of these cytokines in a concentration-dependent manner. Furthermore, malondialdehyde (MDA) and glutathione (GSH) activities were assessed using MDA and GSH assay kits and it was revealed that PINO decreased the significantly increased level of malondialdehyde, while it also decreased the reduction in the level of GSH in LPS-challenged HK-2 cells. In addition, a TUNEL assay and western blotting were performed to examine cell apoptosis, and PINO was identified to significantly inhibit the level of apoptosis in LPS-induced HK-2 cells. Subsequently, the expression levels of endoplasmic reticulum stress (ERS)-associated factors, including activating transcription factor 4, C/EBP homologous protein and phosphorylated/total eukaryotic translation initiation factor 2 subunit 1 were examined by western blotting and it was demonstrated that ERS was triggered in HK-2 cells exposed to LPS, although this was partly circumvented through PINO treatment in a concentration-dependent manner. Furthermore, after the addition of tunicamycin, which acts as an agonist of ERS, the aforementioned experiments were performed again. Tunicamycin led to partial abolition of the protective function of PINO against inflammation, oxidative stress and apoptosis in LPS-challenged HK-2 cells. Overall, the results of the present study demonstrated that PINO was able to ameliorate the injuries sustained by LPS-challenged HK-2 cells via modulating ERS to reduce inflammation, oxidative stress and apoptosis; therefore, PINO may be a novel candidate drug for treating septic AKI.

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“…Hence, great effort was made to develop potent inhibitors targeting cytokines like TNF‐α, IL‐1, and IL‐6 or their corresponding receptors leading to the generation of highly specific and effective clinically validated compounds like etanercept, anakinra, and tocilizumab [134]. Based on their efficacy in preclinical sepsis models, great hope has been placed in these small molecular inhibitors and antagonistic monoclonal antibodies [135–138]. However, none of them did add significant benefit for the treatment of sepsis or septic shock in clinical trials.…”

Section: Summary and Perspectivesmentioning

confidence: 99%

Meprin and ADAM proteases as triggers of systemic inflammation in sepsis

Rahn

Becker‐Pauly

2021

FEBS Letters

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Systemic inflammatory disorders (SIDs) comprise a broad range of diseases characterized by dysregulated excessive innate immune responses. Severe forms of SIDs can lead to organ failure and death, and their increasing incidence represents a major issue for the healthcare system. Protease‐mediated ectodomain shedding of cytokines and their receptors represents a central mechanism in the regulation of inflammatory responses. The metalloprotease A disintegrin and metalloproteinase (ADAM) 17 is the best‐characterized ectodomain sheddase capable of releasing TNF‐α and soluble IL‐6 receptor, which are decisive factors of systemic inflammation. Recently, meprin metalloproteases were also identified as IL‐6 receptor sheddases and activators of the pro‐inflammatory cytokines IL‐1β and IL‐18. In different mouse models of SID, particularly those mimicking a sepsis‐like phenotype, ADAM17 and meprins have been found to promote disease progression. In this review, we summarize the role of ADAM10, ADAM17, and meprins in the onset and progression of sepsis and discuss their potential as therapeutic targets.

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Evaluation of the effect of intraperitoneal etanercept administration on oxidative stress and inflammation indicators in the kidney and blood of experimental sepsis-induced rats

Cited by 8 publications

References 34 publications

Omega-3 fatty acids impair miR-1-3p-dependent Notch3 down-regulation and alleviate sepsis-induced intestinal injury

Omega-3 fatty acids impair miR-1-3p-dependent Notch3 down-regulation and alleviate sepsis-induced intestinal injury

Pinocembrin ameliorates lipopolysaccharide‑induced HK‑2 cell apoptosis and inflammation by regulating endoplasmic reticulum stress

Meprin and ADAM proteases as triggers of systemic inflammation in sepsis

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