Diclofenac attenuates inflammation through TLR4 pathway and improves exercise performance after exhaustive swimming

Abstract

Background:The use of NSAIDs has become a common practice to counteract the pro-inflammatory acute effects of exercise, in order to improve sports performance. The liver, due to its central role in energy metabolism, may be involved primarily in the process of ROS generation and consequently inflammation after exhaustive exercise. Objective: To analyze the influence of diclofenac on the liver TLR4 pathway and time to exhaustion in rats submitted to repeated exhaustive swimming. Methods: An exhaustive test was performed in order to mimic athletes' routine, and inflammatory status and oxidative stress markers were evaluated in the liver.Animals were divided into sedentary and exhaustion groups, with this last performing three exhaustive swimming bouts. At the same time, diclofenac or saline was pre-administered once a day for nine days. Results: Data showed significantly increased COX-2, TLR4, and MyD88 protein content in the liver after exhaustive swimming bouts. The levels of pro-inflammatory cytokines also increased after exhaustive exercise, while these effects were attenuated in the group treated with diclofenac plus exhaustive swimming bouts. The antiinflammatory modulation provoked by diclofenac treatment was associated with an increased time to exhaustion in the exercise bouts. The exhaustive exercise increased TBARS formation, but diclofenac treatment blunted this elevation, while GSH/ GSSG ratios in both exhaustion-saline and exhaustion-diclofenac-treated groups were lower than in the sedentary-saline group. Conclusions: Our findings suggest that diclofenac may improve exercise performance and represent an effective tool to ameliorate the pro-inflammatory status in liver when associated with exhaustive exercise, and the liver may be a possible therapeutic target. K E Y W O R D Sexhaustive swimming, inflammation, nonsteroidal anti-inflammatory drugs, TLR4 pathway | 265 STECKLING ET aL.

N-acetylcysteine alleviates PCB52-induced hepatotoxicity by repressing oxidative stress and inflammatory responses

“…Ã p < 0.05, ÃÃ p < 0.01, compared with the control; # p < 0.05, ## p < 0.01, compared with the PCB52 group. Full-size  DOI: 10.7717/peerj.9720/ fig-4 Notably, the overproduction of ROS promotes the release of inflammatory mediators, including TNF-a and IL-1β, via activation of the TLR4/MyD88 pathway (Gong et al, 2019;Shah, Sharma & Banerjee, 2019;Steckling et al, 2020). The transmembrane protein TLR4 is a vital member of the toll-like receptor family, and its interaction with the adaptors MyD88 and TRAF6 are essential for activation of downstream elements and induction of inflammatory response (Dasu & Jialal, 2013).…”

“…In vitro exposure to PCB52 induces excessive generation of reactive oxygen species (ROS) in hepatocytes (Wang et al, 2018). Subsequently, the high ROS levels increase the release of inflammatory mediators (Song et al, 2020), through their effect on toll-like receptors (TLRs)/myeloid differentiation primary response 88 (MyD88) pathway (Steckling et al, 2020). These effects can also be executed via the Kelch-like ECH-associated protein 1(Keap1)/ nuclear factor-erythroid 2-related factor (Nrf2)/heme oxygenase-1 (HO-1) pathway, which has both antioxidant and anti-inflammatory effects (Nguyen, Nioi & Pickett, 2009;Song et al, 2020;Yamamoto, Kensler & Motohashi, 2018).…”

Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective

“…Owing to the analgesic, anti-pyretic, anti-inflammatory activities these drugs are extensively used in treating pain, fever and inflammation in rheumatic disorders, osteoarthritis and dysmenorrhoea [36,[43][44][45]. They are also implicated in sports medicine and popular among sports persons and soldiers [46][47][48][49]. Owing to the increasing demand for repurposing of already FDA-approved cheaper drugs in treating new diseases (in addition to the canonical purposes), and considering the multiple effects of NSAIDs, these drugs are now also aimed for repurposing against other serious health implications.…”

Peer Review #1 of "N-acetylcysteine alleviates PCB52-induced hepatotoxicity by repressing oxidative stress and inflammatory responses (v0.1)"

“…Notably, the overproduction of ROS promotes the release of inflammatory mediators, including TNF-α and IL-1β, via activation of the TLR4/MyD88 pathway (Gong et al, 2019;Shah et al, 2019;Steckling et al, 2020). The transmembrane protein TLR4 is a vital member of the tolllike receptor family, and its interaction with the adaptors MyD88 and TRAF6 are essential for activation of downstream elements and induction of inflammatory response (Dasu and Jialal, 2013).…”

“…Subsequently, the high ROS levels increase the release of inflammatory mediators (Song et al, 2020), through their effect on toll-like receptors (TLRs)/myeloid differentiation primary response 88 (MyD88) pathway (Steckling et al, 2020). These effects can also be executed via the Kelchlike ECH-associated protein 1(Keap1)/nuclear factor-erythroid 2-related factor (Nrf2)/heme oxygenase-1 (HO-1) pathway, which has both antioxidant and anti-inflammatory effects (Nguyen et al, 2009;Song et al, 2020;Yamamoto et al, 2018).…”